benzoazepines replaced as bell-fold receptor modulators

专利摘要:
BENZOAZEPINES SUBSTITUTED AS MODULATORS OF BELL DOUBLE RECEIVER.Compositions and methods useful for modulating signaling through TLR7 and / or TLR8 bell-type receivers are provided. The compositions and methods have use in the treatment or prevention of disease, including cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft versus host disease.
公开号:BR112012003757A2
申请号:R112012003757-9
申请日:2010-08-18
公开日:2020-08-11
发明作者:James Jeffry Howbert；Gregory Dietsch；Robert Hershberg；Laurence E. Burgess；Joseph P. Lyssikatos；Brad Newhouse；Hong Woon Yang
申请人:Ventirx Pharmaceuticals, Inc.；Array Biopharma , Inc；
IPC主号:

专利说明:

a and Invention Patent Descriptive Report for "BENZOAZE-PINAS REPLACED AS MODULATORS OF RECEIVER TYPE DOUBLE BELL".
RELATED APPLICATIONS This application claims priority for United States Patent Application No. 61 / 234,969 filed on August 18, 2009 and United States Patent Application No. 61 / 235,586 filed on August 20, 2009. The contents of the aforementioned orders are hereby incorporated by reference in their entirety.
BACKGROUND OF THE INVENTION Field of the Invention "This invention relates to methods and compositions for modulating immune function. More specifically, this invention relates to compositions and methods for modulating TLR7-me mediated signaling. 15 and / orTLR8. & Description of the State of the Art Stimulation of the immune system, which includes stimulation of either or both innate and adaptive immunity, is a complex phenomenon that can result in protective or adverse physiological results for the host. There has been an increased interest in the mechanisms that underlie innate immunity, which is believed to initiate and support adaptive immunity This interest was fueled in part by the recent discovery of a family of highly conserved standard recognition receptor proteins known as receptor-like receptors. bell toll (TLRs) believed to be involved in innate immunity as receptors for molecular patterns associated with pathogen (PAMPs). Compositions and methods useful for modulating innate immunity are therefore of great interest, as they can produce therapeutic methods for conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft disease versus GvHD host) , infection, cancer, and immunodeficiency. Bell-like receptors (TLRs) are proteins
Type transmembrane CRM | that allow organisms (including mammals) to detect microbes and initiate an innate immune response (Beutler, B., Nature 2004, 430: 257-263). They contain homologous cytoplasmic domains and leucine-rich extracellular domains and typically form homodimers that sense extracellular (or internalized) signals and subsequently initiate a signal transduction cascade through adapter molecules such as MyD88 (myeloid differentiation factor 88). There is such a high homology in the cytoplasmic domains of TLRs that it was initially suggested that the series of similar signaling reactions exist for all TL-Rs (Re, F., Strominger, J.
L., Immunobiology 2004, 209: 191-198). In fact, all TLRs can activate NF-KkKB and MAP kinases; however, the cytokine / chemokine release profiles derived from TLR activation appear E unique to each TLR.
In addition, the series of signaling reactions that: TLRs stimulate is very similar to the series of reactions that the cyto- .. 15 cina Il-1R receptor induces.
This may be due to the homology that these receptors have. they share, that is, TIR domains (bell fold homology / IL-1R). Since the TIR domain is activated in TLRs and MyD88 is recruited, the activation of the IRAK family of serine / tronin kinase results that eventually promote Ik-B degradation and NF-kB activation (Means T .
And another, Life Sci. 2000, 68: 2417258). While this cascade appears to be designed to allow extracellular stimuli to promote intracellular events, there is evidence that some TLRs migrate to endosomes where signaling can also be initiated.
This process can provide intimate contact with swallowed microbes and adjusts to the role that these receptors play in the innate immune response (Underhill, D.
M., and another, Nature 1999, 401: 811-815). This process can also allow host nucleic acids, released by injured tissues (for example, in inflammatory disease) or apoptosis to release a response through endosomal presentation.
Among mammals, there are 11 TLRs that coordinate this rapid response.
A hypothesis postponed years ago (Ja- neway, C.
A., Jr., Cold Spring Harb.
Syrup.
Quant.
Biol. 1989, 54: 1-13) that the innate immune response initiates the adaptive immune response through the pattern
Pair of TLR activation caused by microbes has now been proven.
In this way, the molecular patterns associated with the pathogen (PAMP's) present by a diverse group of infectious organisms result in an innate immune response involving certain cytokines, chemokines and growth factors followed by an adapted adaptive immune response. for the infectious pathogen by presenting antigen resulting in antibody production and cytotoxic T cell generation.
Gram-negative bacterial lipopolysaccharide (LPS) has long been appreciated as an adjuvant and immunostimulant as a pharmacological tool to induce an inflammatory reaction in mammals similar to septic shock.
Using a genetic method, TLRA4 was identified as the LPS receptor.
The discovery that LPS is a TLRA4 agonist illustrates the usefulness of TLR modulation for vaccine and human disease therapy (Aderem, A .; Ulevitch, R.
J., Nature 2000, 406: 782-787). It is currently appreciated that several TLR agonists can activate B cells, neutrophils,% mast cells, eosinophils, endothelial cells and various types of epithelium in addition to the regulation of proliferation and apoptosis of certain cell types.
To date, TLR7 and TLR8, which are somewhat similar, have been characterized as receptors for single-stranded RNA found in endosomal compartments and, therefore, believed to be important for the immune response to the viral challenge.
Imiquimod, an approved topical antiviral / anticancer drug, was recently described as a TLR7 agonist that has demonstrated clinical efficacy in certain skin disorders (Miller R.
L., and another, Int. J.
Imnunopharm. 1999, 21: 1-14). This small molecule drug has been described as a structural mimetic of ssSRNA.
TLR8 was first described in 2000 (Du, X ,, and another, European Cytokine Network 2000 (Set.), 11 (3): 362-371) and was quickly designated to be involved with the innate immune response to viral infection (Miettinen, M., and another, Genes and Immunity 2001 (October), 2 (6): 349-355). Recently it has been reported that certain imidazoquinoline compounds having antiviral activity are TLR7 and TLR8 binders (Hemmi H., and another, (2002) Nat.
Immunol. 3: 196-200; Jurk M., and another, (2002) Nat.
Immu-
- nol. 3: 499). Imidazoquinolines are potent synthetic activators of immune cells with antiviral and antitumor properties. Using macrophages of wild-type and MyD88-deficient mice, Hemmi and others recently reported that two imidazoquinolines, imiquimod and resiquimod - (R848), induce tumor necrosis factor (TNF) and interleucin-12 (11 -12) and activate NF-icB only in wild-type cells, consistent with activation through a TLR (Hemmi H., and another, (2002) Nat. Immunol. 3: 196-200). Macrophages from TLR7-deficient mice, but not other TLRs, did not produce any detectable cytokine in response to these imidazoquinolines. In addition, imidazoquinolines induced dose-dependent proliferation of splenic B cells and the activation of cascades of 'intracellular signaling in wild-type cells, but not camun-. TLR7 dongles - / -. Luciferase analysis established that the expression of human TLR7, but not TLR2 or TLRA, in embryonic kidney cells - 15 results in activation of NF-KB in response to resiquimod. The findings of 'Hemmi et al. Thus suggest that these imidazoquinoline compounds are unnatural TLR7 ligands that can induce signaling through TLR7. It has recently been reported that R848 is also a linker for human TLR8 (Jurk M., and another, (2002) Nat. Immunol. 3: 499). In view of the great therapeutic potential for compounds that modulate bell-like receptors, and in spite of the work that has already been done, there is a continuing need to expand their use and therapeutic benefits.
SUMMARY OF THE INVENTION The compositions described here are useful for modulating immune responses in vitro and in vivo. Such compositions will find use in a variety of clinical applications, such as in methods for the treatment or prevention of conditions involving unwanted immune activity, including inflammatory and autoimmune disorders. Specifically, the invention relates to a compound having the formula |
: o = Rs Fes Y N NH> (O) or a tautomer, enantiomer or salt thereof, where:
Y is (O) MCH), R "';
x is selected from O and 1;
y is selected from 0, 1,2, and 3;
R ''! is selected from aryl, heteroaryl, and saturated or partially saturated heterocycle, where when x is O, said aryl or heteroaryl is replaced with -C (O) NR'R or T;
"R 'and R are independently selected from hydrogen and alkyl, wherein said alkyl is optionally substituted with - o C (O) O (CHa) R ' or R * and R together with the nitrogen atom to which they are attached they form a saturated heterocyclic ring; and t is selected from 0, 1,2, and 3; R ' is selected from cycloalkyl and aryl; T is selected from heterocycle, - (CHR ”), ORº, - (O). (CH2) .C (O) Rº, -OSOR” , and -CH (OH) CH2OH; R ”is selected from H or -OH; Rº is selected from -OR ** and alkyl; Rº is selected from alkyl and H; R * º is selected from alkyl, - (CH2) R " , and hydrogen, where said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine; R ** is selected from -OH, alkyd, CF3, cycloalkyl, heterocycle, aryl, and heteroaryl; u is selected from O and 1; z is selected from 1.2, e3; s is selected from 1 and 2; Rº is selected from -NRºRº and -OR "º; Rº and Rº are independently selected from H, alkyl, -
- (O) (CH2), P; wherein said alkyl is optionally substituted with one or more -OH; q is selected from O and 1; r is selected from 0, 1,2, and 3; P is selected from aryl, -SO2Rº, -C (O) NH>, and heterocycle; and Rº is selected from -NH>, -NH (alkyl), -N (alkyl) o, provided that when R * is aryl or heteroaryl, then at x + y> 1; or b) —R "” is replaced with T; or í c) Rº is NRºRº and at least one of Rº or Rº is É [(O) (CH2) P] eq + r> 1; or S 15 d) at least one of R * or R 'is alkyl substituted with -. C (O0) O (CHa) R " . The invention also relates to a compound having the formula Il:
O = Rs | 1-f * NH No.> w (11) or a tautomer, enantiomer or salt thereof where: W is selected from N, C-T and CH; and T and Rº are as defined in the formula. The invention also relates to a compound having the formula Il: o = Rs o OS NH2 (1) or a tautomer, enantiomer or salt thereof, where x, y, R and Rº are as defined in formula |; as long as
: when R ** is aryl or heteroaryl, then x + y> 1. The invention also relates to a compound having the formula IV: So = Ra | = Y "NH, (IV) or a tautomer, enantiomer or salt thereof, where Yv, R $, q, r and P are as defined in the formula |, eq + r> 1. The invention also relates to a compound having the formula V: o = Rs Rº CI =: 10º: o V) or a tautomer, enantiomer or salt thereof, where: Ri, R and Rº are as defined in formula |; and at least one of R ' or R 'is alkyl substituted with -C (O) O (CH 2) R' '. The invention also relates to a compound having the formula VI:
O == NRºRº
2. RU No. NH (VI) or a tautomer, enantiomer or salt thereof, where: R * 'is selected from saturated or partially saturated aryl and heterocycle, in which said aryl is replaced with T; T is selected from heterocycle, - (O) L (CH2) .C (O) Rº, e.- CH (OH) CH2OH; Rº is selected from -OR * º and alkyl; R * º is selected from alkyl, - (CH2) R " , and hydrogen, where said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;
. R * is selected from cycloalkyl and aryl; u is selected from O and 1; s is selected from 1e2, and R and Rº are independently alkyl; wherein said alkyl is optionally substituted with one or more -OH. The compounds of the invention can be used in combination with other known therapeutic agents. Accordingly, this invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of the invention, or a salt, in combination with a second therapeutic agent.
This invention also provides methods of modulating TLR7 and / or TLR8-mediated signaling, comprising contacting a cell: expressing TLR7 and / or TLR8 with an effective amount of a compound of the invention, or a salt thereof. In one aspect, the method inhibits TLR7 and / or TRL8-mediated immunostimulatory signaling.
