analogous compounds of aryl sphingosine 1-bicyclic phosphate, their pharmaceutical composition and t

专利摘要:
ANALOG COMPOUNDS OF ARY SPHINGOSINE 1-BICYCLIC PHOSPHATE, ITS PHARMACEUTICAL COMPOSITION AND ITS USE.The present invention relates to compounds that have agonist activity at one or more of the S1P receptors. The compounds are sphingosine analogs that, after phosphorylation, can behave as S1P receptor agonists. The present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a sphingosine analog compound or a pharmaceutically acceptable salt thereof, as well as the use of such a compound.
公开号:BR112012002511A2
申请号:R112012002511-2
申请日:2010-08-05
公开日:2020-08-25
发明作者:Jermaine Thomas；Xiaogao Liu；Edward Yin-shiang Lin；Guo Zhu Zheng；Bin Ma；Richard D. Caldwell；Kevin M. Guckian；Gnanasambandam Kumaravel；Arthur G. Taveras
申请人:Biogen Idec Ma Inc；
IPC主号:

专利说明:

S Invention Patent Descriptive Report for "ARYALPHALOSAL ANALOG COMPOUNDS 1-BICYCLIC PHOSPHATE, ITS PHARMACEUTICAL COMPOSITION AND ITS USE". Background
The present invention relates to sphingosine 1-phosphate (S1P) which is a mediator of lysophospholipid that evokes a variety of cell responses by stimulating five members of the endothelial cell differentiating gene (EDG) receptor family. EDG receptors are coupled protein G receptors (GPCRs) and a stimulation propagates the second messenger signals through the activation of heterotrimeric G protein alpha (G,) alpha subunits and beta-gamma (Gy,) dimers. Ultimately, this signaling controlled by S1P results in cell survival, increased cell migration and, often, mitogenesis.
The recent development of S1P receptors targeting agonists has provided insight into the role of this signaling system in physiological homeostasis.
For example, the immunomodulator, FTY720 (2-amino-2- [2- (4-octylphenyl) ethyl] propane 1,3-diol), which follows phosphorylation, is an agonist at 4 of 5 S1P receptors, revealed that affects S1P receptor activity and influences lymphocyte trafficking.
In addition, S1P type 1 receptor antagonists (S1P1) cause loss of the pulmonary capillary endothelium, which suggests that S1P may be involved in maintaining the integrity of the endothelial barrier in some layers of tissue.
Type 4 S1P (S1P,) receptors are expressed mainly in leukocytes, and specifically S1P, mediate S1P immunosuppressive effects by inhibiting proliferation and secretion of effector cytokines, while intensifying suppressive cytokine secretion 11-10. See, for example, Wang, W. et al. (2005) FASEB J. 19 (12): 1731-3, which is incorporated by reference in its entirety.
Type 5 S1P receptors (S1Ps) are exclusively expressed in oligodentrocyte and oligodendrocyte precursor cells (OPCs) and are vital for cell migration.
Stimulation of S1P; s inhibits OPC migration, which normally migrates considerable distances during development
brain development.
See, for example, Novgorodov, A. et al., (2007) FASEB J, 21: 1503-1514, which is incorporated by reference in its entirety.
: those that result in platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and angiogenesis. For these reasons, S1P receptors are safe for therapeutic applications, such as wound healing, inhibition of tumor growth, and autoimmune diseases.
Sphingosine 1-phosphate signals cells, in part, through a set of receptors coupled to protein G, namely, S1P ,, S1P>, S1P3, S1IP4, and S1Ps (formerly EDG1, EDG5, EDG3, EDG6 and EDG8). EDG receptors are G protein-coupled receptors (GPCRs) and in stimulation propagate second messenger signals through the activation of heterotrimeric G protein alpha (G,) alpha subunits and (G ;,) beta-PP gamma dimers. These receptors share 50 to 55% of the amino acid sequence identity Rs and group with three other receptors LPA ,, LPA ,, and LPAz (formerly EDG2, EDG4 and EDG7) for structurally related lysophosphatidic acid (LPA).
A conformational change is induced in the Protein G Coupled Receptor (GPCR) when the ligand binds to that receptor, causing GDP to be replaced by GTP in the associated G protein a-subunit and causing subsequent release of G proteins into the cytoplasm .
The a-subunit then dissociates from the By-subunit and each subunit can then be associated with effector proteins, which activate second messengers leading to a cellular response. Eventually, the GTP in the G proteins is hydrolyzed to GDP and the G protein subunits re-associate with each other and then with the receptor. Amplification plays an important role in the overall GPCR path. The binding of a ligand to a receptor leads to the activation of many G proteins, each capable of associating with many effector proteins leading to an amplified cellular response. Generally, compounds can change from antagonists to agonists depending on which protein G is downstream of the receptor. When G is downstream a compound targeting the S1P receptor, it can act as an antagonist. It is possible that with a different G protein (G;) downstream an agonist compound could be an agonist.
'S1P receptors become good drug targets because the individual receptors are both tissue and response specific.
The tissue specificity of S1P receptors is desirable due to the development of a selective agonist or antagonist for a receptor that localizes the cellular response to tissues containing that receptor, limiting undesirable side effects.
Specificity the response of S1P receptors is also important, as it allows the development of agonists or antagonists that initiate or suppress certain cellular responses without affecting other responses.
For example, the specificity of SIP receptors' response could allow S1P mimetics that initiate platelet aggregation without affecting cell morphology. "Sphingosine-1-phosphate is formed as a sphinx-sine metabolite in its reaction with sphingosine kinase and is stored, in abundance, in platelet aggregates where high levels of sphingosine kinase exist and sphingosine lyase is lacking.
S1P is released during platelet aggregation, accumulated in serum and is also found in malignant ascites.
Reversible biodegradation of S1P, most likely, proceeds through hydrolysis by ectophosphohydrolases, specifically, sphingosine 1-phosphate phosphohydrolases.
Irreversible degradation of S1P is catalyzed by S1P lyase yielding ethanolamine and hexadecenal phosphate.
Summary Currently, there is a need for new, potent, and selective agents that are S1P receptor agonists having enhanced potency, selectivity, and oral bioavailability.
In addition, there is a need in the art for the identification of, as well as the synthesis and use of, such compounds.
In one respect, a compound can have the formula (1): an Sa So | | | TO 1). In formula (1), A can be -CX '=, -C (X') 2-, -N =, -NX-, -O-, -S-, or a bond; THE it can be -CX =, -C (X2) 2-, -N =, -NX2-, -O-, or -S-; THE powder-
it may be -CX * =, -C (X%)> -, -N =, -NXº ., -O-, -S-, or a bond; A * can be -CXº =, -C (X *) 2-, -N =, -NXÍ-, -O-, -S-, or a bond; Aº can be -CX * =, - CÓ2-, -N =, -NXº-, -O-, or -S-; Aº can be -CXº =, -C (Xº) 2-, -N =, -NXºÉ-, -O-, -S-, or a link; A ”can be -C (R%) =, -C (RºR) -, or -NRº-; and Aº can be -C (W-Cy) =, -C (W-CyX (R-, or -N (-W-Cy) -. If> NO À 1 B'podeser |, Il or! |; eBºpowerser H, Ex, or A In formula (1), not more than 1 of AA, A, and Aº is a bond; B 'and B Are not both simultaneously AN; and not more than 4 ring atoms of A'-Aº and B'-B º are N, O, or S. "Each of X ', X , Xº, Xº, XÉ, and Xô, independently, can: be hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halo-cycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, -N (RR9), -N (RÍSO2RI, -SO2RÍ, -S (O) N (RIR9), -COJR, trialkylamino, aryl, or heteroaryl.
W can be -C (RRº) -, -N (R) -, -O-, -S-, -S (O) -, or -S (0) 2-.
Cy can be cycloalkyl, spirocycloalkyl, cycloalkenyl, spirocycloalkenyl, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl. Cy can optionally be substituted by 1-6 substituents selected from the group consisting of halo, hydroxy, nitro, cyano, -N (RR9), alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkitalkyl, cycloalkenylalkyl, heterocycle! Ialkalkyl, arylalkyl, heteroarylalkyl , alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkylyl, alkylen, aralkyl, aralkyl, aralkyl, alkylen,
R can be -L'-J-L2-T.
L 'can be -C (O) -, -S (O) 2-, -N (RÍC (O) -, -N (R)) -, -C (R'R) -, - C (RÍR9) -C (RRº) -, or a connection.
J can be - [C (RRIn-, -N (RÍHC (RRIn-, or a link, where each den, independently, can be an integer from 0 to 5; or J can be
D2 o Do | In P where each of D 'and D', independently, can be A, or E D can be - [C (RRIlk, “[C (RRIIN (RI-, - [C (RÍRIICO-, -N (R) -, or -N (RÍ-I (CR'R9)] -. D * can be - [C (R'Rº)] nm-. K can be 1 or 2; em can be 0, 1,2, or 3. No more than 2 D'-D ring atoms can be NouO. 1 - can be -C (RIR9) -, -C (R [G) -, -C (G) 2-, -C (R'R9) -C (RR9) -, - CIRÍRI) -C (R'G) - , -C (RÍR9) -C (G)> -, or a bond. 'At least one of L', J, and Lº can be different from a bond. V 10 T 'can be -C (O (OR) , -C (OIN (RÍS (O) LR ', tetrazolyl, -S (0) 2OR', -C (O) NHC (O) -R, -Si (0) OH, -B (OH) 2, - N (RÍS (O) 2RÍ, -S (O) 2aNR ', -OP (O) (ORÍ) ORS, or -P (0) to (OR). Each of G, independently, can be hydrogen, hydrogen, xi, a halogen, or trifluoromethyl.
Each of RÉ, independently, can be hydrogen, hydroxy, halo, alkyl, haloalkite, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH2. Each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle can be optionally substituted by 1 to 5 substituents independently selected from the group consisting of halo, oxo, -CN, -CHO, -CG; 3, -OH, -NO ;, alkyl, -OCG; 3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl, or dialkylaminosulfonyl.
Each of Rº, independently, can be hydrogen, hydroxy, halo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, or heterocyclic. Each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle can be optionally substituted by 1 to 5 substituents independently selected from the group consisting of halo, oxo, -CN, -CHO, -CG3, -OH, - NO ,, alkyl, -OCG ;, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, amino-
scyl, alkylsulfonyl, alkylaminosulfonyl, can be dialkylaminosulfonyl.
The compound can be in the form of a pharmaceutically acceptable salt.
In some circumstances, A ”re be -CR * =, Aº can be -C (W-Cy) =, B 'can be í, and B can be E De A'-Aº, 0, 1, or 2 ring atoms of A'-Aº can be N.
The remaining ring atoms of A'-Aº can each be C.
A 'can be -CX' =, A can be -CX =, and Aº can be -CX * =. THE can be -CX * =, A * can be -CXº =, and Aº can be -CXº =. In some circumstances, A 'can be x ", A Can be -CX =, Aº can be -CXº =, Aº can be -C (-W-Cy) =, B' is f, B Can be is A and A , A ", A, and A5, can be, respectively: -NXº * -, -C (RºRÍ) -, one., And -C (XÓ) 2-; -C (X) 2- , -NRº-, -COX) 2-, and -COÓ2-; -CPP) 2-, -C (RR-, -NX * -, and -COO 2-; -N =, -CR =, -CX * =, and -CXó =; -N =, -CR =, -N =, and -CX =; -CXP =, -CR =, -N =, and -CXP =; -N =, -CR =, -CX * =, and -N =; -CX =, -CR =, -CX =, eN =; - CX =, -CR =, -N =, and -N =; -NDXº , -CR =, A link, and -CX "=; or -CX =, -CR =, A link, and -NX" -. In some circumstances, A Can be Oxs, # can be 2 Aº can be -CXº =, A can be -CRº * =, B 'can be f, B can be “x, and A A, Aº, and Aº, can be, respectively: -CX =, -CX' =, -C (- W-Cy), eN =; -CX =, -N =, -C (W-Cy), and -N =; -NX º., -CX '=, -CÇ- W-Cy) =, and a bond; -NX -, a bond, -C (-W-Cy) =, and -CXô =; or -CX =, A bond, -C (-W- Cy) =, and -NXº- In some circumstances, each ring atom of A ', A , Aº-Aº and B'-B Is C, and each of Aº and Aº is, independently then C or N.
Lº can be-C (RR9-eyJ pda can be -NRÍ- or So né in which 7 F each of D 'and D , is independently, A or to the
Is it D is - [C (RRle, [C (RRIN (RY-, [C (RÍRYIO-, -N (RÍ-, or -N (R) -ICCR'RI) .-; and Dº is JC (RRIm-; in that ké 1o0u2; and mé 0, 1,2, or3; as long as no more than 2 ring atoms of D'-Dº * are N or O.
Each of R 'and Rº, independently, can be hydrogen or alkyl.
T can be -C (O) (OR.
T * can be -C (O) N (RÍS (O2R), -OP (O) (ORÍOR, - P (O2) (ORÍ, tetrazolila or -S (O0) 2OR !. Xº can be a withdrawal group) electron.
X can be halo, alkyl, or haloalkyl.
Each of G, independently, can be fluorine or hydroxy.
In some circumstances, Cy may have the formula: | AA x '2 x pal Rs Z * can be a link, - [C (RºRL, -CRÍ = CRº, -O-, or -NR-. Z Can be a link, - [C (RºR)], - , -CRÍ = CRº-, -O-, or -NRÍ-. Zº can be a link, - [C (RIR)]; -, -CRÍ = CRº-, -O-, or -NRÍ-. x, y, and z, independently, can be 1, 2, or 3. Each of Rº, and each of Rº, independently, can be hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl.
R '* and R'º, independently, can be hydrogen, halo, hydroxy, nitro, cyano, -NRRº, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, heteroarylalkyl , cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclyl, arylacyl, heteroarylacyl, ticalquila, alkenyl, alkenyl, alkenyl, alkenyl, alkenyl, alkenyl, alkenyl, alkenyl
R'º and R'º, when taken together, can be C2Csalkylene or C7-C; alkenylene.
R * and R , Independently, can be hydrogen, halo, hydroxy, nitro, cyano, -NRRS, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroari-
. lalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclyl, arylacyl, heteroarylalkyl, heteroaryl, alkyl, aryl, alkyl, aryl, aryl, alkyl, aryl, alkyl, R ' and Rºº, when taken together, can be C1-Cs alkylene or C7-C5 alkenylene.
R'º, R! º, Rº, and Rº each can be independently substituted by 0-5 substituents selected from halo, hydroxy, nitro, cyano, -NR'Rº, or -CO2R '.
R '* and Rºº can both be hydrogen. Z '* can be -CH2xCH> -. Z can be -CH> -. Zº can be a connection.
7 R * can be fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-7 dimethylpropyl, neopentyl, cyclopentyl, n -hexyl, cyclohexyl, methoxy, trifluoro-romoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy , cyclopentyloxy, n-hexyloxy, or cyclohexyloxy.
In some circumstances, W is O, Zº is - [C (RRIle, 2nd is ACIRR, y-, and 2nd is [C (RR9)) -. In some circumstances, X it's methyl. In some circumstances, W is -O-. In some circumstances, each ring atom of A'-Aº and B! -B is C. In some circumstances, each ring atom of A'-A , Aº-Aº and BI-B is C, and º is N. In some circumstances, each ring atom of A'-A , A * -Aº and BI-B is C, and A is N. The compound can be in the form of a pharmaceutically acceptable salt.
In some circumstances, A can be -CX =, and X it is fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, isopropyl or butyl.
In some circumstances, A 'may be CH; THE can be -CXº =, and Xº is fluorine, chlorine, bromine, methyl, difluoromethyl, trifluoromethyl, ethyl, propyl, i- —propyl or butyl. THE it can be CH; A can be CH; A can be CH; A can be CH; THE it can be C (R ); A can be C (-W-Cy); B 'can be í; eB
h 1 can be Ox. Each ring atom of A ', A , Aº-Aº and B! -B is C, and each of A and Aº, is independently, C or N. L '* can be -C (R'R) - and J can be -NRÍ- or is D: o Soi | Dº in which / o each one of D 'and D , is independently, aunt. or ff à: D is IC (RR9I, LC (RRIIANÇIRY-, LC (RÍRYIO-, -N (RÍ-, or IS -N (RY-ICCR'R9k; and D * is LC (R'RIm-; - 10 where k is 1 ou2; and mé 0, 1,2,0u3; provided that no more than 2 ring atoms of D'-D * are N or O. Each of R and Rº, independently, can be hydrogen or alkyl. -C (O) (OR) .T 'can be -C (O) N (RÍS (O2R), -0-P (O) (ORY) OR, - P (O2) (ORÍ, tetrazolyl or —S ( 0) 2OR !. Xº can be an electron withdrawal group Xº can be halo, alkyl, or haloalkyl Each of G, independently, can be fluorine or hydroxy. In some circumstances, Cy can have the formula:
ANA nal Rs Z * can be a link, - [C (RIR and, -CRÍ = CRº-, -O-, or -NR-. Zº can be a link, - [C (RºR, -, -CRÍ = CRº , -O-, or -NRÍ-. Zº can be a link, - [C (RºRº)]; -, -CRÍ = CRº-, -O-, or -NR-. Each of x, y, ez, independently, it can be 1, 2, or 3. Each of R $, and each of Rº, independently, can be hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl. R '* and R'º, independently, they can be hydrogen, halo, hydroxy, nitro, cyan, -NRÍRºs, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cyclic
f cloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl, alkoxy, cycloalkylalkoxy, cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkyl, cycloalkyl, alkylacyl, cycloalkyl, alkylacyl, cycloalkyl, cycloalkylalkyl - rocyclyl, aryl, or heteroaryl. Rº and R ”º, when taken together, can be C72-Cs alkylene or C2-C; s alkenylene.
R ** and Rºº, independently, can be hydrogen, halo, hydroxy, nitro, cyano, -NRÍRS, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, cycloalkylalkyl, alkoxyalkyl, alkoxyalkyl , cycloalkenylalkoxy, heterocyclylalkoxy, arylalkoxy, heteroarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, heterocyclyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkyl, aryl, aryl, aryl, aryl, aryl, aryl, aryl, aryl. is R'º * and Rºº, when taken together, can be C1-Cs5 alkylene or
15. CC; alkenylene.
R'º, R'º, Rºº, and R each can be independently substituted by 0-5 substituents selected from halo, hydroxy, nitro, cyano, -NRÍRº, or -CO2R.
R '* and Rºº can both be hydrogen. Z 'can be -CH2CH, -.
Z can be -CH7-. Zº can be a connection.
R * can be fluorine, chlorine, bromine, iodine, methyl, trifluoromethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1-dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy.
In some circumstances, W is O, Z 'is JC (RRIe, 2 is AC (RIRy-, and 2' is [C (RIR)) - in some circumstances, X 'is methyl. In some circumstances, W is - O-.
In another aspect, a pharmaceutical composition includes a pharmaceutically acceptable carrier and a compound of formula (1), as defined above.
] In another aspect, a method for preventing or treating a pathological condition or symptom in a mammal, in which the activity of sphingosine 1-phosphate receptors is implicated and agonism of such activity is desired including administering to the said mammal a quantity effective of a compound of formula (1).
In another aspect, a method for preventing or treating a pathological condition or symptom in a mammal, in which S1P lyase activity is involved and inhibition of S1P lyase is desired, including administering to said mammal an effective amount of a compound of formula ()).
In another aspect, a method for preventing or treating a pathological condition or symptom in a mammal, in which the activity of sphingosine 1-phosphate receptors is implicated and antagonism of such activity is desired, including administering to said mammal a quantity - defective of a compound of formula (1).
In another aspect, the pathological condition may be multiple sclerosis, autoimmune diseases, chronic inflammatory disorders, asthma, inflammatory neuropathies, arthritis, transplantation, Crohn's disease, ulcerative colitis, lupus erythematosis, psoriasis, reperfusion-ischemic damage, solid tumors , tumor metastases, diseases associated with angiogenesis, vascular diseases, pain conditions, acute viral diseases, inflammatory bowel conditions, insulin-dependent or non-insulin diabetes, inhibited cell migration, overproliferation and effector cytokine secretion, or lack of secretion of the suppressive cytokine 11-10.
In another aspect, the compound exhibits S1P agonist activity. In another aspect, the compound exhibits S1P agonist activity, and is substantially free of S1P agonist and antagonist activity; 3.
In another aspect, the compound exhibits S1P; antagonistic activity. In another aspect, the compound exhibits S1P5 agonist activity.
In another aspect, the compound exhibits S1P, antagonistic activity. In another aspect, the compound exhibits S1P agonist activity.
In another embodiment, the invention is directed to the examples having the formula (!), Pharmaceutically acceptable salt thereof, or when the example having formula (1) is a salt, a free base of that salt. The compound of formula (1) can be a compound of formulas (I-la) - (d): xP x xXx 0) xi Rº xt Rº CO a Ra di CcyW x CcyW xt XE xx (Ila) (lb) Rx xXx O) x1 Rº xt Rº
LA S - Cy Ww X2 —oyw 02 x 0 x CO - (tc) (11d) * a compound of formulas (Illa) - (lllg): x x x and x x xt NR xt LR xi Ns xt A eyW EXX ow AN ow fo ow NX: Xô xx XE xo (la) (lb) (o) (11d) í xxx 02 x> 1 3> No ey W no eyW 2 CW xt xo xº 0 xº 0 (Ile) (1 (ig); a compound of formulas (IVa) - (IVc): XxX XxX xe x xB xt N xi xt N 2R YV-Rê Rº eyw eyw N Ccyw R x << xe x xé OS (IVa) (IVb) (IVc): a compound of formulas (Va) - (Vc):
1 Pe x x2 and Rx | 2 A Ne 4 CyWw "" N xº CcyWw "N x ow x xs xxx (Va) (Vb) (Vc); or a compound of formulas (Vla) - (Vlc): xp x Ro x and ox N Rê N Rô 4X IWA <XA and w NY xt x M x XX x cw xs xx (Vla) (Vlb) (Vic) In certain circumstances, the compound is of formula (lla), (Na) or (Illb). one or more modalities are determined following the description below Other characteristics, objects, and advantages will be apparent from the description and the claims Detailed Description The following abbreviations are used here: S1P, sphingosine 1-phosphate; S1P1.5 , S1P receptor types 1-5; GPCR, G protein-coupled receptor; SAR, structure-activity relationship; EDG, endothelial cell differentiation gene; EAE, experimental autoimmune encephalomyelitis; Non-obese diabetic NOD; TNFa, factor tumor necrosis alpha; HDL, high-density lipoprotein; and RT-PCR, reverse transcriptase polymerase chain reaction.
The values listed below for radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for radicals and substituents. The compounds described include compounds of the formula | having any combination of values, specific values, plus specific values, and preferred values described here.
The term "halogen" or "halo" includes bromine, chlorine, fluorine, and iodine. The term "haloalkyl" refers to an alkyl radical bearing at least one halogen substituent, non-limiting examples include, but are not limited to
F are limited to, chloromethyl, fluorethyl, trichioromethyl, or trifluoromethyl and the like. The term "C1-C25 alkyl" refers to a linear or branched alkyl group having from one to twenty carbons. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, oroctyl and the like. The term "C2-C2, alkenyl" refers to an olefinically unsaturated linear or branched group having from two to twenty carbon atoms and at least one double bond. Typically, C2-C29 alkenyl groups include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, hexenyl, pentenyl, hexenyl, heptenyl, and the like.
n The term (C> -C>,) alkynyl can be ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, P 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl, and the like.
The term "(C1-C10) alkoxy" refers to an alkyl group attached via an oxygen atom. Examples of (C1-C10) alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy, and the like.
The term "(C3-Ci>) cycloalkyl" refers to a cyclic alkyl group, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, and the like. Cycloalkyl groups include bicyclic groups, such as decalinyl, bridged bicyclic groups, such as norbornyl or bicyclo [2.2.2] octyl, tricyclic, tricyclic bridged, such as adamanttyl, or spiro linked tricyclic or bicyclic groups.
The term "(Cs-C14) aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, naphthyl, tetrahydronaphyl, indinyl, indenyl, or anthracyl, and the like.
The term "aryl (C; -C29) alkyl" or "arylalkyl" or "aralkyl" refers to an alkyl group substituted by a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, such a group as phenyl , naphthyl, tetrahydronaphthyl, indanyl, or indenyl, and the like. Example-
Non-limiting examples of arylalkyl include benzyl, or phenylethyl, and the like.
The term "(C1-C14) heterocyclic group" refers to an optionally substituted mono or bicyclic carbocyclic ring system containing one, two, three, or four hetero atoms (optionally on each ring) where the hetero atoms are oxygen, sulfur, and nitrogen.
The term "(C4-Cu) heteroaryl" refers to an optionally substituted cyclic, mono or bicyclic ring system containing one, two, or three heteroatoms (optionally in each ring) where the heteroatoms are oxygen, sulfur, or nitrogen. Non-limiting examples of heteroaryl groups include furyl, thienyl, or pyridyl, and the like.
The terms "phosphate analog" and "phosphonate analog" comprise phosphate and phosphonate analogs, where the phosphorus atom is in the +5 oxidation state and one or more of the oxygen atoms are replaced by a portion non-oxygen including, for example, phosphates analogous phosphorothicoate, phosphoroditicoate, phosphoroselenoate, phosphorodiselenoate, phosphoranilothioate, phosphoranilidate, phosphoramidate, or boronophosphates, and the like, including associated counterions, for example, H *, NH ”, Na”, ” or K ', and the like if such counterions are present.
The term "alpha-substituted phosphonate" includes phosphonate groups (- CH; PO3H7) which are substituted on alpha-carbon, such as -CHFPO3H>, - CF2PO3H2, -CHOHPO3H>, or -C = OPOzH,> and the like.
The term "pharmaceutically acceptable carrier" includes any of the standard pharmaceutical carriers, such as phosphate buffered saline, hydroxypropyl beta-cyclodextrins (HO-propyl beta cyclodextrins), water, emulsions, such as an oil / water emulsion or water / oil, and various types of wetting agents. The term also includes any of the agents approved by the regulatory agency of the United States federal government or listed in the United States Pharmacopoeia for use in animals, including humans.
The term "pharmaceutically acceptable salt" refers to salts that retain the biological efficacy and properties of the described compounds that are not biologically or otherwise undesirable. In many cases,
It is described compounds that are capable of forming acid salts or base salts due to the presence of amino or carboxyl groups or similar groups thereof.
The term "prodrug" refers to a compound that is converted - under physiological conditions, for example, by liquefaction or metabolically, to a compound that is pharmaceutically active, such as a compound of formula (1). A prodrug can be a derivative of a compound of formula (1) that contains a carboxylic or phosphoric acid ester or amide moiety that can be cleaved under physiological conditions. A prodrug containing such a portion can be prepared according to conventional procedures, for example, by treating a compound of this invention containing amine, starch or hydroxyl moiety with a suitable derivatizing agent, for example, a phosphoric acid halide or carboxylic or anhydride acid, or converting a carboxyl moiety to an ester or amide. Metabolites of the compounds of formula (1) can also be pharmaceutically active.
An "effective amount" means an amount sufficient to produce a selected effect. For example, an effective amount of an S1P receptor agonist is an amount that decreases the cell signaling activity of the S1P receptor.
The described compounds can contain one or more asymmetric centers in the molecule. According to the present description, any structure that does not indicate stereochemistry is to be understood to cover all the various optical isomers (for example, diastereomers and enantiomers), as well as mixtures thereof (such as a mixture racemic). The compounds can be isotopically labeled compounds, for example, compounds including various isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, iodine, or chlorine.
The compounds described can exist in tautomeric forms and the invention includes both mixtures and separate individual tautomers. For example, the following structure:
. HNSN and is understood to represent a mix of structures:
HNSN NÔ NH Sar as well as Tam: An "S1P modulating agent" refers to a compound or composition that is capable of inducing a detectable change in in vivo or in vitro activity of the S1P receptor (for example, at least 10% increase or decrease in S1P activity as measured by a given assay, such as the bioassay described in the examples and known in the art. "S1P receptor," refers to all S1P receptor subtypes (for example, 10 S1P, S1IP receptors ,, SIP>, S1IP3, S1IP4, or S1P5s), in contrast the specific subtype is - indicated.
It will be appreciated by those skilled in the art that the compounds described having chiral centers can exist in and be isolated in racemic and optically active forms. It is to be understood that the compounds described encompass any stereoisomeric, racemic, optically active form or, or mixtures thereof. It should be well known in the art how to prepare such optically active forms (for example, resolution of the racemic form by recrystallization techniques, syntheses from optically active starting materials, by chiral syntheses, or chromatographic separation causing a phase chiral stationary) and how to determine S1P agonistic activity using the standard tests described here, or using other similar tests that are well known in the art. In addition, some compounds may exhibit polymorphism.
Potential uses of an S1P receptor agonist, and selective S1P receptor-type agonists, particularly include, but are not limited to, preventing or treating a pathological condition or symptom in a mammal. For example, the condition can include asthma, inflammatory neuropathies, arthritis, lupus erythematosis, psoriasis, reperfusion-ischemia damage, solid tumors, tumor metastases, diseases associated with angiogenesis, vascular diseases, pain conditions, acute viral diseases,
'or insulin-dependent diabetes and not insulin. The condition can alter lymphocyte trafficking as a treatment method for neuropathic pain, inflammation-induced pain (eg, where prostaglandins are involved) or treatment of autoimmune pathologies, such as uveitis, type 1 diabetes, rheumatoid arthritis, disorders chronic inflammatory diseases, inflammatory internal diseases (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, and in drug-eluting stents. Additional uses may include treatment of degenerative brain diseases, heart disease, cancers, or hematitis C. See, for example, WO 2005/085295, WO 2004/010987, WO 03/097028, and WO 2006/072562, each one is hereby incorporated by reference in its entirety. A class of S1P agonist compounds is described in "Provisional Application US 60 / 956,111, filed on August 15, 2007, and PCT / US2008 / 073378, filed on August 15, 2008, each is incorporated herein by reference in its wholeness.
Potential uses of an S1P receptor antagonist, and particularly selective S1P receptor-type antagonists; include, but are not limited to, preventing or treating a pathological condition or symptom in a mammal. For example, the condition may include inhibited cell migration from oligodendrocyte precursor cells (OPCs). In another example, a selective S1P receptor-type antagonist; it cannot induce lymphopenia, thereby achieving partial efficacy without immunosuppression.
Potential uses of an S1P receptor antagonist, and particularly selective S1P receptor-type antagonists, include, but are not limited to, preventing or treating a pathological condition or symptom in a mammal.
"Treatment" of multiple sclerosis includes treating various forms of the disease including recurrent, chronic progressive, and S1P Receptor agonists / antagonists can be used alone or in conjunction with other agents to relieve the signs and symptoms of the disease as well as bprofilatamente.
In addition, the described compounds can be used to alter lymphocyte trafficking as a method to prolong graft survival, for example, transplantation including solid organ transplants, graft versus host disease, bone marrow transplantation Bone, and the like.
In addition, the described compounds can be used to inhibit autotaxin.
Autotaxin, a plasma phosphodiesterase, has been shown to suffer inhibition of the final product.
Autotaxin hydrolyzes various substrates to yield lysophosphatidic acid and sphingosine 1-phosphate, and has been implicated in the progression of cancer and angiogenesis.
Therefore, S1P receptor agonist prodrugs of the described compounds can be used to inhibit auto-taxin.
This activity can be combined with agonism for S1P receptors or it can be independent of such activity. - Compounds described may be useful to inhibit sphingosine kinase (i.e., sphingosine kinase |, sphingosine kinase | 1, or both). Sphinx gosine kinase is an intracellular enzyme that catalyzes the formation of S1P from sphingosine and a nucleotide triphosphate (eg ATP). Inhibition of sphingosine kinase can reduce the formation of S1P and thereby reduce the supply of S1P available for activated signaling to S1P receptors.
Thus, sphingosine kinase inhibitors may be useful in the function of the immune modulation system.
Therefore, the described compounds can be used to inhibit sphingosine kinase.
This inhibition can be in conjunction with S1P receptor activity, or be independent of activity from any S1P receptor.
In addition, described compounds may be useful for inhibiting SIP lyase.
S1P lyase is an intracellular enzyme that irreversibly degrades S1P.
Inhibition of S1P lyase disrupts lymphocyte trafficking with concomitant lymphopenia.
Thus, S1P lyase inhibitors may be useful depending on the immune modulation system.
Therefore, the described compounds may be useful for inhibiting S1P lyase.
This inhibition can be in conjunction with S1P receptor activity, or be independent of any desSiP receptor activity.
In addition, described compounds may be useful as CB, cannabinoid receptor antagonists.
CB atagonism is associated with a decrease in body weight and an improvement in the blood lipid profile. CB antagonism can be in conjunction with S1P receptor activity, or be independent of activity for any S1P receptor. In addition, described compounds may be useful for inhibiting cytosolic PLA-polyVA (CPLAz). cPLA, catalyzes the release of eicosanoic acids (for example, arachidonic acid). Arachidonic acids are transformed into pro-inflammatory eicosanoids, such as prostaglandins and leukotrienes. Thus, described compounds can be useful as anti-inflammatory agents. This inhibition can be in conjunction with S1P receptor activity, or be independent of the activity of any S1P receptor. Fr In addition, described compounds may be useful for inhibiting multiple lipid kinase (MulK) substrates. MuLK is highly expressed in many human tumor cells and, therefore, its inhibition can delay the growth or spread of tumors.
Pharmaceutical compositions can include compounds of formula |. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carrier, fillers, solubilizing agents and stabilizers known to those skilled in the art. For example, a pharmaceutical composition includes a compound of formula |, or a salt, analogue, derivative, or modification thereof, as described herein, is used to administer the appropriate compound to an individual.
Formula compounds | are useful for treating a disease or - disorder including administering to a subject in need thereof a therapeutically acceptable amount of a compound of formula |, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula |, and a carrier pharmaceutically acceptable.
The described compounds and methods are directed to sphingosine 1-phosphate (S1P) analogs that have activity as an agonist receptor or receptor antagonist to one or more S1P receptors, specifically
. the types of receiver S1P ,, S1P, or S1P5s. The described compounds and methods include both compounds that have a phosphate moiety as well as compounds with hydrolysis-resistant phosphate substitutes, such as phosphonates, alpha-substituted phosphonates (particularly, where the alpha substitution is a halogen), or phosphothionates .
In cases where compounds of formula | are sufficiently basic or acidic to form stable non-toxic acid or base salts, preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form an acceptable physiological anion, for example, tosylate, methanesulfo-: nate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, a- ketoglutarate, or a-glycerophosphate. Inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine with a suitable acid providing a physiologically acceptable anion. Alkali metal (eg sodium, potassium or lithium) or alkaline earth metal salts (eg calcium) of carboxylic acids can also be made.
Pharmaceutically acceptable base addition salts can be prepared from organic and inorganic bases. Inorganic base salts include, but are not limited to, sodium, potassium, lithium, ammonium, calcium or magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary or tertiary amine salts, such as here! amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di (substituted alkyl) amines, tri (substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di (substituted alkenyl) amines, tri (substituted alkenyl) ) amines, cycloalkyl amines, di (cycloalkyl) amines, tri (cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amines, tri-substituted cycloalkyl amines, cycloalkenyl amines, di (cycloalkenyl) amines, tri (cycloalkenyl) amines
and substituted alkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, di-heterocyclic and tri-heterocyclic amines mixed, where at least two of the amine substituents are different and are alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocyclic and the like. Also included are amines, where two or three substituents, together with amino nitrogen, form a heteroaryl or heterocyclic group. Non-limiting examples of amines include, isopropylamine, trimethyl amine, diethyl amine, triliso-propyl) amine, tri (n-propyl), amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucoamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, —morpholine, or N-ethylpiperidine, and the like. It should also be understood that other carboxylic acid derivatives should be useful, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, and the like.
Formula compounds | they can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, for example, orally or parenterally, as eye drops, intravenously, intramuscular, topical or subcutaneous. Thus, the present compounds can be administered systemically, for example, orally, in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier. They can be closed in hard or soft gelatin capsules, can be pressed into tablets, or can be directly incorporated with the patient's diet food. For oral therapeutic administration, the active compound can be combined with one or more excipients and used in the form of ingestible tablets, oral tablets, troches, capsules, elixirs, suspensions, syrups, or lozenges, and the like.
. res. Such compositions and preparations must contain at least about 0.1% of active compound. The percentage of compositions and preparations can, of course, be varied and can conveniently be between about 2 to about 60% by weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
Tablets, troches, pills, capsules, and the like may also contain the following: binders, such as tragacanth, acacia, corn starch or gelatin; excipients, such as dicalcium phosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid and the like; a lubricant, such as magnesium stearate; and a - sweetening agent, such as sucrose, fructose, lactose or aspartame or a flavoring agent, such as peppermint, wintergreen oil, or cherry flavoring can be added. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or polyethylene glycol. Various other materials may be present as coatings or otherwise modify the physical form of the solid dosage unit form. For example, tablets, pills, or capsules can be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl or propylparabens as preservatives, a coloring and flavoring, such as cherry or orange flavor. Certainly, any material used in the preparation of any form of dosage unit must be pharmaceutically acceptable and substantially non-toxic in the amounts used. In addition, the active compound can be incorporated into sustained release devices and preparations.
The active compound can also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils.
Under normal conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
Exemplary pharmaceutical dosage forms for injection or infusion may include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient that is adapted for the extemporaneous preparation of sterile infusible or injectable solutions or dispersions, optionally encapsulated in liposomes.
In all cases, the last dosage form must be sterile, fluid and stable under the conditions of manufacture and storage.
The liquid vehicle or vehicle can be a liquid solvent or dispersion medium comprising, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycols, and the like), oils vegetables, or non-toxic glycerol esters, and mixtures thereof.
Adequate fluidity can be maintained, for example,! by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, or thimerosal, and the like.
In many cases, it should be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride.
Prolonged absorption of injectable compositions can be brought about by using absorption retarding agents in compositions, for example, aluminum monostearate or gelatin.
Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients listed above, as needed, followed by filter sterilization.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and cold drying techniques, which yield an active ingredient powder plus any desired additional ingredient previously present in the filtered solutions sterile.
For topical administration, the present compounds can be applied in pure form, for example, when they are liquid.
However
. Therefore, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Exemplary solid vehicles include finely divided solids, such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid vehicles include water, alcohol or glycols or glycol / alcohol-water mixtures, in which the present compounds can be dissolved or dispersed to effective levels, optionally with the addition of non-toxic surfactants. Adjuvants, such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. The resulting liquid compositions can be applied to absorbent pads, used to impregnate compresses and other dressings, or sprayed on the affected area using aerosol or pump and type sprayers.
Thickeners, such as synthetic polymers, fatty acids, fatty acid salts or esters, fatty alcohol, modified celluloses or modified mineral materials can also be used with liquid carriers to form disseminable pastes, gels, ointments, soaps, and the like , for application directly to the user's skin.
Examples of useful dermatological compositions that can be used to deliver compounds of formula | on the skin they are known in the art; for example, see Jacquet et a /. (US Patent 4,608,392), Geria (US Patent 4,992,478), Smith et al. (US patent 4,559,157) and Wortzman (US patent 4,820,508), each is incorporated by reference in its total Useful dosages of compounds of formula | they can be determined by comparing their activity in vitro, and activity in vivo in animal models. Methods for extrapolating effective dosages in mice, and other animals, in humans are known in the art; for example, see US Patent 4,938,949, which is incorporated by reference in its entirety.
Generally, the concentration of the compound (s) of formula | in liquid composition, such as lotion, it will be about 0.1 to about 25 weight percent, preferably about 0.5 to 10 weight percent. The concentration in a solid or semi-solid composition, such as a gel or powder, will be about 0.1 to 5 weight percent, preferably about 0.5 to 2.5 weight percent based on the total weight of the composition.
The amount of the compound, or an active or derived salt thereof, required for use in the treatment will vary not only with the particular salt selected, but also with the route of administration, the nature of the condition being treated and the age and condition of the patient will ultimately be at the discretion of the doctor or assistant. In general, however, a dose will be in the range of about 0.1 to about 10 mg / kg of body weight per day. ] The compound is conveniently administered in unit dosage form; for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form. In some modalities, a dose of 5 mg / kg or less is adequate.
Ideally, the active ingredient should be administered to achieve peak plasma concentrations of the active compound from about 0.5 to about 75 µM, preferably from about 1 to 50 µM, more preferably, from about 2 to about CU 30. This can be achieved, for example, by intravenous injection of a solution of 0.05 to 5% of the active ingredient, optionally in saline, or orally administered as a cake containing approximately 1 to 100 mg of the active ingredient. Desirable blood levels can be maintained by continuous infusion to provide approximately 0.01 to 5.0 mg / Kkg / h or by intermittent infusions containing approximately 0.4 to 15 mg / kg of active ingredient (s).
The desired dose can conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day. The sub-dose itself can be further divided, for example, into a number of vaguely discreetly spaced administrations; such as multiple inhalations from the insufflator or by applying a plurality of drops to the eye.
F The methods described include a kit comprising a compound of formula | and informational material describing the administration of the compound or a composition comprising the compound to a cell or an individual. It should be constructed to include other modalities of kits that are known to those skilled in the art, such as a kit comprising a solvent (preferably sterile) to dissolve or suspend the compound or composition before administering the compound or composition to a cell or an individual. Preferably, the individual is a human being.
Compounds can have ECs5,9 out of 5 nM and 3 uM when acting as selective agonists for S1P receptors. While ECs, 5 of F certain compounds acting as agonists for S1P, and S1P; 3 receptors may be greater than 5000 nM, these same compounds may have ECs, Á from 0.2 nM to 700 nM when acting as selective antagonists for SIP receptors; and 50 nM to 3 µM when acting as selective antagonists for S1P receptors.
According to the compounds and methods described, as described above or as discussed in the examples below, conventional chemical, cellular, histochemical, biochemical, molecular biology, microbiology, and in vivo techniques that are known to those skilled in the art can be employed. . Such techniques are fully explained in the literature.
The following working examples are provided for illustrative purposes only, and are not to be construed as limiting in any way from the rest of the description. Therefore, the examples must be constructed to encompass any and all variations that will become evident as a result of the teaching provided here.
Examples Example 1: cis-4-tert-butylcyclohexyl methanesulfonate Ms, O, EtaN + OH> To DCM gifts, ta 3-hTI Cis-4-t-butylcyclohexanol (6.0 9, 38.5 mmoles , 1.0 eq.) Was dissolved in dichloromethane (10 ml). Then methanesuylphonic anhydride
: (8.03 g, 46.2 mmoles, 1.1 eq.) Was added to the mixture slowly at 0 ° C.
Then, triethylamine (6.4 ml, 46.2 mmoles, 1.5 eq.) Was added to the mixture and the mixture was stirred at room temperature for 3 hours.
The mixture was extracted with dichloromethane and the organic layer was concentrated to provide product as a white potency (8.0 g, yield: 90%). The product was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 5 4.99-4.98 (m, 1H), 3.02 (s, 3H), 2.14-2.12 (m, 2H), 1.65-1, 28 (m, 7H), 0.84 (s, 9H). Example 2: 2-bromo-6- (trans-4-fer-butylcyclohexyloxy) naphthalene Br CsCO.
Br It is AD AA AA tbutanol / 2butanone + (2/1). 110ºC, 15h 6-bromonatftalen-2-0l (CAS No. 15231-91-1) (3.0 g, 14.8 mmoles, 1.0 eq.) Was dissolved in a mixture of t-butanol / 2-butanone (4 mL / 2 mL). Then, cesium carbonate (12 g, 37.2 mmoles, 2.5 eq.) Was added to the mixture and the mixture was stirred at 110 ° C for 10 min.
Then, trans-d4-tert-butylcyclohexyl methanesulfonate (3.48 g, 16.2 mmoles, 1.1 eq.) Was added to the mixture.
The suspension was stirred at 110ºC under a nitrogen atmosphere for 15 hours.
The reaction mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using petroleum ether as the eluent to provide 2-bromo-6- (trans-d4-tert-butylcyclohexyloxy ) naphthalene as a light yellow solid (1.7 9, yield: 32%). ESI-MS: 361.0 (M + H) *. * H NMR (400 MHz, CDCI; 3) 5 7.89 (s, 1H), 7.63 (d, 1H), 7.56 (d, 1H), 7.47 (d, 1H), 7, 15-7.11 (m, 2H), 4.26-4.24 (m, 1H), 2.27-2.25 (m, 2H), 1.89-1.87 (m, 2H), 1.45-1.09 (m, 5H), 0.89 (s, 9H). Example 3: 6- (trans-4-tert-butylcyclohexyloxy) -2-naphthaldehyde PIO blind fo, Oro 2-bromo-6- (trans-4-tert-butylcyclohexyloxy) naphthalene (2,249 q, 6,25 mmoles1.0 eq.) was dissolved in THF (10 mL) under an atmosphere of
He's a genius.
Then, the mixture was cooled to -78 ° C and a solution of n-BuLi in THF (2.5 M, 7.5 ml, 18.8 mmoles, 3.0 eq.) Was added to the mixture dropwise.
The mixture was stirred at -78 ° C for 15 min.
Then, DMF (2.4 mL, 31.2 mmoles, 5.0 eq.) Was added to the mixture and stirred at -78 ° C for 1 hour.
When the reaction is complete, 1M HCl is added to adjust the pH to 6. The mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using ethyl acetate / petroleum ether (10 / 1) as an eluent to provide 6- (trans-4-fer-butylcyclohexyloxy) -2-naphthaldehyde as a white solid (1.16 g, 60%). EDI-MS: 311.1 (M + H) *. * H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.24 (s, 1H), 7.92-7.87 ( m, 2H), 7.77 (d, 1H), 7.22-7.19 (m, 2H), 4.424,30 (m, 1H), 2.30-2.28 (m,: 2H), 1.93-1.90 (m, 2H), 1.48-1.11 (m, 5H), 0.82 (s, 9H). Example 4: 2-bromo-6- (trans-4-fer-butylcyclohexyloxy) naphthalene (alternative synthesis) Br - DIAD, PPh3, PhMe Br To a solution of 6-bromonaftalen-2-ol (100.0 g, 450.1 mmoles), triphenylphosphine (230 g, 877.8 mmoles, 2.0 eq) and cis-4-t-butylcyclohexane! 1 (105.4 g, 675.7 mmoles; 1, 5 eq) in toluene (1.5 L), diisopropyl azodicarboxylate gum (170 g, 850.0 mmol, 2.0 eq) was added dropwise at 0 ° C.
The addition took —2 hours and the resulting mixture was heated to 26-30ºC.
After 24 hours, thin layer chromatography showed almost complete consumption of 6-bromonaftalen-2-ol.
The mixture was then cooled to 5 ° C and stirred at that temperature for 2 hours, over which precipitated solids were filtered.
The filtrate was concentrated almost to dryness to provide an oil, which was taken in 200 ml of methylene chloride and purified by silica gel chromatography with 100% petroleum ether.
After concentration, 127 g of product were obtained as a white solid (yield: 79.1%). EDI-MS: 361.1 (M + H) *. Example 5: 6-bromo-2- (trans-4-tert-butylcycyl-hexyloxy) -1- iodonaphthalene
A solution of 2-bromo-6- (trans-4-tert-butylcyclohexyloxy) naphthalene (160.0 g, 444.4 mmoles) in methylene chloride (2.5 L) was purged under an argon atmosphere.
N-iodosuccinimide (202.1 g, 888.8 mmoles) and zirconium tetrachloride (20.4 g, 88.9 mmoles) were added and the reaction was stirred at room temperature under an argon atmosphere.
The reaction was monitored by 1H NMR and showed complete conversion to the product after 30 minutes.
The mixture was then concentrated under reduced pressure to provide -250 g of a crude brown solid.
The crude material was: purified by silica gel chromatography with hexanes to provide 200 g of desired product as a brown solid (yield: 92.6%). EDI-MS:. 487.1 (M + H) *. Example 6: 6-bromo-2- (trans-4-tert-butylcyclohexyloxy) -1- (trifluormethyl) naphthalene ho or RR o O “o 1" CF;
A solution of G6-bromo-2- (trans-4-tert-butylcyclohexyloxy) -1- iodonaphthalene (210.0 g, 433 mmoles), hexamethylphosphoramide (386.4 g, 2.16 moles; 5 eq) in N, N-dimethylformamide (2.0 L) was degassed by stirring under vacuum and replacing the vacuum with argon (4 times). To this mixture were added copper (i) iodide (140.0 g, 735 mmoles; 1.7 eq) and methyl fluorosulfonylifluoroacetate (415 g, 2.16 moles; 5 eq). The reaction mixture was heated to 80ºC under an argon atmosphere.
After stirring for 6 hours, thin layer chromatography showed complete conversion to the product.