- This invention also provides methods of modulating TLR7 and / or TLR8-mediated immunostimulation in an individual, comprising administering to a patient having or at risk of developing TLR7-mediated immunostimulation and / or TLR8 a compound of the invention , or even a balance, in an amount effective to inhibit TLR7 and / or TLR8-mediated immunostimulation in the individual.
This invention also provides methods of modulating TLR7 and / or TLR8-mediated immunostimulation in an individual, comprising administering to a patient having or at risk of developing TLR7-mediated immunostimulation and / or TLR8 a compound of the invention, or a salt thereof, in an amount effective to promote TLR7 and / or TLR8-mediated immunostimulation in the individual.
This invention also provides methods of treating or preventing a disease or condition by modulating cellular activities — mediated by TLR7- and / or TLR8, comprising administering to a warm-blooded animal, such as a mammal, for example, a human , having or at risk of developing said disease or condition, a compound of
. invention, or a salt thereof.
This invention also provides methods of modulating a mammal's immune system, comprising administering to a mammal a compound of the invention, or a salt thereof, in an effective amount for the said immune system.
Also provided is a compound of the invention, or a salt thereof for use as a medicament in the treatment of the diseases or conditions described herein (for example, cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft disease see - his host) in a mammal, for example, a human, who is suffering from such a disease or condition. The use of a com- is also provided. of the invention, a salt thereof, in the preparation of a medicine for the treatment of the diseases and conditions described here (for example, 'cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft versus host disease) ) in a mammal, for example, a human, who is suffering from such a disease or condition.
Also provided is a compound of the invention, or a salt thereof for use as a medicament in the prevention of the diseases or conditions described here (for example, cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and host verte disease) in a mammal, for example, a human, exposed to or predisposed to the disease or condition, but the mammal does not yet experience or exhibit the symptoms of such disease or condition. Also provided is the use of a compound of the invention, a salt thereof, in the preparation of a medicament for the treatment of the diseases and conditions described here (for example, cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection , and graft versus host disease) in a mammal, for example, a human, who is suffering from such a disease or condition.
The disease or condition is selected from, for example, cancer, autoimmune disease, infectious disease, inflammatory disorder, graft rejection, and graft versus host disease.
. This invention also provides kits comprising one or more compounds of the invention, or a salt thereof. The Kkit can also comprise a second compound or formulation comprising a second pharmaceutical agent.
Additional advantages and new features of this invention should be mentioned in part in the description that follows, and in part will become apparent to those skilled in the art in examining the following specification or may be instructed by the practice of the invention. The advantages of the invention can be realized and obtained by means of instruments, combinations, compositions, and methods particularly emphasized in the appended claims. . DETAILED DESCRIPTION OF THE INVENTION In certain aspects, the invention provides compositions and methods useful for the modulation of TLR7 and / or TLR8-mediated signaling. More specifically, an aspect of this invention provides a compound having the - formula |: o = R5 eus Y by NH, O) or a tautomer, enantiomer or salt thereof, where: Y is (O) (CHa), R "'; x is selected from O and 1; y is selected from 0, 1,2, e3; R' 'is selected from aryl, heteroaryl, and saturated or partially saturated heterocycle, where when x is O, the referred aryl or heteroaryl is substituted with -C (O) NR'R 'or T; R' and R 'are independently selected from hydrogen and alkyl, where said alkyl is optionally substituted with - C (O) O (CHa); R ' Or R' and R Together with the nitrogen atom to which they are attached form a saturated heterocyclic ring; t is selected from 0, 1,2, and 3;
. R * is selected from cycloalkyl and aryl;
T is selected from heterocycle, - (CHR ”) - OR , - (O) u (CH2) .C (O) Rº, -OSO2R" , and -CH (OH) CH2OH;
R ”is selected from H or -OH;
Rº is selected from -OR "º and alkyl;
Rº is selected from alkyl and H;
R * º is selected from alkyl, - (CH2) R ” , and hydrogen, in which said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;
R ' is selected from -OH, alkyl, CF3, cycloalkyl, heterocycle, aryl, and heteroaryl; "u is selected from O and 1; z is selected from 1,2, and 3; s is selected from 1 and 2;" 5 R $ is selected from -NRºRº and -OR "º;
. R and Rº are independently selected from H, alkyl, - (O0) to (CH2) .P; wherein said alkyl is optionally substituted with one or more -OH;
BR q is selected from 0 and 1; r is selected from 0, 1,2, and 3;
P is selected from aryl, -SO2Rº, -C (O) NH ,, and heterocycle; and
R $ is selected from -NH>, -NH (alkyl), -N (alkyl) 2, provided that when R ** is aryl or heteroaryl, then a) Xx + y> 1;
or b) R ** is replaced with T; or oc) Rº is NR'Rº and at least one of Rº or Rº is [(O) (CH2) .P] and q + r> 1;
or d) at least one of R 'or R be alkyl substituted with -
C (O) O (CHa) R '.
y In one embodiment, the invention relates to a compound having the formula | where R * is aryl or heteroaryl, and x + y> 1. In another embodiment, the invention relates to a compound having the formula | where R * is aryl or heteroaryl, and R * is replaced with T.
In another embodiment, the invention relates to a compound having the formula | where R ** is aryl or heteroaryl, and Rº is NRºRº where at least one of Rº or Rº is [(O) (CH2) .P] and q + r> 1.
In another embodiment, the invention relates to a compound having the formula | where R '' is aryl or heteroaryl, and at least one of R 'or D alkyl substituted with -C (O0) O (CH2) R " . In another embodiment, the invention relates to a compound: having the formula | where R '* is aryl or heteroaryl, R' * is replaced with T, T is: (O) U (CHo) .; C (O) Rº eu + s> 2. In another embodiment, the invention refers to a compound “15 having formular where R" 'is aryl or heteroaryl, R ** is replaced with T, and T. is selected from heterocycle, - (CHR ”), ORº , - (O) (CH2) .C (O) Rº, and -OSO2R ' . In another embodiment, the invention relates to a compound having the formula | where R ** is selected from Cg-C1o aryl, heteroaryl com-: comprising 1 to 4 heteroatoms selected from N, O and S, and saturated or partially saturated heterocycle comprising 1-4 selected heteroatoms from NO and S, wherein when x is 0, said CgÊ-C10 aryl or heteroaryl comprising 1 to 4 heteroatoms selected from N, O and S is replaced with -C (O) NR'R or T. One aspect of the invention relates to a compound having the form: o == Rs | 1-f * n = NH, wW (1) or a tautomer, enantiomer or salt thereof where: W is selected from N, C-T and CH and T and Rº are as defined
- above in the formula |. In one embodiment, the invention relates to a compound having the formula lla: o = Rs T | SS | Nn = 2 NH W (Ila) or a tautomer, enantiomer or salt thereof.
In another embodiment, the invention refers to a compound having the formula llb: o. == Rs | . | and N = NH>! TOW (1lb) or a tautomer, enantiomer or salt thereof where 'W is selected from N, C-T and CH and T and Rº are as defined above in the formula |. In one embodiment, the invention relates to a compound of '10 formula, 11a, or 11b or a salt thereof, where W is CH.
In another embodiment, the invention relates to a compound of formula |, Il, Ila, or llb or a salt thereof, where T is - (O) J (CH2); C (O) Rº.
In one embodiment, the invention relates to a compound or a salt thereof, where u is 1 and s 1. In one embodiment, the invention relates to a compound or a salt thereof, where u is 0 and s 1 In one embodiment, the invention refers to a compound or a salt thereof, where u is Oesé2 In one embodiment, the invention refers to a compound or a salt thereof, where R $ is - O-alkyl.
In one embodiment, the invention refers to a compound or a salt thereof, where Rº is -O-alkyl and alkyl is selected from methyl, ethyl, isopropyl, and isobutyl.
In another embodiment, the invention relates to a compound of formula |, Il, Ila, or Ilb or a salt thereof, where T is heterocycle.
In one embodiment, the invention relates to a compound or a salt thereof,
- where the heterocycle is selected from dihydrofuranone and dioxolanone.
In one embodiment, the invention relates to a compound, in which heterocycle is selected from 8 and - In another embodiment, the invention relates to a compound formula, Il, Ila, or! Lb or a salt thereof, in that T is - (CHR ”), ORº . In another embodiment, the invention relates to a compound of formula |, II, 1, or 1lb or a salt thereof, where T is -OSO.R " . In one embodiment, the invention relates to a compound or a salt thereof, where R "* is -CF3. 210 In another embodiment, the invention relates to a compound of the formula Il, Ila, or Ilb or a salt thereof, where W is N.
In a fashion- the invention relates to a compound or a salt thereof, wherein T. is - (CHR ”); OR . In one embodiment, the invention relates to a compound or a salt thereof, where z is 1 and R 'and Rº are both hydrogen.
In “15 a modality, the invention refers to a compound or a salt thereof, where zé 2, Ré OH or He Rº is H.
Another aspect of the invention relates to a compound having the formula III: o = Rs R! (CH2), (O). | N = NH2 (ql) or a tautomer, enantiomer or salt thereof, where Ró, R, x and y are as defined above in formula |; provided that when R * is aryl or heteroaryl, then x + y> 1. In one embodiment, the invention relates to a compound having the formula Illa: o = Rs Pa | = Rr NH (Illa) V ————— pn
«- or a tautomer, enantiomer or salt thereof. In one embodiment, the invention relates to a compound having the formula Illb: o | R! (CH2); N NH (Illb) or a tautomer, enantiomer or salt thereof, where y is 1,2, or 3. In one embodiment, the invention relates to a compound having the formula lllc: i os ”| . 1 "E IS NH (Wc) or a tautomer, enantiomer or salt thereof, where R * 'is saturated or partially saturated heterocycle'. In one embodiment, the invention relates to a compound or a saldomesmo, having the formula | , III, Illa, or lllb, where x = 0 and y = 3.] In one embodiment, the invention relates to a compound or a salt thereof, having the formula |, III, Illa, or Illb, where R ** is phenyl In one embodiment, the invention relates to a compound or a salt thereof, having the formula |, III, Illa, or Illh, where R * 'is heterocyclic In one embodiment, the invention relates to a compound or a salt thereof, wherein said heterocycle is partially saturated heterocycle.In one embodiment, the invention relates to a compound or a salt thereof, wherein said heterocycle is morpholine In one embodiment, the invention relates to a compound or a salt thereof, wherein said heterocycle is isobenzofuranone In one embodiment, the invention relates to a compound or a salt thereof, wherein said isobenzofuranone is the
DOLO selected from and ”.
«. Another aspect of the invention relates to a compound or a salt thereof having the formula |, II, Ila, Ilb, II, llla, or Illb, where Rº is -OR "º. In one embodiment, the invention relates to to a compound or a salt thereof, where R "º * is alkyl. In one embodiment, the invention refers to a compound or a balance, where R'º is ethyl.
Another aspect of the invention relates to a compound or salt thereof having the formula |, II, Ila, 1lb, III, Illa, or Illb, where Rº is -NRºRº. In one embodiment, the invention relates to a compound or a salt thereof, wherein, R and Rº are both alkyl. In one embodiment, the invention relates to a compound or a salt thereof, where Rº and Rº are both propyl.
In one embodiment, the invention relates to a compound or a salt of the "same, where at least one of Rº or Rº is alkyl substituted with a - OH. In one embodiment, the invention relates to a compound or a salt from Do HD itself, where at least one of R or Rº is FODA. In another modality, the invention refers to a compound or a salt of the same month. R is FO and the remaining R or R is propyl.
Another aspect of the invention relates to a compound having the "formula IV: ese = Re | == ta" NH (VM) or a tautomer, enantiomer or salt thereof, where Y, R $, P, u and t are as defined above in formula |; as long as q + re> 1. In one embodiment, the invention relates to a compound having the formula IVa: E and | > 'Su (IVa)
«
N. or a tautomer, enantiomer or salt thereof, where r is selected from 1.2.0u3.
In one embodiment, the invention relates to a compound having the formula IVb: o o x M Hz (IVb) or a tautomer, enantiomer or salt thereof.
In one embodiment, the invention relates to a compound of formula | or IV or a salt thereof, where t = 3. In one embodiment, the invention relates to a compound of - formula |, IV, IVa, or IVb, or a salt thereof, where P is selected from - 10 aryl, heterocycle and -SO2Rº. In one embodiment, the invention relates to a compound of. formula |, IV, IVa, or IVb, or a salt thereof, where P is heterocycle. In one embodiment, the invention relates to a compound or salt thereof, where P is selected from piperidine and pyrrolidine. In one embodiment, the invention relates to a compound of formula |, IV, IVa, or IVb, or a salt thereof, where P is aryl.
In one embodiment, the invention relates to a compound of formula |, IV, IVa, or IVb, or a salt thereof, where P is -SORg. In one embodiment, the invention relates to a compound or a salt thereof, in which said R ° is -NH7.
In one embodiment, the invention relates to a compound of formula |, IV, IVa, or IVb, or a salt thereof, where x = 0 and y = 0. In one embodiment, the invention relates to a compound or a salt thereof, where R "is aryl. In one embodiment, the invention relates to a compound ouum; even balance, in which said aryl is replaced with -C (O) NR'R '. In one embodiment, the invention relates to a compound or a salt thereof, in which said R' and R 'together with the nitrogen atom to which they are attached form a saturated heterocyclic ring.
Accordingly, the invention relates to a compound or a salt thereof, wherein said heterocyclic ring is a pyrrolidine ring. Another aspect of the invention relates to a compound having the formula V: o = Rs * AU
10. o V) or a tautomer, enantiomer or salt thereof, where R ', R and Rº are E: as defined above in the formula |, and also in which at least one of R 'or R is alkyl substituted with -C (0) O (CH2): R " . E In one embodiment, the invention relates to a compound of formula V or a salt thereof, wherein at least one of R 'or R 'is alkyl substituted with -C (O0) O (CH2), R' . In one embodiment, the invention relates to "a compound or a salt thereof, wherein said R" Is aryl In one embodiment, the invention relates to a compound or a salt thereof, where R 'or D H.' In another embodiment, the invention relates to a compound having the formula VI: o = "NRºRº RN NH, VI) or a tautomer, enantiomer or salt thereof, in which: R * 'is selected from aryl and saturated or partially saturated heterocycle, in which said aryl is replaced with T; T is selected from a heterocycle, - (O) I (CH »). C (O) Rº, and - CH (OH) CHOH; Rº is selected from -OR "* and alkyl; R'º is selected from alkyl, - (CH2) R ' , and hydrogen, in which said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine; R ' Is selected from cycloalkyl and aryl; u is selected from 0 and 1; s is selected from 1 and 2; and R' and Rº are independently alkyl; where said alkyl is optionally substituted with one or more - OH.
In one embodiment, the invention relates to a compound of formula VI or a salt thereof, where R '* is aryl substituted with - (O), (CH) .C (O) RÉ.
In another modality, the referred Rº is -OR "º.
In another embodiment, the invention relates to a compound f having the formula VI, in which:: R ** is selected from aryl and saturated or partially saturated heterocycle, in which said aryl is replaced with T; “5 T is selected from heterocycle and - (O) I (CH2); C (O) Rº; ; Rº is selected from -OR "º and alkyl; R'º is selected from alkyl, - (CHa) R" , and hydrogen, where said alkyl is optionally substituted with halogen, amine, alkyl-; mine, or dialkylamine ; R " is selected from cycloalkyl and aryl; u is selected from 0 and 1; s is selected from 1 and 2; and R and R * are independently alkyl; wherein said alkyl is optionally substituted with one or more -OH.
In another embodiment, the invention relates to a compound having the formula VI, in which: R "'is aryl substituted with T; T is selected from - (O) u (CH2) .C (O) Rº, and -CH (OH) CH2OH; Rº is selected from -OR "º and alkyl; R'º is selected from alkyl, - (CH2) R " , and hydrogen, in which said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine;
R * is selected from cycloalkyl and aryl; u is selected from O and 1; s is selected from 1 and 2; and R and Rº are independently alkyl; wherein said alkyl is optionally substituted with one or more -OH.
In another embodiment, the invention relates to a compound having the formula VI, in which R and Rº are independently alkyl; and also in which one of R and Rº is replaced with one or more -OH at the same time that the other is unsubstituted. In another embodiment, the invention relates to a compound having the formula VI, in which R and Rº are independently unsubstituted alkyl. In another embodiment, the invention relates to a compound having the formula VI, where R "* is aryl. In another embodiment, the invention relates to a compound having the formula VI, where R ''! Is phenyl. In another embodiment, the invention relates to a com- "15 having the formula VI, where R" is a saturated or partially saturated heterocycle.
Another aspect of the invention relates to a compound or a salt thereof, selected from a compound in table 1. In one embodiment,. the invention relates to a compound or a salt thereof, selected from compound 196, 197, 183, 191, 192, 193, 199, 205, 213, 214, 215, 216, 217, 218, 219, 223, 224 , 226, and 225. In one embodiment, the invention relates to a compound or a salt thereof, selected from compound 113, 175, 116, 118, and 177. In one embodiment, the invention relates to a compound or a salt thereof, selected from compound 148, 185, 184, 200, 198, 221, and
222. In one embodiment, the invention relates to a compound or a salt thereof, selected from compound 198, 225, 191, 192, 193, 196, 197, 221, 205, 213, 214, 215, 216, 217 , 218, 219, 222, 223 and 224. In one embodiment, the invention relates to a compound or a salt thereof, selected from compound 198, 225, 191, 192, 193, 197, 221, 205, 213, 214, 215, 216, 217,218,219,222 and 223. In one embodiment, the invention relates to a compound or a salt thereof, selected from compound 191, 196, and 224.
In one embodiment, the invention relates to a compound having the formula | In one embodiment, the invention relates to a compound having the formula Il. In one embodiment, the invention relates to a compound having the formula 11a. In one embodiment, the invention relates to a compound having the formula Ilb. In one embodiment, the invention relates to a compound having the formula Ill. In one embodiment, the invention relates to a compound having the formula Illa. In one embodiment, the invention relates to a compound having the formula Illb. In one embodiment, the invention relates to a compound having the formula Illc. In one embodiment, the invention relates to a compound having the formula IV. In one embodiment, the invention relates to a compound having the formula IVa. In one embodiment, the invention relates to a compound having the formula IVb. In one embodiment, the: invention refers to a compound having the formula V. In one embodiment,. the invention relates to a compound having the formula VI. Another aspect of the invention relates to a compound of the invention, in which the salt is a pharmaceutically acceptable salt.
Another aspect of the invention relates to a kit for the treatment of a condition mediated by TLR7 and / or TLR8, comprising: 1 (a) a first pharmaceutical composition comprising a 'compound of the invention or salt thereof; and (b) optionally pause instructions.
In one embodiment, the kit also comprises (c) the second pharmaceutical composition, in which the second pharmaceutical composition comprises a second compound for the treatment of the condition mediated by TLR7 and / or TLR8.
In one embodiment, the kit also includes instructions for the simultaneous, sequential or separate administration of said pharmaceutical compositions to a patient in need of them.
Another aspect of the invention relates to a pharmaceutical composition, which comprises a compound of the invention or salt thereof, together with a pharmaceutically acceptable diluent or carrier.
Another aspect of the invention relates to a compound of the invention, or salt thereof, for use as a medicament for the treatment of a condition mediated by TLR7 and / or TLR8 in a human or animal. In one embodiment, the invention relates to the use of a compound of the invention or salt thereof, in the manufacture of a medicament for the treatment of an abnormal cell growth condition in a human or animal. Another aspect of the invention relates to a method of treating the condition mediated by TLR7 and / or TLR8, comprising administering to a patient in need of the patient an amount of a compound of the invention or salt thereof. Another aspect of the invention relates to a method of modulating the patient's immune system, comprising administering to a patient: in need of the patient an amount of a compound of the invention or salt thereof. The invention includes a compound selected from the compounds lys- “15 tadosnatabelaf. y Table 1. [is - [estutraquimca - lg | Chemical structure no 113 E CO 116 9 "=. = = H OQ O" a O "o [e O no o 148 Re 118 o 25
N o Nn = NH O O NE o Q f Ro Ro q 175 o Y C &: <Te (> - ”NÔ NH Nº NH; Go | |
G Y o
183 a
N = = X - NO NH UA NO NH in A In 185 à> ”225 S O Y - o 1 st Node NH, O O
CO Y o jim o O
N: + “+:” NÔ NH, ”NÓ NH Q (DS r (CD i Ho Et: 193 e 196 TO N
O A (7 NÔ NH O NÔNHo: O 5 Eto ro o 197 q 198 ——
CR N ”NÔ NH (CD and Ts (CD NÓ NH a” o: o R oEt | 200 R OEt. NO NH, O ff Ho VLW Wo o o 205 n 213 "OO
AL YR Eto, ”nº o CP) ATA NH, o O Meo” 214 s CO 2 "s o CO o Ie NH Ah Q SÃO fe Eto” O Pp 216 O "o 217 o NOT o O Na. 7 NH i oo o OG | 218 QN [219 - AO X SM hs of LISO í PV o 8 221 Lyon | 222 AA: K <<K t (D no g ”no. O NH D O NH O: - o o o 223 n> | 224 nO
OA WS OA VW NAN O Ne NH ooo no da 226 3 ”201 3 <C om 2, ety nety no AA ó oH Q 227" << 228 E CC sy SO. Seas 229 [YO $$ 230 - << o O ã ms bp O CC = O n NH
231 ». CT | 232 ”<q no ao 233 eos lo34 ooo No O NAT oo ON = Nº 235 IS | 236 * é * 237 3 ass DÓ" | 5 g À O no NH HCl no O nz 1 In one aspect, the invention includes a compound , or salt of the same, with an MCs value, <25,000 nM for TLR8. In another aspect, the invention includes a compound or salt thereof, with an MCso value <10,000 nM for TLR8. In another aspect , the invention includes a compound or salt of the same - 5, with an MCso value <1,000 nM for TLR 8. In another aspect, the invention includes a compound or salt of the same, with an MCso value <100 NM for TLR8. , the invention includes a compound or salt of the same, with an MCs value, <25 nM for TLR8 In one aspect, the invention includes a compound or salt of the same, with an MCs value, <25,000 nM for TLR7. In another aspect, the invention includes a compound or salt of the same, with an MCso value <10,000 nM for TLR7 In another aspect, the invention includes a compound or salt of the same, with an MCso value <1,000 nM for TLR7. In another aspect, the invention includes a compound or salt thereof, with an MCso value <100 nM for TLR7. In another aspect, the invention includes a compound or salt thereof, with an MCs5.9 value <25 nM for TLR7.
In one aspect, the invention does not include a compound or salt thereof, with MCs,> 25,000 for TLR7. In one aspect, the invention does not include a compound or salt thereof, with MCs,> 25,000 for TLR8. In one aspect, the invention does not include a compound or salt thereof, with MCro values> 25,000 for both TLR7 and TLR8.
Another aspect of the invention relates to light drugs (also known as "anti-drugs"). "Light drugs" can be defined can be defined as biologically active chemical compounds (drugs) that are metabolically deactivated after they obtain their therapeutic role at their designated site of action. The use of light drugs, instead of their non-deactivable analogues, can prevent unwanted side effects. In one aspect, the metabolic disposition of light drugs occurs at a controllable rate in a predictable manner. One embodiment of the invention relates to compounds that are light drugs. Specifically, the invention relates to compounds that are designated for cleavage in vivo, after obtaining their therapeutic effect, to a less active portion. The invention relates to compounds which are designated for cleavage in vivo, after obtaining. its therapeutic effect, in a non-toxic portion. Light drugs of the invention include compounds such as compounds 225, 192, 193, 197, 198, “15 205,213,214,215,216,217,218,219,221,222 and 223.. The term "compound of the invention" refers to exemplified compounds and compounds covered under the formulas described herein. : The term "substituted," as used here, means that any: one or more hydrogen atoms in the designated atom is replaced with a selection from the indicated group, as long as the normal valence of the designated atom is not exceeded, and the substitution results into a stable compound. When a substituent is keto (ie, = O), then 2 hydrogens on the atom are replaced. Double ring bonds, as used here, are double bonds that are formed between two adjacent ring atoms (for example, C = C, C = N, or N = N).