NaHCO solution; saturated was added to adjust the final pH to 9-10 followed by the addition of EtOAc (3.5 L). The mixture was extracted with EtOAc (2.5 L x 3), and washed with brine (1.0 L x 4), then dried over Na2SO, (500 dg). The solvent was removed under reduced pressure to provide 195 g crude as a white cohesive solid with> 90% purity, which was purified by silica gel chromatography with 0-30% EtOAc in hexanes to provide the final product (156 g, 84.3%). EDI-MS: 430.0 (M + H) *. Example 7: tert-butyl 3-oxo-3- (phenylsulfonamido) propyl carbamate oo AoA, + Dm ED AAA DCM, ta, 2h 3- (Terc-butoxycarbonylamino) propanoic acid (4 g, 21.2 moles, 1.0 equiv) was dissolved in DCM (100 ml). Then, phenylsulfonamide (15.1 mmoles, 0.7 equiv), EDCI (3.45 g, 18.2 mmoles, 0.85 equiv) and DMAP (0.37 g, 3 mmoles, 0.15 equiv) ) were added to the mixture and stirred for 2 hours at room temperature.
The reaction mixture was cooled to 0 ° C, ice water (100 ml) was added.
The mixture was stirred for 15 min, separated and the water layer was extracted twice with dichloromethane.
The combined organic layer was washed with 5% HCl, brine, dried over Na; SO ,, concentrated to provide 5.3 g of ferc-butyl 3-ox0-3- (phenylsulfonamido) propylcarbamate, gray oil, 100% . EDI-MS: 329.0 (M + H) *. * H NMR (400 MHz, CDCl3) 5: 9.52-9.43 (brs, 1H), 8.02-7.96 (m, 2H) , 7.61-7.55 (m, 1H), 7.50-7.45 (m, 2H), 5.02-4.93 (m, 1H), 3.30-3.24 (m, 2H), 2.48-2.41 (m, 2H), 1.34 (s, 9H). Example 8: 3-amino-N- (phenylsulfonyl) bropanamide o. x ANE CF3COOH oo and K O DCM, 0ºC, 2h Ao Terc-butyl 3-0x0-3- (phenylsulfonamido) propylcarbamate (3.6 g, 15.1 mmoles) was dissolved in dichloromethane (60 ml). Then, CF; COOH (1.1 mL, 0.3 mmol, 20 equiv.) Was added to the mixture at 0 ° C and stirred for 2 hours at 0 ° C.
The reaction mixture was concentrated and purified by flash chromatography to provide 3-amino-N- (phenylsulfonyl) propanamide as a white solid (1.4 g, 40%). EDI-MS: 229.0 (M + H) *, * H NMR (400 MHz, DMSO-ds) & 7.79-7.71 (m, 2H), 7.70-7.43 (brs, 3H ), 7.42-7.34 (m, 3H), 2.83 (t, 2H), 2.24 (t, 2H). Example 9: 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-
P il)] methylamino) -N- (phenylsulfonyl) bropanamide * <oo Ao Xo At Qeo H> DO NO LOS NaBH2CN, EtoH, 80%, 16h “CO á IS O 6- (Trans-4-tert-butylcyclo- hexyloxy) -2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N- (phenylsulfonyl) propanamide (1.19 mmol, 1.5 eq) were dissolved in anhydrous ethanol. The mixture was stirred at 80 ° C for 1 hour. Then, NABH; CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80 ° C for 16 hours. The organic layer was concentrated and purified by preparative thin layer chromatography (mobile phase was methanol: dichloromethane 1:10) to provide 3 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl ) methylamino) -N- (phenylsulfonyl) propanamide as. 10 a white solid, 284 mg, white solid, 62%. ESI-MS: 523.0 (M + H) *. H- PLC: 99.42%, '* H NMR (400 MHz, DMSO-ds) 5: 7.91 (s, 1H), 7.85-7.82 (m, 2H), 7.74-7 .72 (m, 2H), 7.53-7.51 (m, 1H), 7.41-7.35 (m, 4H), 7.20-7.15 (m, 1H), 4.45 -4.40 (m, 1H), 4.23 (s, 2H), 2.99 (t, 2H), 2.33 (t, 2H), 2.28-2.16 (m, 2H), 1.89-1.78 (m, 2H), 1.41-1.31 (m, 2H), 1.27-1.17 (m, 2H), 1.13-1.06 (m, 1H ), 0.89 (s, 9H). Example 10: 3 - ((6- (trans-4-tert-butylcycle-hexyloxy) -5- Aeee pre en NgeAn the king TU Po Pro oo * Oo. Ço “POR, ço F F NaBH3CN, EtoH, 80 ºC, 16h the FF
FF 6- (trans-4-tert-butylcyclohexyloxy) -S- (trifluormethyl) -2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N- (phenylsulfonyl) pbropanamide (1, 19 mmol, 1.5 equiv) were dissolved in anhydrous ethanol. The mixture was stirred at 80 ° C for 1 hour. Then, NaABH; CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80 ° C for 16 hours. The organic layer was concentrated and purified by preparative thin layer chromatography (mobile phase was methanol: dichloromethane 1:10) to provide 3 - ((6- (trans-4-tert-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen-2-yl)] methylamino) -N-
. (phenylsulfonyl) bpropanamide as a white solid. 120 mg, white solid, 53%. ESI-MS: 591.0 (M + H) *. HPLC: 98.05%. * H NMR (400 MHz, DMSO-ds) 5: 8.22-8.13 (m, 1H), 8.11-8.04 (m, 2H), 7.79-7.63 (m, 4H ), 7.45-7.30 (m, 3H), 4.63-4.49 (m, 1H), 4.27 (s, 2H), 2.99 (t, 2H), 2.32 ( t, 2H), 2.19-2.07 (m, 2H), 1.85-1.74 (m, 2H), 1.45-1.30 (m, 2H), 125-1.12 ( m, 2H), 1.10-0.97 (m, 1H), 0.86 (s, 9H). Example 11: methyl 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanoate o aah ADCT A AI oNfE o O NaBH3CN, ACOH, DCE, reflux. 2h “o CO” o 7 A mixture of 6- (trans-4-tert-butylcyclohexyloxy) -2-naphthaldehyde (155 mg, 0.5 mmol), methyl 2-aminopropanoate (103 mg, 1.0 mmol, 2.0 equiv) h and AcOH (59 mg, 1.0 mmol, 2.0 equiv) in anhydrous dichloroethane (20 mL) was refluxed for 30 min, cooled to 23ºC, NaBH; CN (60 mg, 1.0 mmol, 2.0 equiv) was added, the resulting mixture was refluxed for 1 hour.
The reaction mixture was concentrated in vacuo and the residue was purified by chromatography with silica gel (dichloromethane: methane! 1 20: 1) to provide methyl —2 - ((6- (trans-4-ester-butylcyclo- hexyloxy) naphthalen-2-yl) methylamino) propanoate as a white solid (277 mg, yield: 70%). ESI-MS: 398.1 (M + H) *. HPLC: 96.09%. * H NMR (400 MHz, CD3OD) à: 7.83 (s, 1H), 7.79 (d, 1H), 7.74 (d, 1H), 7.43 (dd, 1H), 7.22 (d, 1H), 7.10 (dd, 1H), 4.28-4.33 (m, 3H), 413 (q, 1H), 3.80 (s, 3H), 2.21 (d, 2H), 1.85 (d, 2H), 1.56 (d, 3H), 1.31-1.37 (m, 2H), 1.17-1.24 (m, 2H), 1.05 -1.11 (m, 1H), 0.85 (s, 9H). Example 12: 2 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propanoic acid o. 20% aqueous NaOH To a solution of methyl 2 - ((6- (trans4-tert-butylcyclohexyloxyinaphthalen-2-yl) methylamino) propanoate (100 mg, 0.25 mmol) in ethanol (10 mL) was added NaOH aqueous (3 mL, 20%, 5.0 eq.) and refluxed for 1 hour.
Then, the reaction was cooled to 0ºC, the pH of the solution was adjusted
- made to 6 with HCI IM, concentrated and the residue was dissolved in dichloromethane, washed with water, dried and concentrated to provide 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2- acid il)] methylamino) propanoic as a white solid (70 mg, yield: 75%). ESI-MS: 384.1 (M + H) * ”. HPLC: 97.18%. 1 H NMR (400 MHz, CD; OD) à: 7.88 (s, 1H), 7.83 (d, 1H), 7.73 (d, 1H), 7.49 (dd, 1H), 7 , 26 (d, 1H), 7.15 (dd, 1H), 4.29-4.38 (m, 3H), 4.04 (q, 1H), 2.25 (d, 2H), 1, 90 (d, 2H), 1.60 (d, 3H), 1.36-1.44 (m, 2H), 1.21-1.31 (m, 2H), 1.09-1.15 ( m, 1H), 0.89 (s, 9H). Example 13: ethyl 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) butanoate o aa fes LÃ o MOO o onto bp NaBH (0 Ac) 3, ACOH, DCE. ta 16h "o. 6- (trans-4-fer-butylcyclohexyloxy) -2-naphthaldehyde (30 mg, 0.097 mmol), ethyl 3-aminobutanoate (CAS No. 5303-65-1) (19 mg, 0.145 mmol), and acetic acid (17 mg, 0.291 mmol) were dissolved in dichloroethane (2 ml). The mixture was stirred at room temperature for 10 min under a nitrogen atmosphere.
Then, NaBH (OAc) 3 (41 mg, 0.194 mmol) was added to the mixture and the mixture was stirred at room temperature for 15 hours.
Then, NaHCO; saturated was added to the mixture to adjust the pH to 8. The mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using 10: 1 dichloromethane: methanol to provide ethyl 3- product. ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl)] | methylamino) butanoate (40 mg, 88%) as a soft yellow solid.
ESI-MS: 426.1 (M + H) *. * H NMR (400 MHz, CDCl3) 5 7.70- 7.65 (m, 3H), 7.41 (d, 1H), 7.13-7.09 (m, 2H), 4.28-4 , 23 (m, 1H), 4.12 (q, 2H), 3.98-3.88 (m, 2H), 3.22-3.18 (m, 1H), 2.53-2.42 (m, 2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m, 2H), 1.26-1 .09 (m, 9H), 0.90 (s, 9H). Example 14: 3 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) butanoic acid “is oil A,
F Synthesis was performed as described for 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propanoic acid. 9 mg, light yellow oil, yield: 27%. ESI-MS: 398.1 (M + H) *. HPLC: 91.26%. * H NMR (400 MHz, CDCl3) 5 7.70-7.61 (m, 3H), 7.45 (d, 1H) 7.07 (t, 2H), 4.20-4.17 (m , 2H), 3.98-3.95 (m, 1H), 3.18-3.16 (m, 1H), 2.43-2.42 (m, 2H), 2.24-2.18 (m, 2H), 1.87-1.84 (m, 2H), 1.34-1.17 (m, 8H), 0.91 (s, 9H). Example 15: ethyl 2 - (((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (methyl) amino) acetate
NX Ao cê E Xo porn. “NaBH, CN, EtOH, 90ºC, 4h DO to: 10 A mixture of 6- (trans-4-fer-butylcyclohexyloxy) -2-naphthaldehyde (155 mg, 0.5 mmol) and ethyl 2- (methylamino ) acetate (117 mg, 1.0 mmol, 2.0 e-quiv) in anhydrous ethanol (20 mL) was refluxed for 2 hours and evaporated in vacuo to dryness. Anhydrous EtOH was added and refluxed for 1 hour, and afterwards, the mixture was cooled to 23ºC. NaBH3CN (60 mg, 1.0 mmol, 2.0 equiv) was added. The resulting mixture was refluxed for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography with silica gel (20: 1 dichloromethane: methanol) to provide ethyl product 24 ((((6- (trans4-fert-butylcyclohexyloxy) naphthalen-2 -yl) methyl (methyl)> amino) acetate as a white solid (82 mg, yield: 40%). ESI-MS: 411.3 (M + H) *. HPLC: 98.93%. NMR (400 MHz, CDCl3) 5 7.71- 7.67 (m, 3H), 7.00 (d, 1H), 7.14-7.13 (m, 2H), 4.30-4.28 (m, 1H), 4.18 (q, 2H), 3.82 (s, 3H), 3.30 (s, 2H), 2.45 (s, 3H), 2.29-2.27 ( m, 2H), 1.91-1.88 (m, 2H), 1.46-1.42 (m, 2H), 1.29-1.22 (m, 3H), 0.90 (s, 9H) Example 16: 2 - ((((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2yl) methyl) (methyl) amino) acetic acid O. 20% aqueous NaOH "CONT EEE TO LCoNE Synthesis was performed as described for 2 - ((6- (trans-4-
: tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanoic. 14 mg, gray solid, yield: 75%. ESI-MS: 383.3 (M + H) *. HPLC: 95.11%. * H NMR (400 MHz, CD; OD) at 7.98 (s, 1H), 7.91-7.85 (m, 2H), 7.59-7.57 (m, 1H), 7.33 (s, 1H), 7.22 (d, 1H), 4.55 (s, 2H), 4.42-4.40 (m, 1H) 4.10 (s, 2H), 2.95 (s , 3H), 2.32-2.29 (m, 2H), 1.96-1.93 (m, 2H), 1.47-1.41 (m, 2H), 1.35-1.25 (m, 3H), 0.95 (s, 9H). Example 17: ethyl 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanoate: mA o
POLOS MO OMF 9 NaBH (OAc) 3, ACOH, DCE, ta. 5 pm “o 'The title compound was synthesized as described for ethyl 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) butanoate. 730 mg, white solid, 40.9%. ESI-MS: 412.3 (M + H) *. 1H NMR (400 MHz, CDCI;) d: 7.75 (s, 1H), 7.72-7.67 (m, 2H), 7.50 (dd, 1H), 7.12-7.10 ( m, 1H), 7.07 (d, 1H), 4.20 (m, 1H), 4.11 (q, 2H), 4.01 (s, 2H), 3.05 (t, 2H), 2.81 (t, 2H), 2.22-2.20 (m, 2H), 1.87-1.84 (m, 2H), 1.41-1.38 (m, 2H), 1, 22 (t, 3H), 1.17-1.07 (m, 3H), 0.89 (s, 9H). Example 18: 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-imethylamino) propanoic acid o “O, oO EO, OT Synthesis was performed as described for 2 - ((6 - (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanoic 593 mg, beige solid, yield: 87.2% ESI-MS: 384.1 (M + H) *. HPLC: 100%. * H NMR (400 MHz, CD; OD) &: 7.84 (s, 1H), 7.81-7.75 (m, 2H), 7.45 (dd, 1H), 7 , 22 (d, 1H), 7.14 (dd, 1H), 4.34-4.32 (m, 1H), 4.28 (s, 2H), 3.17 (t, 2H), 2, 49 (t, 2H), 2.28-2.25 (m, 2H), 1.92-1.88 (m, 2H), 1.43-1.40 (m, 2H), 1.25- 1.22 (m, 2H), 1.43-1.10 (m, 1H), 0.90 (s, 9H) Example 19: ethyl 3 - (((6- (trans-4-tert-butylcyclo) -hexyloxy) naphtha-len-2-yl)] methyl) (methyl) amino) propanoate
:
T À À A Au amene TEA AA A The title compound was synthesized as described for methyl 2- ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanoate. 100 mg, white solid, yield: 70%. ESI-MS: 426.3 (M + H) *. HPLC: 90.71%. 1H NMR (400 MHz, CD30D) à: 7.73-7.76 (m, 3H), 7.43 (dad, 1H), 7.24 (d, 1H) 7.12 (dd, 1H), 4 , 31-4.37 (m, 1H), 4.12-4.17 (m, 2H), 3.87 (s, 2H), 2.96 (t, 2H), 2.66 (t, 2H ), 2.40 (s, 3H), 2.28 (d, 2H), 1.91 (d, 2H), 1.39-1.46 (m, 2H), 1.22-1.31 ( m, 5H), 1.10-1.17 (m, 1H), 0.93 (s, 9H). Example 20: 3 - (((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) (methyl) amino) propanoic acid Pra CO mrs. antro os, ALII EtoH, 85ºC, 1h LAOS Synthesis was performed as described for 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propanoic acid. 70 mg, white solid, yield: 75%. ESI-MS: 398.3 (M + H) *. HPLC: 94.61%. * H NMR (400 MHz, DMSO-ds) 5: 7.97 (s, 1H), 7.87 (d, 1H), 7.83 (d, 1H), 7.62 (d, 1H), 7 , 43 (d, 1H), 7.19 (dd, 1H), 4.39-4.44 (m, 3H), 3.27 (br, 2H), 2.85 (t, 2H), 2, 67 (s, 3H), 2.21 (d, 2H), 1.82 (d, 2H), 1.32-1.38 (m, 2H), 1.18-1.27 (m, 2H) , 1.03-1.08 (m, 1H), 0.88 (s, 9H). Example 20: methyl 1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate 9 7 AD LC EA Oo + NaBH3CN, ACOH, DCE, refiitxo . 2h o as The title compound was synthesized as described for methyl 2- ((6- (trans4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propanoate. - 150 mg, white solid, yield: 61%. ESI-MS: 410.3 (M + H) * ”. HPLC: 92.03%. 1H NMR (400 MHz, CD3OD) &: 7.88 (s, 1H), 7.84 (d, 1H), 7.82 (d, 1H), 7.44 (dd, 1H), 7.28 ( d, 1H), 7.17 (dd, 1H), 4.51 (s, 2H), 4.32-4.39 (m, 5H), 3.72- 3.77 (m, 4H), 2 , 26 (d, 2H), 1.90 (d, 2H), 1.36-1.47 (m, 2H), 1.24-1.31 (m,
2H), 1.11-1.47 (m, 1H), 0.91 (s, 9H). Example 21: 1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylic acid “o, COCA a and TO OO OA o 9 mOoH.85ºC , 1 am PA 70% Synthesis was performed as described for 2 - ((6- (trans4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propanoic acid. 70 mg, white solid, yield: 70%. ESI-MS: 396.3 (M + H) *. HPLC: 90.04%. * H NMR (400 MHz, CD3OD) &: 7.91 (s, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.47 (dd, 1H), 7.30 (s, 1H), 7.19 (dd, 1H), 4.53 (s, 2H), 4.30- IS 4.51 (m, 5H), 3.66-3.70 (m, 1H) , 2.29 (d, 2H), 1.93 (d, 2H), 1.39-1.48 (m, is 10 2H) 1.24-1.33 (m, 2H), 1.14- 1.17 (m, 1H), 0.93 (s, 9H). Example 22: methyl 1 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) pyrrolidine-3-carboxylate AD O + A EA TOLO.
The title compound was synthesized as described for ethyl 2- (((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) (methyl) amino) acetate. 150 mg, white solid, yield: 55%. ESI-MS: 423.3 (M + H) *. HPLC: 98.59%. 1 H NMR (400 MHz, CDCl 3) 5 7.69-7.67 (m, 3H), 7.42 (d, 1H), 7.12 (t, 2H), 4.27-4.25 (m , 1H), 3.87 (s, 2H), 3.69 (s, 3H), 3.12-3.06 (m, 2H), 2.88-2.84 (m, 2H), 2, 73-2.70 (m, 1H), 2.28-2.25 (m, 2H), 2.18-2.16 (m, 2H), 1.90-1.87 (m, 2H), 1.45-1.42 (m, 2H), 1.25-1.12 (m, 3H), 0.89 (s, 9H). Example 23: 1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) pyrrolidine-3-carboxylic acid LO P amsenoneme sounds A) IO P ÁQ LIS OA maintains EXMO, 70% Synthesis was performed as described for 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propanoic acid. 80 mg, white solid, yield: 55%. ESI-MS: 409.3 (M + H) * ”. HPLC: 93.50%. 1H NMR
(400 MHz, CDs; OD) 5 7.95 (s, 1H), 7.83 (dd, 2H), 7.55 (d, 1H), 7.28 (s, 1H), 7.18 (d , 1H), 4.55-4.47 (m, 2H), 4.41 - 4.34 (m, 1H) 3.63-3.37 (m, 2H), 3.32 (s, 2H) , 3.28-3.20 (m, 1H), 2.42-2.27 (m, 4H), 1.94-1.90 (m, 2H), 1.48-1.38 (m, 2H), 1.33-1.23 (m, 2H), 1.23-1.14 (m, 1H), 0.89 (s, 9H). Example 24: ethyl 1 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methyl) piperidine-4-carboxylate POLO. es OI Oo (1,569) ne o The title compound was synthesized as described for ethyl 2- (((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] Mmethyl) (methyl) amino) acetate. 100 mg, white solid, yield: 46%. ESI-MS: 451.3 (M + H) *. HPLC: It is 10 92.64%. 1 H NMR (400 MHz, CDCl 3) 5 7.75-7.72 (m, 3H), 7.48 (dd, 1H), 7.17. (d, 2H), 4.30-4.28 (m, 1H), 4.16 (q, 2H), 3.96 (s, 2H), 3.09-3.08 (m, 2H), 2.53-2.51 (m, 3H), 2.29-2.26 (m, 2H), 2.10-2.03 (m, 4H), 1.91-1.88 (m, 2H ), 1.43-1.43 (m, 2H), 1.18-1.13 (m, 6H), 0.88 (s, 9H). Example 25: 1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) piperidine-4-carboxylic acid nN 20% aqueous NaOH (5.0 69.) N 87% Synthesis was performed as described for 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) netylamino) propanoic acid. 70 mg, white solid, yield: 87%. ESI-MS: 423.3 (M + H) *. HPLC: 94.25%. * H NMR (400 MHz, CD; OD) at 7.90 (s, 1H), 7.86 (dd, 2H), 7.56 (d, 1H), 7.32 (s, 1H), 7, 20 (dd, 1H), 4.46 (s, 2H), 4.42-4.39 (m, 1H), 3.61-3.59 (m, 2H), 3.19-3.15 ( m, 2H), 2.72-2.60 (m, 1H), 2.31-2.27 (m, 4H), 1.95-1.92 (m, 4H), 1.46-1, 42 (m, 2H), 1.34-1.27 (m, 3H), 0.93 (s, 9H). Example 26: 6- (trans-4-tert-butylcyclohexyloxy) -S- (trifluoromethyl) -2-naphthaldehyde o A INATIIN a ErCaS AA NOS LO THF, -78ºC, 2h “o FTF day FTF A solution of 6-bromo-2- (trans-4-tert-butylcyclohexyloxy) -1- (trifluormethyl) naphthalene (1 g, 2.3 mmol) in THF (30 mL) was added n-BuLi (2.8 mL , 2.5M in THF, 3.0 equiv) dropwise at -78ºC in 30 min, then DMF (840 mg, 11.5 mmoles, 5.0 equiv) was added slowly at - 78ºC. The reaction mixture it was stirred at -78 ° C for 1.5 hours.
Then, a saturated NH, CI solution was added to the mixture to abruptly cool the reaction.
The mixture was extracted with EtOAc and purified by silica gel chromatography (petroleum ether: ethyl acetate 10: 1) to provide product 6- (trans-4-fer-butylcyclohexyloxy) -S- (trifluoromethyl ) -2-naphthaldehyde as: 10 a yellow solid (608 mg, 70%) ESI-MS: 379.2 (M + H) *. * H NMR (400 MHz, CDCl3) 5: 10.13 (s, 1H), 8.28 (d, 2H), 8.08 (d, 1H), 7.98-8.01 (dd, 1H) , 7.41 (d, 1H), 4.39 (m, 1H), 2.21 (d, 2H), 1.90 (d, 2H), 1.49-1.58 (q, 2H), 1.10 - 1.17 (m, 3H), 0.86 (s, 9H). Example 27: methyl 1 - ((6- (trans-4-tert-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl) methyl) azetidine-3-carboxylate SOIL To DOM Fe 2.00q amount 1hr Fr A mixture of 6- (trans-4-fer-butylcyclohexyloxy) -5- (trifluoromethyl) -2-naphthaldehyde (300 mg, 0.8 mmol) and methyl azetidine-3-carboxylate (184 mg, 1.6 mmol , 2.0 equiv) in anhydrous ethanol (20 mL) was refluxed for 2 hours.
Then, the solvent was removed in vacuo, fresh ethanol and Na- —BH3; CN (150 mg, 2.4 mmoles, 3.0 equiv) were added, the resulting mixture was refluxed for 1 hour.
The reaction mixture was concentrated and the residue was purified by chromatography with silica gel (dichloromethane: methane! 20: 1) to provide 1 - ((6- (trans-4-fer-butylcyclohexyloxy) methyl product) -S- (trifluormethyl) naphthalen-2-yl)] methyl) azetidine-3-carboxylate as a white solid (150 mg, yield: 40%). ESI-MS: 477.3 (M + H) *. HPLC:
85.67% * H NMR (400 MHz, CD3; OD) à: 8.09 (dd, 1H), 8.01 (d, 1H), 7.56 (s, 1H), 7.46-7, 51 (m, 2H), 4.42 (m, 1H), 3.77 (s, 2H), 3.71 (s, 3H), 3.57 (t, 2H), 3.45 (t, 2H ), 3.35-3.39 (m, 1H), 2.18 (d, 2H), 1.88 (d, 2H), 1.43-1.52 (q, 2H), 1.09- 1.22 (m, 3H), 0.89 (s, 9H). Example 28: 1 - ((6- (trans-4-fer-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl)] methyl) azetidine-3-carboxylic o OS manamensis TO, OA o 9 HOH , 85% C, 1h Ss oH FTF 70% FF A solution of methyl 1 - ((6- (trans-4-fer-butylcyclohexyloxy) -5- À (trifluoromethyl) naphthalen-2-yl)] methyl) azetidine-3-carboxylate (100 mg, 0.25 mmol) in ethanol (10 mL) aqueous NaOH (3 mL, 20%) was added and refluxed twice. 10 for 1 hour.
Then, the reaction was cooled to 0ºC, the pH of the solution was adjusted to 6 with 1M HCl, and concentrated.
The residue was dissolved in dichloromethane, washed with water, dried and concentrated to provide 1- ((6- (trans-4-tert-butylcyclohexyloxy) -S- (trifluoromethyl) naphthalen-2-yl)] methyl acid ) - azetidine-3-carboxylic as a white solid (70 mg, yield: 70%). ESI-MS: 464.2 (M + H) *. HPLC: 98.64% 7H NMR (400 MHz, DMSO-ds) 5: 8.19 (d, 2H), 8.08 (d, 2H), 7.72 (d, 1H), 7.67 (d , 1H), 4.60-4.58 (m, 1H), 4.51 (s, 2H), 4.21 (d, 4H), 3.55-3.67 (m, 1H), 2, 13 (d, 2H), 1.80 (d, 2H), 1.35-1.43 (q, 2H), 1.03-1.22 (m, 3H), 0.86 (s, 9H) . Example 29: ethyl 3 - ((6- (trans-4-tert-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl) methylamino) propanoate o ºC, 2h: EEA BACK o onto From " 1h o A Syntheses were performed as described for methyl 1 - ((6- (trans-4-tert-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen-2-yl)] methyl) azetidine-3-carboxylate. , white solid (yield: 20%). ESI-MS: 480.3 (M + H) *. HPLC: 89.20% * H NMR (400 MHz, DMSO-ds) 6: 8.22 (d, 1H ), 8.97 (d, 1H), 7.90 (s, 1H), 7.52 (d, 1H), 7.33 (d, 1H), 4.30-4.28 (m, 1H) , 4.14-4.20 (m, 4H), 3.17 (s, 2H), 2.77 (s, 2H), 2.16 (d, 2H), 1.86 (d, 2H), 1.47-1.55 (q, 2H), 1.25
(t, 3H), 1.09-1.13 (m, 3H), 0.87 (s, 9H). Example 30: 3 - ((6- (trans-4-tert-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl)] methylamino) propanoic acid L 20% aqueous NaOH- (5.0-29) . 4 “o. ê a êco: the gp
FTF FTTE Syntheses were performed as described for 1 - ((6- (trans4-tert-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen-2-yl)] methyl) azetidine-3-carboxylic acid. 30 mg, white solid (yield: 70%). ESI-MS: 452.2 (M + H) *. HPLC: 94.35% * H NMR (400 MHz, DMSO-ds) à: 8.12 (d, 1H), 8.01 (d, 1H), 7.91 (s, 1H), 7.62 ( d, 2H), 4.54-4.52 (m, 1H), 3.93 (s, 2H), 2.79 (t, 2H), 2.36 '(t, 2H), 2.12 ( d, 2H), 1.79 (d, 2H), 1.35-1.41 (q, 2H), 1.03-1.22 (m, 3H), 0.86 (s, 9H). f Example 31: methyl 6- (trans-4-tert-butylcyclohexyloxy) -2-naphtoate i ph DIAD, PhMe À Ho o A mixture of cis-4-fer-butylcyclohexanol (927 mg, 0.00593 mol ), 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1560 mg, 0.00593 mol) in toluene (10 ml, 0.1 mol) was heated at reflux, and diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was carried out in dichloromethane and was purified by column chromatography with ethyl acetate: hexane (0: 100 to 40:60) to provide methyl 6- (trans-4-tert-butylcyclohexyloxy) -2-naphtoate as a white solid (0.95 g, 56%). 'H NMR (400 MHz, CDCI;) 5 8.52 (s, 1H), 8.01 (dd, J = 8.7, 1.7 Hz, 1H), 7.84 (d, J = 9, 6 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.17 (m, 2H), 4.34 (m, 1H), 3.97 (s, 3H), 2 , 30 (m, 2H), 1.92 (m, 2H), 1.52-1.14 (m, 5H), 0.91 (s, 9H). Example 32: (6-trans4-fer-butylcyclohexyloxy) naphthalen-2- i) methanol PO LOM O LO "Rs 83% o o
Methyl 6- (trans-4-tert-butylcyclohexyloxy) -2-naphtoate = (950 mo, 0.0028 mol) was dissolved in tetrahydrofuran (20 mL, 0.2 mol) and lithium tetrahydroaluminate 1 0.0 M in tetrahydrofuran (8.4 mL, 0.0084 mol) was then added at 0 ° C.
After stirring at room temperature for 2 hours, ethyl acetate and Rochele salt were added and the mixture was then stirred at room temperature for 1 hour.
After extraction with ethyl acetate followed by concentration under reduced pressure, the product (6-trans-4-tert-Butylcyclohexyloxy) naphthalen-2-yl) methane! it was obtained as a white solid (770 mg, 88%). * H NMR (400 MHz, CDCl3) 5 7.71 (m, 2H), 7.45 (d, J = 10.1Hz 1H), 7.15 (m, 3H), 4.82 (AB, J = 16.1, 16.1Hz, 2H), 4.28 (m, 1H), 2.27-2.31 (m, 2H), 1.89-1.92 (m, 2H), 1.11 1.50 (m, 5H), 0.91 (s, 9H). . Example 33: 6- (trans4-tert-butylcyclohexyloxy) -2-naphthaldehyde. E LO ER da o À AD Ms A “o 100%“ o A (6-trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methanol (150 mg, 0.480 mmol) in methylene chloride (5 ml, 80 mmoles) Dess-Martin pyriodinane (0.285 g, 0.672 mmol) was added and the mixture was stirred at room temperature for 1 hour.
The crude reaction mixture was then passed through a pad of silica gel and the filtrate was then concentrated under reduced pressure to provide the product as a white solid (0.150 g, 100%). * H NMR (400 MHz, CDCl3) 5 10.10 (s, 1H), 8.25 (s, 1H), 7.92-7.87 (m, 2H), 7.78 (d, J = 8 , 5Hz, 1H), 7.23-7.19 (m, 2H), 4.38-4.30 (m, 1H), 2.31 2.29 (m, 2H), 1.94-1 , 91 (m, 2H), 1.54-1.11 (m, 5H), 0.92 (s, 9H). Example 34: 3 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -2,2-difluoropropanoic acid H RF O o NaBH; CN, FIOH * 9 po E a . OO> are:. CO Ro A solution of 6- (4-tert-Butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (150 mg, 0.483 mmol) and 3-amino-2,2-difluoro-propionic acid (60.4 mg, 0.483 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 hours.
The yellow solution was then cooled to room temperature.
sodium chloride and cyanoborohydride (36.4 mg, 0.580 mmol) was added to the stirring solution.
The resulting mixture was heated to reflux for 1 hour.
After cooling to room temperature, citric acid was added, and the solvent removed under vacuum.
The resulting solid was suspended in water and collected through filtration.
The filtrate was washed carefully with water (4x), ether (3x), and hexane (3x). The resulting solid was dried in the filtrate to provide the title compound as a white solid (128, 8 mg, 64%). * H NMR (400 MHz, CDCl3) δ: 7.92 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H) , 7.52 (dd, J = 8.4, 1.8 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.19 (dd / J = 9.0, 2 , 4Hz, 1H), 4.45 (s, 2H), 4.40 (m, 1H), 3.61 (t, J = 13.8 Hz, 2H), 2.28-2.31 (m, 2H), 1.92-1.95 (m, 2H), 1.49-1.14 (m, 5H), 0.94. (s, 9H). Example 35: methyl 6- (spiro [S, S] undecan-3-yloxy) -2-naphtoate 'and PPhz, DIAD, PhMe A mixture of spiro [5.5Jundecan-3-ol (0.999 g, 0.00593 mol) , 6-hydroxy-naphthalene-2-carboxylic acid methyl ester (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 ml, 0.1 mol) heated to reflux.
Diisopropyl azodicarboxylate (1.17 mL, 0.00593 mol) was then added dropwise and the resulting mixture was refluxed for 6 hours.
The mixture was then diluted with dichloromethane and subjected to chromatographic purification with ethyl acetate: hexane (0: 100 to 40:60) to provide methyl 6- (spiro [5.5] undecan-3-yloxy) -2- naphttoate as a white solid. (1.09 9, 62%). 1 H NMR (400 MHz, CDCl 3) 5 8.52 (s, 1H), 8.01 (dd, J = 8.7, 1.7 Hz, 1H), 7.84 (d, J = 9.6 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.17 (m, 2H), 4.45 (m, 1H), 3.97 (s, 3H), 1, 93-1.28 (m, 18H). Example 36: (6- (spiro [5.5] undecan-3-yloxy) naphthalen-2-yl) methanol A À LAH, THF o o A solution of methyl acid ester 6- (spiro [5.5Jundec-3-
yloxy) -naphthalene-2-carboxylic (0.374 g, 0.00106 mol) in tetrahydrofuran (10 mL, 0.1 mol) 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.18 mL) , 0.00318 mol) at 0 ° C.
The reaction was then allowed to warm to room temperature while stirring for 2 hours, Rochelefoiention salt added and a resulting mixture was stirred at room temperature for 1 hour.
After extraction with ethyl acetate, and removal of the solvent under vacuum, (6- (spiro [5.5] Jundecan-3-yloxy) naphthalen-2-methane!] Was obtained as a white solid (0.28 g, 83%) ESI-MS: 307.5 (M + H) *. 100%). * H NMR (400 MHz, CDCl3) 5 7.74-7.70 (m, 3H), 7.44 (d, J = 10.0Hz, 1H), 7.16 (m, 2H), 4.81 (s, 2H), 4.40 (m, 1H), 1.94-1.26 (m, 18H). Example 37: 6- (Spiro [5.5] Jundecan-3-yloxy) -2-naphthaldehyde n AX Periodinate-Dess-Martin, Sa * OH DCM o Ao [6- (Spiro [5.5] Jundec-3-yloxy) -naphthalen-2-yl] -methanol (150 mg, 0.46 mmol) in methylene chloride (5 mL, 80 mmoles) Dess-Martin periodinane (0.274 g, 0.677 mmol) was added and a resulting solution was stirred. - kept at room temperature for 1 hour.
The crude reaction was then passed through a pad of silica gel, the filtrate was removed in vacuo to provide 6- (spiro [5.5] Jundecan-3-yloxy) -2-naphthaldehyde as a colorless solid. (0.150 g, 100%). 1H NMR (400 MHz, CDCl3) 5 10.09 (s, 1H), 8.25 (s, 1H), 7.92-7.89 (m, 2H), 7.78 (d, J = 8, 7Hz, 1H), 7.24-7.19 (m, 2H), 4.48 (m, 1H) 1.96-1.29 (m, 18H). Example 38: 2,2-Diflúor-3 - ((6- (spiro [5.5] undecan-3-yloxy) naphthalen-2-yl)] Mmethylamino) propanoic acid E NaBH3CN, EtoH A COP ss O, CONES One solution of G6- (spiro [5.5Jundec-3-yloxy) -naphthalene-2-carbaldehyde (150 mg, 0.46 mmol) and 3-amino-2,2-difluoro-propionic acid (58.2 mg, 0.465 mmol ) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 hours.
The yellow solution was then cooled to room temperature and sodium cyanoborohydride (35.1 mg, 0.558 mmol) was added in portions.
The resulting mixture was heated to reflux for 1 hour.
The re-
The stock was then cooled to room temperature, and citric acid was added.
The solution was stirred for several minutes and the solvent was removed in vacuo.
The resulting solid was suspended in water and filtered, and the collected solid was washed carefully with water (4x), ether (5x), and hexane (5x) to provide 2.2- (82.1 mg, 41%) acid. diflúor-3 - ((6- (spiro [5.5 Jundecan-3-yloxy) naphthalen-2-iN) Methylamino) propanoic. 'H NMR (400 MHz, CDCI3) & 7.93 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.52 (dd J = 8.4, 1.8 Hz, 1H), 7.30 (d, J = 2.2 Hz, 1H), 7.22 (dd, J = 9.0, 2.4 Hz , 1H), 4.52 (m, 1H), 4.45 (s, 2H), 3.60 (t, J = 15.9 Hz, 2H), 1.76-1.35 (m, 18H) . Example 39: (R) -ethyl 1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) piperidine-3-carboxylate ->, already x NaCNBH; SS R OCT "N MeOH / ACOH OLOIS FM 6- (4-tferc-Butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (500 mg, 2 mmoles) was combined with ethyl acid ester (R) -piperidine- 3-carboxylic (0.51 g, 3.2 mmoles) in methanol (10 mL, 200 mmoles) and acetic acid (9.2 ul, 0.16 mmol). Sodium cyanoborohydride (0.25 g, 4.0 mmoles) was then added and the reaction was stirred overnight at room temperature.
The reaction was then quenched with water and extracted three times with ethyl acetate.
Organics were combined and dried over MgSO4. Solids were removed by filtration and 10 g of silica gel was added.
All solvent was then removed and the resulting silica gel was loaded onto a 24 g column and the product was eluted using a 0-60% ethyl acetate / hexanes gradient and then vacuum dried to provide the title compound as an oil. colorless.
EDI-MS: 438.1 (M + H) *. Example 40: (R) 1 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) piperidine-3-carboxylic o POLOOM E So conoês o Ethyl ester of acid (R ) -1- [6- (4-fer-Butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -piperidine-3-carboxylic (363.4 mg, 0.8046 mmol) was dissolved in ethanol (5 mL, 80 mmoles) then treated with 1 M aqueous sodium hydroxide
(5 mL, 5 mmol). The mixture was stirred vigorously for 18 hours. pH was adjusted to 3-4 with 3N HCl and the reaction was then extracted three times with ethyl acetate.
Organics were combined, then dried over MgSO4, filtered and concentrated to dryness under reduced pressure.
Ethyl ether was then added and a white precipitate formed was removed by filtration to provide a 86% pure white solid by HPLC.
The process was repeated two additional times to provide the title compound as a white solid (156 mg, 44%). EDI-MS: 424.2 (M + H) *. * H NMR (400MHz, MEeOD) 5 = 7.82 (s, 1 H), 7.74-7.62 (m, 2 H), 7.42 (d, J = 2.3, 1H), 7 , 19 (d, J = 2.3Hz, / 1H), 7.08 (d, J = 2.5.1H), 4.43-4.34 (m, 1 H), 4.33 - 4, 22 (m, 2 H), 2.71 (br, s ,, 1 H), 2.16 (d, J = 2.0 Hz, 2 H), 1.88-167 (m, 4 H), 1.40 - 1.25 | (m, 3 H), 1.24 - 1.11 (m, 4 H), 1.10 - 0.95 (m, 5 H), 0.79 (s, 9 H) Example 41: (S) -methyl 1 - ((6- (trans-4-fer-butylcyclo-hexyloxy) naphthalen-2-yl) methyl) piperidine-3-carboxylate>. co NacNBH; So AR Q mo O, CSS 6- (4-tert-Butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (503.27 mg, 1.6212 mmol) was combined with methanol (10 mL, 200 mmoles) and acid acetic (9.2 µL, 0.416 mmol). Sodium cyanoborohydride (252.78 mg, 4.0221 mmoles) was then added and the reaction was stirred overnight at room temperature.
The reaction was then quenched with water and extracted three times with ethyl acetate.
Organics were combined and dried over MgSO4. Solids were removed by filtration and 7 g of silica gel was added.
All the solvent was then removed and the resulting silica was loaded onto a 24 g column and the product was eluted using a 0-60% ethyl acetate / hexanes gradient and then vacuum dried to provide the title compound as a colorless oil (366 mg, 45%). EDI-MS: 438.3 (M + H) *. Example 42: (S) -1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) piperidine-3-carboxylic acid>. Êo 1N NaoH y, à: 9 o CL A iai
Ethyl ester of (S) -1- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -piperidine-3-carboxylic acid (151.23 mg, 0.33484 mmol) was dissolved in ethanol (5 ml, 80 mmoles) then treated with 1 M sodium hydroxide in water (5 ml, 5 mmoles). The mixture was stirred vigorously for 18 hours. pH was adjusted to 3-4 with 3N HCl and the reaction was then extracted three times with ethyl acetate.
Organics were combined, then dried over MgSO4, filtered and concentrated to dryness under reduced pressure.
Diethyl ether was then added and a white precipitate formed which was removed by filtration to provide the title compound as a white solid (21 mg, 13%). EDI-MS: 424.1 (M + H) *. * H NMR (400MHz, MeOD) 5 = 7.82 (s, 1 H), 7.74-7.62 (m, 2 H), 7.44 (d, J = 2.3, 1 H), 7.19 (d, J = 2.3 Hz, 1 H), 7.08 (d, J - = 2.5, 1H), 4.43 - 4.34 (m, 1 H), 4.33 - 4.22 (m, 2 H), 2.71 (br, s ,, 1 H), 2.16 (d, J = 2.0 Hz, 2 H), 1.88-167 (m, 4 H), 1.40 - 1.25 (m, 3 H), 1.24 - 1.11 (m, 4 H), 1.11 - 0.94 (m, 5 H), 0.80 ( s, 9 H). Example 43: 4-f [6- (trans-4-tert- Butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -amino) -butyric acid ferc-butyl ester HO mA, ÁD LOS "AO ONA * OO NaBH (OAc) 3, TEA, DCE, ta.
ATh xo O Í h IS A solution of 6- (4-fer-butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (45 mg, 0.15 mmol, HCI salt of 4-amino acid tert-butyl ester -butyric (115 mg, 0.59 mmol), and triethylamine (81 ul, 0.58 mmol) in 1,2-dichloroethane (1.5 mL) was treated with sodium triacetoxyborohydride (65 mg, 0.29 mmol) After stirring at room temperature overnight, the mixture was diluted with dichloromethane and washed with aqueous sodium bicarbonate.
The organic phase was dried over MgSO2, filtered and concentrated and the residue was purified by a silica gel column eluted with about 100% ethyl acetate in hexane to provide colorless oil (33 mg, yield : 50%). ESI-MS: 454.4 (M + H) *; * H NMR (400 MHz, CDCl3) = 7.65-7.70 (m, 3H), 7.38-7.40 (dd, 1H), 7.10-7.14 (m, 2H), 4 , 22-4.28 (m, 1H), 3.90 (s, 2H), 2.67 (t, 2H), 2.28 (t, 4H), 1.89 (d, 2H), 1, 81 (t, 2H), 1.40 (m, 1H), 1.42 (s, 9H), 1.30 (m 4H), 0.9 (s, 9H).
Example 44: 4-f [6- (trans-4-tert-Butyl-cyclohexyloxy) - naphthalen-2-ylmethyl] -amino) -butyric acid
ÁDLOIN AA SE ADO A solution of 44 [6- (4-fer-butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] | -amino)-butyric acid (33 mg, 0.073 mmol) in HCl 4 M emdioxane (1.50 ml) was stirred at room temperature overnight to form a white precipitate. The precipitate was filtered and washed with ether to provide the product as the HCI salt (20 mg, yield: 63%). ESI-MS: 398.1 (M + H) *; (400 MHz, CD; OD) 5 = 7.90 (s, 1H), 7.84 (d, 1H), 7.81 (d, 1H), 7.49 (dd, 1H), 7.28 ( d, 1H), 7.17 (dd, 1H), (m, 2H), 4.37 (m, 1H), 4.33 (s, BR 10 2H) 3.15 (t, 2H), 2, 47 (t, 2H), 2.28 (t, 2H), 2.0 (m, 2H), 1.92 (d, 2H), 1.43 (qa, 2H), 1.27 (q, 2H ), 1.143 (m, 1H), 0.92 (s, 9H). Example 45: Ethyl ([6- (trans-4-tert-Butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -amino) -acetic acid ester OQ HC! 8 ADO A AD OO ”A NaBH (OAc) ;. TEA, DCE, ta. 5 pm E A solution of 6- (4-tert-butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (90 mg, 0.29 mmol), glycine hydrochloride ethyl ester (162 mg, 1.16 mmol), and triethylamine (0.16 mL, 1.16 mmol) in 1,2-dichloroethane (2 mL) was treated with sodium triacetoxyborohydride (129 mg, 0.58 mmol). The mixture was stirred at room temperature overnight. The solution was diluted with dichloromethane and washed with aqueous sodium bicarbonate. The organic phase was under MgSO, and concentrated. The residue was purified with a silica gel column eluted with about 100% ethyl acetate in hexane to provide the product (64 mg, yield: 55%). ESI-MS: 420.30 (M + 23) *; H NMR (400 MHz, CDCl3) 5 = 7.66-7.70 (m, 3H), 7.41 (dd, 1H), 7.11-7.14 (m, 2H), 4.26 ( m, 1H), 4.19 (q, 2H), 3.93 (s, 2H), 3.43 (s, 2H), 2.28 (d, 4H), 1.89 (d, 2H), 1.44 (q, 2H), 1.27 (t 3H), 1.09-1.20 (m, 3H), 0.89 (s, 9H). Example 46: ([6- (trans-4-tert-Butyl-cyclohexyloxy) - naphthalen-2-ylmethyl] | -amino) -acetic acid
OTTO in ACE CSI, MeOH. OK. —50ºC, 2: h O To A a solution of ethyl ester of ([6- (4-fer-butyl-cyclohexyloxy) -naphthalen-2-ylmethyl) -amino) -acetic acid (60 mg, 0.15 mmol) in methanol (1 mL) aqueous lithium hydroxide (4.2 M, 0.5 mL, 2 mmol) was added to form a white precipitate.
The slurry mixture was stirred at room temperature for 3 hours at 50 ° C for 2 hours.
The slurry was neutralized with 1 N HCI at pH 6 and the white precipitate was filtered and dried in vacuo to provide white precipitate (48 mg, yield: 86%). ESI-MS: 392.3 (M + 23) *; * H NMR (400 MHz, DMSO) δ = 7.77-7.82 (m, 3H), 7.48 (dd, 1H), 7.37 (d, 1H), 7.15 (dd, 1H) , 4.38 (m, 1H), 4.07 (s, 2H), 3.16 (s, 2H), E 10 2.20 (d, 2H), 1.82 (d, 2H), 1, 35 (m, 2H), 1.10-1.25 (m, 3H), 0.89 (s, 9H). : Example 47: (2 - ([6- (trans-4-fer-Butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -amino) -ethyl) -phosphonic acid diethyl ester, CERAAA NaBH3CN, ACOH, DCE, ta. 18h o To a solution of (2-amino-ethyl) -phosphonic acid diethyl ester salt (200 mg, 0.74 mmol) in 1,2-dichloroethane (3 mL) was added 6- ( 4-fer-butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (343 mg, 1.1 mmol). The mixture was stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (329 mg, 1.5 mmol) was added.
After the reaction mixture was stirred at room temperature overnight, it was quenched with water, stirred at room temperature for 30 min, then diluted with ethyl acetate, and washed with NaHCO; aqueous.
The organic layer was dried over MgSO, and purified with a column of silica gel eluted with ethyl acetate (100%), then eluted with about 0 to 15% methanol in dichloromethane to provide sticky oil (130 mg , yield: 25%). ESI-MS: 476.3 (M + H) *. Example 48: Phosphonic (24 [6- (trans-4-fer-butyl-cyclohexyloxy) - naphthalen-2-ylmethyl] -amino) -ethyl) acid
* E, TMSBr “o Ro. ZOO HP: CHHCN, 50ºC, 18h OO 5 Du A solution of diethyl ester (24 [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -amino) -ethyl) - phosphonic (65.00 mg, 0.14 mmol) in acetonitrile (1 mL) bromotrimethylsilane (1 mL, 7.58 mmol) was added. The reaction was then stirred at 50 ° C overnight.