The chemical structure showing a dotted line representation for a chemical bond indicates that the bond is optionally represented. For example, a dotted line drawn next to a single link indicates that the link can be a single link or a double link.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then that substituent can be attached to any atom in the ring.
The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon radical having one to twelve, including one to ten carbon atoms (C1-C10), one to six carbon atoms (C1-C ; s) and a four carbon atom (C1-C4), where the alkyl radical can be optionally substituted independently with one or more substituents described below. Examples of alkyl radicals include hydrocarbon moieties such as, but not limited to: methyl (Me, -CH; z), ethyl (Et, -CHCH;), 1-propyl (n-Pr, n-propyl, -CHCH2 > CH3), 2-propyl (i-Pr, i-propyl, -CH (CH3) 2), 1-butyl (n-Bu, n-butyl, -CHXCHCH2CH3), 2-methyl-1-propyl (i- Bu, i-butyl, -CH; CH (CH3) 2), 2-butyl (s-Bu, s-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t -butyl, -C (CH3) 3), 1-pentyl (n-pentyl, -CHXCH2CH2CH2C0H3), 2-pentyl '(-CH (CH3) CH.CH2CH3), 3-pentyl (-CH (CH2CH3) 2), 2-methyl-2-butyl -C (CH3), CH; CH; 3), 3-methyl-2-butyl -CH (CH3) CH (CH3) 2), 3-methyl-1-butyl -CH2CH2CH “5 (CH3) 2), 2-methyl-1-butyl CCHXCH (CH3) CH2CH3), 1-hexyl -CHXCHCH2CH, r CH3CH3), 2-hexyl -CH (CH3) CHCH2CH2C Hs), 3-hexyl CCH (CH2CH3) ( CH2 CHCH3)), 2-methyl-2-pentyl (-C (CH3) ºCH2CH2C0H3), 3-methyl-2-pentyl (-CH] (CH3) CH (CH3) CH2CH3), 4-methyl-2-pentyl - CH (CH3) CH2CH (CH3) 2), 3-methyl-3- 'pentyl -C (CH3) (CH2CH3) 2), 2-methyl-3-pentyl -CH (CH2CH3) CH (CH3) 2), 2 , 3-dimethyl-2-butyl “C (CH3) 2CH (CH3) 2), 3,3-dimethyl-2-butyl (-CH (CH3) C (CH3) s, 1-heptyl, and 1-octyl.
The term "alkenyl" refers to a monovalent straight-chain or branched hydrocarbon radical having two to 10 carbon atoms (C2-C10), including two to six carbon atoms (C72-Cs) and two to four atoms carbon (C2-C4), and at least one double bond, and includes, but is not limited to, ethylene, propenyl, 1-but-3-enyl, 1-pent-3-enyl, 1-hex-5-enyl and the like, wherein the alkenyl radical can be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E'e" Z 'orientations. The term "alkenyl" includes allyl.
The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms (C2-C12), including
including two to 10 carbon atoms (C2-C109), two to six carbon atoms (C2-Cs) and two to four carbon atoms (C2-C4), containing at least one triple bond. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentin-2-yl and the like, where the alkynyl radical can be optionally substituted independently with one or more substituents described herein.
The terms "carbocycle," "carbocyclyl," or "cycloalkyl" are used interchangeably here and refer to a saturated or partially unsaturated cyclic hydrocarbon radical having three to twelve carbon atoms (C3-Ci2), including three ten carbon atoms (C3-C10) and three to six carbon atoms (C3-Cs). The term "cycloalkyl" includes monocyclic and polycyclic (e.g., bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclic structures optionally include a saturated or partially unsaturated cycloalkyl fused to an aryl or heteroaryl ring or an " 15 cycloalkyl or saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring.
. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Bicyclic carbocycles have 7 to 12 ring atoms, for example, arranged as one. bicycle system [4,5], [5,5], [5,6] or [6,6], or 9 or 10 ring atoms arranged as a bicycle system [5,6] or [6,6], or as bridging systems such as bicycles [2.2.1] Jheptane, bicycles [2.2.2] Joctane, and bicycles [3.2.2] nonane. Cycloalkyl can optionally be substituted independently in one or more substitutable positions with one or more substituents described here. Such cycloalkyl groups can be optionally substituted with, for example, one or more groups independently selected from C1-C; alkyl, C1-Cg alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C; Cs) alkylamino, di (C; -Cs) alkylamino, C2-Cs alkenyl, C2-Cs alkynyl, C1-Cg haloalkyl, C ; -Csg haloalkoxy, amino (C1-Cs) alkyl, mono (C1-Cs) alkylamino (C; -Ce) alkyl and di (C; Ce) alkylamino (C1-Cçs) alkyl.
The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon radical having three to ten carbon atoms (C3-C10), including three to six carbon atoms (C3-Cs) and having at least one double bond within of the carbocycle.
The term "heteroalkyl" refers to a saturated straight or branched chain hydrocarbon radical of one to twelve carbon atoms (C1-C12), including one to six carbon atoms (C; -Cs) and one to four carbon atoms (C; -Cs), where at least one of the carbon atoms is replaced with a heteroatom selected from N, 0, or S, and where the radical can be a carbon radical or heteroatom radical ( that is, the heteroatom can appear in the middle middle or at the end of the radical). The heteroalkyl radical can be optionally substituted independently with one or more substitutes described herein. The term "heteroalkyl" encompasses alkoxy and heteroalkoxy radicals.
, The terms "heterocycloalkyl," "heterocycle" and "heterocyclyl" are R used interchangeably here and refer to a saturated or partially unsaturated carbocyclic radical 3 to 8 ring atoms where at least one “15 ring atom is a selected hetero atom of nitrogen, oxygen and sulfur, the remaining ring atoms being C, where one or more ring atoms can be optionally substituted independently with one or more Y substituents described below. The radical can be a carbon radical: or a heteroatom radical. The term "heterocycle" includes heterocycloalkoxy. The term also includes fused ring systems that include a heterocycle fused to an aromatic group. "Heterocycloalkyl" also includes radicals where heterocyclic radicals are fused with aromatic or heteroaromatic rings. Examples of heterocycloalkyl rings include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidine, morpholino, thiomorpholine, tioxanyl, piperazinyl, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin, piperazinin. , oxepanyl, tiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6- tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H- pyranyl, dioxanil, 1,3-dioxolanyl, pyrazolinyl, dithianyl , dithiolanil, dihydropyranyl, dihydrothienyl, dihydrofuranite, pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicic [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, azabicyclo [2.2.2] hexanyl, 3H-indolyl quinolizinyl and pyridine . Spiro portions are also included in the scope of this definition. The previous groups, when derived from the groups listed above, can be linked by C or linked by N where possible. For example, a pyrrole-derived group can be pyrrol-1-yl (N-linked) or pyrrol-3-yl (C-linked). In addition, an imidazole-derived group may be imidazol-1-yl (N-linked) or imidazol-3-yl (C-linked). An example of a heterocyclic group in which 2 ring carbon atoms are replaced with oxo moieties (= O) is 1,1-dioxo-thiomorpholinyl. The heterocycle groups here are unsubstituted or, when specified, substituted in one or more substitutable positions with several groups. For example, such heterocycle groups can be optionally substituted with, for example, one or more groups independently selected from C1-C; alkyl, C1-C6: alkoxy, halogen, hydroxy, cyano, nitro, amino, mono (C1-Cs) alkylamino, di (C1-Cs): alkylamino, C2-Cg alkenyl, C27-Cs alkynyl, C1-Cs haloalkyl, C1-Ck haloalkoxy, amino (C; -Cs) alkyl, mono (C; -Cs) alkylamino (C1-Ce) alkyl or di (C1-Cs) “15 alkylamino (Ci-Cs) alkyl.
. The term "aryl" refers to a monovalent aromatic carbocyclic radical having a single ring (eg, phenyl), multiple rings' (eg, biphenyl), or multiple condensed rings where at least: one is aromatic, (for example 1,2,3,4-tetrahydronaftila, naphthyl, etc.), which is optionally substituted with one or more substituents independently selected from, for example, halogen, lower alkyl, lower alkoxy, trifluoromethyl, aryl, heteroaryl and hydroxy. In one embodiment, the arila is a 6-membered arila. For example, aryl is phenyl. The term "heteroaryl" refers to a 5-, 6-, or 7-membered monovalent aromatic radical and includes fused ring systems (at least one of which is aromatic) of 5 to 10 atoms containing at least minus one and up to four heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups are pyridinyl, imidazolyl, pyrimidine, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, - oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl, benzyl indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl,
thiadiazolyl, furazanil, benzofurazanil, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, isobenzofuran-1 (3H) -one, and furopiridinyl. Spiro portions are also included in the scope of this definition. Heteroaryl groups are optionally substituted with one or more substituents independently selected from, for example, halogen, lower alkyl, lower alkoxy, haloalkyl, aryl, heteroaryl, and hydroxy.
The term "halogen" represents fluorine, bromine, chlorine, and iodine.
The term "oxo" represents = O.
. In general, the various portions or functional groups of the compounds of the invention can optionally be replaced by one or more substitutes. Examples of suitable substituents for the purposes of this invention include, but are not limited to, oxo, halogen, cyano, nitro, trifluoro- - romethyl, difluoromethoxy, trifluoromethoxy, azido, -NR "SO2R ', -SONR'R", -C (O) R ', - C (O0) OR', -OC (OJR, -NR "C (O) JOR ', -NR" C (OJ) R', -C (O) JNR'R " , -NRC (O) "15 NR", -NRC (NCN) NRR ", -OR ;, aryl, heteroaryl, arylalkyl, heteroarylalkyl, .heterocyclyl, and heterocyclylalkyl, where R ', R" and R "" are independently H , alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl or heteroaryl.
A "(alkyl) aryl" group, as used herein, is an aryl substituent that is attached to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. In one aspect, the aryl substitutent is attached to a compound by a straight or branched chain alkyl group having 1 to 6 carbon atoms. The alkyl portion of the group (alkyljarilla is optionally substituted. In one embodiment, the aryl is a 6-membered aryl. For example, aryl is phenyl.
A "(alkyl) heterocycloalkyl" group, as used herein, is a heterocycle substituent that is attached to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. In one aspect, the heterocycle substituent is attached to a compound by a straight or branched chain alkyl group having 1 to 6 carbon atoms. The alkyl portion of the (alkyl) heterocycle group is optionally substituted. A "(alkyl) cycloalkyl" group, as used here, is a substitute
cycloalkyl inte which is attached to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. In one aspect, the substituent on the cycloalkyl substituent is attached to a compound by a straight or branched chain alkyl group having 1 to 6 carbon atoms. The alkyl portion of the (alkyl) cycloalkyl group is optionally substituted.
A "(alkyl) cycloalkenyl" group, as used herein, is a cycloalkenyl substitute that is attached to a compound by a straight or branched chain alkyl group having from one to twelve carbon atoms. In one aspect, the cycloalkenyl substituent is attached to a compound by a straight or branched chain alkyl group having 1 to 6 carbon atoms. The alkyl portion of the (alkyl) cycloalkenyl group is optionally substituted. : The compounds of this invention can have one or more asymmetric centers; such compounds can, therefore, be produced as individual “15 (R) - or (S) stereoisomers or as mixtures thereof. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual Á enantiomers, mixtures of diastereomers, racemic or other. otherwise, from them. Accordingly, this invention also includes all such isomers, including diastereomeric mixtures, pure diastereomers, and pure enantiomers of the compounds and formulas described herein.