After the solvent was concentrated, the residue was purified with HPLC (acetonitrile-water, 15-85%) to provide white precipitate (33 mg, yield: 58). ESI-MS: 420.2 (M + H) *; * H NMR (400 MHz, DMSO) 5 = 7.81-7.91 (m, 3H), 7.51 (dd, 1H), 7.41 (d, 1H), 7.19 (dd, 1H) , 4.40 (m, 1H), 4.31 (s, 2H), 3.12 (m, 2H), 2.21 (d, 2H), 1.97 (m, 2H), 1.82 ( d, 2H), 1.36 (q, 2H), 1.22 (q, 2H), 1.08 (m, 1H), 0.88 i 10 (s, 9H). p Example 49: 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid ferc-butyl ester 8 ER "LDO Foo ADO A mixture of 2,3-dihydro-1H-indole-5- 0.10 (1.0 g, 7.8 mmoles), di-tert-butyldicarbonate (4.0 g, 18 mmoles), chloroform (20 ml) and aqueous saturated sodium bicarbonate (8 ml) were stirred at room temperature during - at night.
The organic phase was separated and washed twice with water, dried over MgSO;, filtered and concentrated to provide crude product.
The crude material was treated with ether and filtered to provide the product (1.1 g, yield: 60%). ESI-MS: 258.10 (M + 23) *, * H NMR (400 MHz, DMSO) δ 9.00 (s, 1H) 7.48 (ws, 1H), 6.61 (d, 1H), 6.51 (dd, 1H), 3.84 (t, 2H), 2.96 (t, 2H), 1.48 (s, 9H). Example 50: 5- (trans-4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester FO or Boc CsCO; 3, tBuOoH Ms Boc O 2 -butanone, 80ºC, LO nº 100%
A mixture of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid ferc-butyl ester (0.6 g, 2.6 mmol) in tert-butyl alcohol (8 mL) and 2-butanone (4 ml) cesium carbonate (2.59, 7.7 mmoles) followed by 4-tert-Butyl-cyclohexyl ester methanesulfonic acid (1.9 g, 7.7 mmoles) was added. The mixture was heated in a sealed flask at 100 ° C overnight to form a precipitate. The mixture was treated with dichloromethane and the precipitate was filtered and the solvent was concentrated. The residue was purified with a silica gel column eluted with ethyl acetate in hexanes of about 0 to 30% to provide precipitate (0.96 g, yield: 100%). ESI-MS: 373.30 (M) *. Example 51: 5- (trans-4-fer-Butyl-cyclohexyloxy) -2,3-dihydro-. 1H-indole. SN “ho É, O, N QOO —— OOo To a solution of 5- (4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-indole-1-carboxylic acid tert-butyl ester ( 0.92 g, 2.5 mmoles) in THF (10 ml) was added 4 M HCI in dioxane (6 ml, 25 mmoles). The mixture was stirred at room temperature for 48 hours to form a white precipitate. This mixture was partitioned between dichloromethane and aqueous sodium bicarbonate, and the organic phase was dried over MgSO4, filtered and concentrated. The crude was purified with a silica gel column eluted with about 0 to 8% methanol in dichloromethane to provide precipitate (0.67 g, yield: 99%). ESI-MS: 274.2 (M + H) *.
Example 52: tert-butyl! ester of 3-tert-butoxycarbonylamino-4- [5- (trans-4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-indole-1-11] -4-oxo-butyric h OH XX Mo ao MA À AO ra OS x S EDCI, HOBt, DMF 70 ºC To a solution of 5- (4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-1H-
indole (110 mg, 0.4 mmol) in dimethylformamide (2 mL) HOBT monohydrate (10 mg, 0.1 mmol), 2-tert-butoxycarbonylamino-succinic acid 4-tert-butyl ester (230 mg, 0.8 mmol) and finally N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (92 mg, 0.48 mmol). The reaction was heated to 50 ° C overnight.
The solution was diluted with ether and washed twice with water.
The organic phase was dried over MgSO;, filtered and concentrated to provide crude product (220 mg, yield: 100%). The crude was used directly in Example 53. ESI-MS: 545.4 (M + H) *. Example 53: 3-Amino-4- [5- (trans-4-fer-Butyl-cyclo-ema acid and DiterDate - & TFA oa Po ae Tras. Oo a solution of 3-fer-butyl ester ferc-butyl ester butoxycarbonylamino-4- [5- (4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-indole-1-i1] -4-oxo-butyric (220 mg, 0.4 mmol) in dichloromethane (1 ml) was added trifluoroacetic acid (TFA) (0.8 ml, 10 mmoles) The reaction was stirred at room temperature overnight.
The solvent was concentrated and the residue was purified with HPLC to provide white precipitate product of TFA salt (22 mg, yield: 13%). ESI-MS: 389.3 (M + H) *; * H NMR (400 MHz, DMSO) δ 7.96 (d, 1H), 6.92 (d, 1H), 6.76 (dd, 1H), 4.45 (m, 1H), 4.11 4.25 (m, 3H), 3.15 (t, 2H), 3.04 (dd, 1H), 2.70 (dd, 1H), 2.09 (d, 2H), 1.77 (d , 2H), 1.45 (s, 1H), 1.27 (q, 2H), 1.13 (q, 2H), 1.04 (m, 1H), 0.85 (s, 9H). Example 54: 1- [5- (trans-4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-indol-1-i1] -2-chloro-ethanone "O,“ dad,>, r AO = OO To a solution of 5- (4-fer-Butyl-cyclohexyloxy) -2,3-dihydro-1H-indole (0.55 g, 2 mmol), triethylamine (0.56 mL, 4 mmoles) in dichloromethane (8mbL) chloroacetyl chloride (0.2 ml, 2.6 mmoles) was added at 0ºC.
The solution was stirred at 0 ° C at room temperature for 4 hours.
The solution was diluted with dichloromethane and washed with 5% aqueous citric acid, aqueous sodium bicarbonate, and water, dried over MgSO4, and concentrated. The residue was purified with a silica gel column eluted with ethyl acetate in hexane to provide the product (0.37 g, yield: 52%). ESI-MS: 350.2 (MH). Example 55: (2- (2- [5- (trans-4-fer-Butyl-cyclohexyloxy) -2,3-dihydro-indole-1-11] -2-0x0-ethylamino diethyl ester ) -ethyl) -phosphonic
And the o º. to>. Y NH2>. ra OALOO A (OO i A a solution of 1- [5- (4-tert-Butyl-cyclohexyloxy) -2,3-dihydro-Ú indol-1-i1) -2-chloro-ethanone (60 mg, 0.2 mmol) and diethyl ester of (2-amino-ethyl) -phosphonic acid, oxalic acid salt (93 mg, 0.34 mmol) in dimethylformamide (1.5 mL) were added lithium bromide (18 mg, 0.2 mmol) and potassium carbonate (76 mg, 0.55 mmol). After being stirred at 70 ° C overnight, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with 5% aqueous citric acid, aqueous sodium biocarbonate, and water, dried over MgSO, and concentrated. The residue was purified on a silica gel column to provide the product (20 mg, yield: 25%). ESI- MS: 495.3 (M + H) * Example 56: Acid (2- (2- [5- (trans-4-fer-Butyl-cyclohexyloxy) - 2,3-dihydro-indole- 1-i1]) - 2-0x0-ethylamino) -ethyl) -phosphonic NES O. tn Ron>. Q. os crase), O. o om oo To the stirring solution of diethyl ester (2- (2- [5- (4-fer-Butyl-cyclohexyloxy) -2,3-dihydro- indole-1-11] -2-0x0-ethylamino) -ethyl) -phosphonic (16 mg, 0.03 mmol) in acetonitrite (0.5 mL) bromotrimethylsilane (0.5 mL, 4 mmol) was added. The reaction mixture was stirred at 50 ° C overnight. After the solvent was concentrated, the residue was purified by HPLC (acetonitrile-water) to provide white precipitate product (7.5 mg, yield:
53%). ESI-MS: 439.2 (M + H) * Example 57: 3 - (((2 - ((trans) -4-tert-butylcyclohexyloxy) quinolin-6-yl) methylamino) propanoic acid> 1. Mitsunobu o NE & A 6-bromo-2-hydroxyquinoline was treated with cis-4-tert-butylcyclo- —hexanols under Mitsunobu conditions, providing 6-bromo-2 - ((trans) -4-tert-butylcyclohexyloxy) quinoline. 6-bromo-2 - ((trans) -4-fer-butylcyclohexyloxy) quinoline was then exposed to n-butyllithium and DMF, providing 6-formyl-2- ((trans) -4-tert-butylcyclo- hexyloxy) quinoline.
This aldehyde was then treated with 3-aminopropionic acid and sodium cyanoborohydride to provide the title compound, 3 - ((2 - ((trans) -4-tert-butylcyclohexyloxy) quinolin-6- iNmethylamino ) propanoic acid h Example 58: 3 - (((6 - ((trans) -4-tert-butylcyclohexyloxy) quinolin-2-yl)] methylamino) propanoic acid N.
SS N TBHP, SeO, N. i tac Ãok. TBHP = Tertbuti peroxide! hydrogen B-hydroxy-2-methylquinoline was treated with cis-4-tert-butylcyclohexanol under Mitsunobu conditions, providing 6 - ((trans) 4-fert-butylcyclohexyloxy) -2-methylquinoline, which in turn was oxidized with hydrogen-butyl hydrogen peroxide and selenium dioxide in dioxane, providing 6- ((trans) -4-tert-butylcyclohexyloxy) -2-formylquinoline.
This aldehyde was then treated with t-butyl 3-aminopropionate and sodium cyanoborohydride in dichloroethane to provide t-butyl 3 - ((((6 - ((trans) -4-ferc-butylcyclohexyloxy) -quinolin- 2- iNmethyl) amino) propionate.
Treatment with lithium hydroxide in methanol / THF provided the title compound, 3 - ((6 - ((trans) 4-tert-butylcyclohexyloxy) quinolin-2-yl)] methylamino) propanoic acid.
Example 59: tert-butyl 3- (methylsulfonamido) -3-
oxopropylcarbamate Ad CH; SONH, (0.7 equiv) Ah -SO0-CHs BocHN oH EDCI (0.85 equiv), DMAP (0.15 equiv) | BocHN N DCM, rt.16-h, 90% G 3- (Ferc-butoxycarbonylamino) propanoic acid (4 g, 21.2 mmoles, 1.0 equiv) was dissolved in DCM (100 ml). Then methanesulfonamide (1.43 9, 15.1 mmoles, 0.7 equiv), EDCI (3.45 g, 18.2 mmoles, 0.85 equiv) and DMAP (0.37 g, 3 mmoles, 0.15 equiv) were added to the mixture and stirred for 2 hours at room temperature. The reaction mixture was cooled to 0 ° C, ice water (100 ml) was added. The mixture was stirred for 15 min, separated and the water layer was extracted twice with DCM. A: combined organic layer was washed with 5% HCl, brine, dried under. 10 NasSO ,, concentrated to provide ferc-butyl 3- (methylsulfonamido) -3-oxopropylcarbamate as a gray oil (3.6 g, 90%). ESI-MS (M + H) *: 267.1. 1 H NMR (400 MHz, DMSO-d; s) δ: 6.91-6.83 (brs, 1H), 3.36 (s, 3H), 3.19-3.12 (m, 2H), 2.41 (t, 2H), 1.37 (s, 9H). Example 60: 3-amino-N- (methylsulfonyl) oropanamide o Boca Sata Treats in Soc 80% tert-butyl 3- (methylsulfonamido) -3-oxopropylcarbamate (3.6 g, 15.1 mmoles) was dissolved in DCM (60 mL). Then, CF; COOH (1.1 mL, 0.3 mmol, 20 equiv.) Was added to the mixture at 0 ° C and stirred for 2 hours at 0 ° C. The reaction mixture was concentrated. The residue was purified by flash chromatography to provide 3-amino-N- (methylsulfonyl) bpropanamide as a clear solid (1.8 g, 80%). (mobile phase: CH; OH / HzO = 0-5%). E-SI-MS (M + 1) *: 167.0. * H NMR (400 MHz, CD3OD) 5: 3.21 - 3.11 (m, 2H), 3.07 (s, 3H), 2.60-2.54 (m, 2H).
Example 61: 3 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-i) methylamino) -N- (methylsulfonyl) propanamide To the OC CcHo A leaving O) with the NaBH ; CN (2 eq. EtoH, 80 ºC, 16 h “CO H
6 - ((trans) -4-ester-butylcyclohexyloxy) -2-naphthaldehyde (300 mg, 0.96 mmol, 1 equiv) and 3-amino-N- (methylsulfonyl) propanamide (239 mg, 1.19 mmol , 1.5 equiv) were dissolved in anhydrous EtOH. The mixture was stirred at 80 ° C for 1 hour. Then, NaABH3; CN (110 mg, 1.74 mmol, 2 equiv) was added to the mixture and stirred at 80 ° C for 16 hours. The organic layer was concentrated and purified by preparative TLC to provide 3 - (((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -N- (methylsulfonyl) propanamide - as a white solid (62 mg, 14%). (mobile phase: CH; OH / DCM = 1:10). ESI-MS (M + 1) *: 461.2, HPLC: 96.38%. * H NMR (400 MHz, DMSO-d;) δ: 7.93 (s, 1H), 7.85-7.77 (m, 2H), 7.59-7.49 (m, 1H), 7 , 43-7.35 (m, 1H), 7.20-7.11 (m, 1H), 4.45-4.33 (m, 1H), 4.20 (s, 2H), 2.98 (t, 2H), 2.77 (s, 3H), 2.35 (t, 2H),: 2.26-2.14 (m, 2H), 1.86-1.75 (m, 2H) , 1.41-1.30 (m, 2H), 1.27-1.14 (m, 2H), 1.413-1.02 (m, 1H), 0.89 (s, 9H).
T Example 62: 3 - (((6 - ((trans) -4-fer-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl) Õmethylamino) -N- (methylsulfonyl) Dropanamide "7 OO cHo sho a - CO To serum LO NaBH3CN (2 equiv), EtOH, 80 ºC, 16 h ”O CF; fe CFs Preparation was performed as described in Example 61 using 6- ((trans) 4-fer-butylcyclohexyloxy) -5 - (trifluormethyl) -2-naphthaldehyde instead of 6- ((11r, 4r) -4-tert-butylcyclohexyloxy) -2-naphthaldehyde. 71 mg, white solid, yield: 17%. (mobile phase: CHBOH / DCM = 1:10). ESI-MS (M + 1) *: 529.2. H-PLC: 98.69%. '* H NMR (400 MHz, CD; OD) ô: 8.25- 8.20 (m, 1H), 8.13-8.08 (m, 1H), 8.04-8.01 (m, 1H), 7.68-7.63 (m, 1H), 7, 60-7.55 (m, 1H), 4.54-4.43 (m, 1H), 4.40 (s, 2H), 3.36 (t 2H), 3.24 (s, 3H), 2.82 (t, 2H), 2.24-2.16 (m, 2H), 1.94-1.86 (m, 2H), 1.55-1.43 (m, 2H), 1, 29-1.16 (m, 2H), 1.45-1.07 (m, 1H), 0.90 (s, 9H) Example 63: ethyl 3- (ferc-butoxycarbonyl ((6 - ((trans ) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) amino) propanoate (o) o
AX DCM, rt, 18h, 78% Ethyl 3 - (((6- (trans4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl
lamino) propanoate, (491 mg, 1.2 mmol, 1 equiv) was dissolved in DCM (20 ml). Then, Et3N (360 mg, 3.56 mmol, 3 equiv), DMAP (15 mg, 0.13 mmol, 0.1 equiv) and (Boc), O (520 mg, 2.38 mmol, 2 equiv) were added to the mixture and stirred for 18 hours at room temperature.
The reaction was washed with 5% HCl, brine, dried over Na7zSO4, concentrated and purified by preparative TLC to provide ethyl 3- (tert-butoxycarbonyl ((6 - ((trans) -4-tert-butylcyclohexyloxy ) naphthalen-2-yl)] methyl) amino) propanoate as a yellow oil (478 mg, 78%). (mobile phase: EA / PE = 1: 8). ESI-MS (M + 1) *: 512.3. H NMR (400 MHz, CDCl3) & 7.71-7.63 (m, 2H), 7.61-7.53 (m, 1H), 7.38-7.27 (m, 1H), 7, 15-7.10 (m, 2H), 4.57 (s, 2H), 4.30-4.21 (m, 1H), 4.07 (q, 2H), 3.57-3.37 ( m, 2H), 2.60-2.45 (m, 2H), 2.31-2.23 (m, 2H), 1.93-1.85 (m,: 2H), 1.58-1 , 36 (m, 11H), 1.26-1.04 (m, 6H), 0.89 (s, 9H). Example 64: 3- (Ferc-butoxycarbonyl ((6 - ((trans) -4-ferc- butylcyclohexyloxy) naphthalen-2-yl) methyl) amino) propanoic acid 9 NaOH (5 equiv) * S eeration “ o Boc Bos SG 2h “o Boc A a solution of ethyl 3- (ferc-butoxycarbonyl ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) amino) propanoate (485 mg, 0.94 mmol) in EtOH (10 mL) aqueous NaOH (2 mL, 20%, 5.0 equiv) was added and refluxed for 2 hours.
Afterwards, the reaction was cooled to 0ºC, the pH of the solution was adjusted to 6 using 1 M HCl, concentrated and the residue was dissolved in bDCM, washed with water, dried and concentrated to provide 3- (fert-butoxycarbonyl ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-iN) methyl) amino) propanoic as a gray oil (392 mg, 75%). ESI-MS (M + H *): 484.3, '* H NMR (400 MHz, DMSO-d;) & 7.79-7.72 (m, 2H), 7.62-7.57 (m , 1H), 7.35-7.26 (m, 2H), 7.14-7.08 (m, 1H), 4.49 (s, 2H), 4.41 - 4.30 (m, 1H ), 3.38-3.26 (m, 2H), 2.33-2.26 (t, 2H), 2.23-2.15 (m, 2H), 1.95-1.84 (m , 2H), 1.47-1.28 (m, 11H), 1.27-1.15 (m, 2H), 1.11-1.02 (m, 1H), 0.87 (s, 9H ). Example 65: tert-butyl (6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] Mmethyl (3- (cyclopropanesulfonamido) -3- oxopropillcarbamate o. It is 7 equiv) 7 DCM.ta 8 pm. 100% Procedure for tferc-butyl 3- (methylsulfonamido) -3- oxopropylcarbamate was used to provide tert-butyl (6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl (3- ( cyclopropanesulfonamido) -3-oxopropyl) carbamate. 435 mg, gray oil, 100%. ESI-MS (M + 1) *: 587.3. * H NMR (400 MHz, DMSO-ds) à: 7.80-7.73 (m, 2H), 7.64-7.59 (m, 1H), 7.36-7.27 (m, 2H ), 7.15-7.10 (m, 1H), 4.50 (s, 2H), 4.40-4.32 (m, 1H), 3.45-3.45 (m, 2H), 2.94-2.86 (m, 1H), 2.56-2.52 (m, 2H), 2.24-2.15 (m, 2H), 1.85-1.77 (m, 2H ), 1.51-1.27 (m, 11H), 1.25-0.99 (m, 7H), 0.87 (s, 9H). - Example 66: 3 - (((6 - ((trans) -4-fterc-butylcyclohexyloxy) naphthalen-2-iN) methylamino) -N- (cyclopropylsulfonyl) propanamide - ooo ao CON tv aeee do conrágv 25% The procedure for 3-amino-N- (methylsulfonyl) propanamide was used to provide 3 - ((6 - ((trans) -4-ferric-butylcyclohexyloxy) naphthalen-2-iD) methylamino) -N- (cyclopropylsulfonyl) propanamide. 92 mg, white solid, 25%. ESI-MS (M + 1) *: 487.3. * H NMR (400 MHz, DMSO-d; s) 5: 7.94-7.90 (m, 1H),
15. 7.86-7.79 (m, 2H), 7.55-7.50 (m, 1H), 7.41-7.38 (m, 1H), 7.20-7.14 (m , 1H), 4.44-4.34 (m, 1H), 4.23 (s, 2H), 3.02 (t, 2H), 2.79-2.71 (m, 1H), 2, 37 (t, 2H), 2.25-2.16 (m, 2H), 1.86-1.76 (m, 2H), 1.41-1.28 (m, 2H), 1.27- 1.15 (m, 2H), 1.11-1.03 (m, 1H), 0.88 (s, 9H), 0.83-0.78 (m, 2H), 0.73-0, 66 (m, 2H).
Example 67: ethyl 2 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) -5- (trifluoromethyl) naphthalen-2-yl) methylamino) acetate 2 ° O. Fr 0 es FTFO procedure was performed as described in Example 27 to provide ethyl 2 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen-2-iDmethylamino) acetate. ESI-MS (M + H *): 466 , 3. HPLC: 92.65%. * H NMR (400
MHz, CD; OD) à: 8.09 (d, 1H), 7.99 (d, 1H), 7.78 (s, 1H), 7.56 (dd, 1H), 7.45 (d, 1H), 4.43-4.36 (m, 1H), 4.17 (q, 2H), 3.90 (s, 2H), 3.40 (s, 2H), 2.17 (d, 2H ), 1.86 (d, 2H), 1.48 (q, 2H), 1.26-1.13 (m, 5H), 1.10-1.03 (m, 1H), 0.88 ( s, 9H). Example 68: 2 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl) methylamino) acetic acid 20% aqueous NaOH (5.0- TE NT Reset EST FE fre: FA-F
F F The procedure was carried out as described in Example 28 to provide 2 - ((6 - ((trans) -4-tferc-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen: 2-i) methylamino) acetic acid. 50 mg, purified by HPLC preparation (0.05% is 10 TFA / water: MeOH = 0 - 95%), white solid (yield: 44%). ESI-MS (M + H *): 438.2 HPLC: 96.18%. * H NMR (400 MHz, CD3OD) δ: 8.20 (d, 1H), 8.08 (d, 1H), 7.98 (s, 1H), 7.61 (dd, 1H), 7.55 (d, 1H), 4.50-4.45 (m, 1H), 4.33 (s, 2H), 3.53 (s, 2H), 2.20 (d, 2H), 1.90 ( d, 2H), 1.47 (q, 2H), 1.25, (q, 2H), 1.15-1.08 (m, 1H), 0.91 (s, 9H). Example 69: ethyl 4 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl) methylamino) butanoate in AT The procedure was carried out as described in Example 27 to provide ethyl 4 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen-2-iNDmethylamino) butanoate. 160 mg, purified by HPLC preparation (0.05% TFA / water: MeOH = 0-95%), white solid (yield: 61%). E-SI-MS (M + H *): 494.3. HPLC: 95.66%. * H NMR (400 MHz) , CD3OD) à: 8.22 (d, 1H), 8.11 (d, 1H), 8.03 (s, 1H), 7.66 (dd, 1H), 7.58 (d, 1H), 4.50-4.46 (m, 1H), 4.37 (s, 2H), 4.13 (q, 2H), 3.16 (t, 2H), 2.49 (t, 2H), 2 , 21 (d, 2H), 2.04 (t, 2H), 1.90 (d, 2H), 1.49 (q, 2H), 1.34-1.30 (m, 5H), 1, 14-1.09 (m, 1H), 0.91 (s, 9H) Example 70: 4 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) -5- (trifluoromethyl) naphthalenic acid -2-yl) methylamino) butanoic
1M HCl (10.0 H Po o nm Ts TOLO F t F 34% F t FA a solution of ethyl 4 - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) -5- (trifluoromethyl) naphthalen-2 -yl) methylamino) butanoate (150 mg, 0.30 mmol) in THF (15 mL) 1 M HCI (3 mL) was added and refluxed for 1 hour, after which the reaction was concentrated to provide 4 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl)] methylamino) butanoic as a white solid, purified by HPLC preparation (0.05% TFA / water: MeEOH = 0 - 95%), 50 mg, white solid (yield: 34%). ESI-MS (M + H *): 466.3 H- PLC: 96.13%. 'H NMR (400 MHz, CD3OD) à: 8.20 (d, 1H), 8.10 (d, 1H), 8.01. (d, 1H), 7.65 (dd, 1H), 7.57 (d, 1H), 4, 50-4.46 (m, 1H), 4.34 (s, 2H), 3.16 (t, 2H), 2.46 (d, 2H), 2.21 (d, 2H), 1.98 (t, 2H), 1.90 (d, 2H), 1.49 (q, 2H), 1.25 '(q, 2H), 1.14-1.08 (m, 1H), 0.91 (s, 9H) Example 71: methyl 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) -5-fluoronaphthalen-2-yl) methyl) azetidine-3-carboxylate at 80 ° C, free solvent , 4 h, n 24% A mixture of the methyl compound 1 - ((6- (trans-4-fer-butylcyclo-
15. hexyloxy) -S- (trifluormethyl) naphthalen-2-yl) ÕMethyl) azetidine-3-carboxylate (150 mg, 0.37 mmol) and NFSI (175 mg, 0.56 mmol, 1.5 eq.) Was heated to 80ºC and stirred for 4 hours under No. atmosphere. Then, the mixture was purified by silica gel chromatography using PE / EA (6/1) as eluent to provide the product —methyl 1- ( (6- (trans-4-tert-butylcyclohexyloxy) -5- (trifluormeti) naphthalen-2-yl)] methyl) azetidine-3-carboxylate as a mild yellow oil (40 mg, 34%). EDI-MS (M + 1) *: 428.1. * H NMR (400 MHz, CDCI;) δ 7.97 (d, 1H), 7.65-7.62 (m, 1H), 7.52-7.41 (m, 2H), 7.25- 7.22 (m, 1H), 4.22 - 4.17 (m, 1H), 3.74 (s, 2H), 3.71 (s, 3H), 3.59-3.54 (m, 2H), 3.37-3.36 (m, 3H), 2.22-2.19 (m, 2H), 1.86-1.84 (m, 2H), 1.54-1.45 ( m, 2H), 1.19-1.08 (m, 3H), 0.86 (s, 9H).
Example 72: ethyl 1 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) -5-chloronaphthalen-2-yl) methyl) azetidine-3-carboxylate NCS (269) 43% et methyl compound 1- ((6- (trans-4-tert-butylcyclohexyloxy) -5- (trifluormethyl) naphthalen-2-yl) methyl) azetidine-3-carboxylate (140 mg, 0.34 mmol) and NCS (90mg, 0, 68 mmol, 2.0 eq.) Were dissolved in MeCN (5 mL). Then, CF3COOH (12 mg, 0.1 mmol, 0.3 eq.) Was added to the mixture at 0 ° C.
The mixture was warmed to room temperature and stirred for 1 hour.
Afterwards, the pH of the solution was adjusted to 7 with NazxCO; saturated, concentrated and the mixture was extracted by EtOAc.
The organic layer was concentrated and purified by silica gel chromatography using PE / EA (6/1) to provide the product methyl 1 - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) - S-chloronaphthalen-2-iN) methyl) azetidine-3-carboxylate (65 mg, 43%) as a mild yellow oil.
EDI-MS (M + 1) *: 444.0. 7H NMR (400 MHz, CDC) 5 8.16 (d, 1H), 7.69-7.66 (m, 2H), 7.50-7.47 (m, 1H), 7.28-7, 27 (m, 1H), 4.25-4.19 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.59-3.58 (m, 2H) , 3.38-3.37 (m, 3H), 2.23-2.20 (m, 2H), 1.88-1.85 (m, 2H), 1.61-1.52 (m, 2H), 1.12-1.07 (m, 3H), 0.87 (s, 9H). Example 73: 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) -5-fluoronaphthalen-2-yl)] methyl) azetidine-3-carboxylic acid *. SO "o - NacoH (5eq) So, SI P. Im.
CaHsOH / H2O (10: 1) ”= o: DtAAi To a solution of methyl 1 - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) -5-fluoronaphthalen-2-yl)] Methyl) azetidine -3-carboxylate, 40 mg, 0.09 mmol in EtoH (3 mL) were added to the aqueous NaOH (2 mL, 1%, 5.0 eq.) And refluxed for 1 hour.
Afterwards, the reaction was cooled to 0ºC, the pH of the solution was adjusted to 6 with 1 M HCl, concentrated and the residue was washed with DCM and water, dried under vacuum to provide the product of acid 1 - ((6- ((trans) -4-ferc- —Dbutylcyclohexyloxy) -5-fluoronaphthalen-2-yl)] Mmethyl) azetidine-3-carboxylic (30 mg, 78%) as a white solid.
EDI-MS (M + 1) *: 414.0. HPLC: 91.27%. H
NMR (400 MHz, CD; OD) at 8.09-8.01 (m, 2H), 7.74-7.71 (m, 1H), 7.59-7.58 (m, 1H), 7 , 48 (t, 1H), 4.57 (s, 2H), 4.38-4.32 (m, 5H), 3.76-3.70 (m, 1H), 2.21-2.19 (m, 2H), 1.91-1.88 (m, 2H), 1.53-1.44 (m, 2H), 1.24-1.10 (m, 3H), 0.90 (s , 9H). Example 74: 1 - (((6 - ((trans) -4-fer-butylcyclohexyloxy) -5-chloronaphthalen-2-yl)] methyl) azetidine-3-carboxylic acid NaOH (5 eq) * AOL MA a ares NO LIS PA a cr fo) CoHsOH / H2O (10: 1) at 80º, 1h 56% The procedure was performed as exercised for acid 1 - ((6- ((trans) -4-tert-butylcyclohexyloxy) - S5-fluoronaphthalen-2-yl) methyl) azetidine-3 'carboxylic to provide the solid title compound (35 mg, 56%). EDI-MS (M + 1) *: 430.0. HPLC: 91.27%. * H NMR (400 MHz, CD; OD) ô 8.29-8.26 (m, F 1H), 8.00-7.90 (m, 2H), 7.64-7.53 (m, 2H ), 4.49 (s, 2H), 4.45-4.38 (m, 1H), 4.22-4.19 (m, 4H), 3.49-3.42 (m, 1H), 2.28-2.24 (m, 2H), 1.96-1.92 (m, 2H), 1.60-1.51 (m, 2H), 1.30-1.16 (m, 3H ), 0.94 (s, 9H).
Example 75: methyl 3- (benzylamino) -2-methylpropanoate o "BnNH;> 7 (0.8 eq.)" Oo eaoo N MeOH, 2 d, 70 ºC Yield: 65% A mixture of methyl methacrylate (7 mL, 0.067 mol , 1.0 equiv), benzylamine (6 ml, 0.055 mol, 0.8 equiv) in methanol (5 ml) was stirred at 70 ° C for 2 days. After evaporation of volatiles, the crude product was purified by flash chromatography (DCM: MeOH = 20: 1) to provide the methyl 3- (benzylamino) -2-methylpropanoate 9 g, yield: 65%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3) at: 7.32-7.24 (m, 5H), 3.79 (s, 2H), 3.68 (s, 3H), 2.88-2.85 ( m, 1H), 2.71-2.63 (m, 2H), 1.16 (d, 3H).
Example 76: methyl 3-amino-2-methylpropanoate o Pd / C (20%), ACOH (0.1eq. OO (eq.) Oa O MeOH, 16h, ta. Yield: 83%
To a solution of methyl 3- (benzylamino) -2-methylpropanoate (3 9, 14 mmoles, 1.0 equiv) and acetic acid (87 ma, 1.4 mmol, 0.1 equiv) in methanol (30 mL ) Pd / C (10%, 0.3 g) was added. The resulting mixture was stirred under nitrogen at 25ºC for 16 hours. The catalyst was filtered, and the filtrate was concentrated to provide methyl 3-amino-2-methylpropanoate (1.4 g, yield: 83%) as a yellow oil. 1H NMR (400 MHz, CDCI; 3) à: 3.72 (s, 3H), 3.06-3.01 (m, 1H), 2.91-2.86 (m, 1H), 2.77 -2.72 (m, 1H), 1.95 (s, 2H), 1.22 (d, 3H).
Example 77: methyl 3 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) -2-methylpropanoate, * o À, Eaa. Gm) o rn Yield: 35% The preparation of methyl 3 - ((6 - ((trans) 4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -2-methylpropanoate was performed described for the example 27. 110 mg, pale yellow solid, yield: 35%. ESI-MS (M + H) *: 412.1, HPLC: 93.41%, H NMR (400 MHz, CDCl3) 5: 7.70-7.65 (m, 3H), 7.34 (d , 1H), 7.10 (dd, 1H), 7.01 (d, 1H), 4.16-4.09 (m, 1H), 3.96 (s, 2H), 3.65 (s, 3H), 3.143-3.138 (m, 1H), 2.92 (d, 2H), 2.16-2.12 (m, 2H), 1.84-1.81 (m, 2H), 1.39 -1.26 (m, 2H), 1.15-1.05 (m, 6H), 0.88 (s, 9H).
Example 78: 3 - ((6 - (((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -2-methylpropanoic acid “o À a CO o NaOH (5 eq.)“ Oo CO oH .. CO in O, CO 80º, 1h Yield: 94% The acid preparation - 3 - ((6 - ((trans) 4-tert-butylcyclohexyloxy) naphthalen-2-i) methylamino) -2- methylpropanoic was carried out as described, for example, 77. 100 mg, yellow solid, yield: 94%. ESI-MS (M + H) *: 398.1. HPLC: 97.60%. '* H NMR (400 MHz, CDCI;) 5: 7.84 (s, 1H), 7.72-7.68 (m, 2H), 7.59 (d, 1H), 7.15-7, 10 (m, 2H), 4.33-4.24 (m, 3H), 3.11
2.82 (m, 3H), 2.25-2.21 (m, 2H), 1.89-1.86 (m, 2H), 1.48-1.11 (m, 9H), 0, 89 (s, 9H). Example 79: ethyl 2-cyano-2-methylpropanoate o CH3l (3eq.), NaH (4eq) o Ne AÇA THF, ta. 3h Neo 85% A solution of ethyl 2-cyanoacetate (3 g, 0.026 mol, 1.0 equiv) in tetrahydrofuran (80 mL) was cooled in an ice salt bath, followed by the addition of sodium hydride (2.6 g, 0.104 mol, 4.0 equiv) in several portions.
The suspension was stirred at room temperature.
Then, iodomethane (11 g, 0.078 mmol, 3.0 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours, before cooling. 10 suddenly with water.
The mixture was extracted with ethyl acetate and washed with brine, dried over NaSO, and concentrated to obtain the crude ethyl 2-cyano-2-methylpropanoate product (3.2 g, yield: 85%) as a dark green oil. * H NMR (400 MHz, CDCl3) 5: 4.27 (q, 2H), 1.62 (s, 6H), 1.34 (t, 3H). Example 80: ethyl 3-amino-2,2-dimethylpropanoate and Ra / Ni (20%) Ã CIHSOHNH3 H3O (1 o: 1) 2N o Rentato FO A a solution of ethyl 2-cyano-2-methylpropanoate (0 , 6 g, 4.2 mmoles, 1.0 equiv) in 6 mL of ethanol / ammonium hydroxide (10: 1) was added Ra / Ni (20%, 0.12 g). The resulting mixture was stirred under nitrogen at room temperature for 16 hours.
The catalyst was filtered, and the filtrate was concentrated to provide ethyl 3-amino-2,2-dimethylpropanoate (0.43 g, yield: 70%) as a yellow oil. 1H NMR (400 MHz, CDCI; 3) à: 4.15 (q, 2H), 2.77 (s, 2H), 1.76 (s, 2H), 1.26 (t, 3H), 1, 18 (s, 6H). Example 81: ethyl 3 - ((6 - ((trans) 4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -2,2-dimethylpropanoate o
STAINLESS AACD E of Yield: 68% The preparation - of ethyl 3 - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -2,2-dimethylpropanoate was carried out as described in Example 27. 230 mg, colorless oil, yield: 68%. ESI-MS (M + H) *: 440.1. HPLC: 89.40%. 1 H NMR (400 MHz, CDCIs) at: 7.70-7.65 (m, 3H), 7.42 (d, 1H) 7.13-7.11 (m, 2H), 4.29-4 , 23 (m, 1H), 4.12 (q, 2H), 3.95 (s, 2H), 2.70 (s, 2H), 2.29-2.26 (m, 2H), 1, 91-1.88 (m, 2H), 1.48-1.42 (m, 2H),: 1.25-1.09 (m, 12H), 0.90 (s, 9H). Example 82: 3 - ((6 - ((trans) -4-fterc-butylcyclo-. Hexyloxy) naphthalen-2-yl) methylamino) -2,2-dimethylpropanoic acid or ADLODI leave MO LIS NI "Ren Rensimerto: 98% The preparation of 3 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) -2,2-dimethylpropanoic acid was carried out as described in Example 28. 210 mg, yellow solid pale, yield: 98%. ESI-MS (M + H) *: 412.1. HPLC: 96.40%. * H NMR (400 MHz, CDCIs) 5: 7.75 (s, 1H), 7, 69-7.67 (m, 2H), 7.58 (d, 1H), 7.14-7.09 (m, 2H), 4.26-4.21 (m, 3H), 2.78 ( s, 2H), 2.24-2.22 (m, 2H), 1.89-1.86 (m, 2H), 1.45-1.37 (m, 2H), 1.28-1, 08 (m, 9H), 0.89 (s, 9H).
Example 83: G6 - ((trans) 4-ferc-butylcyclohexyloxy) -2-naphtho-nitrile “o Br = CucN (15eq) ON o, DMSO, 125 ºC, 15h“ oo 82% Pp Compound —2-bromo -6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalene (2.09.5.55 mmoles, 1.0 eq.) And CuCN (742 mg, 8.34 mmoles, 1.5 eq.) it was dissolved in DMSO (5 ml). Then, the mixture was stirred at 125ºC for
15 hours.
Water was added and the mixture was extracted with ethyl acetate and the organic layer was purified by silica gel column chromatography using PE / EA (10/1) to provide the product as a soft yellow solid (1.423 g, 82% ). EDI-MS (M + 1) *: 308.0 * H NMR (400 MHz, CDCl3) at 8.12 (s, 1H) 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H), 1.93 -1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H). Example 84: (6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methanamine o CN NHOH (1.2e6q) and H 2, Raney Nickel (0.2 eq.) I AE: “ o MeOH, ta, 15 "o 63% b 10 Compound 6 - ((trans) -4-tert-butylcyclohexyloxy) -2-naphtonitrile (1.7 9, 5.53 mmoles, 1.0 eq.) and NH, OH (0.3 ml, 6.65 mmol, 1.2 eq.) Was dissolved in MeOH (5 ml). Then, Raney's Ni (64 mg, 1.11 mmol, 0.2 eq.) Was added to the mixture and the suspension solution was stirred at room temperature under a nitrogen atmosphere for 15 hours.
The mixture was filtered and purified by silica gel column chromatography using DCM / MeOH (10/1) as an eluent to provide the product as a pale solid (1.76 g, 63%). ESI-MS (M-NH>) *. 295.1. * H NMR (400 MHz, CDCk) 5 7.71-7.65 (m, 3H), 7.38 (dd, 1H), 7.15-7.11 (m, 2H), 4.28-4 , 24 (m, 1H), 3.98 (s, 2H), 2.30-2.26 (m, 2H), 1.91-1.87 (m, 2H), 1.76 (s, 2H ), 1.46-1.40 (m, 2H), 1.21-1.12 (m, 3H), 0.90 (s, 9H). Example 85: ethyl 3 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) -2-hydroxypropanoate (o “O.
AA DA (1069) “as EtOH, reflux.2h,“ oo 35% (6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methanamine (311 mg, 1.0 mmol , 1.0 eq.) And ethyl oxirane-2-carboxolate (116 mg, 1.0 mmol, 1.0 eq.) Were dissolved in EtOH (5 ml). Then, the mixture was refluxed for 2 hours.
The mixture was concentrated and purified by silica gel column chromatography using DCM / MeOH (10/1) as the eluent to provide the product as a mild yellow oil (311 mg, 35%). EDI-MS (M + 1) *: 428.1. HPLC: 92.02%. H NMR (400 MHz, CDCl3) 5 7.70-7.64 (m, 3H), 7.38 (dd, 1H), 7.13-7.11 (m, 2H), 4.31 - 4, 21 (m, 4H), 3.93 (q, 2H), 3.06-2.88 (AB, 2H), 2.60 (b, 2H), 2.28-2.26 (m, 2H) , 1.90-1.87 (m, 2H), 1.45-1.41 (m, 2H), 1.26 (t, 3H), 1.20-1.09 (m, 3H), 0 , 89 (s, 9H). Example 86: 3 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) -2-hydroxypropanoic acid POLITE Eae ro, cond The preparation of 3 - ((6 - ((trans) 4-tert-butylcyclo-] hexyloxy) naphthalen-2-yl)] methylamino) -2-hydroxypropanoic was carried out as described for example 28. 50 mg, white solid, yield: 38%. ESI-MS (M + H) *: 400.2. HPLC: 99.87%. 1 H NMR (400 MHz, CD; OD) à: 7.46-7.36 (m, 3H) 7.24 (s, 1H), 6.93-6.87 (m, 2H), 4.23 -4.20 (m, 1H), 4.04-4.02 (m, 1H), 3.72 (s, 2H), 2.94-2.92 (m, 2H), 2.10-2 .07 (m, 2H), 1.75-1.73 (m, 2H), 1.31-1.24 (m, 2H), 1.07-1.01 (m, 3H), 0.89 (s, 9H). Example 87: ethyl 1-cyanocyclopropanecarboxylate NETO A BP "(2 equi) E K3CO3 (3 equiv), Acetone, 80 ºC, 16h 100% Ethyl 2-cyanoacetate (0.85 g, 7.5 mmoles, 1 equiv), 1.2 dibromoethane (1.3 ml, 15 mmoles, 2 equiv) and KCO; (3.18 g, 22.5 mmoles, 3 equiv) were dissolved in acetone (6 ml), and the mixture was stirred for 16 hours at 80ºC.
The reaction mixture was filtered, concentrated to provide the crude product as a yellow oil (1.84 g, 100%). * H NMR (400 MHz, DMSO-dc) 5: 4.18 (t, 2H), 1.75 (t, 2H), 1.60 (m, 2H), 1.20 (t, 3H). Example 88: ethyl 1- (aminomethyl) cyclopropanecarboxylate oo O Raney Nickel / H2T “o AQ EtOH, ta, 20-h, 73% The preparation of ethyl 1- (aminomethyl) cyclopropanecarboxylate as a yellow oil (783 mg, 73%) was performed as described for the synthesis of ethyl 3-amino-2,2-dimethylpropanoate (Example 80). ESI-MS (M + 1) *: 144.1. 1H NMR (400 MHz, DMSO-ds): 4.03 (t, 2H), 3.59 (s, 2H), 1.17 (t, 3H), 0.99 (t 2H) 0.84 (t 2H). Example 89: ethyl 1 - (((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) methyl) cyclopropanecarboxylate cHo A of NA . x XX, 37% The preparation of etl 1 - ((((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) mMethyl) cyclopropanecarboxylate was performed as described in Example 27 as a mild yellow oil (211 mg, 37%). ESI-MS (M + 1) *: 438.3. * H NMR (400 MHz, CDCl3) 5: 7.73-7.64 (m, 3H), 7.45-7.39 (m, 1H), 7.19-7.09 (m, 2H), 4.31 - 4.20 (m, 1H), 4.16 - 4.07 (m, 2H), 3.66 (s, 2H), 2.73-2.71 (m, 2H), 2, 31-2.23 (m, 2H), 1.93-1.85 (m, 2H), 1.50-1.36 (m, 2H), 1.29-1.04 (m, 8H), 0.89 (s, 9H), 0.82-0.76 (m, 2H). Example 90: 1 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) methyl) cyclopropanecarboxylic acid oo POLONIA ag O ONE "o 94% * o The preparation of 1 - ((((6 - ((trans) A4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) methyl) cyclopropanecarboxylic acid was carried out as described for example 28 as a white solid (162 mg, 94%) . ESIMS (M + 1) ": 410.3. HPLC: 97.07%. '* H NMR (400 MHz, DMSO-d;) 0: 7.93-7.73 (m, 3H), 7.59-7.50 (m, 1H), 7.42-7.36 (m , 1H), 7.19-7.10 (m, 1H), 4.43-4.33 (m, 1H), 4.20-4.09 (brs, 2H), 3.00-2.89 (m, 2H), 2.26-2.14 (m, 2H), 1.85-1.75 (m, 2H), 1.40-1.29 (m, 2H), 1.27-1 , 14 (m, 3H),
* 70/164
E 1.13-1.00 (m, 2H), 0.96-0.76 (m, 11H). Example 91: NH - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methyl) ethanamine; (2equiv) 100% 6 - ((trans) -4-ferc-butylcyclohexyloxy) -2-naphthaldehyde (200 mg, 0.64 mmol, 1 equiv), ethanamine (58 mg, 1.05 mmol, 2 equiv ) and ACOH (62 mg, 1.05 mmol, 2 equiv) were dissolved in DCM (15 ml), and the mixture was stirred at room temperature for 2 hours. Then, NaABH3; CN (101 mg, 1.9 mmol, 3 equiv) was added to the mixture and stirred at room temperature. for 16 hours. The reaction mixture was washed with brine, dried over NaSO4, and concentrated to provide the title compound as a gray oil (250 mg, 100%). ESI-MS (M + 1) *: 340.3. * H NMR (400 MHz, CDCI;) &: 7.73-7.63 (m, 3H), 7.42-7.31 (m, 1H), 7.16-7.09 (m, 2H) , 4.30-4.21 (m, 1H), 3.91 (s, 2H), 2.73 (q, 2H), 2.31-2.23 (m, 2H), 1.93-1 .83 (m, 2H), 1.49-1.36 (m, 2H), 1.27-1.18 (m, 2H), 1.15 (t, 3H), 1.12-1.05 (m, 1H), 0.89 (s 9H). Example 92: methyl 3 - ((((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (ethyl) amino) propanoate o er ”(70 equiv) 7 CON s2 % N - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-iDmethyl) ethanamine (250 mg, 0.64 mmol, 1 equiv) was dissolved in CH; OH (1 mL). Then, methyl acrylate (4 mL, 44 mmoles, 70 equiv) was added to the mixture and stirred at room temperature for 16 hours The reaction was concentrated and purified by preparative TLC to provide the title compound as a solid white (217 mg, 52%). (mobile phase: EA / PE = 1: 8). ESI-MS (M + 1) *: 426.3, HPLC: 97.34%. 'H NMR (400 MHz, CDCI;) 5: 7.71-7.60 (m, 3H), 7.44-7.38 (m, 1H), 7.16-7.09 (m, 2H), 4.30-4, 20 (m, 1H), 3.69 (s, 2H),
. 71/164 3.64 (s, 3H), 2.85 (t, 2H), 2.65-2.46 (m, 4H), 2.31-2.24 (m, 2H), 1.92 -1.85 (m, 2H), 1.49-1.37 (m, 2H), 1.30-1.10 (m, 3H), 1.05 (t, 3H), 0.89 (s , 9H). Example 93: 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] Mmethyl) (ethyl) amino) propanoic acid> oo Good Cc, 2h o The preparation of acid 3 - ((((6 - ((trans) 4-tere-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (ethyl) amino) propanoic was performed as described for example 28 to provide the title compound as a white solid (126 mg, 60%). ESI-MS (M + 1) *: 412.3, HPLC: 96.12%. '* H NMR (400 MHz, DMSO-ds) 5: 7.91 (m, 1H), 7.84-7.76 (m, 2H), 7.61-7.55 (m, 1H), | 10 7.40-7.31 (m, 1H), 7.18-7.12 (m, 1H), 4.43-4.34 (m, 1H), 4.12 (s, 2H), 3 , 03. (t, 2H), 2.90-2.78 (m, 2H), 2.66 (t, 2H), 2.25-2.17 (m, 2H), 1.86-1.76 (m , 2H), 1.41-1.29 (m, 2H), 1.25-1.12 (m, 5H), 1.10-1.02 (m, 1H), 0.89 (s, 9H ). Example 94: N - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) propan-1-amine DCM, ta. 16-h, 100% TA preparation of N - (((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-i) methyl) pbropan-1-amine was performed as described for N - (( 6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) ethanamine (Example 91) to provide the title compound as a gray oil (429 mg, 100%). ESI-MS (M + 1) *: 354.3. '* H NMR (400 MHz, DMSO-ds) &: 7.76-7.66 (m, 3H), 7.44-7.40 (m, 1H), 7.32-7.30 (m, 1H), 7.12-7.06 (m, 1H), 4.40-4.30 (m, 1H), 3.78 (s, 2H), 2.46 (t, 2H), 2.23 -2.15 (m, 2H), 1.85-1.76 (m, 2H), 1.44 (q, 2H), 1.39-1.27 (m, 2H), 1.26-1 , 15 (m, 3H), 0.87 (s, 9H), 0.86 (t, 3H). Example 95: methyl 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) Õmethyl) (propyl) amino) propanoate and (70 equi A con
POLI IT HOLLOW 46%
b 72/164 The preparation of methyl 3 - (((& & 6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (propyl) amino) propanoate was performed as described for methyl 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-iNmethyl) (ethyl) amino) propanoate (Example 93) to provide the title compound as a white solid (195 mg , 46%). (Mobile phase: EA / PE = 1: 8). ESI-MS (M + 1) *: 440.3, HPLC: 95.63%. 'H NMR (400 MHz, CDCI3): 7 , 71-7.60 (m, 3H), 7.44-7.39 (m, 1H), 7.16-7.09 (m, 2H), 4.30-4.20 (m, 1H) , 3.67 (s, 2H), 3.64 (s, 3H), 2.83 (t, 2H), 2.50 (t, 2H), 2.41 (t, 2H), 2.31 2.23 (m, 2H), 1.93-1.84 (m, 2H), 1.55-1.37 (m, 4H), 1.25-1.05 (m, 3H), 0, 89 (s, 9H), 0.84 (13H.
Example 96: 3 - ((((6 - ((trans) -4-tert-butylcyclo-. Hexyloxy) naphthalen-2-yl)] methyl) (propyl) amino) propanoic À À, 78% The preparation of acid 3 - ((((6 - ((trans) 4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) (propyl) amino) propanoic was performed as described for example 28 as a white solid (147 mg, 78%) ESI-MS (M + 1) *: 426.3 HPLC: 99.49%. 1 H NMR (400 MHz, DMSO-ds) 5: 7.86-7.76 (m, 3H), 7.55-7.49 (m, 1H), 7.39-7.34 (m, 1H ), 7.17-7.10 (m, 1H), 4.43-4.33 (m, 1H), 4.02 (s, 2H), 2.96 (t, 2H), 2.70- 2.55 (m, 4H), 2.24-1.16 (m, 2H), 1.86-1.76 (m, 2H), 1.63-1.53 (m, 2H), 1, 40-1.28 (m, 2H), 1.26-1.14 (m, 2H), 1.07-1.02 (m, 1H), 0.89 (s, 9H), 0.82 ( t, 3H). Example 97: N - (((6 - ((trans) -4-ferc-butylcyclohexyloxy) naphthalen-2-i) methyl) cyclobutanamine AD LOOP in AS by “the AcCOH (2 equiv), NaBH3CN (3 equiv)“ DCM, ok. 16-h 100% The preparation of N - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) naphthalen 2-i) methyl) cyclobutanamine was performed described for example 27 to provide the title compound as a gray oil (282 mg, 100%). ESI-MS (M + 1) *: 366.3. * H NMR (400 MHz, CDCI; 3) à: 7.76-7.62 (m, 3H), 7.43-7.37
- 73/164 (m, 1H), 7.17-7.08 (m, 2H), 4.31 - 4.19 (m, 1H), 3.82 (s, 2H), 3.37-3 , 29 (m, 1H), 2.37-2.18 (m, 4H), 1.98-1.84 (m, 4H), 1.76-1.67 (m, 2H), 1.49 -1.36 (m, 2H), 1.26-1.04 (m, 3H), 0.89 (s, 9H).
Example 98: methyl 3 - ((((6 - ((trans) -4-tert-butylcyclohexyloxynaphthalen-2-yl) methyl) (cyclobutyl) amino) propanoate o LO er PO) LOSE 55% Methyl synthesis 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) Nnaftalen-2-yl)] Methyl) (cyclobutyl) amino) propanoate was performed as described for - methyl '- 3 - (((6- ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2- "iNmethyl) (ethyl) amino) propanoate (Example 95) to provide the title compound as a white solid (240 mg, 55%). (phase mobile: EA / PE = 1: 8). ESI- is MS (M + 1) *: 452.3, HPLC: 97.45%. '* H NMR (400 MHz, CDCI3) &: 7.72-7 .58 (m, 3H), 7.44-7.38 (m, 1H), 7.15-7.09 (m, 2H), 4.30-4.20 (m, 1H), 3.62 (s, 2H), 3.60 (s, 3H), 3.20-3.11 (m, 1H), 2.75 (t, 2H), 2.41 (t, 2H), 2.31 2.23 (m, 2H), 1.95-1.83 (m, 4H), 1.71-1.52 (m, 2H), 1.50-1.31 (m, 2H), 1, 26-1.05 (m, 5H), 0.89 (s, 9H).
Example 99: 3 - ((((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (cyclobutyl) amino) propanoic acid x À, POLCIL Tre O LIS LT "65% The preparation of 3 - (((6 - ((trans) A-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) (cyclobutyl) amino) propanoic acid was carried out as described for example 28 to provide the compound of title as a white solid (152 mg, 65%) ESI-MS (M + 1) *: 438.3 HPLC: 98.55%. 1 H NMR (400 MHz, DMSO-ds) at: 7.78 -7.66 (m, 3H), 7.44-7.37 (m, 1H), 7.34-7.30 (m, 1H), 7.14-7.06 (m, 1H), 4 , 41-4.31 (m, 1H), 3.64 (s, 2H), 3.22-3.14 (m, 1H), 2.64 (t, 2H), 2.35 (t, 2H ), 2.257-2.14 (m, 2H), 2.03-1.93 (m, 2H), 1.90-1.76 (m, 4H), 1.64-1.49 (m, 2H ), 1.40-1.27 (m, 2H), 1.26-1.14 (m, 2H), 1.40-1.01 (m, 1H), 0.87 (s, 9H).
Example 100: N - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphtha-
- 74/164 len-2-yl) methyl) cyclopentanamine * S CO Ot pen PO with “ACOH (2 equiv), NaBH3CN (3 equiv)“ DCM, ta, 16h 100% The preparation of N - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen 2-yl) methyl) cyclopentanamine was performed as described in Example 27 to provide the title compound as a gray oil (356 mg, 100%). ESI-MS (M + H) ": 380.3 * H NMR (400 MHz, CDCl3) &: 7.73-7.63 (m, 3H), 7.44-7.39 (m, 1H), 7.15-7.08 (m, 2H), 4.30-4.20 (m, 1H), 3.90 (s, 2H), 3.48-3.10 (m, 1H), 2, 31-2.22 (m, 2H), 1.93-1.84 (m, 2H), 1.78-1.06 (m, 13H), 0.89 (s, 9H).
Example 101: methyl 3 - ((((6 - ((trans) -4-tert-butylcyclo-. Hexyloxy) naphthalen-2-yl) methyl) (cyclopentyl) amino) propanoate o QD e ”(70 equiv) * o nO
DA O CH; OH, ta, 16h, 69% The synthesis of methyl 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (cyclopentyl) amino) propanoate was performed as described for methyl 3 - ((((6 - ((trans) 4-ferc-butylcyclohexyloxy) naphthalen-2-iNDmethyl) (cyclobutyl)) amino) propanoate (Example 98) to provide the title compound as a white solid (258 mg, 69%). (mobile phase: EA / PE = 1: 8) ESI-MS (M + 1) *: 466.3, HPLC: 95.23%. 1 H NMR (400 MHz, CD-Cl 3) &: 7.72-7.61 (m, 3H), 7.45-7.40 (m, 1H), 7.16-7.08 (m, 2H ), 4.30-4.21 (m, 1H), 3.72 (s, 2H), 3.60 (s, 3H), 3.15-3.06 (m, 1H), 2.87 ( t, 2H), 2.45 (t, 2H), 2.31-2.24 (m, 2H), 1.93-1.85 (m, 2H), 1.83-1.73 (m, 2H), 1.69-1.61 (m, 2H), 1.54-1.36 (m, 6H), 1.26-1.03 (m, 3H), 0.89 (s, 9H) .
Example 102: 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (cyclopentyl) amino) propanoic acid | A “+ LO NaOH (5 equiv) 2. vw om“ o Õ EtoH, 80 ºC, 2h “o Õ 58% The preparation of 3 - ((((6 - ((trans) 4-ferc-butylcyclohexyloxy) acid naphthalen-2-yl) methyl) (cyclopentyl) amino) propanoic was performed as described for example 28 to provide the title compound as a single-
. 75/164 white lipid (171 mg, 58%) ESI-MS (M + 1) *: 452.3, HPLC: 95.83%. 1 H NMR (400 MHz, DMSO-d; s) 5: 8.01-7.93 (m, 1H), 7.86-7.77 (m, 2H), 7.70-7.64 (m , 1H), 7.43-7.37 (m, 1H), 7.21-7.14 (m, 1H), 4.45-4.35 (m, 1H), 4.28 (s, 2H ), 3.58-3.45 (m, 1H), 3.11-3.01 (m, 2H), 2.75-2.62 (m, 2H), 2.26-2.14 (m , 2H), 2.06-1.93 (m, 2H), 1.90-1.77 (m, 4H), 1.76-1.65 (m, 2H), 1.59-1.47 (m, 2H), 1.40-1.30 (m, 2H), 1.27-1.16 (m, 2H), 1.12-1.02 (m, 1H), 0.88 (s , 9H). Example 103: N - (((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) cyclohexanamine * O, co ”att“ Oo co. o AcOH (1eq), NaBH; CN (3eq.), “q po Ia, 16h The preparation of N - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) cyclohexanamine was performed described for example 27 to provide the title compound as a white solid (420 mg, 95%). ESI-MS (M + H) *: 394.2. * H NMR (400 MHz, CDCl3) à: 7.82-7.70 (m, 3H), 7.47-7.45 (m, 1H), 7.15-7.07 (m, 2H), 4.23-4.17 (m, 1H), 4.06 (s, 2H), 2.86-2.80 (m, 1H), 2.22-2.18 (m, 2H), 1, 89-1.85 (m, 2H), 1.73-1.59 (m, 4H), 1.43-1.08 (m, 11H), 0.90 (s, 9H). Example 104: methyl 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (cyclohexyl) amino) propanoate O. toco Fam a cor o espnaçaa ov "oo The synthesis of methyl 3 - ((((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) (cyclohexyl) amino) propanoate was performed as described" for methyl 3 - ((((6 - ((trans) 4-tert-butylcyclohexyloxy) naphthalen-2-iNDmethyl) (cyclobutyl)> amino) propanoate (Example 98) to provide the title compound as a white solid (80 mg, 16%) (mobile phase: EA / PE = 1: 8). ESI-MS (M + H) *: 480.2. * H NMR (400 MHz, CDCI3) &: 7.74-7.62 (m , 3H), 7.44-7.41 (m, 1H), 7.14-7.09 (m, 2H), 4.29-4.23 (m, 1H), 3.74 (s,
"76/164 2H), 3.60 (s, 3H), 2.86 (t, 2H), 2.49-2.39 (m, 3H), 2.29-2.26 (m, 2H) , 1.91 1.78 (m, 5H), 1.56-1.10 (m, 12H), 0.90 (s, 9H) Example 105: 3 - (((6 - ((trans ) -4-ferc-butylcyclohexyloxy) naphthalen-2-yl) Mmethyl) (cyclohexyl) amino) propanoic o NaOH (Seq.) “O co“ o In the segment o> how ToH The acid preparation 3 - (((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) (cyclohexyl) amino) propanoic was performed as described for example 28 to provide the compound of title, 65 mg, soft yellow solid, yield: 84%. ESI-MS (M + H) *: 466.1. HPLC: 96.99%. H "NMR (400 MHz, DMSO-d; s) ô: 7.86-7.77 (m, 3H), 7.54 (d, 1H), 7.38 (d, 1H), 7.15 (dd, 1H), 4.41 - 4.35 (m, 1H), 4.10 (br, 2H), 3.04 (t, 2H), 2.86-2.84 (m, IS 1H), 2.22-2.19 (m, 2H), 1, 97-1.94 (m, 2H), 1.83-1.75 (m, 4H), 1.57-1.07 (m, 13H), 0.88 (s, 9H). Example 106: methyl 2- (hydroxymethyl) acrylate or do. paraformaldehyde (4.0 eq.) of Ti K2COg (1.6 eq.), H2O, ta.2n> "44% A saturated aqueous solution (10 mL) of K2CO; 3 (3.5 9, 117 mmoles, 1.6 eq. ) was slowly added to a rapidly stirred trimethylphosphonoacetate solution of (5.46 g, 30 mmoles, 1.0 eq.) and paraformaldehyde (6.63 g, 48 mmoles, 4.0 eq.) at environment.
Afterwards, the addition of the mixture was stirred for 2 hours.
Then, the mixture was extracted with DCM.
The organic layer was concentrated to provide the compound (1.59.44%) as a yellow oil. * H NMR (400 MHz, CD3; OD) δ: 6.29 (s, 1H), 5.83 (s, 1H), 3.75 (s, 3H), 3.72 (s, 2H). Example 107: methyl 3 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -2- (hydroxymethyl) Dropanoate
. 77/164
H “o the fr. (1.0 eq) À P 58% Compounds (6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2- i) methanamine (311 mg, 1.0 mmol, 1.0 eq.) And methyl 2 - (hydroxymethyl) acrylate (116 mg, 1.0 mmol, 1.0 eq.) were dissolved in MeOH (5 ml). The mixture was stirred at room temperature for 2 hours. Then, the mixture was concentrated and purified by silica gel column chromatography using DCM / CH3OH (10/1) to provide the product (250 mg, 58%) as a mild yellow oil. ESI-MS (M + H) *: 428.3. HPLC: 90.18%. 1 H NMR (400 MHz, CDCl 3) δ 7.68 (t, 2H), 7.63 (s, 1H), 7.37 (dd, 1H), 7.14-7.11 (m, 2H), 4.27- '4.25 (m, 1H), 4.01-3.96 (m, 2H), 3.91 (s, 2H), 3.71 (s, 3H), 3.18-2 , 93 (AB, 2H), 2.73-2.71 (m, 1H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 2H), 1.45 -1.40 (m, 2H), 1.25-1.09 (m, 3H), 0.89 (s, 9H). Example 108: 3 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) -2- (hydroxymethyl) propanoic acid TO LINA Estr AO CO ines “oH“ 21% “O or The preparation of 3 - ((6 - ((trans) -4-tert-butylcyclohexyloxyinaphthalen-2-yl)] methylamino) -2- (hydroxymethyl) propanoic acid was carried out as described for example 28 to provide the title compound 50 mg, white solid, yield: 21% ESI-MS (M + H) *: 414.3. HPLC: 94.23%. * H NMR (400 MHz, CDCl3) ô 7, 59 (s, 1H), 7.52 (d, 1H), 7.43 (d, 1H), 7.37-7.35 (m, 1H), 6.93 (d, 1H), 6.88 (s, 1H), 4.07-4.05 (m, 1H), 3.95 (s, 2H), 3.73-3.61 (m, 2H), 3.04-2.83 (AB , 2H), 2.74-2.72 (m, 1H), 2.12-2.09 (m, 2H), 1.79-1.76 (m, 2H), 1.32-1.25 (m, 2H), 1.09-1.01 (m, 3H), 0.85 (s, 9H) Example 109: ethyl 3 - ((6 - ((trans) -4-tert-butylcyclohexyloxy ) naphthalen-2-yl)] | methylamino) cyclobutanecarboxylate: ACOH (2 equiv), NaBH3CN (3 equiv) DCM, 48h The preparation of ethyl 3 - ((6 - ((trans) -4-terc -butilcyclo-
78/164 hexyloxy) naphthalen-2-yl)] methylamino) cyclobutanecarboxolate was performed described for example 27 to provide the title compound ESI-MS (M + 1) *: 438.3. ' H NMR (400 MHz, CDCk) &: 7.73-7.63 (m, 3H), 7.42-7.37 (m, 1H), 7.15-7.08 (m, 2H) , 4.29-4.21 (m, 1H), 4.11 (q, 2H), 3.85 (d, 2H), 3.30-3.24 (m, 1H), 2.75-269 (m, 1H), 2.53-246 (m, 2H), 2.30-2.22 (m, 2H), 2.05-1.98 (m, 2H), 1.92-1.85 (m, 2H), 1.47-1.38 (m, 2H), 1.27-1.15 (m, 5H), 1.14-1.05 (m, 1H), 0.89 (s , 9H). Example 110: 3 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) | methylamino) cyclobutanecarboxylic acid aa The preparation of 3 - ((6 - ((trans) 4- ferc-butylcyclo- (hexyloxy) naphthalen-2-yl) methylamino) cyclobutanecarboxylic was carried out as described for example 28 to provide the title compound ESI-MS (M + 1) *: 410.3. HPLC: 96.18%. 1 H NMR (400 MHz, CD3O0D) 5: 7.85-7.73 (m, 3H), 7.47-7.41 (m, 1H), 7.26-7.21 (m, 1H), 7.16-7.08 (m, 1H), 4.37-4.28 (m, 1H), 4.15-4.07 (m, 2H), 3.65-3.54 (m, 1H ), 2.84-2.77 (m, 1H), 2.58-2.51 (m, 2H), 2.30-2.18 (m, 4H), 1.93-1.85 (m , 2H), 1.46-1.33 (m, 2H), 1.30-1.18 (m, 2H), 1.13-1.08 (m, 1H), 0.89 (s, 9H ). Example 111: (S) -methyl 1 - ((6 ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) pyrrolidine-2-carboxylate LTS as O, O
2.00g 61% »The preparation of (S) -methyl 1 - (((6 - ((trans) 4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methyl) pyrrolidine-2-carboxylate has been described for example 27 to provide the title compound. ESI-MS (M + 1) *: 424.3. * H NMR (400 MHz, CDCl3) à: 7.70-7.64 (m, 3H), 7.45 (d, 1H), 7.13-7.09 (m, 2H), 4.28- 4.23 (m, 1H), 4.06-4.00 (m, 1H), 3.77-3.71 (m, 1H), 3.61 (s, 3H), 3.33-3, 31 (m, 1H), 3.11-3.07 (m, 1H), 2.45-2.41 (m, 1H), 2.27 (d, 2H), 2.20-2.26 ( m, 1H), 2.01-1.96 (m, 1H), 1.89 (d, 2H), 1.73-1.69 (m, 2H), 1.46-1.42
. 79/164 (m, 2H), 1.23-1.09 (m, 3H), 0.89 (s, 9H). Example - 112: - (S) -1 - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) naphthalen-2-yl)] Mmethyl) pyrrolidine-2-carboxylic acid A os ap Neo to AD With the TOLO O 70% The preparation of (S) -1 - ((6 - ((trans) -4-fer-butylcyclohexyloxyinaphthalen-2-yl) methyl) pyrrolidine-2-carboxylic acid was performed as described for example 28 to provide the title compound as a white solid (50 mg, 70%). ESI-MS (M + 1) *: 410.3. HPLC: 98.10%. * H NMR (400 MHz , CDz30D) 5: 7.95 (s, 1H), 7.86 (d, 1H), 7.83 (d, 1H), 7.54 (dd, 1H), 7.29 (d, 1H), WU 7.19 (dd, 1H), 4.69 (d, 1H), 4.46-4.37 (m, 3H), 3.62-3.54 (m, 1H), 3.44-3 , 40 (m, 1H), 2.66-2.62 (m, 1H), 2.28 (d, 2H), 2.25-2.16 (m, 2H), 2.02-1.98 (m, 1H), 1.93 (d, 2H), 1.46-1.41 (m, 2H), 1.30-1.25 (m, 2H), 1.17-1.13 ( m, 1H), 0.91 (s, 9H) Example 113: methyl 1 - (((6 - ((trans) -4-ferric-butylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-2-carboxylate all BERDS, from SOIL EERAO oo The preparation of methyl 1 - (((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) az ethidine-2-carboxylate was performed described for example 27 to provide the title compound.
ESI-MS (M + 1) *: 410.3. * H NMR (400 MHz, CD; OD) δ: 7.73-7.66 (m, 3H), 7.38 (dd, 1H), 7.21 (d, 1H), 7.09 (dd, 1H), 4.37-4.31 (m, 1H), 3.93-3.83 (m, 1H), 3.73 (d, 2H), 3.56 (s, 3H) 3.29- 3.21 (m, 1H), 3.13-3.08 (m, 1H), 2.29-2.25 (m, 4H), 1.92 (d, 2H), 1.45-1, 40 (m, 2H), 1.30-1.09 (m, 3H), 0.93 (s, 9H). Example 114: 1 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-2-carboxylic acid, 20% aqueous NaOH (5.0 eq.) oH o 70% o
- 80/164 The preparation of - 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-2-carboxylic acid was carried out as described for example 28 to provide the title compound as a white solid (50 mg, 70%). ESI-MS (M + 1) *: 396.3. HPLC: 96.99%. '* H NMR (400 MHz, CD; OD) δ: 6th: 7.82 (s, 1H), 7.75 (d, 2H), 7.43 (dd, 1H), 7.14 (d, 2H ), 4.94-4.90 (m, 1H), 4.49-4.41 (m, 2H), 4.30-4.23 (m, 1H), 4.06-4.01 (m , 1H), 3.86-3.81 (m, 1H), 2.64-2.59 (m, 2H), 2.23 (d, 2H), 1.87 (d, 2H), 1, 44-1.38 (m, 2H), 1.22-1.07 (m, 3H), 0.86 (s, 9H). Example 115: tert-butyl 3-amino-3-oxopropyl ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) carbamate NH4CI (5.0 eq) Ao, cons oH Envsoeo , Ao, con. o THF, 45%, 15min o 70%: The mixture of 3- (ferc-butoxycarbonyl ((6 - ((trans) -41-fterc-butylcyclohexyloxy) naphthalen-2-i)) methyl) propanoic acid (483 mg, 1.0 mmol), NH.CI (215 mg, 5.0 mmoles, 5.0 equiv), EtaN (510 mg, 5.0 mmoles, 5.0 eq) and HATU (760 mg , 2.0 mmoles, 2.0 equiv) in anhydrous THF (20 mL) was stirred at 45 ° C for 15 min. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography with silica gel (DCM / MeOH = 20/1) to provide the title compound as a white solid (337 mg, yield: 70% ). ESI-MS (M + H *): 483.3. * H NMR (400 MHz, DMSO-d; s) ô: 7.76 (d, 2H), 7.60 (s, 1H), 7.34 (s, 1H), 7.30 (d, 1H) , 7.12 (dd, 1H), 4.49 (s, 2H), 4.38-4.31 (m, 1H), 3.30 (t, 2H), 2.30 (t, 2H), 2.19 (d, 2H), 1.81 (d, 2H), 1.45-1.33 (m, 11H), 1.23-1.16 (m, 3H), 0.88 (s, 9H).
Example 116: N-acetyl-3 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2- and aminolpropanantion O o ACO / ACOH (1: 5) Ag cone seed for 50% The mixture of ferc-butyl 3-amino-3-oxopropyl (((6 - ((trans) -4-ferc-butylcyclohexyloxy) naphthalen-2-yl)] methyl) carbamate (241 mg, 0.5 mmol) in AcO and ACOH (6 mL, 1: 5) was stirred at 90 ° C for 2 hours, the reaction mixture was concentrated in vacuo and the residue was purified by chromatography with
. 81/164 silica gel (DCM / MeOH = 15/1) to provide the title compound as a white solid (100 mg, yield: 50%). ESI-MS (M + H *): 425.3. HPLC: 94.82%. * H NMR (400 MHz, CDCl3) &: 7.70 (d, 1H), 7.68 (d, 1H), 7.49 (s, 1H), 7.21 (d, 1H), 7.17-7.14 (m, 2H), 6.50 (br, 1H), 5.49 (br, 1H), 4.71 (s, 2H), 4.244,30 (m, 1H), 3.71 (t, 2H) , 2.57 (t, 2H), 2.27 (d, 2H), 2.18 (s, 3H), 1.89 (d, 2H), 1.48-1.42 (m, 2H), 1.09-1.20 (m, 3H), 0.88 (s, 9H). Example 116: 6 - ((trans) -4-tert-butylcyclohexyloxy) -2- naphtonitrile 2 and thia preamp Ai o AA om - toluene, ta, 15h, 86% AD cas: 52927-22-7 dk A flask loaded with 6-hydroxy-2-naphthonitrile (3.38 g, 0.02 mol, 1.0 eq.), cis4-ferce-butylcyclohexanol (6.24 g, 0.04 mol, 2.0 eq. .), PPh; o (10.5 g, 0.04 mol, 2.0 eq.) and toluene (20 ml), DIAD (12 ml, 0.06 mol, 3.0 eq.) was added under a nitrogen atmosphere at room temperature and stirred for 15 hours.
Water was added and extracted with EtOAc.
The organic layer was purified by silica gel chromatography (PE: EA = 10: 1) to provide the title compound (9.0 g, 86%) as a light yellow solid.
EDI-MS (M + 1) *: 308.0. * H NMR (400 MHz, CDCI;) 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29- 2.25 (m, 2H), 1.93-1.90 (m, 2H), 1, 48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H). Example 117: 2- (6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) propan-2-amine AN CeCl (3.0 eq), MeLi (10.0 eq.) AA THF, - 78% C at RT, 1h, 25% So LIST To a flask loaded with 6 - ((trans) -4-tferc-butylcyclohexyloxy) - 2-naphtonitrile (500 mg, 1.63 mmol, 1.0 eq. ), CeCl; (1.2 g, 4.89 mmoles, 3.0 eq.) And THF (10 mL), MelLi (1.5 M dietoxymethane solution, 10mL, 16.3 mmoles, 10.0 eq.) Was added under nitrogen atmosphere at -78ºC.
The mixture was stirred at -78 ° C for 1 hour.
Saturated ammonium chloride solution was added and extracted with EtOAc.
The organic layer was purified by
. 82/164 silica gel chromatography (DCM: MeOH = 10: 1) to provide the title compound (140 mg, 25%) as a mild yellow oil. '* H NMR (400 MHz, CDCl3) à: 7.84 (s, 1H), 7.72-7.66 (m, 2H), 7.59 (d, 1H), 7.13-7.09 (m, 2H), 4.28-4.23 (m, 1H), 2.29 (b, 2H), 2.28-2.25 (m, 2H), 1.90-1.87 (m , 2H), 1.61 (s, 6H) 1.48-1.39 (m, 2H), 1.25-1.09 (m, 3H), 0.89 (s, 9H). Example 118: methyl 3- (2- (6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) propan-2-ylamino) propanoate * ST À 6-0 eq.)> » * o with 7 CO MeOH, - to “CO 2- (6 - ((trans) -4-tferc-butylcyclohexyloxy) naphthalen-2-yl) propan-2-amine (113 mg, 0.33 mmol, 1.0 eq.) And methyl acrylate (86 mg, 0.99 mmol, bi 10 3.0eqg) were dissolved in MeOH (2 ml). The mixture was refluxed for 16 hours.
The mixture was concentrated and purified by silica gel chromatography (DCM: MeOH = 20: 1) to provide the title compound (100 mg, 71%) as a mild yellow oil. * H NMR (400 MHz, CDCl3) à: 7.73-7.68 (m, 3H), 7.60 (dd, 1H), 7.13-7.16 (m, 2H), 4.26- 4.23 (m, 1H), 3.66 (s, 3H), 2.62 (t, 2H), 2.50 (t, 2H), 2.28-2.26 (m, 2H), 1 , 90-1.87 (m, 2H), 1.58 (s, 6H), 1.45-1.38 (m, 2H), 1.19-1.09 (m, 3H), 0.89 (s, 9H). Example - 119: 3- (2- (6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) propan-2-ylamino) propanoic acid: The preparation of 3- (2- ( 6 - ((trans) -4-fer-butylcyclohexyloxyinaphthalen-2-yl) propan-2-ylamino) propanoic was performed as described in Example 28 to provide the title compound as a white solid (75 mg, 78%) HPLC: 96.91%. * H NMR (400 MHz, CD; OD) 6: 7.97 (s, 1H), 7.89-7.83 (m, 2H), 7.64 (dd, 1H ), 7.27 (s, 1H), 7.17 (dd, 1H), 4.39-4.36 (m, 1H), 2.94 (t, 2H), 2.58 (t, 2H) , 2.29-2.27 (m, 2H), 1.94-1.92 (m, 2H), 1.90 (s, 6H), 1.45-1.41 (m, 2H), 1 , 32-1.13 (m, 3H), 0.92 (s, 9H) Example 120: 2 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl )] methylamino) acetonitrile
. 83/164 * o lume, SERES x o "a CO 2 SN Dog. Ta, 15h, CO s 6 - ((trans) -4-tert-butylcyclohexyloxy) -2-naphthaldehyde (310 mg, 1 mmol) , 2-aminoacetonitrile (112 mg, 2 mmoles, 2.0 eq) and acetic acid (180 mg, 3 mmoles, 3.0 eq) in DCE (10 ml) were stirred at room temperature for 10 min.
Then, NaBH (OAc); 3 (636 mg, 3 mmoles, 3.0 eq) was added to the mixture and the mixture was stirred at room temperature for 15 hours.
Then, NaHCO; saturated was added to the mixture until pH = 8. The mixture was extracted with DCM (20 ml x 3). The organic layer was concentrated and the residue was purified by silica gel column chromatography eluting with DCM / CH3OH (20/1) to provide the product of the title compound as a colorless oil (240 mg, yield: 69% ). ESI-MS (M + H *): 351.2. * H NMR (400 MHz, CDCl3) &: 7.70 (dd, 2H), 7.68 (s, 1H), 7.41 (dad,] 1H), 7.13 (d, 2H), 4, 30-4.23 (m, 1H), 4.05 (s, 2H), 3.57 (s, 2H), 2.26 (d, 2H), 1.90 (d, 2H), 1.48 -1.42 (m, 2H), 1.20-1.09 (m, 3H), 0.90 (s, 9H). Example 121: N - (((1H-tetrazol-5-yl)] methyl) -1- (6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methanamine “ZnBR (10 ea ) “K LOONS as O LISA 11% To a solution of 2 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) methylamino) acetonitrile (240 mg, 0.699 mmol) in water and isopropanol (10 ml, 1: 5) were added NaN; (50 mg, 0.76 mmol, 1.1 eq) and ZnBr2 (153 mg, 0.69 mmol, 1.0 eq), then refluxed for 18 hours.
The reaction was cooled to O ºC and NaHCO; saturated was added.
The mixture was extracted with DCM (20 ml x 3) and the aqueous layer was destroyed by Na-CIO solution.
The organic layer was concentrated and the residue was the title compound as a white solid (27 mg, yield: 11%). ESI-MS (M + H *): 394.3. HPLC: 91.15%, '* H NMR (400 MHz, CD3OD) 6: 7.82 (s, 1H), 7.79-7.72 (m, 2H) 7.42 (d, 1H), 7 , 16 (d, 2H), 4.47-4.31 (m, 5H), 2.26 (d, 2H), 1.89 (d, 2H), 1.45-1.41 (m, 2H ), 1.24-1.09 (m, 3H), 0.88 (s, 9H). Example 122: 3 - ((6 - ((trans) -4-tert-butylcyclohexyl
. 84/164 xi) naphthalen-2-iNmethylamino) propanonitrile Ne = N CH; COOH (3.0eg., The procedure was followed as described for 2 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen -2-yl) methylamino) acetonitrile (Example 120) to provide the title compound 240 mg, white solid (yield: 62%).
—ESI-MS (M + H *): 365.3'H NMR (400 MHz, CDCIz) õ: 7.69 (dd, 2H), 7.66 (s, 1H), 7.40 (dd, 1H ), 7.13 (d, 2H), 4.30-4.23 (m, 1H), 3.95 (s, 2H), 2.97 (t, 2H), 2.56 (t, 2H) , 2.29 (d, 2H), 1.90 (d, 2H), 1.46-1.42 (m, 2H), 1.20-1.12 (m, 3H), 0.90 (s , 9H). Example 123: N - ((6 - ((trans) -4-fer-butylcyclo-10-hexyloxy) naphthalen-2-yl) methyl) -2- (1H-tetrazol-S-yl) ethanamine | CONFERENCES CI E Ê “flees at 11% The procedure was followed as described for N - ((1H-tetrazol-B-yl) methyl) -1- (6 - ((trans) -4-fer-butylcyclo -hexyloxy) naphthalen-2-yl) methanamine (Example 121) to provide the title compound 20 mg, white solid (yield: 11%). ESI-MS (M + H *): 408.3 HPLC: 98.66% 1H NMR (400 MHz, CD; OD) 6: 7.93 (s, 1H), 7.85 (dd, 2H), 7.53 (dd, 1H), 7.30 (d, 1H) 7.19 (dd, 1H), 4.45 (s, 2H), 4.42-4.36 (m, 1H), 3.61 (t , 2H), 3.43 (t, 2H), 2.29 (d, 2H), 1.93 (d, 2H), 1.43-1.39 (m, 2H), 1.33-1, 11 (m, 3H), 0.88 (s, 9H).
Example 124: 3 - (((6 - ((trans) -4-ferc-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanamide o CNA AE * o EconFÊ º ago ota ”20-0003b To a solution of 3 - ((6 - (((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) propanonitrile (233 mg, 0.684 mmol) in DMSO (2 mL) was added KxCO; (265 mg, 2 mmol, 3.0 eq). The mixture was then cooled to 0 ° C, followed by the addition of 30% aqueous H2O> (0.3 mL). The reaction mixture was stirred at room temperature for 1 hour, and quenched with water (10 mL). The solvent was removed by freezing
85/164 dry.
The crude product was purified by flash chromatography to provide the title compound as a white solid (111 mg, 45%) (mobile phase: MeOH / H2O: 0% -80%). ESI-MS (M + 1) *: 383.3. HPLC: 97.84%. 1 H NMR (400 MHz, CD; zOD) à: 7.86-7.79 (m, 3H), 7.53-7.50 (m, 1H), 7.33-7.30 (m, 1H ) 7.21-7.16 (m, 1H), 4.42-4.35 (m, 3H), 3.34-3.27 (m, 2H), 2.71 (t, 2H), 2 , 32-2.24 (m, 2H), 1.96-1.87 (m, 2H), 1.51-1.39 (m, 2H), 1.33-1.20 (m, 2H) , 1.17-1.09 (m, 1H), 0.92 (s, 9H). Example 125: methyl 1 - ((6 - ((trans) -4-fer-butylcyclohexyloxy) -5-iodonaphthalen-2-yl)] methyl) azetidine-3-carboxylate NIS (20 eq), 56% i ha 10 Methyl 1 - (((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) jazetidine-3-carboxylate (410 mg, 1 mmol) and NIS (247 mg, 1.1 mmol, 2.0 eq.) Were dissolved in CH3CN (5 ml). Then CF; COOH (35 mg, 0.3 mmol, 0.3 eq.) Was added to the mixture dropwise at 0 ° C.
The mixture was warmed to room temperature and stirred for another 1.5 hours.
Then, the mixture was extracted with EtOAc and the organic layer was concentrated and purified by silica gel chromatography using PE / EA (1/1) as eluent to provide the title compound product as a red solid. weak (300 mg, 56%). ESI-MS (M + H *): 536.2. * H NMR (400 MHz, CD-Cl3) à: 8.19 (d, 1H), 7.93 (s, 1H), 7.81 (d, 1H), 7.62 (d, 1H), 7 , 22 (d, 1H), 4.34-4.28 (m, 4H), 3.91-3.67 (m, 1H), 3.80-3.78 (m, 3H), 3.75 (s, 3H), 2.24-2.21 (m, 2H), 1.90-1.88 (m, 2H), 1.62-1.58 (m, 2H), 1.15-1 , 12 (m, 3H), 0.89 (s, 9H). Example 126: methyl 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) -5-metimmaftaten-2almethylazeltine-s-carboxylate —B- From: DO Your pencil TOLDO Ea. | O K3CO; (3.0 eq) dioxane, 90C, 5 h, 33% A vial loaded with 1 - ((6 - ((trans) -4-fert-butylcyclohexyloxy) -5-iodonaphthalen-2-yl) methyl) azetidine compound 3-carboxylate (300 mg,
. 86/164 0.56 mmol), methylboronic acid (66 mg, 1.1 mmol, 2.0 eq), 2 M K2CO; 3 aqueous (5 mL, 3.0 equiv) and [1,1- bis (diphenylphosphino) ferroene] dichloropalladium (TI) with dichloromethane (1: 1) (45 mg, 0.05 mmol, 0.1 equiv) was obtained by rinsing with nitrogen. 1,4-Dioxane (20 mL) was added and the reaction was stirred at 90 ° C for 5 hours. The solution was cooled to room temperature. The solvent was removed and the residue was purified by column chromatography (PE / EA = 1: 1) to provide the title compound as a white solid (80 mg, 33%). ESI-MS (M + H *): 424.3. * H NMR (400 MHz, CDCl3) à: 7.88 (d, 1H), 7.64-7.61 (m, 2H), 7.40 (dd, 1H), 7.23 (d, 1H) , 4.10 - 4.08 (m, 1H) 3.79 (s, 2H), 3.74 (s, 3H), 3.59-3.56 (m, 2H), 3.39-3, 36 (m, 3H), 2.53 (s, 3H), 2.20-2.17 (m, 2H), 1.86-1.83 (m, 2H), 1.48-1.43 ( m, 2H), 1.10 - 1.26 (m, 3H), 0.86 (s, 9H). 'Example 127: Acid 1 - ((6 - ((trans) -4-ferc-butylcyclohexyloxy) -' S-methylnaphthalen-2-yl) methyl) azetidine-3-carboxylic To the base Ana cano “OA a solution of methyl 1 - (((6 - ((trans) -4-fer-butylcyclohexyloxy) -5-methylnaphthalen-2-yl) methyl) azetidine-3-carboxylate (80 mg, 0.18 mmol) in EtoH (10mL) Aqueous NaOH (2 mL, 20%, 5.0 eq) was added at 85 ° C for 1 hour. Then, the reaction was cooled to 0 ° C, the pH of the solution was adjusted to 6 using 1 M HCl, concentrated and the residue was dissolved in DCM, washed with water, dried and concentrated to provide the title compound as a white solid. (40 mg, yield: 52%). ESI-MS (M + H *): 410.3. HPLC: 97.77% 1 H NMR (400 MHz, CD3; OD) à: 8.04 (d, 1H), 7.92 (s, 1H), 7.77 (d, 1H), 7.50 ( dd, 1H), 7.41 (d, 1H), 4.54 (s, 2H), 4.34-4.26 (m, 5H), 3.74-3.70 (m, 1H), 2 , 52 (s, 3H), 2.21-2.18 (m, 2H), 1.91-1.88 (m, 2H), 1.49-1.44 (m, 2H), 1.23 -1.11 (m, 3H), 0.90 (s, 9H). Example 128: (6-bromonaftalen-2-yloxy) (tert-butyldimethylsilane Br —TBDMSCI (15eq) Sr ADI imidazo! L (2. ease DI NELA
. 87/164 To a solution of the compound 6-bromonaftalen-2-ol (10 g, 0.044 mol, 1.0 equiv.) And imidazo! (6 g, 0.088 mol, 2.0 equiv) in dry DMF (100mL) TBDMSCI (10 g, 0.066 mol, 1.5 equiv) was added at 0 ° C. Then, the reaction mixture was warmed to room temperature and stirred for 3 hours.
Then, DMF was removed under reduced pressure.
The mixture was extracted with ethyl acetate and washed with brine, dried over Na; SO, and concentrated to obtain crude product.
The crude product was purified by silica gel chromatography (PE: EA = 30: 1) to provide the title compound as a yellow solid (23g, 76%). ESI-MS (M + H) *: 336.9. * H NMR (400 MHz, CDCl3) d: 7.91-7.92 (m, 1H), 7.64-7.46 (m, 3H), 7.15-7.08 (m, 2H), 1.01 (s, 9H), 0.24 (s, 6H). - Example 129: 6- (tert-butyldimethylsilyloxy) -2-naphthaldehyde R III n-BuLi (3 eq.) At 7 TBDMSO DMF (10 eq.) TBDMSO THF, -78 ºC, 2h 64% To a solution of (6 -bromonaphthalen-2-yloxy) (tert-butyl) dimethylsilane (4 g, 0.01 mol, 1.0 equiv) in dry THF (30 mL) at -78 ° C under N atmosphere, n-BuLi (2, 5 M, 12 mL, 3.0 equiv) dropwise and stirred for 30 min.
Then DMF (7.3 g, 0.1 mol, 10 equiv) was added and stirred for an additional 1 hour, then quenched with water, extracted with ethyl acetate and washed with brine, dried over NazSO, and concentrated to get crude product.
The crude product was purified by silica gel chromatography (PE: EA = 20: 1) to provide the title compound (2.2 g, 64%) as a yellow liquid.
ESI-MS (M + 1) *: 287.0. * H NMR (400 MHz, CDCl3) à: 10.10 (s, 1H), 8.26 (s, 1H), 7.91-7.88 (m, 2H), 7.78-7.76 ( m, 1H), 7.24-7.16 (m, 2H), 1.03 (s, 9H), 0.28 (s, 6H). Example 130: methyl 1 - ((6- (ferc-butyldimethylsilyloxy) naphthalen-2-illmethyl) azetidine-3-carboxylate TBDMSO NaBH; CN (2 eq), ACOH (2eq) - TBDMSO + PIE Sana
] 88/164 6- (ferc-butyldimethylsilyloxy) -2-naphthaldehyde (4.0 g, 14 mmoles), A-cOH (1.8 g, 28 mmoles) and methyl azetidine-3-carboxylate (3.2 g, 28 mmoles, 2.0 equiv) in DCE (30 mL) were stirred at 85 ° C for 1 hour.
Then, NaABH; CN (1.8 g, 28 mmoles, 2.0 equiv) was added to the mixture at 50 ° C and stirred for 2 hours at 85 ° C.
The reaction mixture was quenched with water, extracted with DCM and washed with brine, dried over NaSO4, and concentrated to obtain the crude product.
The crude product was purified by silica gel chromatography (DCM: MeOH = 40: 1) to provide the title compound (2.7 g, 50%) as a yellow oil.
ESI-MS (M + 1) *: 2 10 3862. 1H NMR (400 MHz, CDCl3) à: 7.72-7.68 (m, 3H), 7.37-7.34 (m, 1H), f - 7.15-7.10 (m, 2H), 3.94 (s, 2H), 3.81-3.76 (m, 4H), 3.74 (s, 3H), 3.50- 3.44 CT (m, 1H), 1.02 (s, 9H), 0.25 (s, 6H). Example 131: methyl 1 - ((6-hydroxynaphthalen-2-yl) methyl) azetidine- '3-carboxylate HCI (5%) in methanol E A and DO O TBDMSO o ”o 1h Ho o A a solution of methyl 1- ((6- (ferc-butyldimethylsilyloxy) naphthalen-2- i) methyl) azetidine-3-carboxylate (4.5 9, 11.7 mmoles) in methanol (50 ml) at 0 ° C Concentrated HCI (5 ml) was added dropwise.
The reaction mixture was stirred at room temperature for 1 hour.
The mixture was neutralized by NaHCO; Most of the solvent is saturated and evaporated, extracted with DCM and washed with brine, dried over Na; SO, and concentrated to obtain crude product.
The crude product was purified by silica gel chromatography (DCM: MeOH = 40: 1), extracted with DCM and washed with brine, dried over Na2SO4, and concentrated to obtain crude product.
The crude product was purified by silica gel chromatography (DCM: MeOH = 40: 1) to provide the title compound (1.5 g, 47%) as a gray solid.
ESI-MS (M + 1) *: 272.0. * H NMR (400 MHz, CDCl3) δ: 8.14 (s, 1H), 7.59-7.52 (m, 2H), 7.39- 7.28 (m, 2H), 7.09- 7.04 (m, 2H), 3.92 (s, 2H), 3.86-3.82 (m, 2H), 3.70 (s, 3H), 3.63-3.59 (m, 2H), 3.52-3.46 (m, 1H). Example 132: methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate
. 89/164 NS bAblDe) Fº No cas: 30129-18-1 5 To a flask was added methyl 1 - ((6-hydroxynaphthalen-2-iN) methyl) azetidine-3-carboxylate (271 mg, 1.0 mmol) , 4- (trifluormethyl) cyclohexanol (252 mg, 1.5 mmol, 1.5 equiv), PPh3 (524 mg, 2.0 mmol, 2.0 equiv) and toluene (0.8 mL) under a N2. While stirring, DIAD (404 mg, 2.0 mmoles, 2.0 equiv) was quickly added to the reaction mixture at room temperature and stirred for 10 min. The reaction mixture was then purified by silica gel chromatography (PE: EA = 5: 1) for P. to provide the title compound (114 mg, 28%) as a mild yellow oil. 4 ESI-MS (M + 1) *: 408.2. * H NMR (400 MHz, CD3OD) 6: 7.76 (d, 1H), 7.70 (d, - 10 1H) 7.66 (s, 1H), 7.36 (dd, 1H), 7, 24 (d, 1H), 7.17 (dd, 1H), 4.86-4.76 (m, 1H), 3.74 (s, 2H), 3.70 (s, 3H), 3.56 -3.51 (m, 2H), 3.32-3.34 (m, 3H), 2.33- 2.22 (m, 1H), 2.20 (d, 2H), 1.82-1 , 67 (m, 6H). Example 133: methyl 1 - ((6 - ((1R, 3s, 5S) -bicyclo [3.1.0] hexan-3-yloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate COMA. SEE COMA e = N O ta, toluene, 10 min Os. In
209.) 27% The preparation of the title compound was carried out as described E for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate (Example 132 ) .100 mg, soft yellow oil, yield: 27% ESI-MS (M + 1): 351.2. * H NMR (400 MHz, CD3OD) &: 7.72 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.36 (dd, 1H), 7.16 (d, 1H), 7.08 (dd, 1H), 4.67-4.61 (m, 1H) 3.75 (s, 2H), 3.72 (s, 3H), 3.55 (t , 2H), 3.44 (t, 2H), 3.39-3.35 (m, 1H), 2.45 (q, 2H), 1.97-1.93 (m, 2H), 1, 44-1.40 (m, 2H), 0.51-0.48 (m, 1H), 0.20 (q, 1H).