Diastereomeric mixtures can be separated into individual diastereomers on the basis of their physical-chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomer mixture into a diastereomeric mixture by reacting with an optically active compound (eg alcohol), separating the diastereomers and converting (for example, hydrolyzing) the individual diastereomers in corresponding pure enantiomer. The enantiomers can also be separated using a chiral HPLC column. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (See description in chapter
Title 4 of "Advanced Organic Chemistry", 4th edition, J.March, John Wiley and Sons, New York, 1992). In the structures shown here, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention.
Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is thereby specified and defined.
A simple stereoisomer, for example, an enantiomer, substantially free of its stereoisomer can be obtained by resolving the racemic mixture using a method such as forming diastereomers, using optically active resolving agents (Eliel, E. and Wilen, S.
Ste-. reochemistly of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C.
H., (1975) J.
Chromatogr., 113 (3): 283-302). The racemic mixtures of chiral compounds of the invention can be separated e.g. isolated by any suitable method, including: (1) formation of di-astereomeric, ionic salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds. with chiral derivatives, separation of diastereomers, and conversion to pure stereoisomers, and (3) separation of enriched or substantially pure stereoisomers directly under chiral conditions.
See: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W.
Wainer, Ed., Marcel Dekker, Inc., New York (1993). In method (1), diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-13-phenylethylamine (amphetamine), and the like with asymmetric compounds that carry acidic functionality , such as carboxylic acid and sulfonic acid.
Diastereomeric salts can be induced to separate by fractional crystallization or ion chromatography.
For separation of optical isomers from amino compounds, the addition of carboxylic acids or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in the formation of diastereomeric salts.
Alternatively, by method (2), the solved substrate is reacted with a chiral compost enantiomer to form a diastereomeric pair (E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiey & Sons, Inc. , 1994, page 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivative agents, such as metal derivatives, followed by separation of the diastereomers and hydrolysis to produce the pure or enriched enantiomer. One method of determining optical urea involves producing chiral esters, for example, a methyl ester such as (-) methyl chloroformate, in the presence of base, or Mosher ester, α-methoxy-a- É (trifluoromethyl) phenyl ( Jacob III, (1982) J. Org. Chem. 47: 4165), of the racemic B mixture, and to analyze the NMR spectrum for the presence of two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by chromatography. reverse or normal phase following methods for the separation of atropisomeric naphthylisoquinolines (WO 96/15111). By method (3), a racemic mixture of two of the enantiomers can be separated by chromatography. using a chiral stationary phase (Chiral Liquid Chromatography (1989) W.J. Lough, Ed., Chapman and Hall, New York; Okamoto, (1990) J. of C-chromatogr. 513: 375-378). Pure or enriched enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
"Tautomer" refers to a compound whose structures differ markedly in the arrangement of atoms, but which require quick and easy balance. It is to be understood that the compounds of the invention can be described as different tautomers. It should also be understood that when the compounds have tautomeric forms, all tautomeric forms are intended to be within the scope of the invention, and the naming of the compounds does not exclude any form of tautomer.
The present invention is intended to include all isotopes of atoms that occur in the present compounds. Isotopes include those atoms having the same atomic number, but different mass numbers. By way of general example and without limitation, hydrogen isotopes including tritium and deuterium, and carbon isotopes include C-13 and C-14. In addition to the compounds of the invention, the invention also includes pharmaceutically acceptable salts of such compounds.
A "pharmaceutically acceptable salt" unless otherwise indicated, includes salts that retain the biological effectiveness of the free bases and acids of the specified compound and that are not biologically or otherwise undesirable. A compound of the invention can have a sufficiently acidic, a sufficiently basic, or both functional groups, and consequently react with any of the various inorganic bases) or organic, and inorganic and organic acids, to form a pharmaceutically acceptable salt . Examples of pharmaceutically acceptable salts include those salts prepared by reacting the compounds of the present invention with a mineral or organic acid or an inorganic base, such salts including sulfates, pyrosulfates, bisulfates, sulfides, bisulfides, phosphates, monoirogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides,. bromines, iodines, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butin-1,4-dioates, hexine-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, i-hydroxybutates, glycates, tartrates, glycates sulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. Since a single compound of the present invention can include more than one acidic or basic moiety, the compounds of the present invention can include mono-, di- or tri-salts in a single compound. If the inventive compound is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an acidic compound, particularly an inorganic acid, such as hydrochloric acid, hydrobromic acid , sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, ivuric acid, oxalic acid, glycolic acid, salicylic acid, a pyanosidyl acid such as glucuronic acid or galacturonic acid, an alpha hydroxy acid such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic acid or cinnamic acid , a sulfonic acid such as p-toluenesulfonic acid or eta-nosulfonic acid, or the like.
If the inventive compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, e.g. example, treatment of the free acid with an inorganic or organic base.
Examples of suitable inorganic based salts include those formed by alkaline earth alkali metals such as lithium, sodium, potassium, barium and pH calcium.
Examples of suitable organic-based salts include, for example, ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis (2-hydroxyethyl)> ammonium, phenylethylbenzylamine, dibenzylethylenediamine, and the like. : Other acidic portion salts may include, for example, those formed with procaine, quinine and N-methylglucosamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.
The present invention also provides salts of compounds of the invention which are not necessarily pharmaceutically acceptable salts, but which can be useful as intermediates for the preparation and / or purification of compounds of the invention and / or for separation of the enantiomers of compounds of the invention. invention.
The inventive compounds can be prepared using the reaction routines and synthesis schemes as described in Scheme |, employing the techniques available in the art using starting materials that are readily available.
(Ph) SP: COoFEt R R ia — o o x o en 1 AX —.s = -.
2. NalO, Y NO Y NO TI "R o R (| A Ss E Rs was Y NO; en Y No. Ho m Ww: Scheme E In scheme |, compounds of formula Il can be prepared from an alkyl arene of formula | by treatment with dimethylformamide dimethyl acetal with or without the use of pyrrolidine (J. Org. Chem, À 5 (1986), 51 (26), 5106-5110) in DMF at 70 to 90 ° C. The raw intermediate (not shown) can be cleaved into the aldehyde of formula 1l with NalO4 in phosphate buffer of THF / pH 7.2 a or around room temperature Aldehyde E of formula Il can be olefined with phosphonium ilide in toluene at temperatures ranging from 70 to 110ºC (1 to 16 hours) to provide compounds of formula III. Compounds of formula IV can be prepared from a compound of formula III using iron powder in acetic acid. The reaction can be carried out at a temperature of about 90 ° C for about 3 - 14 hours It is noted that some of the preparations of compounds of the invention described here may require protection of remote functionalities. The age of such protection will vary depending on the nature of the functionality and the conditions used in the preparation methods and can be easily determined by those skilled in the art. Such protection / deprotection methods are well known to those skilled in the art. The compounds of the invention find use in a variety of applications. For example, in certain aspects the invention provides methods for modulating TLR7 and / or TLR8-mediated signaling. The methods of the invention are useful, for example, when it is desirable to alter TLR7 and / or TLR8-mediated signaling in response to a suitable TLR7 and / or TLR8 ligand or a TLR7 and / or TLR8 signaling agonist. As used herein, the terms "TLR7 and / or TLR8 ligand," "TLR7 and / or TLR8 ligand," and "TLR7 and / or TLR8 signaling agonist" refer to a molecule, rather than a compound of the invention, which interacts directly or indirectly with TLR7 and / or TLR8 and induces TLR7- and / or TLR8-mediated signaling. In certain embodiments, a TLR7 and / or TLR8 ligand is a natural ligand, i.e., a TLR7 and / or TLR8 ligand that is found in nature. In certain embodiments, a TLR7 and / or TLR8 ligand refers to a molecule other than a natural TLR7 and / or 'TLR8 ligand, for example, a molecule prepared by human activity. : The term "modular" as used herein with respect to TLR7 and / or TLR8 receptors means the mediation of a pharmacodynamic response in an individual by (i) inhibiting or activating the receptor, or (ii) directly or indirectly. directly affecting the normal regulation of receptor activity. Compounds that modulate receptor activity include agonists, antagonists, mixed agonists / antagonists and compounds that directly or indirectly affect a. regulation of receptor activity.
The term "agonist" refers to a compound that, in combination with a receptor (for example, a TLR), can produce a cellular response. An agonist can be a ligand that directly binds to the receptor. Alternatively, an agonist may combine with a receptor indirectly, for example, (a) forming a complex with another molecule that directly binds to the receptor, or (b) otherwise resulting in the modification of another compound of so that the other compound directly binds to the receiver. An agonist can be referred to as an agonist for a particular TLR (for example, an agonist for TLR7 and / or TLR8). The term "partial agonist" refers to a compound that produces a partial, but not complete, cellular response. Assays related to TLR7 and TLR8 are known in the art (for example, Gorden et al., Journal of Immunology 177, pages 8164 to 8170 (2006) and Zhu et al, Molecular Immunology, volume
45 (11), pages 3238 to 3242 (2008)).
The term "antagonist" as used here refers to a compound that competes with an agonist or partial agonist for binding to a receptor, thereby blocking the action of a noreceptor agonist or partial agonist. More specifically, an antagonist is a compound that inhibits the activity of a TRL7 or TLR8 agonist at the TLR7 or TLR8 receptor, respectively.
"Inhibit" refers to any measurable reduction in biological activity. Thus, as used here, "inhibit" or "inhibition" can be referred to as a percentage of a normal level of activity. In one aspect of this invention, a method of treating or preventing a condition or disorder treatable by modulating cellular activities mediated by TLR7- and / or TLR8 in an individual comprises administering to said individual a composition comprising a com- “ 5 put the invention in an amount effective to treat or prevent the condition or disorder. The term "mediated by TLR7- and / or TLR8" refers to a biological or biochemical activity that results from the function of TLR7- and / or IS TLR8. i Conditions and disorders that can be treated by the methods of this invention include, but are not limited to, cancer, diseases associated with the immune complex, autoimmune diseases or disorders, inflammatory disorders, immunodeficiency, graft rejection, graft versus host disease, allergies, cardiovascular diseases, fibrotic disease, asthma, infection and sepsis. More specifically, methods useful in the treatment of conditions involving cancer (cancer therapy or vaccine), allergic disease (for example, atopic dermatitis, allergic rhinitis, asthma), infectious disease (vaccine and antiviral prophylaxis), and immunodeficiency will employ compounds of the invention that inhibit TLR7 and / or TLR8-mediated signaling. Alternatively, methods useful in treating conditions involving autoimmune disease, CF, sepsis, graft rejection, and GVHD will generally employ compounds of the invention that enhance TLR7 and / or TLR8-mediated signaling.
In some cases the compositions can be used to inhibit or promote TLR7 and / or TLR8-mediated signaling in response to a TLR7 and / or TLR8 ligand or signaling agonist. In other cases the compositions can be used to inhibit or promote TLR7 and / or TLR8-mediated immunostimulation in an individual.
The term "treating" as used herein, unless otherwise indicated, means at least the mitigation of a disease or condition and includes, but is not limited to, modulation and / or inhibition of an existing disease or condition, and / or relief from a disease or condition to which such terms apply, or one or more symptoms of such a disease or condition. The term, "treatment," as used herein, unless otherwise indicated, is. refers to the action of treating as "treating" is defined immediately above. Therapeutic treatment refers to treatment initiated after observing “15 symptoms and / or a suspected exposure to an agent that causes the disease. or condition. Therapeutic treatment can generally reduce the severity and / or duration of symptoms associated with the disease or condition.