Example 134: methyl 1 - ((6- (bi (cyclohexan) -4-yloxy) naphthalen-2-iN) methyl) azetidine-3-carboxylate II O: O-O = BELOO coma: 280) ta. we are 10 min
- 90/164 The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluoromethyl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate (Example 132). 100 mg, light yellow oil, yield: 26% ESI-MS (M + 1) *: 435.3 '* H NMR (400 MHz, CD; OD) ô: 7.76-7.70 (m, 2H) , 7.66 (s, 1H), 7.36 (dd, 1H), 7.21 (d, 1H), 7.10 (dd, 1H), 4.33-4.39 (m, 1H), 3.77 (s, 2H), 3.72 (s, 3H), 3.57 (t, 2H), 3.46 (t, 2H), 3.39-3.35 (m, 1H), 2 , 26 (d, 2H), 1.89-1.40 (m, 9H), 1.30-1.09 (m, 9H). Example 135: methyl 14 (6- (cyclohexyloxy) naphthalen-2-yl)] Mmethyl) azetidine-3-carboxylate ATO: From BBB O ODAS ”o and tatiana owner o + io The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluoromethyl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate (Example 132). 100 mg, light yellow oil, yield: 20%. ESI-MS (M + 1) *: 354.2 * H NMR (400 MHz, CDCI3) &: 7.71-7.63 (m, 3H), 7.37 (dd, 1H), 7.13 (dd, 2H) , 5.01-4.95 (m, 2H), 4.42-4.36 (m, 1H), 3.78-3.76 (m, 2H) 3.71 (s, 3H), 3, 63-3.61 (m, 1H), 3.40-3.38 (m, 2H), 2.07 (d, 2H), 1.82 (d, 2H), 1.60-1.54 ( m, 3H), 1.43-1.37 (m, 3H). Example 136: methyl 1 - ((6 - ((trans) -4-cyclopentylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate OA Dor (2 equiv) IDOSA O + om DO, OD tolvene, ta . 15 min or 46% The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylate (Example 132 ). 217 mg, light yellow oil, yield: 46%. ESI-MS (M + 1) *: 422.3. * H NMR (400 MHz, CDCl3) &: 7.73-7.59 (m, 3H), 7.38-7.31 (m, 1H), 7.16-7.08 (m, 2H), 4.32-4.22 (m, 1H), 3.72 (s, 2H), 3.71 (s, 3H), 3.57-3.56 (m, 2H), 3.38-3, 34 (m, 3H), 2.26-2.17 (m, 2H), 1.96-1.87 (m, 2H), 1.83-1.71 (m, 2H), 1.68- 1.39 (m, 12H). Example 137: methyl 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylate
"91/164 CO PPh3 (2eq.), DIAD (2ea) / ss .s Ds O ta, toluene, 10 min TOLD (1,569) 17% o The preparation of the title compound was carried out as described for methyl 1 - (( 6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylate (Example 132). 67 mg, light yellow oil, yield: 17%. ESI-MS (M + 1 ) *: 410.3 * H NMR (400 MHz, CDCl3) 5: 7.72-7.65 (m, 3H), 7.38 (d, 1H) 7.16 (dd, 2H), 4.68 -6.66 (m, 1H), 3.80 (s, 2H), 3.72 (s, 3H), 3.66-3.64 (m, 2H), 3.42-3.40 (m , 3H), 2.18 (d, 2H), 1.59-1.49 (m, 7H), 0.89 (s, 9H) Example 138: methyl 1 - ((6- (4-methylcyclo- hexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylate was AD-on (2 equiv) OQ CO «no PPha (2 equiv), DIA (3 equiv), oo Juice 15, 1st min - A preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl)] Methyl) azetidine-3-carboxylate (Example 132). 216 mg, oil soft yellow, yield: 64%. ESI-MS (M + 1) *: 368.2. * H NMR (400 MHz, CDCl3) &: 7.74-7.61 (m, 3H), 7.38 -7.32 (m, 1H), 7.18-7.08 (m, 2H), 4.66-4.24 (m, 1H), 3.75 (s, 2H), 3.71 (s , 3H), 3.62-3.52 (m, 2H), 3.43-3.31 (m, 3H), 2.23-2.01 (m, 2H), 1.65-1.56 (m, 2H), 1.54-1.38 (m, 5H), 0.99-0.90 (m, 3H). Example 139: methyl 1 - ((6- (4-propylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate COPA Ls: BRs Ees ”CO x Oo - Oo, LS The preparation of the title compound was performed as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylate (Example 132). ESI-MS (M + 1) *: 396.3. 1H NMR (400 MHz, CD-Cla) d: 7.72-7.66 (m, 3H), 7.37 (d, 1H), 7.16-7.12 (m, 2H), 4.76 -4.66 (m, 1H), 3.74-3.66 (m, 5H), 3.59-3.52 (m, 2H), 3.40-3.33 (m, 3H), 2 , 25-1.85 (m, 2H), 1.60-1.55 (m, 11H), 0.90 (t, 3H). Example 140: methyl 1 - ((6- (4-butylcyclohexyloxy) naphthalen-2-illmethyl) azetidine-3-carboxylate
92/164 LO o ma OO + toluene, ta., 15 min 76% The preparation of the title compound was performed as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- yl)] methyl) azetidine-3-carboxylate (Example 132). 292 mg, light yellow oil, yield: 76%. ESI-MS (M + 1) *: 410.3. * H NMR (400 MHz, CDCI;) 5: 7.73-7.60 (m, 3H), 7.39-7.32 (m, 1H), 7.18-7.09 (m, 2H) , 4.67-4.20 (m, 1H), 3.75 (s, 2H), 3.71 (s, 3H), 3.65-3.52 (m, 2H), 3.42-3 , 33 (m, 3H), 2.25-2.05 (m, 2H), 1.92-1.83 (m, 2H), 1.61-1.37 (m, 6H), 1.17 -0.98 (m, 5H), 0.93-0.80 (m, 3H). "Example 141: methyl 1 - ((6- (4-butylcyclohexyloxy) naphthalen-2-PPyl)] methyl) azetidine-3-carboxylate OA PO DIA (2.00) Oo Co.: e» o ta, totuene , fo min (e. nm. The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylate (Example 132). ESI-MS (M + 1) *: 424.3. * H NMR (400 MHz, CD3OD) à: 7.73-7.64 (m, 3H), 7.34 (dd, 1H ), 7.20 (d, 1H), 7.09 (dd, 1H), 4.40-4.30 (m, 1H), 3.76-3.66 (m, 5H), 3.55- 3.32 (m, 5H), 2.28-2.25 (m, 2H), 1.85-1.82 (m, 2H), 1.39-1.27 (m, 7H), 0, 91-0.81 (m, 9H) Example 142: (trans) -methyl 4-hydroxycyclohexanecarboxylate Ho, SOC (2.0 eq) o DC Don —YOº € º “- IA Don o MeOH, 70ºC, 18h O 100 % To a solution of (trans) -4-hydroxycyclohexanecarboxylic acid (4.32 g, 30 mmol) in MeOH (20 mL) was added SOCI, (7.08 g, 60 mmol, 2.0 eq) dropwise drop at room temperature, then the mixture was stirred at 70 ° C for 18 hours, and the solvent was removed in vacuo title compound as a colorless oil (4.74 g, yield: 100%). 1 H NMR (400 MHz, DMSO-ds) δ: 4.33 (br, 1H), 3.68-3.60 (m , 1H), 3.57 (s, 3H), 2.37-2.31 (m, 1H), 1.82-1.74 (m, 2H), 1.53-1.45 (m, 6H ).
Example “143: (trans) -methyl 4- (tetrahydro-2H-pyran-2-
yloxy) cyclohexanecarboxylate á THP (12 eq), p-TSOH (0.2 eq) q From CD o AOLULE 43% O o To a solution of (trans) methyl 4-hydroxycyclohexanecarboxylate (4.74 g, 30 mmoles ) and THP (3.06 9, 3.6 mmoles, 1.2 eq) in DCM (20 ml) p-TsOH (1.18 g, 6 mmoles, 0.2 eq) was added slowly at room temperature.
Then, the mixture was stirred at room temperature for 18 hours, and the solvent was removed in vacuo.
The residue was purified on silica gel (EA / FOOT = 1:20) to provide the title compound as a "colorless oil (3.12 g, yield: 43%). 'H NMR (400 MHz, CDCl3) & 4.68 (t, 1H), R 3.91-3.88 (m, 1H), 3.84-3.81 (m, 1H), 3.67 (s, 3H), 3.51-3 , 46 (m, 1H), 2.40-2.36 (m, 1H), 2.00-1.82 (m, 4H), 1.76-1.51 (m, 10H). 'Example 144 : 2 - ((trans) -4- (tetrahydro-2H-pyran-2-yloxy) cyclohexyl) propan-2-ol À MeLi (5.0 eq) AQ su MOO o “THF, 75%. 2h 0 o To a solution of (trans) methyl 4- (tetrahydro-2H-pyran-2-yloxy) 9cyclohexanecarboxylate (3.12 9, 13 mmoies) in THF (10 mL) was added MelLi ( 65mL, 1M, 5.0 g) drop by drop at -78 ° C.
Then, the mixture was stirred at -78 ° C for 2 hours.
Water (20 ml) was added and the mixture was extracted with EA (30 ml x 3), dried and concentrated.
The residue was purified on silica gel (EA / PE = 1:10) to provide the title compound as a colorless oil (1.56 g, yield: 50%). 1H NMR (400 MHz, CDCIa) 6: 4.65 (t, 1H), 3.93-3.89 (m, 2H), 3.51-3.47 (m, 1H), 2.05-1 , 84 (m, 3H), 1.73-1.68 (m. 1H), 1.59-1.53 (m, 7H), 1.35-1.31 (m, 4H), 1.17 (d, SH). Example 145: 2 - ((trans) -4- (2-methoxypropan-Z-yl) cyclohexyloxy) tetrahydro-2H-pyran Ca = AI.
O THF, 50º, 2h oo 72%
- 94/164 To a solution of 2 - ((trans) -4- (tetrahydro-2H-pyran-2-yloxy) cyclohexyl) propan-2-ol (1.56 g, 6.5 mmoles) in THF (10 mL) NaH (300 mg, 13 mmoles, 2.0 eq) was added slowly at room temperature and then CH3l (1.96 g, 13 mmoles, 2.0 eq) was added in one portion . The mixture was stirred at 50 ° C for 2 hours. Water (10 ml) was added and the mixture was extracted with EA (30 ml x 3), dried and concentrated to provide the title compound as a colorless oil (1.2 g, yield: 72%). H NMR B (400 MHz, CDCl3) 5: 4.64 (t, 1H), 3.93-3.89 (m, 2H), 3.51-3.47 (m, 1H), 3.17 ( s, 3H), 1.97-1.85 (m, 3H), 1.70-1.67 (m, 1H), 1.58-1.43 (m, 9H), 1.34-1, 27 (m, 2H), 1.09 (d, 6H). 'Example 146: (trans) -4- (2-methoxypropan-2-yl) cyclohexanol «A" p-TsOH (1.0 eq) SO FR O os E oo THF, 50ºC, 2h 82% To a solution of 2 - ((trans) - € 4- (2-methoxypropan-2-yl) cyclohexyloxy) tetrahydro-2H-pyran (1.2 g, 4.7 mmoles) in MeOH (10 ml) was added p-TsOH (8.9 g, 4.7 mmoles, 1.0 eq) slowly at room temperature, then the mixture was stirred at room temperature for 2 hours, and the solvent was removed in vacuo. The residue was purified on silica gel (EA / PE = 1: 3) to provide the title compound as a colorless oil (660 mg, yield: 82%). * H NMR (400 MHz, CDCl3) 5: 4.07-4 , 05 (m, 1H), 3.17 (s, 3H), 1.87-1.82 (m, 2H), 1.55-1.38 (m, 7H), 1.10 (s, 6H ).
Example 147: methyl 1 - ((6 - ((trans) 4- (2-methoxypropan-2-yl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate Co | Bias (20 6) To Ho CO Dé Do ta. foluene 10 min, OO N The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate. ESI-MS (M + 1) *: 426.3. * H NMR (400 MHz, CDCl3) &: 7.80-7.75 (m, 3H), 7.37 (d, 1H), 7.17-7.14 (m, 2H), 4.32- 4.26 (m, 1H), 3.73-3.68 (m, 10H), 3.20 (s, 3H), 2.30-2.28 (m, 2H), 1.89-1, 87 (m, 2H), 1.69-1.65 (m, 2H), 1.48-1.42 (m, 3H), 1.12 (s, 6H).
- 95/164 Example 148: methyl 1 - ((6- (4-isopropylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylate DOS. bind (2000) À. CO | "e .. a. FO ta, toluene, 10 min, CO a. The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- il) Õmethyl) azetidine-3-carboxylate ESI-MS (M + 1) *: 396.3. * H NMR (400 MHz, CD3OD) 8: 7.73-7.64 (m, 3H), 7 , 38 (dd, 1H), 7.20-7.17 (m, 2H), 4.29-4.25 (m, 1H), 3.82 (s, 2H), 3.73-3.67 (m, 5H), 3.45-3.39 (m, 3H), 2.30-2.10 (m, 2H), 1.85-1.82 (m, 2H), 1.52-1 , 43 (m, 4H), 1.27-1.15 (m, 2H), 0.90 (d, 6H) - Example 149: Acid 1 - ((6- (4- (trifluoromethyl) cyclo-: 10 hexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylic 20% aqueous NaOH (5,069) - F; C o 52% To a solution of methyl 1 - ((6- (4- (trifluormethyl) cyclo- hexyloxy) naphthalen-2-yl)] Mmethyl) azetidine-3-carboxylate (100 mg, 0.26 mmol) in EtOH (15 mL) Aqueous NaOH (3 mL, 20%, 5.0 eq.) was added and refluxed then the reaction was cooled to 0 ° C, the pH of the solution was adjusted to 6 using 1M HCI, concentrated and the residue was dissolved in DCM, washed with water, dried and concentrated to provide the title compound as a soft yellow solid (50 mg, yield: 52%). ESI-MS (M + 1) *: 408.2 HPLC: 94.97% .1 H NMR (400 MHz, CD; OD) &: 7.77 (d, 1H), 7.69 (d, 1H) , 7.64 (s, 1H), 7.33 (d, 1H), 7.31 (s, 1H), 7.16 (dd, 1H), 4.80-4.71 (m, 1H), 3.57 (s, 2H), 3.25 (t, 2H), 3.09 (t, 2H), 2.79-2.73 (m, 1H), 2.41 (br, 1H), 2 , 07 (d, 2H), 1.80-1.60 (m, 6H).
Example 150: 1 - ((6 - ((trans) -4- (1,1-difluorethyl) cyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylic acid AS OA LES.
3 a. Cs2CO3 (4.5 eq.) OLITA or Eca is 18%
96/164 (trans) -4- (1,1-difluorethyl) cyclohexyl methanesulfonate (WO 2010051030) (0.98 mmol, 236 mg, 1.0 eq.), Methyl 1 - ((6-hydroxynaphthalen) 2- iDmethyl) azetidine-3-carboxylate (1.17 mmol, 317 ma, 1.2 mmol) and Cs; CO; (4.41 mmol, 1.4 g, 4.5 eq.) Were dissolved in t-butanol (4 mL ) and 2-butanone (2mbL). The mixture was stirred at 110 ° C for 16 hours. 1M aqueous HCI solution was added to the mixture to adjust pH = 6. Then, the mixture was extracted with EtOAc. The organic layer was purified by chromatography on a silica gel column using DCM / CH3O0H (10/1) as an eluent to provide the product (7 mg, 1.8%) as a white solid ESI-MS (M + 1) *: 404 , 1. HPLC: 89.46%. 'H NMR (400 MHz, CD3OD) 5: 7.89 (s, 1H), 7.86-7.81' (m, 2H), 7.46 (dd, 1H) , 7.31 (s, 1H), 7.19 (dd, 1H), 4.47 (s, 2H), 4.43-4.41 (m, s 1H), 4.21 (d, 4H) , 3.45-3.41 (m, 1H), 2.32-2.30 (m, 2H), 2.02-1.99 (m, 2H), 1.64-1.54 (m, 3H), 1.51-1.45 (m, 3H), 1.36-1.28 (m, 2H). Example 151: Acid 1 - ((6 - ((trans) -4- (1, 1-difluoropr opyl) cyclohexyloxy) naphthalen-2-yl) Mmethyl) azetidine-3-carboxylic Megane at 10% The preparation of the title compound was carried out as described for 1 - ((6 - ((trans) -4- ( 1,1-difluorethyl) cyclohexyloxy) naphthalen-2-iNmethyl) azetidine-3-carboxylic (Example 150). 22 mg, soft yellow solid, yield: 10%. ESI-MS (M + 1) *: 418.1. HPLC: 93.94%. 1 H NMR (400 MHz, CD; O0D) δ: 7.91 (s, 1H), 7.87-7.82 (m, 2H), 7.46 (dd, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 4.53 (s, 2H), 4.44-4.40 (m, 1H), 4.34 (d, 4H), 3.74-3.69 (m, 1H), 2.32-2.30 (m, 2H), 1.98-1.85 (m, 5H), 1.51-1.46 (m, 4H), 1.02 (t , 3H).
Example 152: 1 - ((6 - ((1R, 3s, 5S) -bicyclo [3.1,0] hexan-3-yloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylic acid VOTES TIMES 0 00, oo EtoH, 60ºC, 1h: o 19-0006e 60% The preparation of the title compound was carried out as described
. 97/164 for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-iNmethyl) azetidine-3-carboxylic acid. 50 mg, light yellow solid, yield: 60%. ESI-MS ( M + 1) *: 338.2. HPLC: 97.96%. * H NMR (400 MHz, CD; OD) à: 7.85 (s, 1H), 7.80-7.78 (m, 2H ), 7.45 (d, 1H), 7.19 (dd, 1H), 7.14 (s, 1H), 4.65-4.58 (m, 1H), 4.41 (s, 2H) , 4,214.15 (m, 4H), 3.39-3.37 (m, 1H), 248 (q, 2H), 2.04-1.98 (m, 2H), 1.46-1.42 (m, 2H), 0.56-0.53 (m, 1H), 0.17-0.15 (m, 1H) Example 153: Acid 1 - ((6- (bi (cyclohexan) - 4-yloxy) naphthalen-2-iN) methyl) azetidine-3-carboxylic 20% aqueous NaOH (5.0 eq.) Or 58% o - «- 10 The preparation of the title compound was carried out as described for acid 1- ( (6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylic acid. 50 mg, light yellow solid, yield: 58%. ESI-MS (M + 1) * : 422.3 HPLC: 93.30%. * H NMR (400 MHz, CD; OD) &: 7.81-7.77 (m, 3H), 7.41 (d, 1H), 7.20 (s, 2H), 4.75-4.72 (m, 1H), 4.33 (s, 2H), 4.16-4.14 (m, 2H), 4.08- 4.06 (m, 2H) , 3.39-3.37 (m, 1H), 2 , 27 (d, 2H), 1.91-1.46 (m, 9H), 1.30-1.02 (m, 9H). Example “154: 1 - ((6- (cyclohexyloxy) naphthalen-2-iN) methyl) azetidine-3-carboxylic acid 2% aqueous NaOH (50 eq) NO LOO A EtoH, 80ºC, 1h OD" stuck: o 65% The preparation of the title compound was performed as described for methyl 1 - ((6- (4- (trifluoromethyl) cyclohexyloxy) naphthalen-2- i) methyl) azetidine-3-carboxylic acid 50 mg, solid soft yellow, yield: 65%. ESI-MS (M + 1) *: 340.2 HPLC: 95.48%. 'H NMR (400 MHz, CD; OD) à: 7.76-7.73 (m , 3H), 7.39 (d, 1H), 7.16 (dd, 2H), 4.45-4.40 (m, 1H), 4.21 (s, 2H), 3.97 (br, 4H), 3.37-3.32 (m, 1H), 2.04 (dd, 2H), 1.83 (dd, 2H), 1.63-1.48 (m, 3H), 1.46 -1.33 (m, 3H) Example - 155: Acid - 1 - ((6 - ((trans) -4-cyclopentylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylic t 98/164 NaOH (5 equiv) NA Preparation of the title compound was performed as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- i) metiN) azetidine-3-carboxylic acid. , soft yellow solid, yield: 46% ESI-MS (M + 1) *: 408.3 HPLC: 98.97%. 'H NMR (400 MHz, CD; OD) à: 7.89 (s, 1H), 7.83 (dd, 2H), 7.44 (dd, 1H), 7.27 (d, 1H), 7.18 (dd, 1H), 4.51 (s, 2H), 4.42-4.37 (m, 1H), 4.33-4.31 (m, 4H), 3.72-3.64 (m, 1H) , 2.21 (dd, 2H), 1.95 (dd, 2H) 1.83-1.78 (m, 2H), 1.65-1.42 (m, 7H), 1.22-1, 14 (m, 5H). Example - 156: Acid - 1 - ((6 - ((trans) 4-tert-butylcyclophyte eat behind: m “| DOS" à NaoHísea S CO: O. CO tia Lol dio>. 80ºC, 1h 7% A preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- i) methyl) azetidine-3-carboxylic acid.27 mg, light yellow solid, yield : 77%. ESI-MS (M + 1) *: 396.3 HPLC: 100%. * H NMR (400 MHz, CD3; OD) &: 7.90 (s, 1H), 7.85 (dd, 2H), 7.45 (dd, 1H), 7.29 (d, 1H), 7.24 (dd, 1H), 4.77- 4.75 (m, 1H), 4.47 (s, 2H ), 4,224.20 (m, 4H), 3.45-3.40 (m, 1H), 2.20 (d, 2H), 1.65-1.49 (m, 6H), 1.20- 1.14 (m, 1H), 0.93 (s, 9H).
Example 157: 1 - ((6- (4-methylcyclohexyloxy) naphthalen-2- i) methyl) azetidine-3-carboxylic acid The preparation of the title compound was carried out as described for 1 - ((6- ( 4- (trifluormethyl) cyclohexyloxy) naphthalen-2-iNmethyl) azetidine-3-carboxylic.83 mg, light yellow solid, yield: 40% ESI-MS (M + 1) *: 354.2 HPLC: 96, 69%. 'H NMR (400 MHz, CD; OD) &: 7.87 (s, 1H), 7.81 (dd, 2H), 7.43 (dd, 1H), 7.25 (d, 1H ), 7.20 (dd, 1H), 4.73- 4.69 (m, 1H), 4.50 (s, 2H), 4.35-4.30 (m, 4H), 3.71 3.64 (m, 1H), 2.02-1.98 (m, 2H), 1.83-1.38 (m, 7H), 0.94 (d, 3H).
. 99/164 Example 158: 1 - ((6- (4-propylcyclohexyloxy) naphthalen-2-iNmethyl) azetidine-3-carboxylic acid Juicy No. (5.0 The preparation of the title compound was carried out as described for 1- ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2-iNmethyl) azetidine-3-carboxylic, 65 mg, yield: 69% ESI-MS (M + 1) *: 382.2 HPLC: 96, 32%. * 'H NMR (400 MHz, CD3OD) &: 7.85-7.78 (m, 3H), 7.43 (dd, 1H), 7.22-7.15 (m, 2H), 4.75-4.71 (m, 1H), 4.36 (s, 2H), 4.12-4.10 (m, - 4H), 3.41-3.36 (m, 1H), 2 , 23-1.86 (m, 2H), 1.68-1.57 (m, 3H), 1.46-1.24 (m, 8H), 0.93 (t, 3H). "10 Example 159: 1 - ((6- (4-butylcyclohexyloxy) naphthalen-2--yl) methyl) azetidine-3-carboxylic acid The preparation of the title compound was performed as described for 1 - ((6- ( 4- (trifluormethyl) cyclohexyloxy) naphthalen-2-iNmethyl) azetidine-3-carboxylic. 680 mg, light yellow solid, yield: 31%. ESI-MS (M + 1) *: 396.3 HPLC: 98, 15%. 'H NMR (400 MHz, DMSO-ds) δ: 7.94 (s, 1H), 7.85 (dd, 2H), 7.53 (dd, 1H), 7.39 (dd, 1H ), 7.20 ( dd, 1H), 4.76-4.74 (m, 1H), 4.45 (s, 2H), 4.15-4.13 (m, 4H), 3.66-3.60 (m, 1H), 2.16 (d, 1H), 1.95 (d, 1H), 1.82 (d, 1H), 1.64-1.11 (m, 12H), 0.90 (t, 3H ). Example 160: 1 - ((6 - ((trans) A-ferc-pentylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylic acid 20% aqueous NaOH (5.0 eq.) LA rt EtOH, 80ºC , 1h OCO: o 63% o The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- i) methyl) azetidine-3-carboxylic acid . 50 mg, yield: 63% ESI-MS (M + 1) *: 410.3 HPLC: 93.22%. 'H NMR (400 MHz, CD3OD) &: 7.91-7.82 (m, 3H) , 7.46 (dd, 1H) 7.29 (d, 1H), 7.19 (dd, 1H), 4.53 (s, 2H), 4.39-4.34 (m, 5H), 3 74-
. 100/164 3.70 (m, 1H), 2.30-2.27 (m, 2H), 1.89-1.86 (m, 2H), 1.45-1.26 (m, 7H) , 0.85 - 0.88 (m, 9H). Example 161: 1 - ((6 - ((trans) -4- (2-methoxypropan-2-yl) cyclohexyloxy) naphthalen-2-yl)] methyl) azetidine-3-carboxylic acid Ae N o (5.0 PO AO LOM £ Fame AS Now s2% o The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- i) methyl) azetidine acid 3-carboxylic. 60 mg, yield: 52% SI-MS (M + 1) *: 412.2 E PLC: 92.12%. * H NMR (400 MHz, CD3OD) at: 7.80-7.75 (m, 3H), 7.37 (d, 1H), 7.17-7.14 (m, 2H), 4.36-4.30 (m, 3H), 4.13-4.07 (m , 4H), 3.36-3.31 (m, 1H), * - 10 3, / 19 (s, 3H), 2.29-2.26 (m, 2H), 1.88-1.85 (m, 2H), 1.59-1.10 (m, 3H), 1.31 - 1.21 (m, 2H), 1.14 (s, 6H) i Example 162: Acid 1 - (( 6- (4-isopropylcyclohexyloxy) naphthalen-2-yl) methyl) azetidine-3-carboxylic 20% aqueous-NaOH (5.0-e9.) OLTIA LEE O with 72% o The preparation of the title compound was carried out as described for methyl 1 - ((6- (4- (trifluormethyl) cyclohexyloxy) naphthalen-2- i) methyl) azetidine-3-carboxylic acid.
The mg, yield: 72% SI-MS (M + 1) *: 382.2 PLC: 92.20%. * H NMR (400 MHz, CD3; OD) &: 7.83-7.76 (m, 3H), 7.40 (dd, 1H), 7.23-7.15 (m, 2H), 4, 39-4.34 (m, 3H), 4.16-4.11 (m, 4H), 4.38-4.34 (m, 1H), 2.26-2.10 (m, 2H), 1.87-1.84 (m, 1H), 1.61-1.43 (m, 5H), 1.22-1.46 (m, 2H), 0.94-0.90 (m, 6H ). Example 163: 6-Methoxy-2-methyl-4-trifluormethyl-quinoline [9 o Ne and one Ns “. For ES CUL HMPA, - O F Br DMF FE A solution of 4-Bromo-6-methoxy-2-methyl-quinoline (0.202 9, 0.801 mmol), Hexamethylphosphoramide (697 ul, 3.97 mmoles) in NN-
101/164 Dimethylformamide (4.30 mL) was degassed by stirring under vacuum and replacing the vacuum with argon (4 times). To this was added copper (i) iodide (263 mg, 1.38 mmol) and methyl fluorosulfonylifluoroacetate (520 ul, 3.97 mmoles) and the reaction was stirred under an argon atmosphere for 2 hours 55 ° C, then at 80 ° C for 16 hours. The reaction was evaporated, then diluted with methylene chloride. Silica gel was added and the solvent was removed. The material was purified by silica gel chromatography using 0-50% ethyl acetate in hexanes as eluent (Rf = 0.78 in 1: 1 ethyl acetate / hexanes) to provide the product in 40.5 mg yield (21%). ESI-MS (M + H +): 242.10. Ú Example 164: 2-Methyl-4-trifluormethyl-quinolin-6-ol. No. Ns - e. BBr3, CHCl LO It's F
FF FF 6-Methoxy-2-methyl-4-trifluoromethyl-quinoline (0.894 g, 3.71 mmoles) was dissolved in Methylene Chloride (60 mL), and stored at -78 ° C. A solution of 1 M boron tribromide in methylene chloride (11.0 mL, 11.0 mmoles) was then added dropwise. The reaction mixture was then heated to 23ºC. The reaction was allowed to stir 22 hours at room temperature. After cooling in an ice bath, saturated sodium bicarbonate solution was added with stirring. The mixture was extracted with methylene chloride and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using 0-15% methanol in methylene chloride to provide the product (Rf = 0.49 in 10% methanol in methylene chloride) in 771 mg yield (92%) . ESI-MS (M + H +): 228.10. Example 165: 6- (trans-4-fer-Butyl-cyclohexyloxy) -2-methyl-4-trifluoromethyl-quinoline o Ns o Ns LF Ex LG r F DIAD, PPh; r Yeah
: 102/164 2-Methyl-4-trifluormethyl-quinolin-6-ol (0.771 g, 0.00339 mol, cis-4-tert-Butyl-cyclohexanol (0.8570 g, 0.005484 mol) and triphenylphosphine (1.423 9, 0.005425 mol) were placed in a flask, and dissolved in toluene (25 mL). For the Mitsunobu reaction of certain analogs, THF was substituted for toluene as a solvent. Diisopropyl azodicarboxylate (1,137 mL, 0, 005430 mol) was then added dropwise After 3 days of stirring at room temperature, the reaction was evaporated to dryness The residue was purified by silica gel chromatography using 0-30% acetate ethyl in hexanes as eluent (Rf = 0.38 in 3: 1 hexanes / ethyl acetate). The product was isolated in 0.739 g (60%). ESI-MS (M + H +): 366.20. 'Example 166 : 6- (trans-4-tert-Butyl-cyclohexyloxy) -4-. Trifluoromethyl-quinoline-2-carbaldehyde | q Ns tBuO Ot Bu, No o: o E
FÓTE FÓE Di-tert-butyl peroxide (0.186 mL, 1.01 mmol) was added to a suspension of selenium dioxide (0.252 g, 2.27 mmol) in 1,4-Dioxane (6.0 mL). was stirred for 30 minutes, then 6- (4-tert-Butyl-cyclohexyloxy) -2-methyl-4-trifluormethyl-quinoline (0.368 g, 1.00 mmol) was added as a solution in 1.4- Dioxane (2.0 mL). The mixture was sealed and heated at 50 ° C for 20 hours. The reaction was filtered through Celite and washed with dioxane. The solvent was evaporated and the residue was purified on a silica gel column using 0-20% ethyl acetate in hexanes as the eluent. The product was isolated (Rf = 0.70 in 3: 1 hexanes / ethyl acetate) (212 mg, 56%). ESI-MS (M + H +): 380.20. Example 167: 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) -4-trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid * ne) aà * on * HCl o | Di Ao LO NaCNBH ;, DC iPraNEt FE, DCE FTF N, N-Diisopropylethylamine (39 ul, 0.22 mmol) was added to
. 103/164 a solution of 6- (4-trans-tert-Butyl-cyclohexyloxy) -4-trifluoromethyl-quinoline-2-carbaldehyde (61 ma, 0.16 mmol) and azetidine-3-carboxylic acid methyl ester of hydrochloride salt (34 mg, 0.22 mmol) in 1,2-Dichloroethane (2.50 ml) and the mixture was stirred for 1 hour at room temperature.
Sodium triacetoxyborohydride (54 mg, 0.25 mmol) was then added and stirring was continued.
After 1.5 hours, the reaction was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate.
The organic phase was dried over magnesium sulfate, filtered, evaporated and purified by flash chromatography (0-5% methanol in methylene chloride) to provide the product (Rf = 0.30 in 5% methanol / methylene chloride) in 65.8 mg yield '(86%). ESI-MS (M + H +): 479.30. Ss Example 168: 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) -4-trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid - POr, FR O Loma. “O ———“ o ”r E o 'Á oH 2 M lithium hydroxide, monohydrate in water (0.500 mL, 1.00 mmol) were added to a 1- [6- acid acid methyl ester solution (4-trans-tert-Butyl-cyclohexyloxy) -4-trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic (0.0658 g, 0.137 mmol) in Tetrahydrofuran (0.500 mL) and Meta- nol (0.500 mL). The mixture was stirred at room temperature.
After 1 hour, the solvent was concentrated under reduced pressure.
The residue was dissolved in methylene chloride and treated with 1.00 M hydrogen chloride in water (1.00 mL). The organic phases were dried over magnesium sulfate, filtered and concentrated.
Purification by preparative HPLC provided the product in 37.0 mg yield (39%) as bis-TFA salt.
ESI-MS (M + H +): 465.3; 1H NMR (400 MHz, METANOL-d4) Displacement 8.16 (d, J = 9.29 Hz 1H) 7.83 (s, 1H), 7.58 (dd, J = 2.51.9.29 Hz , 1H), 7.39 (br, s ,, 1H), 4.90 (s, 2H), 4.35 - 4.44 (m, 1H), 3.83 (t, J = 7.78 Hz , 1H), 2.29 (d, J = 10.79 Hz, 2H), 1.89 - 2.00 (m, 2H), 1.42 - 1.56 (m, 2H), 1.08 - 1.34 (m, 3H), 0.94 (s, 9H). 1.6 TFA per molecule.
Example 169: 3-4 [6- (trans-4-fer-Butyl-cyclohexyloxy) -4- acid
. 104/164 trifluormethyl-quinolin-2-ylmethyl] -amino) -propionic Synthesized as by 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) - 4-trifluormethyl-quinolin-2-ylmethyl] - azetidine-3-carboxylic (Example 168) using the appropriate amine.
ESI-MS (M + H +): 453.2; 1H NMR (400 MHz, META - NOL-d4) Displacement 8.15 (d, J = 9.29 Hz, 1H), 7.85 (s, 1H), 7.56 (dd, J = 2.26 , 9.29 Hz, 1H), 7.38 (br. S., 1H), 4.65 (s, 2H), 4.28 - 4.45 (m, 1H), 3.48 (t, J = 6.65 Hz, 2H), 2.88 (t, J = 6.78 Hz, 2H), 2.27 (d, J = 10.79 Hz, 2H), 1.74 - 2.03 (m , 2H), 1.38 - 1.54 (m, 2H), 1.18 - 1.32 (m, 2H), 1.04 - 1.18 (m, 1H), 0.79 - 0.94 (m, 9H). 1.6 TFA per molecule.
Example 170: 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) -4- trifluoromethyl-quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic acid s Synthesized as 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) - 4-trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic (Example 168) using the appropriate amine.
ESI-MS (M + H +): 479.2; 1H NMR (400 MHz, META-NOL-d4) Displacement 8.17 (d, J = 9.29 Hz, 1H), 7.85 (s, 1H), 7.58 (dd, J = 2.38, 9.41 Hz, 1H), 7.39 (br., 1H), 4.85 (br., 2H), 4.32 - 4.44 (m, 1H), 3.39 - 3 , 53 (m, 1H), 2.51 (br. S., 1H), 2.41 (br. S., 1H), 2.27 (d, J = 10.79 Hz, 2H), 1, 86 - 1.99 (m, 2H), 1.34 - 1.55 (m, 2H), 1.19 - 1.34 (m, 2H), 1.03 - 1.19 (m, 1H), 0.91 (s, 9H). 1.3 TFA per molecule.
Example 171: 4-Bromo-2-methyl-quinolin-6-ol Ns BBr3, CH2Cla Ns SOS —— ADI Br Br Synthesized as by 2-Methyl-4-trifluormethyl-quinolin-6-o0l using 4-Bromo-6- methoxy-2-methyl-quinoline “as starting material.
ESI-MS (M + H +): 238.00 / 240.00. Example 172: 4-Bromo-6- (trans-4-tert-Butyl-cyclohexyloxy) -2-methyl-quinoline "Ns Ç o Ns
- 105/164 Synthesized as 6- (trans-4-fer-Butyl-cyclohexyloxy) -2-methyl- 4-trifluormethyl-quinoline using 4-Bromo-2-methyl-quinolin-6-0l as starting material .
ESI-MS (M + H +): 378.1. Example 173: 4-Bromo-6- (trans-4-ester-Butyl-cyclohexyloxy) -quinoline-2-carbaldehyde o “Oo Nx SeO;>, dioxane '* o Ns» AI E “o Ó Br Br A a suspension of selenium dioxide (0.333 g, 3.00 mmol) in 1,4-Dioxane (8.0 mL) was added a solution of 4-Bromo-6- (4-fer-Butyl-cyclohexyloxy) - 2-methyl-quinoline (0.469 g, 1.25 mmol) in 1,4-Dioxane É (4.0 mL). The mixture was sealed and heated to 50ºC in an oil bath. .- 10 After 4 days, sand was filtered through Celite and washed with dioxane.
The solvent was evaporated and the residue was purified on a silica gel column using 0-25% ethyl acetate in hexanes as the eluent.
The product was isolated (Rf = 0.68 in 3: 1 hexanes / ethyl acetate) in 362 mg yield, 74%. ESI (M + H +): 390.10 / 392.10. Example 174: 1- [4-Bromo-6- (trans-4-tert-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -azetidine-3-carboxylic acid methyl ester o “oo SO OO“ o P - E Do Br iPUNEL DÊE Br 7º Synthesized as by methyl ester of 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) -4-trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid using 4-Bromo-6- (trans-4-fer-Butyl-cyclohexyloxy) -quinoline-2-carbaldehyde —— as a starting material.
ESI-MS (M + H +): 489.20 / 491.20. Example 175: 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid methyl ester a.
CI o Eh, Ne UN Br o o
- 106/164 A mixture of 1- [4-Bromo-6- (trans-4-tert-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -azetidine-3-carboxylic acid methyl ester (0.100 g, 0.204 mmol), methylborôeonic acid (39 mg, O65 mmol), [1,1-Bis (diphenylphosphino) ferrocene] dichloropalladium (Il) complex with dichloromethane (1: 1) (17 mg, 0.021 mmol), 2 M carbonate potassium in water (0.306 mL, 0.613 mmol) and N, N-Dimethylformamide (2.5 mL) was added to a 40 mL flask equipped with a magnetic stirrer bar.
The flask was degassed by stirring under a flow of air.
The reaction mixture was stirred at 60 ° C under Ar for 3 days.
The reaction was cooled, diluted with water and extracted with ethyl acetate.
The organics were washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated.
The residue - was purified by silica gel chromatography using 0-10% methanol in methylene chloride as the eluent (Rf = 0.44 in 10% methanol / methylene chloride). Appropriate fractions were combined and evaporated.
The product was further purified by preparative HPLC to provide the product in 33 mg yield (25%) as a bis-TFA salt.
ESI-MS (M + H +): 425.30. Example 176: 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid * Oo Coma.
Do AI LAW the> .- THF, MeOH. CS Do OH Synthesized as per 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) - 4trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid using 1-I6- acid methyl ester (trans-4-tert-Butyl-cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl] - azetidine-3-carboxylic as starting material.
ESI-MS (M + H +): 411.30; 1H NMR (400 MHz, METANOL-d4) Displacement 7.97 (d, J = 9.29 Hz, 1H), 7.41 (dd, J = 2.64, 9.16 Hz, 1H), 7.36 (d, J = 2.51 Hz, 1H), 7.27 (s, 1H), 4.73 (s, 2H), 4.45-4.59 (m, 4H), 4.36-4, 45 (m, 1H), 3.71 - 3.86 (m, 1H), 2.69 (s, 3H), 2.28 (d, J = 11.29 Hz, 2H), 1.92 (d , J = 10.79 Hz, 2H), 1.37 - 1.52 (m, 2H), 1.19 - 1.36 (m, 2H), 1.06 - 1.149 (m, 1H), 0, 92 (s, 9H). Example 177: 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic acid Synthesized as 1- [6- (trans -4-tert-Butyl-cyclohexyloxy) -
. 107/164 4-methyl-quinolin-2-ylmethyl] | -azetidine-3-carboxylic using the appropriate amine.
ESI-MS (M + H +): 425.3; 1H NMR (400 MHz, METANOL-d4) Displacement 8.00 (d, J = 9.29 Hz, 1H), 7.43 (dd, J = 2.51, 9.29 Hz, 1H), 7.38 (d, J = 2.51 Hz, 1H), 7.32 (s, 1H), 4.63 - 4.76 (m, 2H), 4.36 - 4.49 (m, 1H), 3, 68 - 3.90 (m,
2H) 3.54-3.68 (m, 2H), 3.37 -3.51 (m, 1H), 2.71 (s, 3H), 245 - 2.57 (m, 1H), 2, 34 - 2.45 (m, 1H), 2.29 (d, J = 10.54 Hz, 2H), 1.87 - 1.98 (m, 2H), 1.37 - 1.53 (m, 2H), 1.20 - 1.37 (m, 2H), 1.07 - 1.20 (m, 1H), 0.92 (s, 9H). Example 178: 3 - ([6- (trans-4-fer-Butyl-cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl] -amino) -propionic acid Synthesized as 1- [6- (trans -4-tert-Butyl-cyclohexyloxy) - S 4-methyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic using the appropriate amine. - ESI-MS (M + H +): 399.3; 1H NMR (300 MHz, METANOL-d4) Displacement 7.88 (d, J = 9.06 Hz, 1H), 7.26 - 7.35 (m, 2H), 7.21 (s, 1H), 4 , 40 (s, 2H), 4.27: - 4.38 (m, 1H), 3.31 - 3.38 (m, 2H), 2.77 (t, J = 6.61 Hz, 2H) , 2.61 (s, 3H), 2/19 (d, J = 9.44 Hz, 2H), 1.77 - 1.89 (m, 2H), 1.28 - 1.43 (m, 2H ), 1.10 - 1.26 (m, 2H), 0.97 - 1.40 (m, 1H), 0.83 (s, 9H). Example 179: 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) -4-cyclopropyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid methyl ester. DO To Cs2COs, H $ O, THF * O, E oo Í = —so D To methyl ester of 1- [4-Bromo-6- (trans-4-tert-Butyl-cyclohexyloxy) -quinolin-2 acid -ylmethyl] -azetidine-3-carboxylic (0.100 g, 0.000204 mol), cyclopropyl trifluoroborate potassium salt (0.050 g, 0.00034 mol),. [1 1-Bis (diphenylphosphino) ferrocene] dichloropalladium (II), complex with dichloromethane (1: 1) (0.019 g, 0.000023 mol), Cesium carbonate (0.215 g, 0.000660 mol), Tetrahydrofuran ( 2.50 ml) and water (0.25 ml) were added to a 40 ml bottle equipped with a magnetic stir bar.
The flask was degassed by stirring under an air flow.
The reaction was stirred under Ar for 3 days at 80 ° C.
The reaction was cooled, diluted with water and extracted with ethyl acetate.
The organics were washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated.
The residue was purified
"108/164 by silica gel chromatography using 0-10% methanol in DCM as eluent (Rf = 0.44 in 10% methanol / DCM). The product was further purified by preparative HPLC.
Appropriate fractions were combined to provide the product in 76 mg yield (55%) as a bis-TFA salt.
E- SIMS (M + H +): 451.30. Example 180: 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) -4-cyclopropyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic acid aaa YEARS OL Ao: Synthesized as by acid 1- [6- (trans-4-tert-Butyl-cyclohexyloxy) - 4-trifluormethyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic using 1- [6- (trans-4- methyl acid ester tert-Butyl-cyclohexyloxy) -4-cyclopropyl-quinolin-2-ylmethyl] - - azetidine-3-carboxylic as starting material.
ESI-MS (M + H +): 437.3; 1H NMR (400 MHz, METANOL-d4) Displacement 7.97 (d, J = 9.04 Hz, 1H), 7.70 (d, J = 2.76 Hz, 1H), 7.41 (dd, J = 2.64, 9.16 Hz, 1H), 7.08 (s, 1H), 4.71 (s, 2H), 4.36 - 4.59 (m, 5H), 3.70 - 3, 86 (m, 1H), 2.38 - 2.51 (m, 1H), 2.30 (d, J = 10.54 Hz, 2H), 1.85 - 1.99 (m, 2H), 1 , 37 - 1.53 (m, 2H), 1.49 - 1.34 (m, 4H), 1.05 - 1.19 (m, 1H), 0.92 (s, 9H), 0.81 - 0.89 (m, 2H). Example 181: 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) -4-cyclopropyl-quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic acid Synthesized as 1- [6- (trans -4-ferc-Butyl-cyclohexyloxy) - A4-cyclopropyl-quinolin-2-ylmethyl] -azetidine-3-carboxylic using the appropriate intermediate available from 1- [6- (trans-4-tert-Butyl) syntheses -cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic.— ESI-MS (M + H +): 451.3; 1H NMR (400 MHz, METANOL-d4) Displacement 7.99 (d, J = 9.29 Hz, 1H), 7.70 (d, J = 2.51 Hz, 1H), 7.42 (dd, J = 2.64, 9.16 Hz, 1H), 7.13 (s, 1H), 4.60-4.72 (m, 2H), 4.35 - 4.49 (m, 1H), 3, 81 (dd, J = 6.53, 12.05 Hz, 1H), 3.72 (dd, J = 8.66, 11.92 Hz, 1H), 3.50 - 3.66 (m, 2H) , 3.37 - 3.49 (m, 1H), 2.42 - 2.55 (m, 2H), 2.38 (td, J = 6.96, 13.68 Hz, 1H), 2.29 (d, J = 10.29 Hz, 2H), 1.85 - 1.98 (m, 2H), 1.36 - 1.52 (m, 2H), 1.18 - 1.34 (m, 4H ), 1.03 - 1.18 (m, 1H), 0.91 (s, 9H), 0.79 - 0.89 (m, 2H).
. 109/164 Example 182: 3 - [[6- (trans-4-fer-Butyl-cyclohexyloxy) -4-cyclopropyl-quinolin-2-ylmethyl] -amino) -propionic acid Synthesized as by 1- [6 - (trans-4-tert-Butyl-cyclohexyloxy) - 4-cyclopropyl-quinolin-2-ylmethyl) -azetidine-3-carboxylic using the appropriate intermediate available from 34 [6- (trans-4-tert) acid syntheses -Butyl-cyclohexyloxy) -4-methyl-quinolin-2-ylmethyl) -amino) -propionic. ESI-MS (M + H +): 425.3; 1H NMR (400 MHz, METANOL-d4) Displacement 8.00 (d, J = 9.29 Hz, 1H), 7.72 (d, J = 2.51 Hz, 1H), 7.43 (dd, J = 2.64, 9.16 Hz, 1H), 7.14 (s, 1H), 4.50 (s, 2H), 4.40 - 4.49 (m, 1H), 3.44 (t, J = 6.78 Hz, 2H), 2.87 (t, J = 6.65 Hz, 2H), 2.44 -2.54 (m, 1H), 2.32 (d, J = 11.04 Hz, 2H), 1.91 - 1.99 (m, 2H), 1.42: - 1.54 (m, 2H), 1.21 - 1.36 (m, 4H), 1.07 - 1 , 21 (m, 1H), 0.94 (s, 9H), 0.84 -. 0.92 (m, 2H). Example 183: 6-Bromo-2- (4-tert-Butyl-cyclohexyloxy) - Is quinoline
H «Br Ç“ o Ss Br HO DIAD, PPh; Synthetic lipid as per 6- (trans-4-tert-Butyl-cyclohexyloxy) -2-methyl-4-trifluoromethyl-quinoline using 6-Bromo-quinolin-2-0l as the starting material. Alkylation was confirmed to be on oxygen by 2D NMR (HMQC) of the subsequent intermediate. ESI-MS (M + H +): 362.1 / 364.10). Example 184: 2- (trans-4-tert-Butyl-cyclohexyloxy) -quinoline- G6-carbaldehyde o A going east NT OA “ON“ ON À 6-Bromo-2- (trans-4-tert-Butyl- cyclohexyloxy) -quinoline (1.0933 9, 3.0176 mmol) in Tetrahydrofuran (24 mL) 1.6 M n-Butyllithium in hexane (5.6 mL, 9.0 mmol) was added at -78 ° C and the reaction was stirred for 15 min. N, N-Dimethylformamide (1.2 ml) was added and the reaction was stirred for 30 minutes. 1M HCl was added and the reaction allowed to warm to
'110/164 room temperature. Saturated sodium bicarbonate solution was added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride, dried with sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using hexanes / ethyl acetate (0-50%) as the eluent to provide the product in 603 mg yield (64%). ESI-MS (M + H +): 312.20.
Example 185: 1- [2- (trans-4-ester-Butyl-cyclohexyloxy) -quinolin-6-ylmethyl] -azetidine-3-carboxylic acid methyl ester "Oo PESO LOM., SS tr" a, 2 á SO NaCNBH ;, Sar IProNEt, DCE E. Synthesized as 1- [6- (trans-4-fer-Butyl-cyclohexyloxy) -4-trifluormethyl-quinolin-2-ylmethyl) -azetidine methyl ester -3-carboxylic using 2- (trans-4-tert-Butyl-cyclohexyloxy) -quinoline-6-carbaldehyde as starting material ESI-MS (M + H +): 411.30.
Example 186: 1- [2- (trans-4-tert-Butyl-cyclohexyloxy) -quinolin-6-ylmethyl] -azetidine-3-carboxylic acid «LiOH, H20, SS SS Synthesized as by 1- [6 - (trans-4-fer-Butyl-cyclohexyloxy) - 4-trifluormethyl-quinolin-2-ylmethyl) -azetidine-3-carboxylic using 1- [2- (trans-4-tert-Butyl-) acid methyl ester cyclohexyloxy) -quinolin-6-ylmethyl] -azetidine-3-carboxylic as starting material. ESI-MS (M + H +): 397.39; 1H NMR (400 MHz, METANOL-d4) Displacement 8.15 (d, J = 8.78 Hz, 1H), 7.89 - 7.94 (m, 1H), 7.86 (d, J = 8, 78Hz, 1H), 7.67 (dd, J = 1.88, 8.66 Hz, 1H), 6.96 (d J = 8.78 Hz, 1H), 5.10 - 5.22 (m, 1H), 4.55 (s, 2H), 4.20 - 4.47 (m, 4H), 3.71 (quin, J = 8.28 Hz, 1H), 2.28 (d, J = 9 , 54 Hz, 2H), 1.92 (d, J = 14.31 Hz, 2H), 1.36 - 1.52 (m, 2H), 1.19 - 1.36 (m, 2H), 1 , 06 - 1.49 (m, 1H), 0.92 (s, 9H).
Example 187: 1- [2- (trans-4-fer-Butyl-cyclohexyloxy) -quinolin-6-ylmethyl] -pyrrolidine-3-carboxylic acid Synthesized as by 1- [2- (trans-4-ferc -Butyl-cyclohexyloxy) -
. 111/164 quinolin-6-ylmethyl) -azetidine-3-carboxylic using the appropriate amine. ESI-MS (M + H +): 411.41; 1H NMR (400 MHz, METANOL-d4) Displacement 8.14 (d, J = 8.78 Hz, 1H), 7.90 - 7.98 (m, 1H), 7.86 (d, J = 8, 53 Hz, 1H), 7.72 (dd, J = 1.88, 8.66 Hz, 1H), 6.95 (d, J = 8.78 Hz, 1H), 5.04 - 5.27 ( m, 1H), 4.54 (br, s, 2H), 3.31 - 4.11 (m, 5H), 2.15 -2.61 (m, 4H), 1.90 (d, J = 13.05 Hz, 2H), 1.35 - 1.52 (m, 2H), 1.17 - 1.35 (m, 2H), 1.03 - 1.17 (m, 1H), 0.91 (s, 9H).
Example 188: 6- (trans-4-tert-butylcyclohexyloxy) -2-methylquinoline. O "Í LS PPha3, DIAD TO IDO - Ho Ê W" o Ê To a solution of 2-Methyl-quinolin-6-ol (4.13 g, 0.0259 mol), cis Ú 4-tert-Butyl-cycle -hexane (4.86 g, 0.0311 mol) and triphenylphosphine (9.53 g, 0.0363 mol; Supplier = Aldrich) in tetrahydrofuran (100 mL, 1 mol; Supplier = Acros), cooled in an ice bath, diisopropyl azodicarboxylate (7.61 mL, 0.0363 mol; Supplier = Acros) in Tetrahydrofuran (10mL, 0.1 mol; Supplier = Acros) was added. The reaction mixture was stirred for 72 hours. hours allowing to reach room temperature The solvent was removed under reduced pressure and the residue was taken up in methylene chloride, absorbed on silica gel and purified by flash chromatography (0-30% ethyl acetate in hexanes) to provide the title compound in 56% yield ESI-MS (M + H +): 298.3 Example 189: 6- (trans-4-tert-butylcyclohexyloxy) quinoline-2-carbaldehyde
POLES EE AO AI dioxane “PP Di-tert-butyl peroxide (1.93 mL, 10.5 mmoles) was added to a suspension of selenium dioxide (2.68 g, 24.1 mmoles) in 1, 4- —Dioxane (24.00 mL, 307.5 mmoles). The mixture was stirred for 30 minutes.
. 112/164 tos, then 6- (trans-4-fer-Butyl-cyclohexyloxy) -2-methyl-quinoline (3.12 9, 10.5 mmoles) was added as a solution in 1,4-Dioxane and the mixture was heated overnight at 50 ° C. The reaction mixture was then cooled to room temperature, diluted with chloroform and filtered through a celite pad. The filtrate was washed with water. The layers were separated and the combined organic phase was dried over MgSO;, filtered, concentrated under reduced pressure, absorbed on silica gel and purified by flash chromatography (0-30% EtOAc in hexanes) to provide the title compound as a pale yellow solid in 20% yield. ESI-MS (M + H +):
31227. Example 190: tert-butyl 3 - ((6- (trans-4-fer-butylcyclohexyloxy). Quinolin-2-yl)] methylamino) Po - k HaN oo “o DP A triethylamine solution (0 , 07356 mL, 0.5278 mmol), 6- (trans-4-fer-Butyl-cyclohexyloxy) -quinoline-2-carbaldehyde (0.1259 g, 0.4043
15. mmol) and H-salt B-alanine t-butyl ester (0.08813 g, 0.4885 mmol) in 1,2-Dichloroethane (5.00 mL, 63.5 mmol) was stirred for 1 hour at room temperature. Sodium triacetoxyborohydride (0.1714 g, 0.8086 mmol) was then added and the mixture was stirred overnight. The reaction was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over MgSO;, filtered, absorbed on silica gel and purified by flash chromatography (0-5% MeOH in methylene chloride) to provide the title compound in 66% yield. ESI-MS (M + H +): 441.50. Example 191: 3 - ((6 - (((trans-4-fer-butylcyclohexyloxy) quinolin-2-yl) methylamino) propanoic acid o Ns A LioH * o No COH 2 M lithium hydroxide, monohydrate in water (1.00 mL, 2.00 mmoles) were added to a solution of ferc-butyl acid ester 34 [6-
, 113/164 (trans-4-tert-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -amino) -propionic (0.2416 g, 0.5483 mmol) in Tetrahydrofuran (1.00 mL, 12.3 mmol) and Methanol (1.00 mL, 24.7 mmol). The mixture was stirred overnight at room temperature.
The solvent was removed under reduced pressure and the residue was dissolved in methylene chloride and washed with water.
The organic phase was concentrated under reduced pressure to provide the title compound.
ESI-MS (M + H +): 385.42. 1H NMR (400 MHz, MeOD) Displacement 8.16 (d, J = 8.53 Hz, 1H), 7.86 (d, J = 9.04 Hz, 1H), 7.51 (d, J = 8.53 Hz, 1H), 7.31 (dd J = 2.76, 9.04 Hz, 1H), 7.24 (d, J = 2.51 Hz, 1H), 4.29 - 4.39 (m, 1H), 3.99 (s, 2H) 2.86 (t / J = 6.90 Hz, 2H), 2.42 (t, J = 6.90 Hz, 2H), 2.22 - 2.30 (m, 2H), '1.85 - 1.93 (m, 2H), 1.34 - 1.47 (m, 2H), 1.419 - 1.31 (m, 2H), 1.04 - 1, 45 (m,. 1H), 0.89 (s, 9H). Ki The following compounds were synthesized as 3- (6- - (trans-4-fer-butylcyclohexyloxy) quinolin-2-yl) methylamino) propanoic acid using appropriate cyclohexanols and aminoesters: Example 192: 1- [6 - (trans 4-fer-Butyl-cyclohexyloxy) - quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic ESI-MS (M + H +): 411.64; 1H NMR (400 MHz, METANOL-d4) Displacement 8.56 (d, J = 8.53 Hz, 1H), 8.11 (d, J = 9.29 Hz, 1H), 7.75 (d, J = 8.53Hz, 1H), 7.55 (dd, J = 2.76.9.29 Hz, 1H), 7.48 (d, J = 2.76 Hz, 1H), 4.90 (d, J = 2.51 Hz, 2H), 4.40 - 4.51 (m, 1H), 3.78 - 3.93 (m, 2H), 3.60 - 3.74 (m, 2H), 3 , 45 - 3.55 (m, 1H), 2.54 (dt, J = 6.96, 8.91 Hz, 1H), 2.37 - 2.47 (m, 1H), 2.29 (d , J = 2.76 Hz, 2H), 1.89 - 1.98 (m, 2H), 1.41 - 1.53 (m, 2H), 1.24 - 1.37 (m, 2H), 1.11 - 1.20 (m, 1H), 0.92 (s, 9H). Example 193: 1- [6- (trans 4-fer-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -azetidine-3-carboxylic acid ESI-MS (M + H +): 397.44; 1H NMR (400 MHz, MeOD) Displacement 8.26 (d, J = 8.03 Hz, 1H), 7.97 (d, J = 9.04 Hz, 1H), 7.37 - 7.42 (m, 2H), 7.30 - 7.34 (m, 1H), 4.79 (s, 2H), 4.48 - 4.59 (m, 4H), 4.34 - 4.44 (m , 1H) 2.66 (s, 1H), 2.25-2.33 (m, J = 11.55 Hz, 2H), 1.89 - 1.97 (m, 2H), 1.38 - 1 , 51 (m, 2H), 1.22 - 1.35 (m, 2H), 1.07 - 1.49 (m, J = 11.80 Hz, 1H), 0.93 (s, 9H).
Example 194: 1- [6- (trans 4-fer-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic acid Enantiomer 1, separated by chiral HPLC.
ESI-MS (M + H +): 411.35; 1H NMR (400 MHz, DMSO-d6) Displacement 8.16 (d, J = 8.28 Hz, 1H) 7.83 (s, 1H), 7.50 (d, J = 8.28Hz, 1H), 7.38 (s, 1H), 7.31 (dd, J = 2.76, 9.04 Hz, 1H), 4.31 - 4.42 (m, 1H), 3.77 (d, J = 5.02 Hz, 2H), 2.80 - 2.90 (m, 1H), 2.69 - 2.77 (m, 1H), 2.52 - 2.67 (m, 4H), 2.15 - 2.24 (m, 2H), 1.88 - 2.00 (m, 2H), 1.76 - 1.85 (m, 2H), 1.28 - 1.40 (m, 2H), 1 , 14 - 1.27 (m, 2H), 0.87 (s, 9H). Example 195: 1- [6- (trans 4-fer-Butyl-cyclohexyloxy) -] quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic acid. Enantiomer 2, separated by chiral HPLC.
ESI-MS (M + H +): 411.36; 1H NMR (400 MHz, DMSO-d6) Displacement 8.16 (d, J = 8.53 Hz,: 1H), 7.82 (d, J = 9.04 Hz, 1H), 7.50 (d, J = 8.53 Hz, 1H), 7.38 (s, 1H), 7.28 - 7.34 (m, 1H), 4.32 - 4.42 (m, 1H), 3.78 (d , J = 5.02 Hz, 2H), 2.83 - 2.92 (m, 1H), 2.71 - 2.77 (m, 1H), 2.51 - 2.68 (m, 4H), 2.17 - 2.24 (m, 2H), 1.89 - 2.00 (m, 2H), 1.77 - 1.85 (m, 2H), 1.29 - 1.41 (m, 2H ), 1.44 - 1.27 (m, 2H), 0.87 (s, 9H). Example 196: 1- [6- (trans 4-Cyclopentyl-cyclohexyloxy) -quinolin-2-ylmethyl] -pyrrolidine-3-carboxylic acid ESI-MS (M + H +): 423.33; 1H NMR (400 MHz, MeOD) Displacement 8.29 (d, J = 8.28 Hz, 1H), 8.01 (d, J = 9.29 Hz, 1H), 7.40 - 7.48 (m, 2H), 7.34 (d, J = 2.76 Hz, 1H), 4.77 (d, J = 6.27 Hz, 2H), 4.38 - 4.49 (m, 1H) , 3.79 (d, J = 2.51 Hz, 2H), 3.65 (br. S., 2H), 3.43 - 3.52 (m, 1H), 2.52 (da, J = 7.02.8.82 Hz, 1H), 2.43 (dt, J = 6.87, 13.62 Hz, 1H), 2.20 - 2.29 (m, 2H), 1.93 - 2 , 02 (m, 2H), 1.78 - 1.89 (m, 2H), 1.41 - 1.71 (m, 7H), 1.11 - 1.30 (m, 5H). Example 197: 1- [6- (trans 4-Cyclopentyl-cyclohexyloxy) -quinolin-2-ylmethyl] -azetidine-3-carboxylic acid ESI-MS (M + H +): 409.33; 1H NMR (400 MHz, MeOD) Displacement 8.26 (d, J = 8.53 Hz, 1H), 7.98 (d, J = 9.29 Hz, 1H), 7.41 - 7.43 (m, 1H), 7.38 - 7.41 (m, 1H), 7.32 (d, J = 2.51 Hz, 1H), 4.80 (s, 2H), 4.48 - 4, 61
+ 115/164 (m, 4H), 4.38 - 4.47 (m, 1H), 3.81 (quin, J = 8.35 Hz, 1H), 2.20 - 2.28 (m, 2H ), 1.93 - 2.01 (m, 2H), 1.79 - 1.88 (m, 2H), 1.40 - 1.71 (m, 7H), 1.12 - 1.29 (m , 5H). Example 198: 3 - ([6- (trans 4-Cyclopentyl-cyclohexyloxy) - quinolin-2-ylmethyl] -amino) -propionic acid ESI-MS (M + H +): 397.01; 1H NMR (400 MHz, MeOD) Displacement 8.27 (d, J = 8.28 Hz, 1H), 7.99 (d, J = 9.29 Hz, 1H), 7.44 (d, J = 8.53 Hz, 1H), 7.41 (dd, J = 2.76, 9.29 Hz, 1H), 7.32 (d, J = 2.76 Hz, 1H), 4.56 (s , 2H), 4.38 - 4.47 (m, 1H), 3.47 (t, J = 6.65 Hz, 2H), 2.88 (t, J = 6.78 Hz, 2H), 2 , 20-2.28 (m, 2H), 1.93-2.00 (m, 2H), 1.78 - 1.88 (m, 2H), 1.40 - 1.71 (m, á 8H ), 1.11 - 1.29 (m, 5H). - Example 199: 1-f6- [trans 4- (1,1-Dimethyl-propyl) -cyclohexyloxy-quinolin-2-imethyl) -pyrrolidine-3-carboxylic acid 'ESI-MS (M + H +): 425 , 31; 1H NMR (400 MHz, MeOD) Displacement 8.29 (d, J = 8.28 Hz, 1H), 8.01 (d, J = 9.29 Hz, 1H), 7.40 - 7.47 (m, 2H), 7.34 (d, J = 2.76 Hz, 1H), 4.77 (d, J = 6.02 Hz, 2H), 4.36 - 4.46 (m, 1H) , 3.73 - 3.93 (m, 2H), 3.65 (br, s ,, 2H), 3.42 - 3.53 (m, 1H), 2.36 - 2.59 (m, 2H ), 2.26 - 2.34 (m, 2H), 1.83 - 1.93 (m, 2H), 1.40 - 1.52 (m, 2H), 1.23 - 1.39 (m , 5H), 0.82 - 0.91 (m, 9H). Example 200: 1-f6- [trans 4- (1,1-Dimethyl-propyl) -cyclohexyloxy-quinolin-2-ylmethyl) -azetidine-3-carboxylic acid ESI-MS (M + H +): 411.32 ; 1H NMR (400 MHz, MeOD) Displacement 8.26 (d, J = 8.28 Hz, 1H), 7.97 (d, J = 9.29 Hz, 1H), 7.41 - 7.43 (m, 1H), 7.37 - 7.40 (m, 1H), 7.32 (d, J = 2.51 Hz, 1H), 4.80 (s, 2H), 4.48 - 4, 60 (m, 4H) 4.35 -4.44 (Mm, 1H), 3.81 (quin, J = 8.35 Hz, 1H), 2.25 - 2.34 (m, 2H), 1, 84 - 1.92 (m, 2H), 1.23 - 1.51 (m, 7H), 0.82 - 0.91 (m, 9H). Example 201: 3- (f6- [trans 4- (1,1-Dimethyl-propyl) -cyclohexyloxy-quinolin-2-ylmethyl) -amino) -propionic acid ESI-MS (M + H +): 399.32 ; 1H NMR (400 MHz, MeOD) Displacement 8.27 (d, J = 8.28Hz, 1H), 7.98 (d, J = 9.29Hz, 1H), 7.44 (d J = 8, 53 Hz, 1H), 7.40 (dd, J = 2.76, 9.29 Hz, 1H), 7.32 (d, J = 2.76 Hz, 1H), 4.56 (s, 2H) , 4.35 - 4.44 (m, 1H), 3.46 (t, J = 6.78 Hz, 2H), 2.88 (t, J = 6.78 Hz, 2H),
-> 116/164 2.26 - 2.33 (m, 2H), 1.84 - 1.91 (m, 2H), 1.38 - 1.51 (m, 2H), 1.23 - 1, 38 (m, 5H), 0.82 - 0.90 (m, 10H). Example 202: (18.2R) -2 - ([6- (trans 4-tert-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -amino) -cyclohexanecarboxylic acid ESI-MS (M + H +) : 439.35; 1H NMR (400 MHz, MeOD) Displacement 8.28 (d, J = 8.28 Hz, 1H), 7.99 (d, J = 9.04 Hz, 1H), 7.46 (d, J = 8.28 Hz, 1H), 7.42 (dd, J = 2.76, 9.29 Hz, 1H), 7.34 (d, J = 2.76 Hz, 1H), 4.60 (s , 2H), 4.36 - 4.45 (m, 1H), 3.50 (dt, 1H), 2.04 - 2.35 (m, 2H), 1.89 - 1.99 (m, J = 12.05 Hz, 3H), 1.59 - 1.69 (m, 2H), 1.40 - 1.53 (m, 3H), 1.14 - 1.36 (m, 3H), 0, 93 (s, 9H). . Example 203: (18,28) -24 [6- (trans-4-fer-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl] -amino) - cyclohexanecarboxylic acid ESI-MS (M + H +) : 439.36; 1H NMR (400 MHz, MeOD) Displacement - 8.29 (d, J = 8.28 Hz, 1H), 7.98 (d, J = 9.04 Hz, 1H), 7.47 (d, J = 8.53
15. Hz, / 1H), 7.41 (dd, J = 2.76.9.29 Hz, 1H), 7.34 (d, J = 2.76 Hz, 1H), 4.69 (d, J = 15.31 Hz, 1H), 4.56 (d, J = 15.31 Hz, 1H), 4.36 - 4.46 (m, 1H), 3.48 - 3.60 (m, 1H ), 2.65 - 2.75 (m, 1H), 2.26 - 2.39 (m, 4H), 1.90 - 1.99 (m, 3H), 1.86 (d, 1H), 1.36 - 1.60 (m, 5H), 1.24 - 1.36 (m, 2H), 1.17 (dt, 1H), 0.94 (s, 9H). Example 204: (18.2R) -2 ([6- (trans-4-fer-Butyl-cyclohexyloxy) -quinolin-2-ylmethyl-amino) -cyclopentanecarboxylic acid ESI-MS (M + H +): 425, 52; 1H NMR (400 MHz, MeOD) Displacement 8.26 - 8.31 (m, 1H), 7.96 - 8.02 (m, 1H), 7.43 - 7.48 (m, 1H), 7.41 (dd, J = 2.76, 9.29 Hz, 1H), 7.34 (d, J = 2.76 Hz, 1H), 4.51 - 4.66 (m, 2H), 4 , 36 - 4.46 (m, 1H), 3.82 - 4.13 (m, 1H), 2.22 - 2.34 (m, 3H), 2.10 - 2.21 (m, 1H) , 1.89-2.06 (m, 4H), 1.74-1.85 (m, 1H), 1.39 - 1.52 (m, 2H), 1.23 - 1.36 (m, 2H), 1.11 - 1.20 (m, 1H), 0.95 (s, 9H). Example 205: 7- (trans 4-tert-butylcyclohexyloxy) -3-methylisoquinoline FO "OO PPha, DIAD Oo IDO Ho AN" o 2N Triphenyphosphine (5.14 g, 19.6 mmoles) was added to a solution
tion of 3-Methyl-isoquinolin-7-ol (2.08 g, 13.1 mmol) and cis-4-tert-butylcyclohexane! (3.06 g, 19.6 mmoles) in toluene (60 mL, 600 mmoles). The mixture was stirred for 15 minutes, then Diisopropyl azodicarboxylate (3.86 ml, 19.6 mmol) was added.
The mixture was then stirred at room temperature overnight.
The solvent was removed in vacuo.
The crude product was dissolved in methylene chloride, absorbed on silica gel and purified by flash chromatography (0-30% EtOAc in hexanes) to provide the title compound in 52% yield.
ESI-MS (M + H +): 298.46. Example 206: 7- (trans-4-tert-butylcyclohexyloxy) isoquinoline-3-carbaldehyde: E TI TBHP, SeO, ÀS To o. “O N“ o 2N Selenium dioxide (2.25 g, 20.3 mmoles) was added to a solution of 7- (trans-4-tert-Butyl-cyclohexyloxy) -3-methyl-isoquinoline (2 , 01 g, 6.76 mmoles) in diphenyl ether (50 mL, 300 mmoles) and the mixture was heated to 200ºC in a sealed tube for 4 hours.
The reaction was then cooled to room temperature.
Silica gel was added and the flask was placed in a cold water bath to solidify the diphenyl ether solvent.
This solid mixture containing the crude product was purified by flash chromatography (0-30% EtOAc in hexanes) to provide the title compound in 50% yield.
ESI-MS (M + H +): 312.27 Example 207: tert-butyl 3 - (((7- (trans-4-tert-butylcyclohexyloxy) isoquinolin-3-yl) methylamino) propanoate À In Se aBH (OAc o Triethylamine (0.07356 mL, 0.5278 mmol) was added to a solution of 7- (trans-4-tert-Butyl-cyclohexyloxy) -isoquinoline-3-carbaldehyde (0.1174 g, 0, 3770 mmol) and 3-aminopropionic acid ethyl ester of HCl salt; (0.08107g, 0.5278 mmol) in 1,2-Dichloroethane (5.00 mL, 63.5 mmol) and the mixture was stirred for 1 hour at room temperature.
Sodium triacetoxyborohydride (0.1118 g, 0.5278 mmol) was then added and the mixture
. 118/164 was stirred for 2 hours.
The reaction was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate.
The organic phase was dried over MgSO;, filtered, absorbed on silica gel and purified by flash chromatography (0-5% MeOH in methylene chloride) to provide the title compound in 97% yield.
ESI-MS (M + H +): 413.35. Example 208: 3 - ((7- (trans-4-fer-butylcyclohexyloxy) i -soquinolin-3-yl) methylamino) propanoic acid EA NOAH OO os CA ASA E Oo 2 M lithium hydroxide, mono- hydrate in water (1.00 mL, 2.00 E mmoles) were added to a solution of ethyl ester of 3-f [7- (trans- - 10 4tert-Butyl-cyclohexyloxy) -isoquinolin-3-ylmethyl acid ] -amino) -propionic (0.1505 9, 0.3648 mmol) in Tetrahydrofuran (1.00 mL, 12.3 mmol) and Methanol (1.00 mL, 24.7 mmol). The mixture was stirred for 2 hours.
The solvent was then evaporated under reduced pressure.
The resulting residue was dissolved in methylene chloride and washed with a 1 M hydrogen chloride solution in water (1.999 mL, 1.999 mmol). The organic layer was then concentrated to dryness under reduced pressure.
The crude product was dissolved in DMSO and purified by HPLC to provide the title compound as a bis-TFA salt.
ESI-MS (M + H +): 385.51 [M + 1]. 1H NMR (400 MHz, MeOD) Displacement 9.22 (s, 1H), 7.86 (d, J = 9.04 Hz, 1H), 7.82 (s, 1H), 7.50 (d , J = 2.51 Hz, 1H), 7.43 (dd, J = 2.51.9.04 Hz, 1H), 4.46 (s, 2H), 4.40 - 4.46 (m, 1H), 3.37 (t, J = 6.65 Hz, 2H), 2.81 (t, J = 6.78 Hz, 2H), 2.25 - 2.34 (m, 2H), 1, 89 - 1.98 (m, 2H), 1.40 - 1.52 (m, 2H), 1.24 - 1.37 (m, 2H), 1.10 - 1.20 (m, 1H), 0.90 - 0.95 (m, 9H). The following compounds were synthesized as 3 - ((7- (trans4-tert-butylcyclohexyloxy) isoquinolin-3-yl) methylamino) propanoic acid using the appropriate cyclohexanols and aminoesters: Example 209: Acid 1- [7 - (trans-4-fer-Butyl-cyclohexyloxy) - isoquinolin-3-ylmethyl] -pyrrolidine-3-carboxylic ESI-MS (M + H +): 411.33; 1H NMR (400 MHz, MeOD) Displacement 9.23 (s, 1H), 7.87 (d, J = 9.04 Hz, 1H), 7.83 (s, 1H), 7.51 (d , J = 2.26
- 119/164 p Hz, 1H), 7.44 (dd, J = 2.51, 8.78 Hz, 1H), 4.56 - 4.68 (m, 2H), 4.39 - 4.49 (m, 1H), 3.61 - 3.78 (m, 2H), 3.52 (t, J = 7.28 Hz, 2H), 3.37 - 3.47 (m, 1H), 2, 33 - 2.52 (m, 2H), 2.25 - 2.33 (m, 2H), 1.88 - 1.97 (m, 2H), 1.39 - 1.51 (m, 2H), 1.23 - 1.35 (m, 2H), 1.09 - 1.18 (m, 1H), 0.91 (s, 9H). Example 210: 1- [7- (trans-4-fer-Butyl-cyclohexyloxy) -isoquinolin-3-ylmethyl] -azetidine-3-carboxylic acid ESI-MS (M + H +): 397.32; 1H NMR (400 MHz, MeOD) Displacement 9.20 (s, 1H), 7.87 (d, J = 9.04 Hz, 1H), 7.80 (s, 1H), 7.50 (d , J = 2.51 Hz, 1H), 7.44 (dd, J = 2.51, 9.04 Hz, 1H), 4.65 (s, 2H), 4.39 - 4.50 (m, 5H), 3.70-3.81 (m, 1H), 2.26-2.35 (m, 2H), 1.90 - 1.99 (m, 2H), 1.41 - 1.53 ( m, '2H), 1.30 (qd, 2H), 1.09 - 1.21 (m, J = 2.54, 2.54, 11.48 Hz, 1H), 0.93 (s, 9H ). Example 211: 1- [7- (trans-4-Cyclopentyl-cyclohexyloxy) -isoquinolin-3-ylmethyl] -pyrrolidine-3-carboxylic acid F ESI-MS (M + H +): 423.28; 1H NMR (400 MHz, MeOD) Displacement 9.24 (s, 1H), 7.88 (d, J = 9.04 Hz, 1H), 7.84 (s, 1H), 7.51 (d , J = 2.26 Hz, 1H), 7.45 (dd, J = 2.38, 8.91 Hz, 1H), 4.59 - 4.69 (m, 2H), 4.43 - 4, 54 (m, 1H), 3.63 - 3.79 (m, 2H), 3.53 (t, J = 7.28 Hz, 2H), 3.38 - 3.48 (m, 1H), 2 , 32 - 2.54 (m, 2H), 2.21 - 2.29 (m, 2H), 1.93 - 2.02 (m, 2H), 1.79 - 1.88 (m, 2H) , 1.42 -1.71 (m, 6H), 1.11 - 1.31 (m, 6H). Example 212: 1- [7- (trans-4-Cyclopentyl-cyclohexyloxy) -isoquinolin-3-ylmethyl] -azetidine-3-carboxylic acid ESI-MS (M + H +): 409.29; 1H NMR (400 MHz, MeOD) Displacement 9.20 (s, 1H), 7.87 (d, J = 9.04 Hz, 1H), 7.80 (s, 1H), 7.49 (d , J = 2.26 Hz, 1H), 7.44 (dd, J = 2.38, 8.91 Hz, 1H), 4.65 (s, 2H), 4.39 - 4.52 (m, 5H), 3.70-3.81 (m, 1H), 2.25 (dd, J = 3.64, 13.18 Hz, 2H), 1.93 - 2.01 (m, 2H), 1 , 78 - 1.88 (m, 2H), 1.41 - 1.71 (m, 7H), 1.11 - 1.31 (m, 5H). Example 213: 34 [7- (trans-4-Cyclopentyl-cyclohexyloxy) - isoquinolin-3-ylmethyl] -amino) -propionic acid ESI-MS (M + H +): 397.29; 1H NMR (400 MHz, MeOD) Displacement 9.23 (s, 1H), 7.87 (d, J = 8.78Hz, 1H), 7.82 (s, 1H), 7.50 (d, J = 2.26 Hz, 1H), 7.44 (dd, J = 2.51, 9.04 Hz, 1H), 4.43 - 4.53 (m, 3H), 3.35 - 3.41 (m, 2H), 2.82 (t, J = 6.65 Hz, 2H), 2.21 - 2.30 (m, 2H), 1.93 - 2.02 (m, 2H), 1, 80 -
1.80 (m, OH), 1.79 - 1.88 (m, J = 6.02 Hz, 2H), 1.41 - 1.71 (m, 7H), 1.02 - 1.30 ( m, 5H). Example 214: 1- (7- (trans-4-fer-pentylcyclohexyloxy) isoquinolin-3-yl) methyl) pyrrolidine-3-carboxylic acid ESI-MS (M + H +): 425.31; 1H NMR (400 MHz, MeOD) Displacement 9.23 (s, 1H), 7.86 (d, J = 9.04 Hz, 1H), 7.83 (s, 1H), 7.50 (d , J = 2.26 'Hz, 1H), 7.43 (dd, J = 2.38, 8.91 Hz, 1H), 4.57 - 4.67 (m, 2H), 4.38 - 4.49 (m, 1H), 3.61 - 3.78 (m, 2H), 3.52 (t, J = 7.28 Hz, 2H), 3.37 - 3.46 (m, 1H), 2, 25 - 2.52 (m, 4H), 1.83 - 1.91 (m, 2H), 1.38 - 1.51 (m, 2H), 1.20 - 1.38 (m, 5H), 0.81-0.89 (m, 9H) Ô Example 215: 1- (7- (trans-4-fer-pentylcyclohexyloxy) ss isoquinolin-3-yl) methyl) -azetidine-3-carboxylic acid MS (M + H +): 411.31; 1H NMR (400 MHz, MeOD) Displacement 9.20 (s, 1H), 7.86 (d, J = 9.04 Hz, 1H), 7.80 (s, 1H), 7.49 (d, J = 2.26 Hz, 1H), 7.43 (dd, J = 2.51.9.04 Hz, 1H), 4.65 (s, 2H), 4.39 - 4.49 (m, 5H), 3 , 70 - 3.80 (m, 1H), 2.26 - 2.34 (m, J = 11.04 Hz, 2H), 1.84 - 1.92 (m, 2H), 1.39 - 1 , 51 (m, 2H), 1.21 - 1.39 (m, 5H), 0.83 - 0.90 (m, 9H). Example 216: 3 - ((7- (trans-4-fer-pentylcyclohexyloxy) isoquinolin-3-yl) methylamino) propanoic acid ESI-MS (M + H +): 399.33; 1H NMR (400 MHz, MeOD) Displacement 9.22 (s, 1H), 7.86 (d, J = 8.78 Hz, 1H), 7.82 (s, 1H), 7.50 (d , J = 2.51 Hz, 1H), 7.43 (dd, J = 2.51, 9.04 Hz, 1H), 4.46 (s, 2H), 4.39 - 4.45 (m, 1H), 3.37 (t, J = 6.65 Hz, 2H), 2.81 (t, J = 6.65 Hz, 2H), 2.26 - 2.34 (m, J = 2.76 , 13.05 Hz, 2H), 1.83 - 1.91 (m, 2H), 1.39 - 1.51 (m, J = 11.63, 11.63, 11.63 Hz 2H), 1 , 20-1.38 (m, 5H), 0.82-0.90 (m, 9H). Example 217: 6-bromo-2- (trans-4-tert-butylcyclohexyloxy) -1- (trifluormethyl) naphthalene * o Br nBuLi Oo 3 From DMF, THF "o CO
FÓTE FE 6-bromo-2- (trans-4-tert-butylcyclohexyloxy) -1- (trifluormethyl) naphthalene (2.58 g, 6.01 mmoles) was dissolved in Tetra-
hydrofuran (100 mL, 1000 mmoles) and cooled to -78 ºC in an acetone / dry ice bath. 1.6 M n-Butyllithium in Hexane (7.512 mL, 12.02 mmol) was added slowly and the mixture was stirred for 30 minutes. NN- Dimethylformamide (1.396 mL, 18.03 mmoles) was then added slowly and the mixture was allowed to reach room temperature. The reaction mixture was purged in 1 N HCl and extracted with ethyl acetate. The combined organic phase was washed with saturated aqueous sodium bicarbonate solution, brine, then dried over MgSOSO, filtered, concentrated and purified by flash chromatography (0-20% EtOAc in hexanes) to provide the title compound in 80% yield. ESI-MS (M + H +): 379.41 | Example 218: 2 - ([6- (trans-4-tert-Butyl-cyclohexyloxy) -5-trifluormethyl-naphthalen-2-ylmethyl] -amino) -ethanesulfonic acid - o: O. ABL GOO Go o F EE “o F
FA FE Taurine (0.03737 g, 0.2986 mmol) was added to a solution of 6- (trans-4-fer-butylcyclohexyloxy) -5- (trifluoromethyl) -2-naphthaldehyde (0.1130 g, 0 , 2986 mmol) in ethanol (3.00 mL, 51.4 mmol) and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature and sodium cyanoborohydride (0.02252 g, 0.3583 mmol) was added. The mixture was then refluxed overnight. The reaction mixture was cooled to room temperature, washed with saturated aqueous citric acid solution (4 ml), then concentrated to dryness under reduced pressure. The resulting solid was washed with water and filtered. The residue was washed with water (10 ml), ether (10 ml) and hexane (10 ml) consecutively, then filtered. The residue was purified by preparative HPLC to provide the title compound. ESI-MS (M + H +): 488.3; 1H NMR (400 MHz, DMSO-d6) Displacement 8.46 - 8.52 (m, 1H), 7.83-7.88 (m, 1H), 7.73 -7.80 (m, 2H), 7.35 - 7.40 (m, 2H), 4.21 - 4.30 (m, 1H), 4.02 (br, s ,, 2H), 2.88 (t, J = 6.78 Hz , 2H), 2.50 (d, J = 13.80 Hz, 2H), 1.77 - 1.85 (m, 2H), 1.43 - 1.52 (m, 2H), 1.00 - 1.43 (m, 2H), 0.67 - 0.92 (m, 3H), 0.53 (s, 9H). The following compound was synthesized as 2-f [6- (trans-4-
tert-Butyl-cyclohexyloxy) -5-trifluormethyl-naphthalen-2-ylmethyl) -amino) - ethanosuifonic using the appropriate aminosulfone:
Example 219: [6- (trans-4-tert-Butyl-cyclohexyloxy) -5-trifluormethyl-naphthalen-2-ylmethyl] - (2-methanesulfonyl-ethyl) -amine ESI-MS (M + H +): 486.52 ; 1H NMR (400 MHz, MeOD) Displacement 8.13 (dd, J = 1.88, 8.91 Hz, 1H), 8.03 (d, J = 9.29 Hz, 1H), 7.83 (d J = 1.51 Hz, 1H), 7.58 (dd, J = 2.01, 9.04 Hz, 1H), 7.49 (d, J = 9.04 Hz, 1H), 4, 39 - 4.49 (m, 1H), 3.96 (s, 2H), 3.36 (d, J = 7.78 Hz, 2H), 3.13 (t, J = 6.27 Hz, 2H ), 3.04 (s, 3H), 2.17 - 2.26 (m, 2H), 1.87 - 1.95 (m, 2H), 1.43 - 1.56 (m, 2H), 1.06-1.30 (m, 3H), 0.90 (s, 9H). f Example 220: 24 [6- (trans-4-tert-Butyl-cyclohexyloxy) - "naphthalen-2-ylmethyl]) - amino) -ethanesulfonic acid at and at O.
ARO “oH A solution of 6- (trans-4-fer-butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (0.1662 g, 0.5354 mmol) and Taurine (0.06700 g, 0.5354 mmol ) in anhydrous ethanol (4.00 mL, 68.5 mmoles) was refluxed for 2 hours.
The mixture was cooled to room temperature and sodium cyanoborohydride (0.04037 g, 0.68425 mmol) was added.
The mixture was then refluxed overnight.
The reaction mixture was cooled to room temperature and washed with saturated aqueous citric acid (4 ml). The mixture was then concentrated to dryness under reduced pressure.
The resulting solid was suspended in water and filtered.
The residue was washed with water, air-dried and purified by preparative H-PLC to provide the title compound.
ESI-MS (M + H +): 420.34; 1H NMR (400 MHz, DMSO-d6) Displacement 8.68 (br, s ,, 1H), 7.84 (br, s ,, 1H), 7.73 - 7.81 (m, 2H), 7, 45 (dd, J = 1.76, 8.53 Hz, 1H), 7.32 - 7.35 (m, 1H) 7.12 (dd, J = 2.51.8.78 Hz, 1H), 4.29 - 4.38 (m, 1H), 4.24 (br, s ,, 2H), 3.13 (d, J = 13.80 Hz, 2H), 2.76 (d, J = 13 , 55 Hz, 2H), 2.10 - 2.48 (m, 2H), 1.72 - 1.80 (m, 2H), 1.23 - 1.36 (m, 2H), 1.09 - 1.22 (m, 2H), 0.96 - 1.06 (m, 1H), 0.81 (s, 9H) The following compounds were synthesized as 2-f / 6- (trans4-fer-butyl- cyclohexyloxy) -naphthalen-2-ylmethyl) -amino) -ethanesulfonic using the appropriate amines: Example 221: 3-f [6- (trans-4-fer-Butyl-cyclohexyloxy) acid - naphthalen-2-ylmethyl ] -amino) -propane-1-sulfonic ESI-MS (M + H +): 434.44; 1H NMR (400 MHz, MeOD) Displacement7.90 (br.s., 1H), 7.85 (d, J = 8.53 Hz, 1H), 7.81 (d, J = 9.04 Hz , 1H), 7.51 (dd, J = 1.76, 8.53 Hz, 1H), 7.29 (d, J = 2.26 Hz, 1H), 7.18 (dd, J = 2, 51, 9.04 Hz, 1H), 4.34 - 4.43 (m, 1H), 4.33 (s, 2H), 2.96 (t, J = 6.65 Hz, 2H), 2, 25 - 2.33 (m, 2H), 2.19 (quin, J = 6.90 Hz, 2H), 1.89 - 1.97 (m, 2H), 1.38 - 1.50 (m, 2H), 1.23 - 1.35 (m, 2H), 1.08 - 1.19 (m, 1H), 0.92 (s, 9H). Example 222: N- (24 [6- (trans-4-tert-Butyl-cyclohexyloxy) - - naphthalen-2-ylmethyl] -amino) -ethyl) - 4-trifluormethyl-benzenesulfonamide ESI-MS (M + H + ): 563.50; 1H NMR (400 MHz, DMSO-d6) De- and location 7.91 - 8.00 (m, 5H), 7.69 - 7.75 (m, 3H), 7.62 - 7.66 (m, 1H) , 7.30 - 7.38 (m, 3H), 7.08 - 7.13 (m, 1H), 4.30 - 4.40 (m, 1H), 3.70 - 3.75 (m, 2H), 2.90 (tJ = 6.53Hz, 2H), 2.15-2.23 (m, 2H), 1.77 - 1.85 (m, 2H), 1.28 - 1.40 ( m, 2H), 1.15 - 1.27 (m, 2H), 1.02 - 1.42 (m, 1H), 0.87 (s, 9H). Example 223: 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) -4-methylpyrrolidine-3-carboxylic acid F un P o “DSO LLSHÁ f-. NaCNBH ;, »- iPraNEt, DCE A solution of 6- (4-fer-butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (140 mg, 0.46 mmol) and 4-methylpyrrolidine-3-carboxylic acid (60 , 1 mg, 0.465 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 hours.
The yellow solution was cooled to room temperature and sodium cyanoborohydride (35.1 mg, 0.558 mmol) was added and was heated to reflux for 1 hour.
After cooling to room temperature, DCM, water and citric acid were added together with some brine to clean the layers.
Concentration of the cloudy organic layer gave the precipitate which was dissolved in methane! and filtered before purification by preparative HPLC. 'H NMR (400 MHz, DMSO-ds) 5 7.81 - 7.98 (m, 3H), 7.53 (d, J = 7.28 Hz, 1H), 7.42 (d, J = 2 , 26 Hz, 1H), 7.17 - 7.25 (m, J = 2.38, 8.91 Hz,
1H), 4.34 - 4.55 (m, 3H), 3.61 (br, s ,, 2H), 3.05 (br, s ,, 1H), 2.94 (d, J = 5, 52 Hz, 1H), 2.63 - 2.80 (m, 1H), 2.21 (d, J = 10.54 Hz, 2H), 1.83 (d, J = 12.05 Hz, 2H) , 1.29 - 1.43 (m, 2H), 1.19 - 1.28 (m, 2H), 1.02 - 1.18 (m, 5H), 0.88 (s, 9H) [M +1] 424.30.
The procedure used for 1 - ((6 - ((1r, 4r) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) -4-methylpyrrolidine-3-carboxylic acid was used with the appropriate amine for do the following: Example 224: N- (3 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl) methylamino) propyl) methanesulfonamide 1H NMR (400 MHz, DMSO-ds) 5 7.79 - 8.01 (m, 3H), 7.48 - 7.57 Á (m, 1H), 7.42 (d, J = 2.01 Hz, 1H), 7.21 (dd, J = 2.26, 9.04 Hz, 1H), 4.34 -. 4.55 (m, 2H), 3.92 - 4.02 (m, 1H), 3.55 - 3.76 (m, 1H), 2.93 - 3.12 (m, 2H), 2, 77 - 2.90 (m, 1H), 2.21 (d, Jy = 10.54 Hz, 2H), 1.60 - 1.94 (m, 6H), 1.15 - B 1.43 (m , 3H), 1.01 - 1.14 (m, 1H), 0.88 (s, 9H) [M + 1] 447.30 Example 225: Acid 2 - ((6 - ((trans) -4-tert- butylcyclohexyloxy) naphthalen-2-yl)] Mmethyl) octahidrocyclopenta [c] pyrrole-3a-carboxylic 1H NMR (400 MHz, DMSO-ds) 5 7.80 - 7.98 (m, 3H), 7.49 - 7.58 (m, 1H), 7.42 (d, J = 2.01 Hz, 1H), 7.21 (dd, J = 2.26, 9.04 Hz, 1H), 4.36 - 4 , 54 (m, 3H), 3.92 - 4.00 (m, 1H), 3.57 - 3.66 (m, 1H), 2.93 - 3.11 (m, 2H), 2.77 -2.89 (m, 1H), 2.21 (d, J = 10.54 Hz, 2H), 1.72 - 1.95 (m, 5H), 1.66 (br, s ,, 2H) , 1.29 - 1.44 (m, 3H), 1.14 - 1.28 (m, 3H), 1.10 (d, J = 11.55 Hz, 1H), 0.88 (s, 9H ) [M + 1] 450.30. Example 226: 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methyl) -4,4-dimethylpyrrolidine-3-carboxylic acid [M + 1] 438.30 . Example 227: 1 - ((6 - ((trans) -4-tert-butylcyclohexyloxy) naphthalen-2-yl)] Mmethyl) -3-methylpyrrolidine-3-carboxylic acid 1H NMR (400 MHz, DMSO-d6) Displacement 7.93 (s, 1H), 7.85 (t, Jy = 9.54 Hz, 2H), 7.54 (d, Jy = 8.03 Hz, 1H), 7.41 (d, J = 2.01 Hz, 1H), 7.20 (dd, J = 2.38 8.91Hz, 1H), 4.34 -4.50 (m, 2H), 2.21 (d, J = 9.79 Hz, 2H), 1.82 (d, J = 12.30 Hz, 2H), 1.29 - 1.43 (m, 6H), 1.14 - 1.28 (m, 2H), 1.10 (d, J = 11.80 Hz, 1H), 0.88 (s, 9H) [M + 1] 424.3.
Example 228: 2 - (((6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) ethanesulfonamide 1H NMR (400 MHz, CHLOROPHORM) d 7.75 - 7.93 (m, 3H), 7.49 (d, J = 8.03 Hz, 1H), 7.28 (br. s, 1H), 7.17 (d, J = 8.78 Hz, 1H), 4 , 40 (br.
s 3H) 3.52 (d, J = 4.02 Hz, 4H), 2.27 (d, J = 10.79 Hz, 2H), 1.91 (d J = 11.55 Hz, 2H), 1.34 - 1.50 (m, 2H), 1.27 (d, J = 12.55 Hz, 2H), 1.07 - 1.48 (m, 1H), 0.85 - 0.96 ( m, 9H) [M + 1] 441.3. Example - 229: Acid - 3- (3- (6 - ((trans) -4-fer-butylcyclohexyloxy) naphthalen-2-yl) oxetan-3-ylamino) propanoic 1.EtOH, reflux NE. - AOL TI Po oo CO 2 CO 9 "THF To a mixture of 3- [6- (4-fer-butyl-cyclohexyloxy) -naphthalen-2-yl] -: oxetan-3-ylamine (70 mg , 0.2 mmol) and methyl acrylate (21 mg, 0.25 mmol) in ethanol (1.0 mL, 17 mmol) was heated to reflux for 2 days LCMS monitoring shows 1: 1 starting material / product, new peak of 1.63 min (m / z 440.30 [M + 1], 20%). After concentration and HPLC provided the product as a solid (18mg, 20%). 1H NMR (400MHz, MeOD) d = 7.91 (dy J = 8.7 Hz, 1 H), 7.87 (s, 1 H), 7.84 (d, J = 9.0 Hz, 1 H), 7.38 (dd, J = 2.0, 8.6 Hz, 1H), 7.30 (d, J = 2.3 Hz, 1 H), 7.20 (dd, J = 2.4, 9.0 Hz , 1 H), 5.26 (d, J = 8.4 Hz, 2 H), 5.43 (d, J = 8.5 Hz, 2 H), 4.43 - 4.31 (m, 1 H), 3.68 (s, 3 H), 3.08 (t, J = 6.3 Hz, 2H), 2.70 (t J = 6.3 Hz, 2 H), 2.27 (d , J = 10.4 Hz, 2 H), 1.91 (d, J = 13.0 Hz, 2H), 1.42 (q, J = 12.9 Hz, 2H), 1.32 - 1.19 (m, 2H), 1.17 - 1.04 (m, 1 H), 0.91 (s, 9 H).
A solution of 3- (3- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] -oxetan-3-ylamino) -propionic acid methyl ester (18.0 mg, 0, 0409 mmol) and lithium hydroxide (6.41 mg, 0.268 mmol) in tetrahydrofuran (0.6 mL, 8 mmoles) and water (0.2 mL, 9 mmoles) was stirred at room temperature overnight . LCMS showed a single desired product peak M + Na at m / z 448.20, room temperature 1.56 min. The solvent was concentrated and neutralized with citric acid and concentrated and purified on HPLC to provide the product (5.8 mg, 33%). 1H NMR (400MHz, MeOD) d = 7.91 (dy J =
8.4 Hz, 1 H), 7.87 (s, 1 H), 7.83 (d, J = 8.9 Hz, 1 H), 7.38 (d, J = 8.2 Hz, 1 H), 7.31 (s, 1 H), 7.20 (d, J = 6.8 Hz, 1 H), 5.26 (d, J = 7.9 Hz, 2H), 513 (d, J = 7.7 Hz, 2 H), 4.43 - 4.32 (m, 1 H), 3.05 (t, J = 5.1 Hz, 2 H), 2.70 - 2.62 ( m, 2 H), 2.27 (d, J = 11.2 Hz, 2 H), 1.96 - 1.85 (m, 2 H), 1.50 - 1.35 (m, 2 H) , 1.34 -1.18 (m, 2H), 1.17-1.04 (m, 1H), 0.91 (s, 9H).
Example 230: 1- (6 - ((trans) -4-fer-butylcyclohexyloxy) quinolin-2-yl) ethanone "o A 2. Dess-Martin" o D IS 6- (trans-4-tert-butylcyclo -hexyloxy) quinoline-2-carbaldehyde (1.63 g, 5.23 mmol) was dissolved in ether (17 mL, 160 mmol). At 0 ºC, 3.0 M of - 10 methylmagnesium bromide in diethyl ether (2.62 mL, 7.85 mmol) was added. And, after 2 hours at room temperature, Rochelle salt was added. The reaction mixture was stirred and extracted with EtOAc. LCMS showed a single peak. LCMS Rf = 1.47 min, m / z 328.20 ([M + 1], 100%). MeOH / DCM CC provided the product (1.739, 100%). 1H NMR (400MHz CHLORINE-FORUM-d) d = 8.03 (d, J = 8.5Hz, 1H), 7.97 (d, J = 9.1 Hz, 1 H), 7.37 (dd, J = 2.8,9.2 Hz, 1 H), 7.30 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 2.7 Hz, 1 H), 5 , 08 - 4.89 (m, 2 H), 4.33 - 4.21 (m, 1 H), 2.28 (d, J = 14.5 Hz, 2 H), 1.92 (d, J = 11.1 Hz, 2H), 1.57 (d, J = 6.4 Hz, 3 H), 1.53 - 1.36 (m, 1 H), 1.30 - 1.01 (m , 4 H), 0.91 (s, 9 H).
1- [6- (4-tert-Butyl-cyclohexyloxy) -quinolin-2-yl) -ethanol (1.40 g, 4.28 mmol) in methylene chloride (24.5 mL, 382 mmol) was Dess-Martin periodinane (3.2 g, 7.8 mmoles) was added and stirred at room temperature for 1 hour. After passing through the silica gel pad, the solvent was concentrated to provide the product as an oil (1.29 g, 93%).
LCMS2.28min / z 326.20 ([M + 11.100%).
Example 231: methyl 1- (1- (6 - ((trans) -4-tert-butylcyclohexyloxy) quinolin-2-yl) ethyl) azetidine-3-carboxylate NaBH (OAc) 3 ALII o ICN moon o " O pray ooo
1- [6- (4-tert-Butyl-cyclohexyloxy) -quinolin-2-yl - ethanone (688 mo, 0.00021 mol) and azetidine-3-carboxylic acid methyl ester (23.9 mg, 0.000207 mol) were dissolved in ethanol (0.50 mL, 0.0086 mol) and heated to reflux for 2 hours.
After cooling to room temperature, sodium cyanoborohydride (32.4 mg, 0.000516 mol) was added and heated to reflux for 1 hour.
After cooling to room temperature and concentration, the mixture was dissolved in DCM and quenched with NEt; 3 and concentrated.
The residue was chromatographed with MeOH / CH2 Cl, to provide the product (57.2 mg, 65%). LCMS 1.66 min, at m / z 425.30 ([M + 1], 100%). : Example 232: 1- (1- (6 - ((trans) -4-tert-butylcyclo- ”hexyloxy) quinolin-2-yl) ethyl) azetidine-3-carboxylic acid LiOoH o
A solution of 1- (1- [6- (4-tert-Butyl-cyclohexyloxy) -quinolin-2-yl] -ethyl) -azetidine-3-carboxylic acid methyl ester (57.2 mg, 0.135 mmol ) and lithium hydroxide (20.9 mg, 0.874 mmol) in Tetrahydrofuran (2 mL, 20 mmol) and water (0.5 mL, 30 mmol) was stirred at room temperature overnight.