À As used here, "preventing" means preventing the clinical symptoms of a disease or condition from developing ie, inhibiting the onset of a disease or condition in an individual who may be exposed to or predisposed to the disease or condition , but you still don't experience or exhibit the symptoms of the disease or condition. Prophylactic treatment means that a compound of the invention is administered to an individual prior to the observation of symptoms and / or a suspected exposure to an agent causing the condition (for example, a pathogen or carcinogen). Generally, prophylactic treatment can reduce (a) the likelihood that an individual receiving treatment will develop the condition and / or (b) the duration and / or severity of symptoms in the event that the individual develops the condition.
As used here, the terms "autoimmune disease," "autoimmune disorder" and "autoimmunity" refer to chronic or acute immunologically mediated injury to a tissue or organ derived from the host. The terms cover both cell-mediated autoimmune and
po, as well as organ-specific or non-organ-specific autoimmunity. Autoimmune diseases include insulin-dependent diabetes mellitus, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, atherosclerosis, and inflammatory bowel disease. Autoimmune diseases also include, without limitation, ankylosing spondylitis, autoimmune hemolytic anemia, Bechet's syndrome, Goodpasture's syndrome, Graves' syndrome, Guillain Barre syndrome, Hashimoto's thyroiditis, idiopathic thrombocytopenia, severe myasthenia, pernicious anemia, polyarteritis nodosa, polymyositis / dermatomyositis, primary biliary sclerosis, psoriasis, sarcoidosis, sclerosing cholangitis, Sjogren's syndrome, systemic sclerosis (scleroderma and CREST syndrome), Takayasu's arteritis, temporal arteritis, and Wege- "ner granulomatosis. also include certain diseases associated with & the immune complex.as used here, the term "fibrotic disease" refers to diseases “15 disorders involving excessive and persistent tissue formation of: scar associated with organ failure in a variety of diseases chronic diseases affecting the lungs, kidneys, eyes, heart, liver and skin. Although a: remodeling and tissue healing is part of the c H atrization of a normal wound, injury, or repeated insult can induce excessive persistent scarring and, ultimately, organ failure.
Fibrotic conditions include diffuse fibrotic lung disease, chronic kidney disease, including diabetic kidney disease; Hepatic fibrosis (for example, chronic liver disease (CLD) caused by continuous and repeated insults to the liver from causes such as viral hepatitis B and C, alcoholic cirrhosis or non-alcoholic fatty liver disease (NAFLD), or sclerotic cholangitis primary rosant (PSC), a rare disease characterized by inflammatory fibrous destruction of the bile ducts inside and outside the liver, inducing biliary stasis, liver fibrosis, and finally cirrhosis, and end-stage liver disease); pulmonary fibrosis (for example, idiopathic pulmonary fibrosis (IPF)); and systemic sclerosis (a degenerative disorder in which excessive fibrosis occurs in multiple organ systems, including the skin, blood vessels, heart, lungs, and kidneys).
Other examples include cystic fibrosis of the pancreas and lungs; injection fibrosis, which can occur as a complication of intramuscular injections, especially in children; endomyocardial fibrosis; mediastinal fibrosis, myelofibrosis; retroperitoneal fibrosis; progressive massive fibrosis, a complication of pneumoconiosis in coal workers; nephrogenic systemic fibrosis; and complication of certain types of surgical implants (for example, occurrence in attempts to create an artificial pancreas for the treatment of diabetes mellitus.
As used herein, the term "cardiovascular disease" refers to diseases or disorders of the cardiovascular system involving an inflammatory component, and / or platelet accumulation, including without limitation coronary artery disease, cerebrovascular disease, peripheral arterial disease , up until- . rosclerosis, and arteriosclerosis. As used herein, the terms "cancer" and, "tumor" refer to a condition in which abnormally replicating cells of host g origin are present in a detectable amount in an individual. Cancer can be malignant or non-malignant. Cancers or tumors' include, but are not limited to, biliary tract cancer; brain cancer,. cancer; choriocarcinoma; colon cancer; endometrial cancer; esophageal cancer; gastric cancer (stomach); intraepithelial neoplasms; leukemias; lymphomas; liver cancer; lung cancer (for example, small cell or non-small cell); melanoma; neuroblastomas; oral cancer; ovarian cancer; pancreatic cancer, prostate cancer; rectal cancer; kidney (kidney) cancer; sarcomas; skin cancer; testicular cancer; thyroid cancer; as well as - other carcinomas and sarcomas. Cancers can be primary or metastatic.
As used here, the terms "inflammatory disease" and inflammatory disorder "refer to a condition characterized by inflammation, for example, a localized protective reaction of tissue to irritation, injury, or infection, characterized by pain, redness, swelling, and sometimes loss of function. Diseases or inflammatory disorders include, for example, allergy, asthma, and allergic rash.
As used herein, the term "disease associated with the immune complex" refers to any disease characterized by the production and / or deposition of immune complex tissue (i.e., any conjugate including an antibody and an antigen specifically bound by the antibody ), including but not limited to systemic lupus erythematosus (SLE) and related connective tissue diseases, rheumatoid arthritis, immune complex disease related to hepatitis C- and hepatitis B (eg cryoglobulinemia), Bechet's syndrome, autoimmune glomerulonephritis, and vasculopathy associated with the presence of LDL / anti-LDL immune complexes.
As used here, "immunodeficiency" refers to a disease or disorder in which the individual's immune system is not functioning at home. It is normal or where it would be useful to stimulate an individual's immune response, for example, to eliminate a tumor or cancer (for example, tumors of the brain, lung (for example, small cell and non-small cell), ovary, breast, prostate, colon as well as other carcinomas and sarcomas) or a infection in an individual.
Immunodeficiency can be acquired or it can be congenital. 1 As used herein, "graft rejection" refers to the hyperacute, acute or chronic immunologically mediated injury to a tissue or organ derived from a source rather than the host.
The term thus encompasses both cell and antibody-mediated rejection, as well as rejection of both allografts and xenografts. "Graft-versus-host disease" (GVHD) is a donated bone marrow reaction compared to the patient's own tissue.
GVHD is most often seen in cases where the bone marrow donor is not related to the patient or when the donor is related to the patient, but not a perfect comparison.
There are two forms of GVHD: an early form called acute GVHD that occurs shortly after transplantation when these white cells are increasing and a late form called chronic GVHD.
Atopic diseases mediated by Tn2 include, but are not limited to, atopic dermatitis or eczema, eosinophilia, asthma, allergy, rhinitis a-
allergic, and Ommen's syndrome.
As used here, "allergy" refers to the hypersensitivity acquired to a substance (allergen). Allergic conditions include eczema, allergic rhinitis or runny nose, hay fever, asthma, hives (wheal) and food allergies, and other atopic conditions.
As used here, "asthma" refers to a disorder of the respiratory system characterized by inflammation, narrowing of the airways and increased reactivity of the airways to inhaled agents. Asthma is often, though not exclusively, associated with allergic or atopic symptoms. For example, asthma can be precipitated by exposure to an allergen, exposure to cold air, respiratory infection, and exertion. : As used here, the terms "infection" and, equivalently, BR "infectious disease" refer to a condition in which an infectious agent or organism is present in a detectable amount in the blood or. 15 in normally sterile fabric or normally sterile compartment of the individual. Infectious agents or organisms include viruses, bacteria, fungi, and parasites. The terms cover both acute and chronic infections, as well as sepsis. : As used here, the term "sepsis" refers to the presence of bacteria (bacteremia) or other infectious organisms or their toxins in the blood (septicemia) or other tissue in the body.
Also provided is a compound of the invention, or a salt thereof, for use as a medicament in the treatment of the diseases or conditions described above in a mammal, for example, a human, who is suffering from such a disease or condition. Also provided is the use of a compound of the invention, or a salt thereof, in the preparation of a medication for the treatment of the diseases and conditions described above in a mammal, for example, a human, who is suffering from such a disorder.
This invention also encompasses pharmaceutical compositions - containing a compound of the invention and methods of treating or preventing conditions and disorders by modulating cellular activities mediated by TLR7- and / or TLR8 by administering a pharmaceutical composition comprising
endowing a compound of the invention, or a salt thereof, to a patient in need thereof.
In order to use a compound of the invention or a salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
In accordance with this aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention, or a salt thereof, as defined herein above in association with a pharmaceutically acceptable diluent or carrier. To prepare the pharmaceutical compositions according to: this invention, a therapeutically or prophylactically effective amount of a compound of the invention or a salt thereof (alone or together with an additional therapeutic agent as described here) is intimately mixed, for example, with a pharmaceutically acceptable carrier according to conventional pharmaceutical composition techniques to produce a dose. A vehicle can take a variety of forms depending on the form of preparation desired for administration, for example, oral or parenteral. Examples of suitable vehicles include any or all solvents, dispersion media, adjuvants, coatings, antibacterial agents , and antifungals, absorption retarding and isotonic agents, sweeteners, stabilizers (to promote long-term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, dispersion media, coatings, agents anti-bacterial and antifungal agents, absorption and isotonic retarding agents, flavoring agents, heterogeneous materials such as tampons and absorbents that may be necessary in order to prepare a particular therapeutic composition. - maceutically active is well known in the art, except to the extent that any conventional means or agents are incompatible available with a compound of the invention, their use in therapeutic preparations and compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions and preparations as described here.
The compositions of the invention may be in a form suitable for oral use (for example, as tablets, lozenges, hard or soft capsules, emulsions, aqueous or oily suspensions, dispersible powders or granules, syrups or elixirs), for use topical (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, as a finely divided powder or liquid aerosol), for administration by insufflation (for example, as a finely divided powder) or for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing or as a suppository for rectal dosing).
For example, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, flavors and / or preservatives.
Pharmaceutically acceptable excipients suitable for a: tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algae acid -. unique; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid, or talc; preserving agents such as ethyl or propyl p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Tablet formulations can be uncoated or coated to modify their disintegration and subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve its stability and / or appearance, in any case, using conventional coating agents and procedures well known in the art.
Compositions for oral use can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, or kaolin, or as mold gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions generally contain the active ingredient in finely powdered form along with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth gum and acacia gum; dispersing agents or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example, polyoxyethylene stearate), or ethylene oxide condensing products with long chain aliphatic alcohols, for example, heptadecaethyleneoxyethanol |, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbite monooleate |, or condensation products of ethylene oxide with partial esters derived: from fatty acids and hexitol anhydrides, for example, polyethylene monoelate : leno sorbitan. Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, NT antioxidants) (such as ascorbic acid), coloring agents, flavoring agents, Ss and / or sweetening agents (such as sucrose, saccharin or aspartame). Oily suspensions can be formulated by suspending the in-. active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). Oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those mentioned above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.
Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those previously mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.
The pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as, for example, liquid paraffin or a mixture of any of these. Suitable emulsifying agents can be, for example, naturally occurring gum such as acacia or tragacanth gum, naturally occurring phosphatides such as soybeans, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides ( (eg, sorbitan monoleate) and condensation products of said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweetening, flavoring and preserving agents. . Syrups and elixirs can be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and “A5 may also contain a demulcent, preservative, flavoring agent. and / or coloring.
The pharmaceutical compositions can also be in the form of a sterile injectable aqueous or oily suspension, which can be formulated. according to known procedures using one or more of the appropriate dispersing agents or wetting agents and suspending agents, which have been mentioned above. For parenteral formulations, the carrier will generally comprise sterile water, aqueous sodium chloride solution, 1,3-butanediol, or any other non-toxic parenterally acceptable solvent or diluent. Other ingredients including those that aid dispersion can be included. Certainly, where sterile water must be used and maintained as sterile, the compositions and vehicles must also be sterilized. Injectable suspensions can also be used, in which case, liquid vehicles, appropriate suspending agents and the like can be used. Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at usual temperatures but liquid at the rectal temperature and therefore melts.
it will go into the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
Topical formulations, such as creams, ointments, gels and aqueous or oily solutions or suspensions, can generally be obtained by formulating an active ingredient with a topically acceptable carrier or diluent using conventional procedures well known in the art.