LCMS showed a single desired product peak, room temperature, 1.60 min M + 1 at m / z 413.30, 100%. The solvent was concentrated and neutralized with citric acid and concentrated and purified on HPLC to provide the product (26.2 ma, 37%). 1H NMR (300MHz, MeOD) d = 8.25 (d, J = 8.3 Hz, 1 H), 7.94 (d, J = 9.4 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.37 (dd, J = 2.6.9.1 Hz, 1 H), 7.28 (d, J = 3.0 Hz, 1 H), 4, 54 - 4.43 (m, 2 H), 4.42 - 4.18 (m, 3 H), 3.78 - 3.59 (m, 1 H), 2.25 (d, J = 10, 2 Hz, 2 H), 1.89 (d, J = 11.3 Hz,
2H), 1.57 (d, J = 6.8 Hz, 3 H), 1.51 - 0.99 (m, 6 H), 0.89 (s, 9 H). Example 233: (R, Z) -N- (1- (6 - ((trans) -4-tert-butylcyclo-
hexyloxy) quinolin-2-yl) ethylidene) -2-methylpropane-2-sulfinamide
Ti (OEY4 “o ZÉ“ o É x
To the solution of 1- [6- (4-fer-Butyl-cyclohexyloxy) -quinolin-2-yl] -
ethanone (0.2227 g, 0.0006843 mol) and (s) - (-) - 2-Methyl-2-propanesulfinamide (0.0829 g, 0.000684 mol) in Methylene chloride (1.4 mL, 0.021 mol) Ti (OEt) 4 (0.488 mL, 0.00171 mol) was added. The reaction was stirred at room temperature for 1 day. The mixture was then cooled to O “C, an equal volume of brine was added, filtered through celite, and extracted with EtOAc. After drying under Na> SO, the residue was chromatographed at 0-50%, EA / HE provided the product (132 mg, 45%). LCMS 2.39 min. m / z 429.30 ([M + 1], 100%). Example 234: 2- (6 - ((trans) -4-tert-butylcyclohexyloxy) quinolin-2-yl) propan-2-amine
1. MeMgBr, PhMe. * J LS 2. 4M HCI, dioxane o) [E 7 A ÇÃ8 », DP ooo K o A a solution of (S) -2-Methyl-propane-2-sulfinic acid [1- [6- (4- tert-Butyl-cyclohexyloxy) -quinolin-2-yl] -et- (E) -ylidene] -amide (132.2 mg, 0.3084 mmol) in toluene (1.0 mL, 9.4 mmol) at -25 ° C under N2, MeMgBr (3M ether solution, 0.41 mL / g 3, 4 equiv) was added dropwise. The reaction mixture was stirred at - -20 ° C for 15 minutes. TLC indicated a complete reaction. The reaction mixture was quenched by the addition of saturated NHA4CI to 0ºC. The cooled mixture was diluted with E-tOAc. The aqueous layer was removed. The organic layer was washed with brine and dried over Na7zSO4. The dehydrator was removed and the dried solution was concentrated in vacuo to a residue, which was chromatographed to provide the product (76.3 mg, 56%). LCMS 1.82 min m / z 445.30 ([M + 1], 100%).
2-Methyl-propane-2-sulfinic acid, (1- [6- (4-tert-Butyl-cyclohexyloxy) -quinolin-2-yl] -1-methyl-ethyl; -amide (76.3 mg, 0.172 mmol) in Methanol (1.9 mL, 48 mmol) 4.0 M hydrogen chloride in 1.4-Dioxane (0.97 mL, 3.9 mmol) was added and stirred overnight. Upon removal of the solvent, the residue was dissolved in DMSO, then HPLC provided the product as a gel (53 mg, 91%). LCMS Rf = 1.58 min m / z 341.20 ([M + 1], 100% 1H NMR (400MHz, CHLOROPHORUM-d) Displacement = 8.22 (d, J = 8.4Hz, 1H), 8.00 (d, J = 9.2Hz, 1H), 7.48 (d , J = 8.3Hz, 1
H), 7.45 (dd, J = 2.6, 9.2 Hz, 1 H), 7.15 (s, 1 H), 4.38 - 4.24 (m, 1 H), 2, 28 (d, J = 10.4 Hz, 2 H), 1.93 (d, J = 12.9 Hz, 2 H), 1.88 (s, 6 H), 1.58 - 1.40 ( m, 2 H), 1.31 - 1.01 (m, 3 H), 0.91 (s, 9 H). Example - 235: 3- (2- (6 - ((trans) -4-fer-butylcyclohexyloxy) quinolin-2-yl) propan-2-ylamino) propanoic acid “o” Ao o 2 "FE The mixture of 1- [6- (4-tert-Butyl-cyclohexyloxy) -quinolin-2-yl] -1-methyl-. Ethylamine (53.0 mg, 0.156 mmol) and methyl acrylate (0.014 mL, 0.16 mmol; Supplier = Aldrich) in ethanol (0.32 mL, 5.5 mmoles) was heated to reflux overnight. LCMS monitoring showed a new 1.60 min peak: 10 (m / z 427.30 [M +1], 20%) After concentration and cc with MeOH / DCM it provided the product as an oil (35mg, 53%).
A 3- (1- [6- (4-fer-butyl-cyclohexyloxy) -quinolin-2-yl] -1-methyl-ethylamino) -propionic acid methyl ester solution (36.0 mg, 0, 0844 mmol) and Lithium hydroxide (20.2 mg, 0.844 mmol) in Tetrahydrofuran (1 mL, 20 mmoles) and water (0.3 mL, 20 mmoles) was stirred at room temperature overnight. LCMS showed a single desired product peak, room temperature 1.57 min M + 1 at m / z 413.30, 100%. The solvent was concentrated and neutralized with citric acid and concentrated and purified on HPLC to provide the product (20 mg, 57%). 1H NMR (400MHz, CHLOROPHORUM-d) d = 8.30 (d, J = 8.7Hz, 1H), 7.97 (d, J = 9.2Hz, 1H), 7.59 (d J = 8, 7Hz, 1H), 7.39 (dd, J = 2.7, 9.2 Hz, 1 H), 7.30 (d, J = 2.5 Hz, 1 H), 4.43 - 4.28 (m, 1 H), 3.23 (t, J = 6.6 Hz, 2 H), 2.84 (t, J = 6.6 Hz, 2 H), 2.26 (d, J = 104 Hz, 2H), 1.90 (d, J = 13.6 Hz, 2H), 1.79 (s, 6 H), 1.49 - 1.32 (m, 2 H), 1.32 - 1 , 17 (m, 2H), 1.17 - 1.00 (m, 1 H), 0.90 (s, 9H). Example 236: N- (2-Formyl-4-methoxyphenyl) acetamide: & sv No NH OO makes OO 5-Methoxy-2-nitro-benzaldehyde (5.00 g, 0.0276 mol), platinum dioxide (400 mg , 0.002 mol) and sodium acetate trihydrate (300 mg, 0.002 mol) were placed in a pressure flask, followed by ethyl acetate (200 mL, 2 moles). The reaction mixture was then purged under N for at least 3 times, and H, 7 was introduced (purged 3 times) and maintained at 52 psi for 3 hours.
The reaction mixture was then filtered, and cooled to -20 ° C.
N, N-Di-isopropylethylamine (7.21 ml, 0.0414 mol) was added to the solution by acetyl chloride (2.36 ml, 0.0331 mol). The reaction mixture was allowed to stir for 2 hours, and quenched with KHCO; (sat). Organic layer was separated, and washed with water, brine and dried over Na-SO. Removal of the solvent provided a crude product, which was then purified through. chromatography (SiO2, 80 g, 0-100% ethyl acetate / hexanes; 4.28 g, 80%). * H NMR (300 MHz, CHLOROPHORM)-ppm 2.25 (s, 3 H) 3.88 (s, IS 3 H) 7.10 - 7.26 (m, 2 H) 8.69 (d, J = 9 , 06 Hz, 1 H) 9.90 (s, 1 H) 10.75 - 11.04. (m, 1 H), MS (ESI, M + 1): 194.10. Example 237: 6-Methoxy-2-methylquinazoline: o. dh - O) o AA: N- (2-Formyl-4-methoxyphenyl) acetamide (2, 2.50 g, 12.9 mmoles) was dissolved in Ethanol (300 mL, 5000 mmoles) and cooled to -78 ºC in a high pressure reactor.
A solution of NH3 saturated in ethanol was added.
The reaction mixture was then heated to 135 ° C for 2 hours.
Cooled to 23 ° C, and the solvent was removed to provide a crude product, which was then purified by chromatography (SiO ,, 120 g, 0-20% Me-OH / DCM; 1.879, 83%). * H NMR (400 MHz, CHLOROPHORM-d) δ ppm 2.91 (s, 3 H) 3.97 (s, 3 H) 7.15 (d, J = 2.51 Hz, 1 H) 7.56 (dd, J = 9.04, 2.51 Hz, 1 H) 7.93 (d, J = 9.04 Hz, 1 H) 9.27 (s, 1H), MS (ESI, M + 1) : 175.10. Example 238: 6-Methoxy-2-quinazolinylmethylaldehyde: the Ns ESRENASSA! Ns 6-Methoxy-2-methyl-quinazoline (3, 2.50 g, 14.4 mmoles) was dissolved in 1,4-Dioxane (200 mL, 3000 mmoles), followed by selenium dioxide
(11.15 g, 100.4 mmoles). The reaction mixture was then heated to 90 ° C for 12 hours.
The reaction mixture was filtered.
Solvent was removed, and the crude mixture was purified by chromatography (SiO2, 80 g, 0-100% ethyl acetate / hexanes; 1.85 g, 69%). 'H NMR (400 MHz, CHLOROPHORUM-d) δppm 4.02 (s, 3H) 7.23-7.31 (m, 1H) 7.69 (dd, J = 9.29, 2.76 Hz , 1 H) 8.16 (d, J = 9.29 Hz, 1 H) 9.49 (s, 1 H) 10.23 (s, 1 H), MS (ESI, M + 1): 189, 10. Example 239: (R) -1- (6-Methoxyquinazolin-2-ylmethyl) pyrrolidine-3-carboxylic acid methyl ester: CX - rot> ZN o 4N o - 10 6-Methoxy-2-quinazolinylmethylaldehyde (4, 2.40 g, 12.7 mmoles) was dissolved in methanol (50 ml, 1000 mmoles), followed by (R) -pyrrolidine-3-carboxylic acid ester (3.29 g, 25.5 mmoles) ) at 23ºC.
The reaction mixture was stirred for 30 minutes, then sodium cyanoborohydride (1.60 g, 25.5 mmoles) was added at -30ºC.
The reaction mixture was gradually heated to 23 ° C, and stirred for 1 day.
Solvent was removed, and the residue was treated with DCM / water.
Organic layer was washed with a washer (300 X 2 mL), then brine and dried over Na2SO4. The product was purified by chromatography (SiO ,, 220 g, 0-10% Me-OH / DCM) to provide a pure product. 1H NMR (CHLOROPHORM-d) ppm: 9.23 (s, 1H), 7.89 (d, J = 9.3Hz, 1H), 7.47 (d, J = 9.3 Hz, 1H), 7 , 07 (br. S., 1H), 4.02 (d, J = 3.3 Hz, 2H), 3.88 (s, 3H), 3.61 (s, 3H), 3.03 - 3 , 25 (m, 2H), 2.96 (d, J = 4.5 Hz, 1H), 2.68 (t, J = 8.2 Hz, 1H), 2.59 (q, J = 8, 0 Hz, 1H), 2.11 (d, 2H), MS (ESI, M + 1): 302.10. Example 240: (R) -1- (6-hydroxy-quinazolin-2-ylmethyl) -pyrrolidine-3-carboxylic acid methyl ester N o LIOO q - COOL o Ho 2N> (R) -1- methyl acid ester (6-Methoxy-quinazolin-2-ylmethyl) - pyrrolidine-3-carboxylic (600.00 mg, 1.9911 mmol) was dissolved in methylene chloride (20 mL, 300 mmol), and cooled to -78 ° C.
A solution of 1 M boron tribromide in methylene chloride (11.947 mL, 11.947 mmol) was then added dropwise.
The reaction mixture was then gradually heated to 23 ° C and then heated to 50 ° C for 3 hours.
The reaction mixture was then cooled to -78 ° C, and cold MeOH (30 ml) was added.
The mixture was then allowed to rest for 15 hours at 23ºC.
Solvent was removed in vacuo, and the residue was treated with K2CO; (sat) at pH-9, and then adjusted to pH-7.5. Extracted with DCM (100 X 2 mL). Organic layers were washed with water, brine and dried over Na2SO4. The brutofipurified product by chromatography (SiO>, 40 g, 0-10% MeOH / DCM) to provide a pure product (540 mg, 94%). 1H NMR (MeOD) δ ppm: 9.26 3 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.55 (dd, J = 9.2, 2.6 Hz , 1H), 7.23 (dy J = 2.5 Hz, 1H), 4.00 (d, J = 3.0 Hz, 2H), 3.67 (s, 3H), 3.04 - 3.18 ( m, 2H), 2.86 1 (d, J = 2.5 Hz, 2H), 2.66 - 2.77 (m, 1H), 2.10 (s, 2H), MS (ESI, M + 1): 288.10. Example 241: 146- [4- (1,1-Dimethylpropyl) cyclohexyloxyquinazolin-2-ylmethyl) -pyrrolidine-3-carboxylic acid methyl ester: LEroA - to wax .. ZN o 7 2N o Methyl ester of (R) -1- (6-Hydroxyquinazolin-2-ylmethyl) - pyrrolidine-3-carboxylic acid - (150.00 mg, 5.2208E4 moles) cis4- (1,1-dimethyl) propylcyclohexanol (133, 36 mg, 7.8312E-4 moles) and triphenylphosphine (273.87 mg, 0.0010442 mol) were placed in a 40 ml flask, followed by Toluene (5 ml, 0.04 mol). A THF solution (5 mL) was then added dropwise to a reaction mixture at 23 ° C.
The reaction mixture was allowed to stir for 12 hours.
The reaction mixture was then filtered through a pad of celite, and concentrated.
The crude mixture was purified by chromatography (SiO ,, 20 g, 0-35% ethyl acetate / hexanes) to provide the desired product (388 mg, 80%). 1H NMR (CHLOROPHORM-d) 5 ppm: 9.25 (s, 1H), 7.93 (d, J = 9.3 Hz, 1H), 7.50 (dd, J = 9.3, 2.8 Hz, 1H), 7.13 (d, 1H), 4.28 (ddd, J = 10.9, 6.6, 4.4 Hz, 1H), 3.99 - 4.16 (m, 2H), 3 , 67 (s, 3H), 3.22 - 3.34 (m, 1H), 3.16 (dd, J = 8.9, 7.4 Hz, 1H),
2.98 - 3.10 (m, 1H), 2.76 (t, J = 8.4 Hz, 1H), 2.66 (q, J = 8.2 Hz, 1H), 2.26 (d , J = 13.1 Hz, 2H), 2.06 - 2.21 (m, 2H), 1.76 - 1.92 (m, 2H), 1.36 - 1.55 (m, 2H), 1.29 (q, J = 7.6 Hz, 2H), 1.09 - 1.24 (m, 3H), 0.72 - 0.90 (m, 9H). MS (ESI, M + 1): 440.30. Example - 242: 1- (6- [4- (1,1-Dimethylpropyl) cyclohexyloxyquinazolin-2-ylmethyl) pyrrolidine-3-carboxylic acid No. Ns o A ONO A PO LOCO, 146- [4- (1,1-Dimethyl-propyl) -cyclohexyloxy] - quinazolin-2-ylmethyl) -pyrrolidine-3-carboxylic (229.50 mg, 5.2208E-4 moles) i was dissolved in methanol (5 mL, 0.1 mol) and Tetrahydrofuran (5 mL, 0.06 mol), followed by 2 M lithium hydroxide in water (2 mL, 0.004 mol) at 23 ° C for 10 minutes. Excess solvents were removed in vacuo, and the solid residue was treated with HCI (2N, 3 ml), and extracted with DCM (20 X 3 ml). The organic layers were dried over Na2SO4. Removal of the solvent provided a crude product (200 mg, 90%). '* H NMR (400 MHz, CHLOROPHOR)
15. MIO-d) 0,69 -0,94 (m, 12 H) 1.13 - 1.37 (m, 10 H) 1.39 - 1.59 (m, 2H) 1.76 - 1 , 96 (m, 3 H) 2.18 - 2.37 (m, 2 H) 4.84 (br, s ,, 1 H) 7.16 - 7.38 (m, 2H) 7.55 - 7 , 71 (m, 1 H) 7.99 (br, s ,, 1 H) MS (ESI, M + 1): 426.30. The two step procedures used to make 1- (6- [4- (1,1-Dimethylpropyl) cyclohexyloxyquinazolin-2-ylmethyl) pyrrolidine-3-carboxylic acid were used with the appropriate alcohol to do the following: Example 243 : 1- [6- (4-tert-Butylcyclohexyloxy) quinazolin-2-ylmethyl] pyrrolidine-3-carboxylic acid (88% yield). * H NMR (400 MHz, CHLOROFORM-d) δ ppm: 0.88 - 1.02 (m, 10 H) 1.09 - 1.17 (m, 2 H) 1.17 - 1.35 (m, 8 H) 1.39 - 1.61 (m, / 2H) 1.82-2.01 (m, 3 H) 2.18 - 2.37 (m, 2 H) 4.32 (br. S., OH ) 7.17 - 7.37 (m, 2 H) 7.60 (br. S, 1 H) 7.99 (br. S., 1 H). MS (ES, M + 1): 412.20. Example 244: 1- [6- (4-Cyclopentylcyclohexyloxy) quinazolin-2-ylmethyl] pyrrolidine-3-carboxylic acid (95% yield). * H NMR (400 MHz, CHLOROPHORMUM -d) at ppm: 1.00 - 1.49 (m, 10 H) 1.37 - 1.57 (m, 8 H) 1.57 - 1.70 (m, 2 H) 1.70 - 1.87 (m, 2 H) 1.87 - 2.02 (m, 3 H) 2.21 (br, s ,, 2 H) 4.34 (br, s ,, 1 H) 7.10 - 7.34 (m, 1 H) 7.55 - 7.68 (m, 1 H) 7.85 - 8.07 (m, 2 H) 9.24 - 9.44 ( m, 1 H), MS (ESI, M + 1): 424.30. Example 245: 1- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] - ethanone
O "O co - * o" o "o A a solution of 2-Bromo-6- (4-tert-Butyl-cyclohexyloxy) - 'naphthalene (5 g, 0.01 mol) in 15 mL of dry THF , stirred at -78ºC, 2.0 M butane in hexane (8.3 mL, 0.017 mol) was added dropwise.The reaction ** 10 was stirred at -78ºC for 15 minutes, resulting in a yellow color. Methoxy-N-methyl-acetamide (1.6 ml, 0.015 mol) in 5 ml of THF was then added dropwise while the reaction was stirred at -78 ° C (rxn was colorless on addition of B). then quenched with water and extracted three times with ethyl ether .. Organics were dried over MgSOSO, filtered, and concentrated to dryness under reduced pressure. Material was purified by column chromatography using a 0-10% gradient of EtO-AC / Hexanes (pure hexanes for 5 min to elute desbromo SM) in 125 g of SiO, to provide the title compound as a white solid Example 246: 1-N-Azetidine-3-ethoxycarbonyl-1-ethyl [6- (4-tert- Butyl-cyclohexyloxy) naphthalene AI Lo TO CO | - OI “oo Y Ethyl ester of azetidine-3-carboxylic acid (407.10 mg, 0.0031520 mol) (HCI salt) was combined with potassium carbonate (653.01 mg, 0.0047249 mol) in Methanol ( 10 mL, 0.2 mol) and stirred for 15 minutes. The solids were removed by filtration. Acetic acid (8.9 ul, 0.00016 mol) was then added followed by 1- [6- (4-fer-butyl-cyclohexyloxy) -naphthalen-2-yl - ethanone (511.01 mg, 0 , 0015750 mol) and sodium cyanoborohydride (245.55 mg, 0.0039074 mol) and the reaction was stirred overnight at room temperature.
SM solubility was very poor.
Methylene chloride was added (2.5 ml, 0.039 mol). Mixture became homogeneous after a few minutes.
The reaction mixture was then heated to 50 ° C for 5 hours.
The reaction was then allowed to stir overnight at 50 ° C.
The reaction was then quenched with water and extracted three times with ethyl ether.
Organics were combined and dried over MgSO4. Solids were removed by filtration and 5 g of SiO> was added.
All solvents were then removed and the resulting silica was loaded onto a 24 g column and the reaction was purified using a 0-60% EtO-Ac / Hexanes gradient and then dried in a high vacuum to provide the compound. title as a colorless oil.
Material will be carried out without further purification. Example 247: 1-Ethyl [6- (4-tert-Butyl-cyclo- and hexyloxy) naphthal-2-yl-N-azetidine-3-carboxylic acid AA MO aum AA Mia oo 1-N-Azetidine-3 -ethoxycarbonyl-1-ethyl [6- (4-fer-Butyl-cyclohexyloxy) naphthalene (140.1 mg, 0.3307 mmol) was dissolved in Ethanol (2 mL, 40 mmol), then treated with 1 M sodium in water (2 mL, 2 mmol). The mixture was vigorously stirred for 1 hour.
LCMS showed approximately 10% conversion to the new most polar point, room temperature = 1.75 min M + 1 = 410. Reaction allowed stirring overnight.
LCMS indicated no remaining SM. pH was adjusted to 3-4 with 3N HCl and the reaction was then extracted three times with EtOAc.
Organics were combined, then dried over MgSOa, filtered and concentrated to dryness under reduced pressure.
Ethyl ether was then added and a white ppt formed.
The ppt. was removed by filtration to provide a 99% pure white solid by NMR and HPLC. 1H NMR (400 MHz, CHLORINE-FORM-d) δ ppm 0.89 (s, 9 H) 1.02 - 1.29 (m, 3 H) 1.43 (q, J = 11.38 Hz, 2 H) 1.53 - 1.72 (m, 3 H) 1.88 (d, J = 11.55 Hz, 2 H) 2.26 (d, J = 10.54 Hz, 2 H) 3.18 - 3.38 (m, 1 H) 3.72 - 3.98 (m, 2 H) 3.98 - 4.17 (m, 2 H) 4.18 - 4.33 (m, 1 H) 438 (br.s, 1H) 7.05-7.18 (m, 2H) 7.54 (d, J = 8.28 Hz, 1 H) 7.72 (t,
J = 8.28 Hz, 2 H) 7.83 (br. S, 1 H), MS (ESI, M + 1): 410.30.
The same step 2 procedure used for 1-Ethyl [6- (4-tert-Butyl-cyclohexyloxy) naphthal-2-yl-N-azetidine-3-carboxylic acid was used to make the following compound with the appropriate amine .
Example 248: —3- (1- [6- (4-tert-Butyl-cyclohexyloxy) - naphthalen-2-yl] -ethylamino) -propionic acid.
1H NMR (400 MHz, DMSO-ds) δ ppm 0.81 (br. S., 1 H) 0.87 (s, 9 H) 0.99 - 1.14 (m, 1 H) 1.414 - 1, 42 (m, 4 H) 1.64 (d, J = 6.78 Hz, 3 H) 1.81 (d, J = 12.05 Hz, 2 H) 2.20 (d, J = 10.29 Hz, 2 H) 2.57 - 2.72 (m, 2 H) 2.72 - 2.88 (m, 1H) 2.97 (br s, 1H) 3.32 (br s., 1H) 4 , 30 - 4.54 (m, 2 H) 7.18 (dd, 'J = 8.91, 2.13 Hz, 1 H) 7.35 - 7.45 (m, 1 H) 7.66 ( d, J = 7.78 Hz, 1 H) 7.79 (d, y J = 8.78 Hz, 1 H) 7.86 (d, J = 8.53 Hz, 1 H) 7.94 (s , 1H). Example 249: (R) -1- [6- (4-fer-Butyl-cyclohexyloxy) - "naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid: oo” AI COM - POC ot, Acid (R ) -pyrrolidine-3-carboxylic; compound with GENERIC INORGANIC NEUTRAL COMPONENT (98 mg, 0.65 mmol) was combined with potassium carbonate (114.44 mg, 0.82203 mmol) in Methanol (5 mL, 100 mmoles ) and stirred for 15 min The solids were then removed by filtration and 6- (4-tert-Butyl-cyclohexyloxy) -naphthalene-2-carbaldehyde (76.7 mg, 0.247 mmol) was added to the solution followed by acetic acid (91 µL, 1.6 mmol). Solubility was poor, thus adding methylene chloride (0.8 mL, 10 mmol). The mixture was heated to 55 ° C for 30 minutes and then cooled to room temperature. Sodium cyanoborohydride (0.077630 g, 1.2353 mmol) was then added in two small portions and the reaction was stirred at room temperature for 4 hours The reaction was then treated with an additional 2 eq. Of sodium cyanoborohydride and heated to 55ºC during the night. Approximately 3 mL of MeOH was removed in rotovap and the reaction mixture was treated with 2 mL of DMSO to dissolve precipitated solids. The reaction was then directly purified through preparative HPLC on a 19X150 C18 column using a gradient of
10-100% CH3CN / Water (0.1% TFA) to provide the title compound. 1H NMR (400 MHz, MeOD) Displacement = 8.01 - 7.73 (m, 3 H), 7.59 - 7.43 (m, 1 H), 7.37 - 7.26 (m, 1 H ), 7.26 - 7.12 (m, 1 H), 4.61 - 4.49 (m, 2H), 4.48 - 4.31 (m, 1 H), 3.91 - 3.33 (m, 6 H), 2.60 - 2.09 (m, 5 H), 2.06 - 1.81 (m, 3H), 1.58-1.04 (m, 7H), 1.01 -0.80 (m, 9 H), MS (ESI, M + 1): 410.30.
The procedure for (R) -1- [6- (4-fer-Butyl-cyclohexyloxy) - naphthalen-2-ylmethyl) -pyrrolidine-3-carboxylic acid was used to prepare the following compounds using the appropriate amine .
Example 250: (R) -1- [6- (Bicyclohexyl-4-yloxy) -naphthalen-2-ylmethyl-pyrrolidine-3-carboxylic acid: "1H NMR (400 MHz, MeOD) Displacement = 7.98 - 7.71 (m, 3 H), 7.59 - 7.45 (m, 1 H), 7.39 - 7.09 (m, 2 H), 4.69 - 4.48 (m, 1 H ), 4.48 - 4.32 f (m, 1 H), 2.51 - 2.08 (m, 4 H), 1.83 (d, J = 7.0 Hz, 7 H), 1, 71 - 1.38 (m, 7 H), -: 1.12 (none, 6 H) .MS (ES, M + 1): 436.30. Example 251: (R) -1- [6- (4 -Cyclopentyl-cyclohexyloxy) - naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic 1H NMR (400 MHz, METANOL-ds) 5 ppm 1.05 - 1.34 (m, 7 H) 1.40 - 1 , 70 (m, 8 H) 1.72 - 1.88 (m, 2 H) 1.89 - 2.07 (m, 2 H) 2.23 (d, J = 11.04 Hz, 2 H) 3.41 - 3.53 (m, 2 H) 3.53 - 3.68 (m, 2 H) 4.35 - 4.48 (m, 1 H) 4.53 (br's, 2H) 7.20 (dd, J = 8.91, 2.38 Hz, 1 H) 7.25 - 7.34 (m, 1 H) 7.52 (dd, J = 8.53, 1.51 Hz, 1 H) 7.87 (d, J = 8.53 Hz, 1 H) 7.82 (d, J = 9.04 Hz, 1 H) 7.93 (s, 1 H). MS (ESI, M + 1) : 422.20.
Example 252: (S) -1- [6- (4-tert-Butyl-cyclohexyloxy) - naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid.
1H NMR (400 MHz, MeOD) Displacement = 7.96 - 7.92 (m, 2 H), 7.90 - 7.79 (m, 3 H), 7.56 - 7.49 (m, 1 H ), 7.33 - 7.28 (m, 1 H), 7.24 -7.15 (m, 1 H), 4.60 - 4.47 (m, 2 H), 4.44 - 4, 33 (m, 1 H), 3.74 - 3.34 (m, 4 H), 2.62 - 2.35 (m, 1 H), 2.33 - 2.20 (m, 2 H), 1.99 - 1.85 (m, 2 H), 1.53 - 1.03 (m, 5 H), 0.93 (s, 9 H), MS (ESI, M + 1): 410.30 .
Example 252: (R) -1- [6- (trans-4-trifluormethyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid: 1H NMR (400 MHz, METANOL-ds) 5 ppm 1.39 - 1.69 (m, 4 H)
1.99 - 2.14 (m, 3 H) 2.19 - 2.49 (m, 5 H) 3.34 - 3.45 (m, 2 H) 3.45 - 3.70 (m, 2 H) 4.40 - 4.62 (m, 3 H) 7.21 (dd, J = 8.91, 2.38 Hz, 1 H) 7.36 (d, J = 2.01 Hz, 1 H ) 7.53 (dd, J = 8.53, 1.51 Hz, 1 H) 7.79 - 7.87 (m, 1 H) 7.89 (d, J = 8.28 Hz, 1 H) 7.95 (s, 1 H). MS (ESI, M + 1): 422.20. Example 253: (R) 1- [6- (cis-4-trifluormethyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid: 1H NMR (400 MHz, METANOL-ds) pm ppm 1 , 60 - 1.90 (m, 6 H) 2.17 - 247 (m, 6 H) 3.43 - 3.70 (m, 4 H) 4.54 (br., 2 H) 4, 83 (br. S., 1 H) 7.27 (dd, J = 9.04, 2.26 Hz, 1 H) 7.31 - 7.38 (m, 1 H) 7.54 (dd, J = 8.53, 1.51 Hz, 1H) 7.81-7.92 (m, 2 H) 7.96 (s, 1 H), MS (ESI, M + 1): 422.20. Example 254: 34 [6- (4-Cyclopentylcyclohexyloxy) - acid. naphthalen-2-ylmethyl] -amino) -propionic: 1H NMR (400MHz, DMSO-d6) Displacement = 7.87 - 7.61 (m, 3 µH), 7.56 - 7.39 (m, 1 H ), 7.32 - 7.20 (m, 1 H), 7.15 - 6.96 (m, 1 H), 4.39 - 4.25
15. (m, 1H), 4.20-4.04 (m, 2H), 3.20 (s, 2 H), 3.09 - 2.83 (m, 3 H), 2.71 - 2 , 49 (m, 3 H), 2.14 - 1.90 (m, 3 H), 1.88 - 1.55 (m, 6 H), 1.46 (none, 10 H). Example 256: (R) -1- [6- (4-tert-Pentyl-cyclohexyloxy) - naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid: 1H NMR (400MHz, MeOD) Displacement = 7.91 - 7.66 (m, 2H), 7.43 (s 1H), 7.20 (d, J = 2.0 Hz, 1H), 4.43 (s, 1H), 4.35-4.21 (mM, 1H), 3.72 - 3.25 (m, 4 H), 2.18 (d, J = 11.0 Hz, 3 H), 1.75 (br. s., 1 H), 1.38 - 1.06 (m, 5 H), 0.88 - 0.62 (m, 6 H). MS (ESI, M + 1): 424.30. Example 257: (R) -1- [6- (4-Ethyl-cyclohexyloxy) -naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid: 1H NMR (400MHz, MeOD) Displacement = 8.04 - 7 , 74 (m, 2H), 7.59 - 7.43 (m, 1 H), 7.37 - 7.20 (m, 1 H), 4.80 - 4.72 (m, 1 H), 4.63 - 4.41 (m, 1H), 3.80 - 3.37 (m, 4 H), 2.19 - 1.97 (m, 1 H), 1.79 - 1.22 (m , 6 H), 0.94 (s, 3 H), MS (ES |, M + 1): 382.20. Example 258: (R) -1- [6- (4-Butyl-cyclohexyloxy) -naphthalen-2ylmethyl-pyrrolidine-3-carboxylic acid. 1H NMR (400MHz, MeOD) Displacement = 7.92 - 7.684 (m, 2H), 7.42 (d, J = 7.5 Hz, 1 H), 7.19 (d, J = 1.8 Hz, 2 H), 4.68 - 4.57 (m, OH), 4.43
(s, OH), 4.37 - 4.22 (m, OH), 3.74 - 3.25 (m, OH), 2.11 (br. s., OH), 1.77 (br. s., OH), 1.68 - 1.43 (m, OH), 1.43 - 0.95 (m, OH), 0.82 (t, J = 6.3 Hz, 3 H), MS (ESI, M + 1): 410.30. Example 259: (R) -1- [6- (4-Methoxymethyl-cyclohexyloxy) - naphthalen-2Lmethyl-pyrrolidine-3-carboxylic acid: 1H NMR (400 MHz, MeOD) Displacement = 7.70 - 7.47 (m, 3 H), 7.43 - 7.29 (m, 1 H), 7.23 - 7.06 (m, 1 H), 7.04 - 6.89 (m, 1 H), 445 -4.10 (m, 1 H), 3.79 - 3.53 (m, 2 H), 3.20 - 3.11 (m, 5 H), 3.01 - 2.64 (m, 3 H), 2.55 - 2.32 (m, 2 H), 1.79 (s, 7 H), 1.30 (none, 5H), MS (ESI, M + 1): 398.10. Example 260: (1- [6- (4-fer-Butyl-cyclohexyloxy) - It is naphthalen-2-ylmethyl] -pyrrolidin-3-yl) -acetic acid. f “1H NMR (400 MHz, MeOD) Displacement = 8.00 - 7.77 (m, 5 H), 7.58 - 7.47 (m, 2 H), 7.30 (d, J = 1, 5 Hz, 2 H), 7.26 - 7.11 (m, 2 H), 4.50 Ê (s, 3 H), 4.45 - 4.32 (m, 2 H), 3.79 - 3.38 (m, 5 H), 3.19 - 2.65 (m, 3 H), 2.65 - 2.10 (m, 9H), 2.04-1.62 (m, 5 H) , 1.52 - 1.04 (m, 9 H), 0.93 (s, 9 H), MS (ES, M + 1): 424.30. Example 261: 5- (4-tert-Butyl-cyclohexyloxy) -2-methyl-benzothiazole. ds - NO AS.
Ho N “o N 2-Methyl-benzothiazol-5-ol (2.5 g, 0.015 mol), cis-4-tert-butylcyclohexanol (2.84 g, 0.0182 mol), and Triphenylphosphine (4, 76 g, 0.0182 mol) were combined in dry toluene (100 mL, 1 mol) and stirred under nitrogen.
Diisopropyl azodicarboxylate (3.6 mL, 0.018 mol) was added dropwise.
The reaction was then stirred at room temperature overnight.
The reaction was then concentrated to dryness, and then the residue was dissolved in DCMe5g of SiO, were added.
Solvent was removed under reduced pressure and the resulting powder was loaded onto a 40 g column and purified by column chromatography using a 0-60% EtO-AC / Hexanes gradient.
Example 262: 5- (4-tert-Butyl-cyclohexyloxy) -benzothiazole-2-aldehyde.
Ss.
AA AOL - OLA Selenium dioxide (180 mg, 1.6 mmol) was combined with 1,4-Dioxane (5 mL, 60 mmoles) and water (0.5 mL, 30 mmoles) at an open atmosphere temperature .
The mixture was then treated with 5- (4-fer-butyl-cyclohexyloxy) -2-methyl-benzothiazole (250 mg, 0.82 mmol) and the resulting mixture was heated at 65 ° C for 2 hours.
The heat was increased to 90ºC and 4 eq. additional SeO, z were added.
Reaction was stirred for an additional 5 hours.
LCMS showed close to complete conversion.
Reaction became: dark and solids were formed in the reaction mixture.
Reaction was cooled to room temperature and left to stand overnight.
Solid were. 10 removed through filtration.
Concentrated to dryness, then directly purified by column chromatography using a 0-40% Ethylacetate / hexane gradient to provide the title compound as a dark solid.
Example 263: (R) -1- [5- (4-tert-Butyl-cyclohexyloxy) -benzothiazol-2-ylmethyl] -pyrrolidine-3-carboxylic acid EA A "NH" o N O. = " (R) -pyrrolidine-3-carboxylic acid (100 mg, 0.9 mmol) (HCI salt) was combined with N N-Di-isopropylethylamine (300 ul, 2 mmol) in methanol (4.0 mL, 98 mmol) ) and stirred for 15 min. 5- (4-fer-Butyl-cyclohexyloxy) -benzothiazole-2-carbaldehyde (1.0E2 mg, 0.33 mmol) was then added and the mixture was stirred at room temperature for 30 minutes. minutes.
After 30 minutes, the reaction was cooled to 0ºC and sodium cyanoborohydride (100 mg, 2 mmoles) was added in two portions.
The reaction was then allowed to warm to room temperature while stirring overnight.
The reaction was then directly purified on Gilson (10 to 90% CH; CN / HO (0.1% TFA), 19x150 cm C18, room temperature = 8.6 min). The product was then dried in a high vacuum to provide the title compound as a white solid. 1H NMR (400MHz, MeOD) Displacement = 8.00 - 7.78 (m, 1 H), 7.69 - 7.51 (m, 1 H), 7.27 - 7.05 (m, 1 H) , 5.09 - 4.93 (m, 3 H), 4.39 - 4.21 (m, 1 H), 4.01 - 3.39 (m, 4 H), 2.65 - 2.18 (m, 3 H), 2.01 - 1.80 (m, 2 H), 1.53 - 1.04 (m, 6 H), 0.92 (s, 9 H), MS (ESI, M +1): 417.30. Example 264: 1- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] - 2,2,2-trifluoro-ethanone. toco - Po co AI - VLS E To a solution of 2-Bromo-6- (4-tert-Butyl-cyclohexyloxy) - - naphthalene (2 g, 0.006 mol) in 15 mL of dry THF, stirred at -78ºC , was added drop by drop. The reaction was then stirred at -78ºC for 15 minutes, É 10 resulted in yellow color. 2,2,2-Trifluoro-N-methoxy-N-methyl-acetamide (1.0 ml, "0.0083 mol) in 10 ml of THF was then added dropwise while the reaction was stirred at -78 ° C. Once all the starting materials were added, the reaction was allowed to warm to room temperature while stirring for 2 hours.The reaction was then quenched with water and extracted three times with EtOAc. Organics were dried over MgSO:;, filtered , and concentrated to dryness under reduced pressure. Crude NMR showed approximately 80% purity (looks like de-bromine starting material). Material was purified by column chromatography using a gradient of hexanes to a column volume followed by 0 -10% EtO-AC / Hexanes in 25 g of SiO, to provide the title compound as a yellow solid. Material will be carried out without further purification. Example 265: 3- (1- [6-] acid tert-butyl ester (4-ferc-Butyl-cyclohexyloxy) -naphthalen-2-i1] -2,2,2-trifluoro-ethylamino) -propionic
ALF ro color - the color
LOT O The Terc-butyl ester of 3-amino-propionic acid (106 mg, 0.727 mmol) was combined with N, N-Di-isopropylethylamine (575 µL, 3.380 mmol) and 1- [6- (4-tert-Butyl- cyclohexyloxy) -naphthalen-2-i1] -2,2,2-trifluoroethanone (250 mg, 0.66 mmol) in Methylene chloride (4 mL, 60 mmol). Titanium (IV) chloride
1 M in Methylene chloride (727 µL, 0.727 mmol) was added and the mixture was stirred at room temperature for 5 hours.
TLC (20% EtO-AC / Hex) showed only traces of SM with a new lower point Rf.
The reaction was cooled to 0ºC and sodium cyanoborohydride (208 mg, 3.30 mmoles) in methanol (5 mL) was carefully added in two portions (a lot of bubbling removes the cap). The reaction was then diluted with mL of DCM and the solids were removed by filtration. pH was adjusted to 10 with 1 M NaOH and the reaction was extracted three times with methylene chloride.
Organics were combined and dried over MgSO4. Solids 10 were removed by filtration and the crude reaction was absorbed on silica É (1 g) and purified by column chromatography on 12 g of SiO2 using a 0-15% ethyl acetate / hexane gradient to provide material which was impure by NMR and LCMS (compound eluted around 1% EtOAc.) Material was repurified on 24 g of ISCO gold column using a long gradient of 0-10% EtOAc / Hex under 30 minutes (desired compound was the second largest peak) to provide the title compound as a colorless solid.
Example 266: 3- (1- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-i1] -2,2,2-trifluor-ethylamino) -propionic acid methyl ester AAA Sn e " the comet No ont Terc-butyl ester of 3- (1- [6- (4-tert-Butyl-cyclohexyloxy) - naphthalen-2-i1] -2,2,2-trifluor-ethylamino) -propionic acid ( 0.174 g, 0.343 mmol) was dissolved in 4 M hydrogen chloride in 1,4-Dioxane (3 mL, 10 mmol) and stirred at room temperature for 2.5 hours.
All solvent is removed after purification from the previous step.
The reaction was then concentrated to dryness under reduced pressure to provide the title compound which occurred directly in the next step.
Example 267: 3- (1- [6- (4-tert-Butyl-cyclohexyloxy) - naphthalen-2-i1] -2,2,2-trifluor-ethylamino) -propionic acid (BIO-021973).
Apr FLF * o cont Ao “oo Methyl ester of 3- (1- [6- (4-fer-Butyl-cyclohexyloxy) -naphthalen-2- 11) -2,2,2-triflor-ethylamino) -propionic (164 mg, 0.352 mmol) was dissolved in Ethanol (2 mL, 40 mmol) then treated with 1 M sodium hydroxide in water (2 mL, 2 mmol). The mixture was stirred vigorously for 1 hour. pH was adjusted to 34 with 6 N HCl and the reaction was then extracted three times with EtOAc. Organics were combined, then dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Ethyl ether was then added and a white ppt formed. The ppt. it was removed by filtration to provide a 99% pure white solid by trace NMR and HPLC 10 10 of remaining ethanol. '* H NMR (400 MHz, METANOL-ds) δ ppm 0.83 (s, 9 H) 0.93 - 1.10 (m, 1 H) 1.11 - 1.27 (m, 2 H) 1 , 27 - 1.42 (m, 2 H) 1.73 - 1.89 (m, 2 H) 2.19 (d, J = 10.29 Hz, 2 H) 2.67 (t, J = 6 , 53 Hz, 2 H) 3.03 - 3.18 (m, 2 H) 4.22 - 4.37 (m, 1 H) 5.33 - 5.51 (m, 1 H) 7.13 ( dd, J = 8.91, 2.38 Hz, 1 H) 7.21 -7.29 (m, 1 H) 7.46 (d, J = 8.78 Hz, 1 H) 7.76 (d , J = 9.04 Hz, 1 H) 7.85 (d, J = 8.78 Hz, 1H) 7.93 (s 1H). Example 268: 4-methoxypent-3-en-2-one HC (OMe) 3
ART A solution of 2,4-pentanedione (100 g, 1 mol), trimethyl orthoformate (106 g, 1 mol), p-TsOHH2O (2.16 g, 11.4 mmol) in MeOH (248 mL) heated to 55ºC for 5 hours. The mixture was cooled to room temperature and concentrated. The residue was diluted with CCla (100 ml) and the mixture was concentrated again to provide the crude product as a dark brown oil (-100 ° C). This residue was subjected to vacuum distillation to provide colorless oil (58.0 g, yield: 50%). mp 32-33ºC / 3 Torr). Example 268: 3-methoxy-1-methylnaphthalene Br OMe O O A NaNH2, t- BULONE CO THF Nes
A solution of t-BuOH (44.5 g, 600 mmoles) in dry THF (240 ml) was added dropwise to a suspension of NaNH, (84.4 9, 2.2 mmoles) in dry THF (480 ml) ) under nitrogen.
The resulting mixture was heated for 2 hours at 40-45 ° C.
Then, the mixture was cooled, a solution of 4-methoxypent-3-en-2-one (68.5 g, 600 mmoles) in dry THF (480 ml) was added dropwise at 30-40 ° C.
The resulting mixture was stirred at 45 ° C for 2 hours.
A solution of bromobenzene (47.1 g, 300 mmoles) in dry THF (240 ml) was added and the mixture was stirred at 55 ° C for 6 hours.
The mixture was allowed to cool to room temperature overnight.
The mixture was poured onto ice, acidified with an aqueous solution of 3 M HCI at pH 4-5 and extracted with EtOAc.
Organic extracts. Combined were concentrated under reduced pressure, and the residue was diluted with acetone (480 ml) and stirred with concentrated HCI solution (247 ml) for 10 min.
The mixture was diluted with EtOAc (200 ml) and washed with —saturated brine (200 ml). The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated.
The residue was subjected to flash chromatography (700 g of silica gel with dry loading, eluting 2% EtOAc in heptanes to provide orange oil (19 g, yield: 37%). Example 269: 4-Methylnaphthalen 2-ol n-Bu, 4NI = MeO HO A solution of the compound 4-methylnaphthalen-2-ol (22 g, 128 mmoles) and n-Bual (52 g, 141 mmoles) in dry dichloromethane (650 mL) were added to the 1.0 M BCl3 solution in dichloromethane (192 mL, 192 mmoles) at -78ºC under nitrogen.
After 5 min, the solution was allowed to warm to 0 ° C and stirred for 1 hour.
The reaction was quenched with ice water (200 mL) and extracted with dichloromethane.
The combined extracts were washed with saturated brine, dried over sodium sulfate, filtered, and concentrated.
The residue was subjected to flash chromatography, eluting with a gradient of 10% to 50% EtOAc in heptanes to provide a brown solid product (16 g, yield: 79%).
Example 270: 3- (4-tert-Butyl-cyclohexyloxy) -1-methyl-naphthalene Tokg = - "O.
Ho oo A mixture of 4-methyl-naphthalen-2-ol (0.60 g, 3.8 mmoles), 4-tert-butyl-cyclohexyl ester of methanesulfonic acid (1.9 g, 7.6 mmoles) and cesium carbonate (3.7 g, 11 mmoles) in t-BuOH (10 mL) and 2-butanone (7 -mbL) was heated to 80 ° C overnight.
After cooling to room temperature, the mixture was treated with water and ether.
The organic phase was dried over MgSO;, filtered and concentrated.
The crude was treated with methanol to provide. the solid product (0.55 g, yield: 48%). ESI-MS: 297.20 (M + H) *. Example 271: 6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalene- - 10 2-carbaldehyde (13467-25) AQE——— PO LO "“ o “o A a mixture of 3- (4-fer-Butyl-cyclohexyloxy) -1-methyl-naphthalene (450 mg, 1.5 mmol) in 1,2-dichloroethane (9 mL) was added tin tetrachloride (236 µL, 2 mmol) at 0 ° C .
After stirring at 0 ° C for 1 hour, dichloromethyl methyl ether (183 µl, 2 mmol) was added.
The solution was stirred at 0 ° C for 1 hour and then heated to room temperature.
To the mixture, ice water was added and stirred for 1 hour, then a dark solution was diluted with dichloromethane and washed with water.
The organic phase was washed with aqueous sodium bicarbonate, and dried over MgSO4. The dehydrator was filtered and the solvent was concentrated to dryness to provide the dark solid product (0.48 g, yield: 97%). ESI-MS: 325.20 (M + H) *. Example 272: ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid methyl ester * ZA O POLO "—— TO LLONT A solution of 6- (4-fer-Butyl-cyclohexyloxy) -8-methyl-naphthalene-2-carbaldehyde (50 mg, 0.15 mmol), glycine methyl ester, hydrochloride (27 mg, 0.22 mmol) and N, N-diisopropylethylamine (DIEA) (34 µl) in 1,2-dichloroethane (2 ml) was stirred for 1 hour at room temperature.
Then, triacetoxibo-
sodium hydrochloride (52 mg, 0.25 mmol) was added and stirred for 3 hours.
The reaction was diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, dried over MgSO;, filtered, and concentrated.
The crude was purified by silica gel column chromatography eluted with 0-5% MeOH in methylene chloride to provide the light brown solid (53 mg, yield: 86%). ESI-MS: 420.30 (M + 23) *. Example 273: ([6- (4-tert-Butyl-cyclohexyloxy) -B-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid.
LiOH, HO h.
OH TO LEE ES ÁC ONCE. A solution of methyl ester ([6- (4-tert-Butyl-cyclo-2 10 hexyloxy-ô8-methyl-naphthalen-2-ylmethyl-amino) -acetic (40 mg, 0.1 mmol) and hydr - lithium oxide (16 mg, 0.67 mmol) in THF (1.4 mL) and water (0.5) was stirred at 22 ° C overnight.
After, the solvent was concentrated, the residue was treated with water.