Compositions for administration by insufflation may be in the form of a finely divided powder containing particles with an average diameter of, for example, 30 microns or much smaller, the powder itself comprising the active ingredient alone or diluted with one or more physiologically acceptable vehicles such like lactose. The insufflation powder is then conveniently retained in a capsule containing, for example, 1 to 50 mg of in-. active ingredient for use with a turbo-inhaler device as used for insufflation of the known sodium chromoglycate agent.
“A5 Compositions for administration by inhalation can be in the form of a conventional pressurized aerosol arranged to deliver the active ingredient as an aerosol containing liquid droplets or finely divided solid. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used and the aerosol device is conveniently arranged to deliver a metered amount of active ingredient.
Compositions for transdermal administration may be in the form of those transdermal skin patches that are well known to those skilled in the art. Other release systems may include release systems released over time, delayed release, or extended release. Such systems can avoid repeated administrations of the compounds, increasing convenience for the individual and the physician. Many types of delivery systems are available and known to those skilled in the art. They include polymer-based systems such as poly (lactide-glycolide), copolyoxalates, polycaprolactones, polystyramides, polyesters, polyhydroxybutyric acid, and polyanhydrides. Microcapsules of drugs containing previous polymers are described in, for example,
United States Patent No. 5,075,109. Delivery systems also include non-polymeric systems which are: lipids including sterols such as cholesterol, fatty acids and esters of cholesterol or neutral fats such as mono-di- and tri-glycerides; hydrogel delivery systems; systems - silastics; peptide-based systems; wax coatings; compressed tablets using binders and excipients; partially fused implants; and the like. Specific examples include, but are not limited to: (a) erosional systems in which an agent of the invention is contained in a form within the matrix such as those described in United States Patent No. * 4,452,775, 4,675,189, and 5,736,152, and (b) diffusion systems in which an active component permeates at a controlled rate of: a polymer as described in United States Patent No. 3,854,480, 5,133,974 and 5,407,686. In addition, pump-based hardware release systems can be used, some of which are “15 adapted for implantation.
. Compositions can be administered in the form of a solution, for example, water or isotonic saline, buffered or non-buffered, IS or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic with respect to nasal secretions and about the same pH, ranging, for example, from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7, 0. The buffers must be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a representative nasal decongestant is described as being buffered at a pH of about 6.2 (Remington's Pharmaceutical Sciences, Ed. By Arthur Osol, p. 1445 (1980)). In fact, the usual technician can readily determine an appropriate saline content and pH for an innocuous aqueous vehicle for nasal administration. Others, non-limiting examples of intranasal dosage forms containing the composition include gels, creams, pastes or nasal ointments with a viscosity of, for example, from about 10 to about 3000 cps, or from about 2500 to 6500 cps, or greater, which can provide more sustained contact with nasal mucosal surfaces. Such viscous vehicle formulations can be based on, simply by way of example, polymeric vehicles such as alkyl celluloses and / or other high viscosity biocompatible vehicles well known in the art (see, for example, Remington's, above). The vehicle containing a composition can also be soaked in a tissue material, such as gauze, which can be applied to nasal mucosal surfaces to allow active substances in the isolated fraction to penetrate the mucosa.
Other ingredients, such as preservatives, dyes, lubricants or vegetable oils or viscous minerals, perfumes, natural or synthetic plant extracts known in the art such as aromatic oils, and viscosity enhancers and humectants such as, for example, glycerol, . they can also be included to provide more viscosity, moisture retention and a pleasant texture and odor for the formulation.
“5 In addition, for nasal administration of solutions or suspensions of a composition, several devices are available in the art for the generation of drops, droplets and sprays. For example, solutions comprising the isolated fraction can be administered in na- passages. salts by means of a simple dropper (or pipette) that includes a glass, plastic or metal distribution tube from which the contents are expelled dropwise by means of air pressure provided by a manually operated pump, by example, a flexible rubber ampoule, attached to the end.
Fine droplets and sprays can be supplied by a manual or electrically driven intranasal pump dispenser or pressurized vial as well known in the art, for example, which is designed to blow up a mixture of air and fine droplets in the nasal passages.
An amount of a compound of this invention that is combined with one or more excipients to produce a single dosage form will necessarily vary depending on the individual treated, the severity - disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage in the range of about 0.001 to about 100 mg per kg of body weight per day,
for example, about 0.05 to about 35 mg / kg / day, in single or divided doses. For example, a dosage is about 0.0005 to about 2.5 gfidia. For example, a dosage is about 0.0005 to about 1 gallon in single or divided dosages. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effects, provided that such larger doses are first divided into several small doses. doses for administration throughout the day. For further information on administration routines and dosing regimens, see Chapter 25.3 in Volume 5 of Comprehensive Medi-: Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon. Press 1990, which is specifically incorporated here by reference. The dose size for therapeutic or prophylactic purposes “15 of a compound of the invention will naturally vary according to nature. za and severity of conditions, the age and sex of the animal or patient and the administration routine, according to well-known principles of medicine. It will be understood that the specific dosage level and frequency of: dosage for any particular individual can be varied and will depend on a variety of factors including the activity of the specific compound of the invention, species, age, body weight, general health, sex and diet of the individual, the mode and time of administration, excretion rate, drug combination, and severity of the particular condition, but may not however be routinely determined by someone skilled in the art.
A compound of the invention, or salt thereof, is in some ways administered to an individual in combination (for example, in the same formulation or in separate formulations) with another therapeutic agent ("combination therapy"). The compound of the invention is administered in admixture with another therapeutic agent or is administered in a separate formulation. When administered in separate formulations, a compound of the invention and another therapeutic agent are administered substantially, simultaneously or sequentially. In one aspect, a compound of the invention is administered to an individual in combination with another therapeutic agent for the treatment of a condition or disease. In one aspect, a compound of the invention is administered to an individual in combination with another therapeutic agent for preventing a condition or disease. In one aspect, a compound of the invention is administered to an individual in combination with a vaccine for the prevention of a condition or disease. In one aspect, a compound of the invention is administered to an individual in combination with an infectious disease vaccine. In one aspect, a compound of the invention is administered to an individual in combination with a cancer vaccine.
A compound of the invention can be useful as an adjuvant vaccine for use in conjunction with any material that elicits the response. humor and / or cell-mediated immune, such as, for example, live viral, bacterial, or parasitic immunogens; deactivated viral immunogens, de- “15 tumor-derived, protozoa, organism-derived, fungal, or bacterial, toxoids, toxins; self-antigens; polysaccharides; proteins; glycoproteins; peptides; cellular vaccines; DNA vaccines; recombinant proteins; glycoproteins; peptides; and the like, for use in connection with: for example BCG, cholera, plague, typhoid, hepate A, hepatitis B, hepate C, influenza A, influenza B, parainfluenza, polio, rabies, measles, pigeon pea, rubella, yellow fever , tetanus, diphtheria, hemophilic influenza b, tuberculosis, meningococcal and pneumococcal vaccines, adenovirus, HIV, chickenpox, cytomegalovirus, dengue, feline leukemia, poultry pest, HSV-1 and HSV-2, swine cholera, Japanese encephalitis, respiratory syncytial virus, rotavirus, papilloma virus, yellow fever, and Alzheimer's disease.
A compound of the invention may also be useful in individuals having compromised immune function. For example, a compound of the invention can be used for the treatment of or prevention of opportunistic infections and tumors that occur after suppression of cell-mediated immunity in, for example, transplant patients, cancer patients and patients with HIV.
Such combination treatment may involve, in addition to a
the invention, chemotherapy or radiotherapy or conventional surgery. Such chemotherapy may include one or more of the following categories of antitumor agents: (i) antiproliferative / antineoplastic drugs and combinations thereof; (ii) cytostatic agents; (iii) agents that inhibit cancer cell invasion; (iv) growth factor function inhibitors; (v) antiangiogenic agents; (vi) vascular damage agents; (vii) antisense therapies; (viii) gene therapy methods; (ix) interferon; and (x) immunotherapy methods.
Therapeutic agents for the treatment of or prevention of respiratory diseases that can be administered in combination with a compound of the invention in an individual method include, but are not] limited to beta adrenergics that include bronchodilators including albute-. rol, isoproterenol sulfate, metaproterenol sulfate, terbutaline sulfate, pyrbuterol acetate and salmeterol formotorol; steroids including dipropi- “15 becometasone, flunisolid, fluticasone, budesonide and acetonide. triamcinolone. Anti-inflammatory drugs used in connection with the treatment or prevention of respiratory diseases include steroids such as: becometasone dipropionate, triamcinolone acetonide, flunisolide and fluticasone. Other anti-inflammatory drugs include cromoglycates such as sodium chromoline. Other respiratory drugs that would qualify as bronchodilators include anticholinergics including ipratropium bromine. Antihistamines include, but are not limited to diphenhydramine, carbinoxamine, clemastine, dimenhydrinate, prylamine, tripelinenamine, chlorpheniramine, brompheniramine, hydroxyzine, cyclizine, meclizine, chlorcyclizine, promethazine, doxylamine, loratadine and loratadine. Particular antihistamines include rhinolast (Astelin &), claratin (Claritin &), claratin D (Claritin DO), teifast (AllegraO), ZyrtecO, and beconase. In some embodiments, a compound of the invention is administered as a combination therapy with interferon-gamma (IFN-gamma), a corticosteroid such as prednisone, prednisolone, methyl prednisolone, hydrocortisone, cortisone, dexamethasone, betamethasone, etc., or a combination of these, for the treatment or prevention of internal lung disease
tstitial, for example, idiopathic pulmonary fibrosis.
In some embodiments, a compound of the invention is administered in combination therapy with a known therapeutic agent used in the treatment of cystic fibrosis ("CF"). Therapeutic agents used to treat CF include, but are not limited to, antibiotics; anti-inflammatory agents; DNAse (for example, recombinant human DNAse; pulmozyme; dornase alfa); mucolytic agents (for example, N-acetylcysteine; MucomistTM; MucosilTM); decongestants; bronchodilators (for example, theophylline; ipatropium bromine); and the like.
In some embodiments, a compound of the invention is administered prophylactically for the prevention of cardiovascular disease, for example, atherosclerosis. :: In another embodiment of the invention, an article of manufacture, or "kit", containing materials useful for the treatment or prevention of the diseases described above is provided. : In one embodiment, the kit comprises a container comprising a composition of the invention, or a pharmaceutically acceptable salt thereof. In one embodiment, the invention provides a Kit for treatment; of or prevention of a disorder mediated by TLR7- and / or TLR8. In another way, the invention provides a Kit for a condition or disorder treatable by selective modulation of the immune system in an individual. The Kit may also comprise a label or packaging supplement on it or associated with the container.
Suitable containers include, for example, bottles, vials — syringes, syringes, blister packs, etc. The container can be formed from a variety of materials such as glass or plastic. The container holds a compound of the invention or a pharmaceutical formulation thereof, in an amount effective for treating or preventing the condition, and may have a sterile access port (for example, the container may be a bag of intravenous solution or a frasconette with a plug piercable by a hypodermic injection needle). The label or insertion of the package indicates that the composition is used to treat or prevent the condition of selection. In one embodiment, the label or package insert indicates that the composition comprising a compound of the invention can be used, for example, to treat or prevent a disorder treatable by modulating cellular activities mediated by TLR7- and / or TLR8.O package label or insertion may also indicate that the composition can be used to treat or prevent other disorders. Alternatively, or in addition, the kit may also comprise a second container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringere solution and dextrose solution. It may also include other materials desired from a commercial and user point of view, including others] buffers, thinners, filters, needles and syringes. . The Kkit can also comprise directions for administering the compound of the invention and, if present, the second pharmaceutical formulation. For example, if the kit comprises a first composition containing | a compound of the invention and a second pharmaceutical formulation, the kit can also comprise directions for simultaneous, sequential or separate administration of the first and second pharmaceutical compositions: to a patient in need thereof.