The resulting solid was filtered and washed with water and purified using HPLC to provide the white precipitate as TFA salt (24 mg, yield: 48%). ESI-MS: 406.30 (M + 23) *; '* H NMR (400 MHz, MeOD) 3 = 8.075 (d, 1H), 8.065 (d, 1H), 7.62 (t, 1H), 7.48 (dd, 1H), 7.38 (s, 1H), 4.78 (s, 2H), 4.52 (m, 1H), 3.86 (s, 1H), 2.75 (s, 3H), 2.66 (s, 1H), 2, 27 (d, 2H), 1.926 (d, 2H), 1.557 (m, 2H), 1.256 (m, 2H), 1.152 (m, 1H), 0.92 (s, 9H). Example 274: 4 - ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl-amino) -butyric acid * lr. o POLLS —— TOO E A solution of 6- (4-fer-Butyl-cyclohexyloxy) -8-methyl-naphthalene-2-carbaldehyde (50 mg, 0.15 mmol) and 4-aminobutanoic acid (20 mg, 0.19 mmol) in ethanol (0.5 mL) was heated to reflux for 2 hours.
The yellow solution was cooled to room temperature and sodium cyanoborohydride (52mg) was added. The mixture was heated to 50ºC overnight.
The crude product was purified by HPLC to provide the white solid as a TFA salt (9 mg, yield: 11%). ESI-MS: 412.30 (M + H) *; 1H NMR (400 MHz, MeOD) δ 8.06 (d, 1H), 8.03 (d, 1H), 7.58 - 7.65 (m, 1H), 7.48 (t, J
= 7.15 Hz, 1H), 7.38 (s, 1H), 4.68 (s, 2H), 4.53 (m, 1H), 3.20 (t, 2H), 2.75 (s , 3H), 2.48 (t, J = 6.90 Hz, 2H), 2.29 (d, J = 10.54 Hz, 2H), 2.04 (quin, J = 7.34 Hz, 2H ), 1.94 (d, 2H), 1.54 (m, 2H), 1.28 (m, 2H), 1.16 (m, 1H), 0.93 (s, 9H). Example 275: 1- [6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -azetidine-3-carboxylic acid methyl ester REPORT AA AA IN Cias LO AOLT Oy: Synthesis was performed as described for ([6- (4-fer-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid methyl ester (40 mg, yield: 51%) . ESI-MS: 424.30 (M + H) *. Example 276: 1- [6- (4-fer-Butyl-cyclohexyloxy) -8-methyl- - 10 naphthalen-2-methyl] 1-azetidine-3-carboxylic acid EDS »CLIP, Synthesis was performed as described for acid ([6- (4-fer-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic.
The product was treated with 1N aqueous HCl which provided a light yellow solid as HCI salt (30 mg, yield: 86%). ESI-MS: 410.30 (M + H) *. * H NMR (400 MHz, DM-SO) 5 8.10 (d, 1H), 7.97 (d, 1H), 7.55 (t, 1H), 7.47-7.41 (m, 2H ), 4.60-4.45 (m, 2H), 3.97 (s, 3H), 3.50-3.33 (m, 2H), 2.68 (s, 3H), 2.16 ( d, 2H), 1.81 (d, 2H), 1.47 (quin, 2H), 1.20 (quin, 2H), 1.09 (m, 2H), 0.88 (s, 9H). Example 277: Ethyl ester of 3 - ([[6- (4-fer-Butyl-cyclohexyloxy) -B-methyl-naphthalen-2-ylmethyl] -amino) -propionic acid A to AA AaATi Ena: Synthesis was performed as described for ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid methyl ester (38 mg, yield: 41%) . ESI-MS: 426.30 (M + H) *. Example 278: Acid 3 - ([6- (4-ferc-Butyl-cyclohexyloxy) -8-methyl- Eescerstetêta arrtuitaua: eita OS ow SNCT and ATI Sc swim aros
Synthesis was performed as described for ([6- (4-fer-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl) -amino) -acetic acid.
The crude was purified by HPLC to provide white solid as TFA salt (22 mg, yield: 48%). ESI-MS: 398.20 (M + H) *. * H NMR (400 MHz, CDCl3) ô 8.89 (s, 2H) 7.95 (d, 1H), 7.91 (d, 1H), 7.52 (m, 1H), 7.41 (t , 1H), 7.13 (s, 1H), 4.64 (s, 2H), 4.35 (m, 1H), 3.14 (s, 2H), 2.74-2.65 (m, 5H), 2.18 (d, 2H), 1.85 (d, 2H), 1.47 (m, 2H), 1.20-1.02 (m, 3H), 0.88 (s, 9H ). Example 279: 1- [6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylic acid methyl ester 210 Synthesis was performed as described for methyl ester of ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl) -amino) -acetic acid as sticky oil (57 mg, yield: 70%). ESI-MS: 438.30 (M + H) *. Example 280: 1- [6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylate f. o fo, PH Melvbeass: 7 OLLIOR Synthesis was performed as described for ([6- (4-fer-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid. (36 mg, yield: 69%). ESI-MS: 424.30 (M + H) *. * H NMR (400 MHz, DMSO) δ 8.14 (d, 1H), 7.88 (d, 1H), 7.44 (t, 1H), 7.35 (m, 1H), 7.27 ( s, 1H), 4.31 (m, 1H), 3.89 (s, 2H), 2.73 (t, 1H), 2.62 (s, 3H), 2.53 (m, 3H), 2.36 (m, 1H), 2.12 (d, 2H), 1.90 (m, 1H), 1.78 (d, 2H), 1.64 (m, 1H), 1.36 (m , 2H), 1.20-1.00 (m, 3H), 0.85 (s, 9H). Example 281: 3- (4-fer-Butyl-cyclohexyloxy) -1-iodo-naphthalene! 1 ————. Ciwq— LO “OCO A mixture of 4-iodine-naphthalen-2-ol (1.0 g, 3.7 mmol) (See, for example, Australian Journal of Chemistry (1963), 16 401 -10 b.
Journal of the Chemical Society (1943), 468-9, which is incorporated by reference in its entirety), 4-tert-Butyl-cyclohexyl ester of methanesulfonic acid (1,8
9, 7.4 mmoles) and cesium carbonate (3.6 g, 11 mmoles) in tert-butyl alcohol (10 ml) and 2-butanone (7 ml) was heated in a sealed bottle at 100ºC for 4 hours. The mixture was partitioned between water and dichloromethane. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified through a silica gel column eluted with approximately 0 to 30% EtOAc in hexanes to provide light yellow precipitate (1 , 10 g, yield: 73%). ESI-MS: 409.10 (M + H) *.
Example 282: 6- (4-fer-Butyl-cyclohexyloxy) -8-iodo-naphthalene- Rrrarhaldeido.
- ADLLO PO ÉOP “o“ o. 10 Synthesis was performed as described for 6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalene-2-carbaldehyde acid (sticky oil, 700 mg, yield: 98%). ESI-MS: 437.10 (M + H) *.
Example 283: Ethyl ester of 3 - ([6- (4-tert-Butyl-cyclohexyloxy) -8-iodo-naphthalen-2-ylmethyl] -amino) -propionic acid Es com GOODBYE OLINTO Synthesis was performed as described for methyl ester of ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid - (light brown solid, 110 mg, yield: 40%). ESI-MS: 538.20 (M + H) *.
Example 284: 3 - ([6- (4-fer-Butyl-cyclohexyloxy) -B-iodo-naphthalen-2-ylmethyl] -amino) -propionic acid; compound with trifluoroacetic to tono Ao LonNrts Synthesis was performed as described for ([6- (4-fer-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid. The crude was purified by HPLC to provide the white solid as the TFA salt (7 mg, yield: 30%). ESI-MS: 510.20 (M + H) *. * H NMR (400 MHz, MeOD) δ 8.13 (d, 1H), 8.12 (s, 1H), 8.05 (d, 1H), 7.66 (m, 1H), 7.54 ( m, 1H), 4.72 (s, 2H), 4.54 (m, 1H), 3.14 (t 2H), 2.81 (t 1H), 2.66 (s, 1H), 2, 28 (d, 2H), 1.94 (d, 2H), 1.60 (m, 2H), 1.380 (m, 2H), 1.16 (m, 1H), 0.93 (s, 9H).
Example 285: [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] -acetic acid ethyl ester To a solution of 2-bromo-6- (4-tert-Butyl-cyclohexyloxy ) - naphthalene (2 g, 5.5 mmoles) in ether (10 mL) under nitrogen 1.5 M n-butyllithium in hexane (4 mL, 6.4 mmoles) was added at 0ºC.
The solution was stirred for 30 min at 0 ° C, then treated with a copper (1) dimethyl sulfide-bromide complex (0.8 g, 3.9 mmol). After 2 hours of stirring, a solution of ethyl bromoacetate (0.7 mL, 6 mmol) in ether (4 mL) was added. cated.
The solution was stirred at 0 ° C for 2 hours, then warmed -— 10 to room temperature for 3 hours.
The reaction was quenched with 10% aqueous HCI.
Then, an insoluble was filtered.
The organic layer was washed with water, aqueous sodium bicarbonate, dried over MgSO4, filtered and concentrated.
The crude was purified through a silica gel column eluted with EtOAc in hexanes of approximately 0 to 10% to provide the light yellow solid (0.45 g, yield: 22% yield). ESI-MS: 369.20 (M + H) *. Example 286: 2- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] -ethanol o OH MOLEOE ——— TO COM A solution of ethyl ester of acid [6- (4- ferc-Butyl-cyclohexyloxy) -naphthalen-2-ill-acetic acid (250 mg, 0.68 mmol) in THF (10 mL) was added 1.0 M lithium tetrahydroaluminate in THF (2 mL, 2 mmoles) at 0ºC.
After stirring at room temperature for 2 hours, the solution was quenched with ethyl acetate (1 ml), then aqueous Rochelle salt (1.5 ml) added. The solution was stirred for 1 hour, then extracted with ethyl acetate.
The organic phase was dried over MgSO4, filtered and concentrated.
The resulting crude was purified through a silica gel column eluted with EtOAc in approximately 60% hexanes to provide the white precipitate (0.17 g, yield: 77%). ESI-MS: 327.20
(M + H) *. Example 287: [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] - acetaldehyde OH 20 AOL> TOCO ”To a solution of 2- [6- (4-tert-Butyl-cyclo- hexyloxy) -naphthalen-2-yl] -ethanol (170mg, 0.52mmol) in methylene chloride (5ml) was added Dess-Martin periodinane (0.31g, 0.73mmol). After stirring at room temperature for 1 hour, the solution was diluted with methylene chloride, washed with aqueous sodium thiosulfate, dried over Na72 SO4, and concentrated. The crude was purified through a silica gel column to provide the white solid δ 10 (120 mg, yield: 70%). ESI-MS: 325.20 (M + H) *. Example 288: 3- (2- [6- (4-tert-Butyl-cyclohexyloxy) -naphthalen-2-yl] -ethylamino) -propionic acid tert-butyl ester
H AD LOOP - “o nos oo Synthesis was performed as described for methyl ester of ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid as white-solid (13 mg, yield: 30%). ESI-MS: 454.40 (M + H) *. Example 289: 342- [6- (4-tert-Butyl-cyclohexyloxy) - naphthalen-2-yl] -ethylamino) -propionic acid
N TOLO, - TO COR O. Oo f% A solution of 3- (2- [6- (4-fer-butyl-cyclohexyloxy) -naphthalen-2-yl) -ethylamino acid-butyl ester - - propionic (13 mg, 0.028 mmol) in HCI4M in 1,4-dioxane (0.50 mL) was stirred at room temperature overnight. Then, the solvent was concentrated, the crude was purified by HPLC to provide the white solid (7 mg, yield: 49%). ESI-MS: 398.30 (M + H) *. * H NMR (400 MHz, MeOD) 5 7.73 (d, 1H), 7.70 (d, 1H), 7.65 (s, 1H), 7.33 (dd, 1H), 7.21 (d, 1H), 7.09 (dd, 1H), 4.31 (m, 1H), 3.41-3.31 (m,
4H), 3.14 (t, 2H), 2.74 (t, 2H), 2.25 (d, 2H), 1.89 (d, 2H), 1.40 (m, 2H), 1, 24 (m, 2H), 1.10 (m, 1H), 0.90 (s, 9H). Example 290: (R) -1- (2- [6- (4-fer-Butyl-cyclohexyloxy) - naphthalen-2-yl] -ethyl) -pyrrolidine-3-carboxylic acid oH AQ LOSS —— MO co TA oo A mixture of (R) -pyrrolidine-3-carboxylic acid, HCI salt (54 mg, 0.35 mmol) and potassium carbonate (0.11 g, 0.79 mmol) in methanol (1.4 mL ) was stirred for 15 min. The solids were removed by filtration, and the filtrate was concentrated. The residue was added to [6- (4-tert-1 Butyl-cyclohexyloxy) -naphthalen-2-yl - acetaldehyde (57 mg, 0.18 mmol) and sodium triacetoxy-—borohydride (200 mg, 1 mmol) in 1,2-dichloroethane (2 mL) and acetic acid (0.14 mL, 2.4 mmol). After heating at 80ºC for 2 hours, the reaction was diluted with dichloromethane and washed with 5% aqueous citric acid. The organic phase was concentrated and the residue was purified by HPLC to provide the solid as the TFA salt (42 mg, yield: 44%). ESI-MS: 424.30 (M + H) *. Example 291: 6-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester oO - OO
HO HO A solution of 1,2,3,4-tetrahydro-isoquinolin-6-ol, HCI salt (2,9, 10 mmoles) and di-tert-butyldicarbonate (4 g, 18 mmoles) in bi solution - saturated aqueous sodium carbonate (20 ml) and chloroform (20 ml) was stirred at room temperature overnight. The organic phase was washed with water, dried over MgSO4, filtered and concentrated. The crude was purified through a silica gel column eluted with EtOAc in approximately 100% hexanes to provide the desired product (1.7 g, yield: 65%). Example 292: 6- (4-tert-Butyl-cyclohexyloxy) -3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester o o LOM - TOLO "HO o A mixture of tert -butyl ester of 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid (1.1 g, 4.4 mmoles), cesium carbonate (4.3 9, 13 mmoles), and 4-tert- Butyl-cyclohexyl ester of methanesulfonic acid (2.2 9,
8.8 mmoles) in t-BuOH (12 mL) and 2-butanone (6.0 mL) was heated in a sealed flask at 100ºC overnight. The mixture was partitioned between water and ether. The organic phase was washed with water, dried over MgSO;, filtered and concentrated. The residue was purified through a silica gel column eluted with approximately 0 to 30% EtOAc in hexanes to provide the white precipitate (1.0 g, yield: 58%). 1H NMR (400 MHz, CDCl3) 5 6.99 (d, 1H), 6.74 (dd, 1H), 6.67 (d, 1H), 4.49 (s, 2H), 4.07 (m, 1H ), 3.61 (s, 2H), 2.78 (m, 2H), 2.18 (d, 2H), 1.85 (d, 2H), 1.48 (s, 9H), 1.37 (m, 2H), 1.48-1.00 (m, 3H), 0.87 (s, 9H). Example 293: 6- (4-fer-Butyl-cyclohexyloxy) -1,2,3,4-tetrahydro-isoquinoline + AQ LOM - TO ooo A solution of ferric-butyl ester 6- (4- ferc-Butyl-cyclohexyloxy) -3,4-dihydro-1H-isoquinoline-2-carboxylic (0.89 g, 2.3 mmol) in 4 M HCI in 1,4-dioxane (10 mL, 40 mmoles) and ether (40 ml) was stirred at room temperature for 3 hours to form the white precipitate. The solid was collected by filtration to provide the desired product as HCl salt (0.73g, yield: 98%). (400 MHz, DMSO) ô 7.09 (d, 1H), 6.81 (d, 1H), 6.80 (s, 1H), 4.20 (m, 1H), 4.14 (m, 2H ), 3.31 (m, 2H), 2.95 (t, 2H), 2.09 (d, 2H), 1.77 (d, 2H), 1.27 (m, 2H), 1.20 -0.98 (m, 3H), 0.85 (s, 9H). Example 294: Terc-butyl ester of 3-tert-butoxycarbonylamino-4- [6- (4-ferc-Butyl-cyclohexyloxy) -3,4-dihydro-1H-isoquinolin-2-i1] -4 -oxo-butyric
É Te TOLO - TOCA oo A mixture of 6- (4-tert-Butyl-cyclohexyloxy) -1,2,3,4-tetrahydro-isoquinoline, HCI salt, (80 mg, 0.25 mmol) , 2-tert-butoxycarbonylamino-succinic acid 4-tert-butyl ester (143 mg, 0.49 mmol), triethylamine (41 uL), N- (3-dimethylaminopropyl) hydrochloride -N'-ethylcarbodiimide (57 mg, 0.30 mmol) HOBT emonohydrate (10 mg, 0.068 mmol) in DMF (2.0 mL) was heated to 50 ° C for 4 hours. The solution was diluted with ether and washed with water. The] organic phase was dried over MgSO;, filtered and concentrated. The residue was purified through a silica gel column eluted with approximately 20 to 20% EtOAc in hexanes to provide the desired product (90 mg, yield: 65%).
Example 295: 3-Amino-4- [6- (4-fer-Butyl-cyclohexyloxy) -3,4-dihydro-1H-isoquinolin-2-yl] -4-oxo-butyric acid . and Lo
TMOLEOAA TI TÁAQNCOP (o) o A solution of 3-fer-butoxycarbonylamino-4- [6- (4-tert-Butyl-cyclohexyloxy) -3,4-dihydro-1H-isoquinolinic acid-butyl ester -2-yl - 4-oxo-butyric (90 mg, 0.416 mmol) in methylene chloride (1.0 ml) and acetic trifluoroacid (0.3 ml) was stirred at room temperature overnight. Then, the solvent was concentrated, the residue was purified by HPLC to provide the white solid as TFA salt (48 mg, yield: 58%). ESI-MS: 403.80 (M + H) *; 1H NMR (400 MHz, CDCI;) δ 6.95 (dd, 1H) 6.70 (d, 1H), 6.62 (d, 1H), 4.86 (m, 1H), 4.61 - 4 , 41 (m, 2H), 4.04 (m, 1H), 3.73-3.51 (m, 2H), 2.95-2.75 (m, 3H), 2.70 (m, 1H ), 2.14 (d, 2H), 1.83 (d, 2H), 1.34 (q, 2H), 1.17-0.99 (m, 3H), 0.86 (s, 9H) .
Example 296: Terc-butyl ester of 5-hydroxy-2,3-dihydro-indole-1-carboxylic acid
Y% o o -
HO HO Synthesis was performed as described for 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid ferc-butyl ester (1.1 g, yield: 60%). ESI-MS: 258.10 (M + 23) *. Example 297: Terc-butyl acid ester 5- (4-Trifluormethyl- Edit for Aga gde all vo, O, - tas. O Ads rr LA Ho o A mixture of ferc-butyl ester of 5-hydroxy-2,3 acid -dihydro-indole-1-carboxylic acid (0.33 g, 1.4 mmol), cesium carbonate (0.93 g, 2.8 mmoles), and 4-trifluormethyl-cyclohexyl acid ester methanesulfonic (0.70 g, 2.8 mmoles) in t-BuOH (5 ml) and 2-butanone (2.5 ml) was heated in a sealed flask at 100 ° C overnight. The mixture was treated with dichloromethane to the solid was filtered and the filtrate was concentrated. The residue was treated with the minimum amount of dichloromethane to form the solid for 2 days. The solid was filtered and washed with ether to provide the desired product (200 mg, yield : 40%) ESI-MS: 408.20 (M + 23) * Example 298: 5- (4-Trifluormethyl-cyclohexyloxy) -2,3-dihydro-1H-indole v E Yo E: OO - OLEO “o“ o Synthesis was performed as described for 3-amino-4- [6- (4- tert-Butyl-cyclohexyloxy) -3,4-dihydro-1H-isoquic acid inolin-2-yl] -4-0xo-butyric - (130 mg, yield: 88%). ESI-MS: 286.10 (M + H) *. Example 299: 2-chloro-1- [5- (4-trifluormethyl-cyclohexyloxy) -2,3-dihydro-indol-1-i] -ethanone O. F. NH F.
Fe “O DO -" O Do "oo A mixture of 5- (4-trifluormethyl-cyclohexyloxy) -2,3-dihydro-1H-indole (130 mg, 0.46 mmol) and DIEA (103 uL ) in methylene chloride (2 mL) was added to chloroacetyl chloride (47 ul, 0.59 mmol) at room temperature.
The black solution was stirred for 30 min.
The solvent was concentrated to provide the crude product.
The crude was used directly in the next step without further purification (80 mg, yield: 77%). ESI-MS: 362.10 (M + H) *. "Example 300: Ethyl ester of 3- (2-0x0-2- [5- (4-trifluormethyl-cyclohexyloxy) -2,3-dihydro-indol-1-yl] -ethylamino) -propionic et xa * O TA A crude mixture of 2-chloro-1- [5- (4-trifluormethyl-cyclohexyloxy) -2,3-dihydro-indol-1-yl) -ethanone (80 mg, 0.22 mmol), 3-aminopropionic acid ethyl ester as HCI salt (68 mg, 0.44 mmol) and potassium carbonate (98 mg, 0.71 mmol) in acetonitrile (2 mL) was heated to reflux for 4 hours.
The mixture was treated with water and extracted with ether.
The organic phase was dried over MgSO4, concentrated, and purified through a column of silica gel to provide desired product (11 mg, yield: 10%). ESI-MS: 443.20 (M + H) *. Example 301: 3- (2-0x0-2- [5- (4-trifluormethyl-cyclohexyloxy) -2,3-dihydro-indol-1-iI] -ethylamino) -propionic acid Y o XY o Synthesis was performed as described for ([6- (4-tert-Butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid (3.8 mg, yield: 35%). ESI-MS: 415.20 (M + H) *. * H NMR (400 MHz, MeOD) at 8.03 (d, 1H), 6.89 (s, 1H), 6.78 (dd, 1H), 4.58 (m, 1H), 4.15- 4.03 (m, 4H), 3.22 (t, 2H), 2.79 (q, 1H), 2.64 (t, 2H), 2.22 (m, 1H), 2.11 (d , 2H), 1.78-1.69 (m, 5H), 1.67-1.56
(m, 2H). Example 302: 2 - ((trans) -4-tert-butylcyclohexyloxy) quinoline-6-carbaldehyde
1. Mitsunobu NS ma POLIS ALI 2. BuLi, DMF “o | nNê The mixture of 6-bromo-quinolin-2-ol (500 mg, 0.002 mol), cis-tert-Butyl-cyclohexanol (418.5 mg, 0.002678 mol), and triphenylphosphine (702.4 mg, 0.002678 mol) in toluene (4.754 ml, 0.04463 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.5273 ml, 0.002678 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was carried out in DCM and subjected to chromatographic purification with EtOAc / hexane 10 (0: 100 to 40:60) to provide the product as a white solid (253 mg, 30%). LCMS Rt = 2.82 min (m / z = 364.45, M + 2, 100%). 6-Bromo-2- (4-tert-Butyl-cyclohexyloxy) -quinoline (115 mg, 0.317 mmol) in tetrahydrofuran (2.6 mL, 32 mmol) was added with 2.0 M butylithium in cyclohexane. hexane (0.48 mL, 0.95 mmol) at -78 ° C and were stirred for 15 min. N, N-dimethylformamide (0.12 ml, 1.6 mmoles) was added and was stirred for 30 minutes. When the reaction is complete, 1M HCl was added and, after 5 min at -78ºC, NaHCO; saturated was added and extracted with EtOAc. The organic layer was concentrated and purified by silica gel chromatography using PE / EA (0-50%) as the eluent to provide the product as a gel (30.6 mg, 31%). LCMS Rt = 2.49 min m / z = 312.51 ([M + 1], 100%). Example 303: 3 - ((2 - ((trans) -4-tert-butylcyclohexyloxy) quinolin-6-yl) methylamino) propanoic acid 9 pa 02H A
POLI PEN OO “o Le“ o - o A solution of 2- (4-ferc-Butyl-cyclohexyloxy) -quinoline-6- —carbaldehyde (30.8 mg, 0.0983 mmol) and Beta-alanine (8 , 75 mg, 0.0983 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 hours. The yellow solution was cooled to room temperature and sodium cyanoborohydride (7.41 mg, 0.118 mmol) was added and heated to reflux for 1 hour. Afterwards, it was cooled to room temperature, citric acid was added and concentrated low. The solid was suspended in water and filtered, and the collected solid was washed thoroughly with water. HPLC purification from the solid gave the product (7.5 mg, 15%). LCMS Rt = 1.60 min m / z = 385.49 [M + 1]. 1H NMR (400MHz, MeOD) ô = 8.14 (d, J = 8.8 Hz, 1 H), 7.92 (s, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.72 (d, J = 10.7 Hz, 1 H), 6.96 (d J = 8.8 Hz, 1 H), 5.29 - 5.09 (m, 1 H), 4.40 (s, 2 H), 3.36 (t, J = 5.8 Hz, 2 H), 2.79 (t, J = 6.7 Hz, 2 H), 2.30 (d, J = 10.9 Hz, 2 H), 1.94 (d, J = 12.9 Hz, 2H), 1.55 -1.06 (m, 5H) 0.94 (s 9H). Ú Example 304: methyl 6- (spiro [4.5] decan-8-yloxy) -2-naphthoate
OO y Cf M itsunobu dx fe Ho o The mixture of spiro [4.5] decan-8-ol (0.915 g, 0.00593 mol), methyl ester of 6-hydroxy-naphthalene-2-carboxylic acid (1.00 g, 0.00494 mol) and triphenylphosphine (1.56 g, 0.00593 mol) in toluene (10 mL, 0.1 mol) was heated to reflux, and diisopropyl azodicarboxylate (1.17 mL, 0, 00593 mol) was added dropwise and was stirred and refluxed for 6 hours. The mixture was carried out in DCM and subjected to chromatographic purification with EtO-Ac / hexane (0: 100 to 40:60) to provide the product as a white solid (1.029, 61%). LCMS Rt = 2.58 min, m / z = 339.34, (M + 1, 100%). Example 305: (6- (spiro [4.5] decan-8-yloxy) naphthalen-2-yl)] methanol
C o with La A. OS o 5 o 6- (Spiro [4.5] Jdec-8-yloxy) -naphthalene-2-carboxylic acid methyl ester (0.312 g, 0.000922 mol) in tetrahydrofuran (9 mL, 0 , 1 mol) and 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (2.76 mL, 0.00276 —mol) were added at 0 ° C. After stirring at room temperature for 2 hours, quenched with EtOAc, then Rochele's salt was added and stirred at room temperature for 1 hour. Extra-
EtOAc, c / c gave the product as a white solid (257.2 mg, 90%). LCMS Rt = 2.21 min m / z = 293.30 ([M-17], 100%). Example 306: 6- (spiro [4.5] decan-8-yloxy) -2-naphthaldehyde oo [6- (spiro [4.5] dec-8-yloxy) -naphthalen-2-yl] -methanol (2572 mg, 0, 8285 mmol) in methylene chloride (9 mL, 100 mmol) was added in Dess-Martin periodinane (0.492 g, 1.16 mmol) and was stirred at room temperature for 1 hour. After passing through the gel pad, the solvent was concentrated low to provide the product as a solid (256 mg, 100%). LCMS Rt = 2.44 min m / z = 309.56 ([M + 1], 100%). 7 10 Example 307: 3 - ((6- (Spiro [4.5] decan-8-yloxy) naphthalen-2-yl) methylamino) propanoic acid À Han CO AD cs NaBH; CN Ss eo
ATI TO CO A solution of 6- (spiro [4.5] dec-8-yloxy) -naphthalene-2-carbaldehyde (229.5 mg, 0.7441 mmol) and Beta-Alanine (66.3 mg, 0.744 mmol) in ethanol ( 1 mL, 20 mmol) was heated to reflux for 2 hours. The yellow solution was cooled to room temperature and sodium cyanoborohydride (56.1 mg, 0.893 mmol) was added and heated to reflux for 1 hour. Afterwards, it was cooled to room temperature, citric acid was added and concentrated low. Extraction with DCM and preparative HPLC provided the product as a white solid (88 mg, 31%). LCMS Rt = 1.52 min / z = 382.30 [M + 1]. * H NMR (400 MHz, MeOD) ô = 7.89 (s, 1 H), 7.83 (d, J = 8.5 Hz, 1 H), 7.80 (d, J = 9.0 Hz , 1 H), 7.48 (dd, J = 1.7, 85Hz, 1H), 7.27 (s, 1 H), 7.19 (dd, J = 2.3, 8.9 Hz, 1 H), 4.55 - 4.44 (m, 1 H), 4.35 (s, 2 H), 3.36 - 3.32 (m, 2 H), 2.76 (t, J = 6 , 8 Hz, 2 H), 2.09 - 1.33 (m, 16 H). The sequence used to make 3 - ((6- (spiro [4.5] decan-8-yloc) naphthalen-2-yl) Mmethylamino) propanoic acid was used to synthesize the compound below using the appropriate alcohol as the starting material. Example 308: Acid 3 - ((6- (spiro [5.5] undecan-3-
yloxy) naphthalen-2-yl)] methylamino) propanoic Ê Ha CH oo A solution of G6- (spiro [5.5Jundec-3-yloxy) -naphthalene-2-carbaldehyde (150 mg, 0.46 mmol) and Beta- Alanine (41.4 mg, 0.465 mmol) in ethanol (0.7 mL, 10 mmol) was heated to reflux for 2 hours.
The yellow solution was cooled to room temperature and sodium cyanoborohydride (35.1 mg, 0.558 mmol) was added and was heated to reflux for 1 hour.
Afterwards, it was cooled to room temperature, citric acid was added and concentrated low.
LCMS showed 1.59 min 396.30 [M + 1]. The solid was suspended in water and extracted with DCM.
Preparative HPLC CC “10 provided the product (42 mg, 23%). LCMS Rt = 1.59 min m / z = 396.30 [M + 1]. 1H NMR (400 MHz, MeOD) δ = 7.89 (br. S, 1 H), 7.86 - 7.74 (m, 2H), 7.48 (d, J = 8.3 Hz, 1 H) , 7.26 (br. S., 1 H), 7.19 (br. S., 1 H), 448 (br. S., 1H), 4.35 (br. S., 2 H), 3.34 (s, 2H), 2.76 (s, 2H), 1.91 (br. S., 2H), 1.68 (br. S., 4 H), 1.55 - 1.21 (m, 10 H). Example 309: Additional compounds of formula (1) Each of the following additional compounds of formula (1) was prepared in a manner analogous to those described above: 4 - (((2- (trans-4-fer-butylcyclohexyloxy) naphthalenic acid I) methyl) amino) butyric; (R) -1 - ((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6- iNmethyl) piperidine-3-carboxylic acid; (S) -1 - ((2- (trans-4- tert-butylcyclohexyloxy) naphthalen-6-iN) methyl) piperidine-3-carboxylic acid 4 - ((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6-ylmethyl) butyric acid; (2- (trans-4-fer-butylcyclohexyloxy) naphthalen-6-yl) methyl) pentanoic; 6 - ((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6- i) methyl) hexanoic; 4- (6- (trans-4-tert-butylcyclohexyloxy) -3,4-dihydroisoquinolin-
2 (1H) -yl) butanoic; —4- (6- (cis-4-tert-butylcyclohexyloxy) -3,4-dihydroisoquinolin-2 (1H) -yl) butanoic acid; 2- (2- (5- (trans-4-tert-butylcyclohexyloxy) indolin-1-i1) -2-oxoethylamino) ethylphosphonic acid; and 3-amino-4- (5- (trans-4-tert-butylcyclohexyloxy) indolin-1-i1) -4-oxo-butanoic acid.
Example 310: Additional compounds of formula (1) Each of the following additional compounds of formula (1) was prepared in a manner analogous to those described above: acid 1 - ((6- (spiro [5.5] undecan-3-yloxy) ) naphthalen-2-iNmethyl) azetidine-3-carboxylic; It is 1 - ((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-iN) sulfonyl) azetidine-3-carboxylic; 3 - (( (6- (trans4-fer-butylcyclohexyloxy) naphthalen-2-i) methyl) amino) -N- (methylsuifonyl) propionamide; 5- (2 - (((6- (trans-4-tert-butylcyclohexyloxy ) naphthalen-2-iNmethyl) amino) ethyl) tetrazo |; - 1-hydroxy-2 - ((((6- (trans-4-fer-butylcyclohexyloxy) naphthalen-2-ylmethyl) amino) ethylphosphonic acid; - ((((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2- iNmethyl) amino) propylphosphonic acid; 3 - (((6- (trans-4-tert-butylcicio-hexyloxy) quinoxalin-2- iN) methyl) amino) propionic acid; 3 - ((((7- (trans- 4- (trans- 4-fer-butylcyclohexyloxy) quinolin-3-iDmethyl) amino); 3 - ((((7- (trans-4- ferc-butylcyclohexyloxy) cinnolin-3- i) methyl) amino) propionic; 3 - (((5- (trans-4-te) acid rc-butylcycle-hexyloxy) -1-methylindol-2-ylmethyl)> amino) propionic; 3 - (((6- (trans-4-fer-butylcyclohexyloxy) -1-methylindol-2-yl) methyl) amino) propionic acid;
3 - (((2- (trans-4-tert-butylcyclohexyloxy) quinazolin-6-iN) methyl) amino) propionic acid; 3 - (((2- (trans-4-fer-butylcyclohexyloxy) -1-methylindol-6- i) methyl) amino) propionic acid; 3 - (((2- (trans-4-fer-butylcicio-hexyloxy) -1-methylindol-5- i) methyl) amino) propionic acid; and 3 - (((((3- (trans-4-tert-butylcyclohexyloxy) -1-methylindol-6- i) methyl) amino) propionic acid.
Example 310: Calcium Mobilization Compounds that are not specific for the S1P, 1 receptor, for example, have S1P3 activity, may cause undesirable side effects. . Thus, compounds are tested to identify those that are specific for S1P activity, and have little or no activity, or are antagonists of S1P activity; 3. Thus, the test compounds are tested in a calcium mobilization test to determine agonist activity at both S1P receptors; human or S1P, human, and antagonistic activity only at the S1P receptor; human.
The procedure is essentially as described in Davis et al. (2005) Journal of Biological Chemistry, vol. 280, pp. 9833-9841, which is incorporated by reference in its entirety with the following modifications.
Calcium mobilization assays were performed on recombinant CHEM cells expressing S1P1, S1P2, S1P3, S1Pa, or S1Ps; acquired from Millipore (Billerica, MA). To detect free intracellular calcium, S1P ,, S1P>, S1P3, S1P4, or S1P; s cells were loaded with FLIPR Calcium 4 dye from Molecular Devices (Sunnyvale, CA). Cells were explored for calcium mobilization using FLIPRTETRA equipped with a 96-well dispensing lid.
Example 311: In vivo Evaluation Assays Measurement of circulating lymphocytes: Compounds are dissolved in 30% HPCD.
Mice (C57bl / 6 male, 6 to 10 weeks of age) - are administered at 0.5 and 5 mg / kg of a compound via a 30% HPCD oral probe is included as a negative control.
Blood is collected from the retro-orbital sinus 5 and 24 hours after
drug administration under short isoflurane anesthesia.
Complete blood samples are subjected to hematological analysis.
Peripheral lymphocyte count is determined using an automated analyzer (HEMAVETTM 3700). Subpopulations of peripheral blood lymphocytes are stained by specific fluorochrome-conjugated antibodies and analyzed using a fluorescently activated cell classifier (FACSCALIBUR "" "). Three mice are used to assess the lymphocyte depletion activity of each compound evaluated.
Compounds of formula (1) can induce complete lymphopenia at times as short as 4 hours or less while 48 hours or more; per ! example, 4 to 36 hours, or 5 to 24 hours.
In some cases, a compound of the formula can induce complete lymphopenia at 5 hours and partial lymphopenia at 24 hours.
The dosage required to induce lymphopenia can be in the range, for example, 0.001 mg / kg to 100 mg / kg; or 0.01 mg / kg to 10 mg / kg.
The dosage can be 10 mg / kg or less, such as 5 mg / kg or less, 1 mg / kg or less, or 0.1 mg / kg or less.
Example 312: Evaluation of the Heart Effect A related undesirable effect of an S1P agonist can be, for example, bradycardia.
Assays are conducted to determine the effect of test compounds on cardiac function.
The effects of the compounds on cardiac function are monitored using the ECG gene recording system.
ECGs are recorded in conscious mice (C57bl / 6 male, 6 to 10 weeks of age) before and after administration of the compound.
Compounds were administered by oral tube.
Three mice are used to cease the heart rate of each compound.
Compounds are found to have little or no effect on heart rate at therapeutic levels.
The abbreviations used here have their conventional meanings within clinical, chemical, and biological techniques.
In the case of any inconsistencies, this description, including any definitions, will prevail.
The disclosures of any and all patents, patent applications and publications mentioned in this document are expressly incorporated into this document by reference in their entirety in this disclosure.
Illustrative modalities of this disclosure are discussed and reference is made to possible variations within the scope of this disclosure.
These and other variations and - modifications to the description will be apparent to those skilled in the art without departing from the scope of the disclosure and it should be understood that this disclosure and the claims shown below are not limited to the illustrative modalities set forth herein.

权利要求:
Claims (13)
[1]
1. Compound, characterized by the fact that it has the formula (lla), (Illa) or (Illb):. Rx x x2 xx O Ô Rº DOS DON CcyWw O ô "eyWw ÓX ew AN XP xxx XP x (Ila) (Ma) (Hb) where: each of X ', X , X , Xº, Xº and Xº is independently , hydrogen, halo, hydroxy, nitro, cyano, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, alkoxy, haloalkoxy, cycloalkoxy, halocycloalkoxy, acyl, aminoacyl, -N (RR9), -N (RÍSO2RS, -SO2R "" , -S (O) 2N (RR9), -CO2R, trialkylamino, aryl, or heteroaryl; Wé-O-; Cy has the formula: | Ria
ADE “And when: Z! is - [C (RRIL; 7º is [C (RRY] y; Zº is [C (RIRI] -; each of x, y, and z is independently 1, 2, or 3; each of Rº is, independently, hydrogen, halo, hydroxy, alkyl, alkenyl, alkoxy, or cycloalkyl; each of Rº is independently hydrogen, halo, hydroxy, alkyl, alguenyl, alkoxy, or cycloalkyl; R ' and R' * are, independently , hydrogen, halo, hydroxy, nitro, cyan, -NRRº, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, heterocyclylalkyl, arylalkyl, heteroarylalkyl,
roarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, ticalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl; : or R ”* and R'º”, when taken together, are C2-Cs alkylene or C2-Cs alkenylene;
R ** and R are independently hydrogen, halo, hydroxy, ni- tro, cyano, -NRÍRS, alkyl, haloalkyl, cycloalkyl, cycloalkenyl, cicloalqui- lalquila, cicloalquenilalquila, heterociclilalquila, arylalkyl, heteroarilalquila, alkoxy, cycloalkylalkoxy, cicloalquenilalcóxi heterocyclylalkoxy, arylalkoxy, het -
roarylalkoxy, acyl, cycloalkylacyl, cycloalkenylacyl, heterocyclylacyl, arylacyl, heteroarylacyl, thioalkyl, alkenyl, alkynyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl;
or R ' and Rº , when taken together, are C1-Cs alkylene or C2-Cs alkenylene;
where R'º, R'º, Rº, and R are each independently substituted by O to 5 substituents selected from halo, hydroxy, nitro, cyano, -NRÍRº, or -CO2R ';
R is -JILILZT;
L is -C (O) -, -S (O) a-, -N (RÍC (O) -, -N (R) -, -C (RR9) -, -C (RR9) -
C (RIR9) -, or a link;
J is - [C (RÍRIJn-, -N (RÍ- [C (R'R9)], -, or a bond, where each n is independently an integer from 0 to 5; or J is
D2 o> o— | D in which AN - &
each of D 'and D , is independently, N, or Ns
D is - [C (RRIl, [C (RRIINIR-, - [C (RRIO-, -N (RÍ-, or -N (RÍ-ICCR'R9); and
Dº is [C (RRIIm-;
am io ká Ton ID eméN 1929 naun
: or O; 1st is -C (RIR9) -, -C (RÍG) -, -C (G) 2-, -CI (RIRI) -C (R'R9) -, -C (RÍR9) - CIR'G) -, -C (RÍRY) -C (G) 2-, or a bond; as long as at least one of L ', J, and 1st is not a bond; T 'is -C (O) ORI, -C (OINIRÍS (O) LR', tetrazolyl, -S (0) OR, -C (O) NHC (O) -Ró —-SiO) OH, -B (OH ), - -N (RÍS (OLR, - -S (O) .NRS, -OP (OX (OR $ OR, or -P (0) (OR; each of G is independently, hydrogen, hydroxy, one ha - logene or trifluoromethyl; each of RI, independently, is hydrogen, hydroxy, halo, alkyl, haloalkyl, alguenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl or NH>; in which each of alkyl, cycloalkyl , cycloalkenyl, aryl, heteroaryl and heterocycle is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halo, oxo, -CN, -CHO, -CG; 3, -OH, -NO ,, alkyl, -OCG ; 3, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulfonyl, alkylaminosulfonyl and dialguylaminosutlphonyl; each of Rº, independently, is hydrogen, hydroxy, halo, alkyl, alkyl, halo, alkyl, haloalkyl, haloalkyl, alkyl , cycloalkenyl, aryl, heteroaryl, or het erocyclic; wherein each of alkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycle is optionally substituted by 1 to 5 substituents independently selected from the group consisting of halo, oxo, -CN, -CHO, -CG; 3, -OH , -NO ;, alkyd, -OCG ;, alkoxy, cycloalkoxy, cycloalkenoxy, amino, alkylamino, dialkylamino, acylamino, aminoacyl, alkylsulphonyl, alkylaminosulfonyl, and dialkylaminosulfonyl; or a pharmaceutically acceptable salt thereof.
[2]
2. Compound, according to claim 1, characterized by the fact that L 'is -C (RR9) - and Jé “NR or So
No in .
each of D 'and D , is independently, - N, or D is [C (RRIJc, IC (RRIINIRY-, LC (RRII-O-, -N (RÍ-, or -N (R) -ICCRR9] :; and Dº is [C (RRIIm-; where k is 1 or 2, and m is 0, 1,2, or 3, provided that no more than 2 ring atoms from D 'to D * are N or O, or a pharmaceutically acceptable salt thereof.
[3]
3. Compound according to claim 1 or 2, characterized by the fact that Tº is -C (O) (ORÍ, -C (O) N (RÍS (O2RÍ, -OP (O) (ORÍOR, - P (O2) (OR, tetrazolyl or -S (0) 2OR; or a pharmaceutically acceptable salt thereof.
[4]
4. A compound according to claim 1, characterized by the fact that Z * is -CH2CH7-, 2 is -CH7-, and Zº is a link, or a sa! pharmaceutically acceptable.
[5]
5. Compound according to claim 1, characterized by the fact that R ' and Rºº are both hydrogen, and R'º is fluorine, chlorine, bromine, iodine, methyl, trifluroromethyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, t-butyl, n-pentyl, isopentyl, 1,1 -dimethylpropyl, neopentyl, cyclopentyl, n-hexyl, cyclohexyl, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy , 1,1-dimethylpropoxy, neopentyloxy, cyclopentyloxy, n-hexyloxy, or cyclohexyloxy or a pharmaceutically acceptable salt thereof.
[6]
6. Compound, characterized by the fact that it is selected from the group consisting of: 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl)] methylamino) -N- (phenylsulfonyl) propanamide ; 3 - ((6- (trans-4-tert-butylcyclohexyloxy) -S- (trifluormethyl) naphthalen-2-iN) methylamino) -N- (phenylsulfonyl) propanamide; 2 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-ylmethylamino) propanoic acid;
2 - (((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-iN) methyl) (methyl) amino) acetic acid; 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-: yl) methylamino) propanoic acid; 3 - (((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-methyl) (methyl) amino) propanoic acid; 1 - ((6- (trans-4-tert-butylcyclohexyloxy)) naphthalen-2-yl)] methyl) azetidine-3-carboxylic acid 1 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-yl) methyl) pyrrolidine-3-carboxylic; 1 - ((6- (trans-4-ferc-butylcyclo) naphthalen-2-yl)] methyl) piperidine-4-carboxylic acid 1 - ((6- (trans-4-ferc-butylcyclo) -hexyloxy) -5- (trifluormethyl) naphthalen-2-yl)] methyl) azetidine-3-carboxylic acid 3 - ((6- (trans-4-tert-butylcyclohexyloxy) -5- (trifluormetiN) naphthalen- 2-yl)] methylamino) propanoic acid; 3 - ((6- (trans-4-tert-butylcyclohexyloxy) naphthalen-2-iNmethylamino) -2,2-difluoropropanoic acid - 2,2-difluoro-3- ((6- (spiro [5.5] Jundecan-3-yloxy) naphthalen-2-yl) methylamino) propanoic acid 2 - (((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6- iN) methyl) amino) acetic acid; 4 - (((((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6- iNmethyl)> amino) butyric acid; 4 - ((((2- (trans-4-tert -butylcyclohexyloxy) naphthalen-6-methylmethyl) butyric; (R) -1 - ((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6-yl)] methyl!) piperidine-3-carboxylic acid; (S) -1 - ((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6-yl) methyl!) piperidine-3-carboxylic acid; acid 4 - ((O- (trans-4-tare-butylicio-hexyloxytaphthalen-6-
. 5 - ((2- (trans-4-fer-butylcyclohexyloxy) naphthalen-6-yl) Õmethyl) pentanoic acid; 6 - ((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-S-yl) methyl) hexanoic acid; 4- (6- (trans-4-fer-butylcyclohexyloxy) -3,4-dihydroisoquinolin-2 (1H) -i) butanoic acid; —4- (6- (cis-4-fer-butylcyclohexyloxy) -3,4-dihydroisoquinolin-2 (1H) -yl) butanoic acid; 2 - ((((2- (trans-4-tert-butylcyclohexyloxy) naphthalen-6-ylmethyl) amino) ethylphosphonic acid; 2- (2- (5- (trans-4-tert-butylcyclohexyloxy) indolin -1-11) -2- oxoethylamino) ethylphosphonic; 3-amino-4- (5- (trans-4-tert-butylcyclohexyloxy) indolin-1-i1) -4-oxo-butanoic acid —34 [ 6- (4-tert-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -propionic; f1 [6- (4-tert-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -amino) -acetic acid; —44 [6- (4-tert-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] - aminol-butyric acid; 1- [6- (4-tert-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -azetidine-3-carboxylic acid; and 1- [6- (4-tert-butyl-cyclohexyloxy) -8-methyl-naphthalen-2-ylmethyl] -pyrrolidine-3-carboxylate; or a pharmaceutically acceptable salt thereof.
[7]
7. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and a compound, as defined in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof.
[8]
8. Use of a compound, as defined in any of the claims 193 8 Aariim sal pharmacrnarniticamenta acaitával of the mechanism ca.
. therapy for the treatment or prevention of multiple sclerosis, autoimmune diseases, chronic inflammatory disorders, asthma, inflammatory neuropathies, | arthritis, transplant rejection, Crohn's disease, ulcerative colitis, lupus eri. thematic, psoriasis, ischemia-reperfusion injury, solid tumors, tumor metastases, diseases associated with angiogenesis, vascular diseases, pain conditions, acute viral diseases, intestinal inflammatory conditions, insulin dependent or non-insulin diabetes .
[9]
9. Use, according to claim 8, characterized by the fact that the pathological condition is neuropathic pain or an autoimmune disease.
[10]
10. Use according to claim 8, characterized by the fact that the autoimmune disease is uveitis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel diseases or multiple sclerosis.
[11]
11. Use, according to claim 8, characterized by the fact that it additionally includes the use of a drug selected from the group consisting of: corticosteroids, bronchodilators, antiasthmatics, anti-inflammatories, antirheumatics, immunosuppressants, antimetabolites, immunomodulators , antipsoriatics and antidiabetics.
[12]
12. Use according to claim 8, characterized by the fact that the autoimmune disease is multiple sclerosis.
[13]
A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, characterized in that it is for use in the treatment or prevention of multiple sclerosis, autoimmune diseases, chronic inflammatory disorders, asthma, neuropathies inflammatory, arthritis, transplant rejection, Crohn's disease, ulcerative colitis, lupus erythematosus, psoriasis, ischemia-reperfusion injury, solid tumors, tumor metastases, diseases associated with angiogenesis, vascular diseases, pain conditions, diseases acute viruses, inflammatory bowel conditions, insulin-dependent or non-insulin diabetes.

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法律状态:
2020-10-13| B25D| Requested change of name of applicant approved|Owner name: BIOGEN MA INC. (US) |

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2020-10-20| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-10-27| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-12-01| B15K| Others concerning applications: alteration of classification|Free format text: A CLASSIFICACAO ANTERIOR ERA: A01N 43/42 Ipc: A61K 31/085 (2006.01), A61P 37/00 (2006.01), A61K |

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2021-04-13| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-04-20| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-08-31| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-11-23| B350| Update of information on the portal [chapter 15.35 patent gazette]|

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2021-12-07| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US23153909P| true| 2009-08-05|2009-08-05|

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US61/231,539|2009-08-05|

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PCT/US2010/044607|WO2011017561A1|2009-08-05|2010-08-05|Bicyclic aryl sphingosine 1-phosphate analogs|

---