In another embodiment, the kits are suitable for the release of oral forms of a compound of the invention, such as tablets or capsules. Such a Kit includes, for example, several unit dosages. Such kits may include a card with the dosages oriented in the order of their intended use. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms. If desired, a memory aid can be provided, for example, in the form of numbers, letters, or other markers or with a calendar insert, designating the days on the treatment scale on which dosages can be administered.
According to one embodiment, the kit can comprise (a) a first container with a compound of the invention contained therein; and optional-
(b) a second container with a second pharmaceutical formulation contained therein, wherein the second pharmaceutical formulation comprises a second compound that can be effective in treating or preventing a condition or disorder by selective modulation of cellular activities mediated by TLR7- and / or TLR8. Alternatively, or in addition, the Kit may also comprise a third container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BW-FI), phosphate buffered saline, Ringer's solution and dextrose solution.
It may include other materials desirable from a commercial and user perspective, including other buffers, thinners, filters, needles, and syringes.
In certain other embodiments in which the Kkit comprises one, pharmaceutical formulation of a compound of the invention and a second formulation comprising a second therapeutic agent, the kit may comprise a container for containing separate formulations, such as a “15 split flask or a thin sheet package of split metal; however, overpriced. separate compositions can also be contained within a single, undivided container.
Typically, the kit comprises directions for the administration of the separate components.
The form of the Kit is particularly advantageous when the separate components are administered in different dosage forms (for example, oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired prescribing doctor.
Compound activity can be assessed according to procedures described in, for example, Gorden et al., Joumal of Immunlogy177, pages 8164-8170 (2006) and Zhu et al, Molecular Immunology, volume 45 (11), pages 3238-3242 (2008). MC values, for TLR8 activity are, for example, as shown below:
TLRB (MCs; 183 o. - NR NO NH HO N Z
No. 214 ANITA 54 nM
NO NO JS NH Eto 'O
Q 222 nO TOH 33 nM
WS: the ”” NO NH
DO Oo: 223 nO 195 nM
OA WS - NNH, 2 O ': O o 224 y B Ss Ho du MC values, for TLR7 activity are, for example, as shown below: TLR7 (MCs o nMNOoH 358 nM (CJ) AND WS o = NO NH, Only
EXAMPLES In order to illustrate the invention, the following examples are included
From.
However, it should be understood that these examples do not limit the invention and are only intended to suggest a method of practicing the invention.
Persons skilled in the art will recognize that the chemical reactions described can easily be adapted to prepare various compounds of the invention, and alternative methods for preparing the compounds of this invention are also believed to be within the scope of this invention.
For example, the synthesis of compounds not exemplified according to the invention can be carried out successfully by evident modifications for those skilled in the art, for example, by groups that appropriately interfere with protection, using other suitable reagents known in the technique instead of those described, and / or making routine changes to reaction conditions.
Alternatively, other reactions described. herein or known in the art will be recognized as having applicability for the preparation of other compounds of the invention. “A5 In the examples described below, unless otherwise indicated, all temperatures are set in degrees Celsius.
The reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, Acros, TCI, Alfa Aesar or Maybridge, and: were used without further purification unless otherwise indicated.
In the examples described below, the term "Example tHHt" refers to "Compound ttf". For example, Example 113 is directed to compound 113 and / or synthetic procedures relating to compound 113. The reactions set out below were generally carried out under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise established) in anhydrous solvents, and the reaction flasks are typically fitted with rubber septa for the introduction of substrates and reagents by syringe.
The utensils were oven dried and / or dried by heating.
Microwave reactions were carried out on the Biotage starter system.
Column chromatography was performed on a Biotage system or Isolute Flash Si SPE column (manufacturer: Biotage AB) with a silica gel column or on a SepPak silica column (Waters). The 'H and "* F NMR spectra were recorded on a Varian instrument operating at 400 MHz and 376 MHz, respectively. The * H-NMR spectra were obtained with CDCI3 or ds-DMSO solutions (reported in ppm), using chloroform (7.26ppm) or tetramethylsilane (O ppm) as the reference standards.When maximum multiplicities are reported, the following abbreviations are used: s (singlet), d (doublet), t (triplet), q (quartet), br (extended), dd (doublet of doublets), dt (doublet of doublets), m (multiplets) Example 1 Synthetic Procedure Scheme | 1. General Synthetic Routine No, No, No, NANA - os EN LO taco, LS "N Br Br Br Toluene reflux f SM 15 COOEt COOEt. COLE Las i: Br NOZCN Aco LÃ. ".o. 16 17 17B - COCEt CODE COOEt Boron RB (OH) 2 Br DOM. E, R H> HBoc HBoc 17 18 20 CoDEt
TFA DCM, rt R Ha 2
1. Synthetic compound 15 NO NO, NO, Bram Gene, E Br Br Br SM 15 In a three-necked flask supplied with a stirrer
panic, drip funnel, and thermometer, surrounded by an ice-salt bath, 400 ml of acetic anhydride and 50 g (0.23 mole) of 4-bromo-1-methyl-2-nitrobenzene are placed. 54 ml of concentrated sulfuric acid are slowly added to this solution with stirring. When the mixture has cooled to 0 ° C, a solution of 64 g of ammonium trioxide in 360 ml of acetic anhydride is added slowly with stirring; at such a rate that the temperature does not exceed 10 and stirring is continued for 2 hours at 5-10ºC in an ice water bath after the addition is complete. The contents of the flask are poured into the mixture of ice and water. The solid was filtered and washed with water until the washings are colorless. The product is suspended in 300 ml of 2% aqueous sodium carbonate and stirred. After thorough mixing, the solid fan was filtered and washed with water and dried. : A suspension of diacetate in a mixture of 272 ml of concentrated hydrochloric acid, 250 ml of water, and 80 ml of ethanol! “15 was stirred for 45 minutes. The mixture was then cooled to RT e. the solid was filtered and washed with water. The crude product is purified by column (22 g, 42%).
2. Synthetic compound 16 Ph3P: 26: ”A eos Dr toluene, reflux Lo, A mixture of aldehyde (0.73g, 3.17mmol) and ilidium (1.429, 3.65 mmol) in toluene (8mL) was gently refluxed for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the raw material that was used directly without further purification.
3. Synthetic compound 17 and 17B COOEt COOEt
AOC AND AOC OR Noz “N AcoH Br N = No Br pn 16 17 17B
To a solution of the raw nitrile in AcCOH (25 ml) was added iron (1.15 g, 20.61 mmol) at room temperature. The resulting mixture was heated to 85 ° C for 4 hours. The reaction mixture was cooled to room temperature and diluted with CH2Clz (8mL). The resulting mixture was filtered, the solids were washed with CH2Ch7. The filtrate was concentrated under reduced pressure to provide viscous oil. To the crude material, CH2Cl2 (8 mL) was added. Aqueous Na2CO3 followed by water was slowly added with stirring until its pH = 9-10. The mixture was filtered and washed with CHz2Cl>. The organic layer was separated. The aqueous layer was extracted with CH2Cb. The organic layer was separated. The aqueous layer was extracted with CH2CL. The combined organic layers were washed with brine, dried over Na> SO ;, the mixture was concentrated under reduced pressure to provide S the raw material which was purified by flash column chromatography on silica gel to provide 0.329 g (33% for two steps) of the desired product that “15 was based on * H-NMR. ; 4. Synthetic compound 18 L COooEt COODEt
CA f At NHz f- AN xHBOc 7 18 To benzazepine (2.34 g, 7.57 mmol) in DCM (25 mL) Boc2O (2.06 g, 9.46 mmol) was added at room temperature. The reaction mixture was stirred for 20 hours. The resulting mixture was consecutively washed with NaHCO; saturated aqueous and brine. The organic layer was separated and dried and dried over NazSO ,,, filtered, and concentrated under reduced pressure to provide the crude product which was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to provide 1.64 g (52.9%) of the desired product.
5. Synthesis of species Example 113
OM “q AD ew“ o (1E 4E) -2-amino-N- (piperidin-4-ylmethyl) -N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b ] azepine-4-carboxamide Step A: Preparation of tert-butyl 4 - ((benzyloxycarbonylamino) methyl) methyl) piperidine-1-carboxylate: tert-butyl 4- (aminomethyl) piperidine-1-carboxylate (0.611 g , 2.851 mmol) and diisopropylethylamine (0.479 9, 3.706 mmol) were dissolved in 30 mls of dry dichloromethane. To this - mixture was added benzyl chloroformate (0.552 g, 3.136 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was then diluted with 50 ml of dichloromethane, washed once with 1N aqueous HCI, once with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure at 950 mg (96%) title compound and used directly without further purification.
, 15 Step B: Preparation of tert-butyl 4 - (((benzyloxycarbonyl) (propyl) amino) tert-butyl mettypiperidine-1-carboxylate: 4 - tert-butyl (((benzyloxycarbonylamino) methyl) methyl) piperidine-1-carboxylate (0.950 g, 2.726 mmol) was dissolved in dry DMF (25 mls). To this was added sodium hydride (0.164 9, 4.090 mmol, 60% dispersion in mineral oil) and the reaction mixture was stirred at room temperature for 30 minutes. propyl lodide (0.695 g, 4.090 mmol) was then added and the mixture stirred at room temperature for 16 hours, then diluted with brine (200 ml), extracted twice with EtOAc, the extracts washed twice with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (100 g Bio-Snap Snap cartridge, 30% EtOAc / Hexanes) to provide 0.280 g (26%) of the title compound.
Step C: Preparation of 4 - ((propylamino) methyl) piperidine-1-car-
tert-butyl boxylate: To a solution of tert-butyl 4 - (((benzyloxycarbonyl) (propyl) amino) methyl) piperidine-1-carboxylate (0.280 g, 0.717 mmol) in 7 mls of methanol was added palladium hydroxide (ll) (0,200g, 20% by weight of Pd (OH), in carbon, Degussa type). This mixture was hydrogenated under a hydrogen balloon for 1.5 hours, then filtered through GF / F filter paper and the filtrate concentrated. 0.169 g (92%) of the title compound was obtained and used directly without further purification.
Step D: Preparation of (1E, 4E) -2-amino-N- (piperidin-4-ylmethyl) - N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxamide: The title compound was prepared by these procedures using (1E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-f benzo [b] azepine-4-carboxylic and tert-butyl 4 - ((propylamino) methyl) piperidine-1-carboxy-Dylate. Preparation of (1E, 4E) -4- (propylcarbamoyl!) - 8- (tert-butyl 4- (pyrrolidine -1-carbonyl) phenyl) -3H-benzo [b] azepin-2-ylcarbonate: A mixture of “ 15 grade (11E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl). Phenyl) -3H-benzo [b] azepine-4-carboxylic (200 mg, 0, 42 mmol), HOBt (114 mg, 0.84 mmol), and EDCI (161 mg, 0.84 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature. To this mixture, triethylamine y (0.12 mL, 0.84 mmol) and propan-1-amine (0.043 mL, 0.53 mmol) were added at room temperature. The resulting solution was stirred for an additional 2 hours. The reaction mixture was diluted with EtOAc (5 ml) and washed with NH, aqueous saturated CI. The aqueous layer was separated and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), NaH-CO; saturated aqueous (5 ml), and brine (5 ml). The organic layer was dried over MgSO2, filtered, and concentrated under reduced pressure to provide (16E, 4E) -4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-benzo [b] raw tert-butyl azepin-2-ylcarbonate which was used directly without further purification. Preparation of (1E, 4E) -2-amino-N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxamide: To a solution of (1E, 4E) tert-Butyl 4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] a-zepin-2-ylcarbonate (450 mg, 0.87 mmol) CH2Ch7 (5 ml) 2,2,2-trifluoroacetic acid (1.36 ml, 17.4 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours.
The reaction mixture was concentrated under reduced pressure to provide the crude material which was diluted with CH2Cl2 (10 ml) and NaHCO; saturated aqueous solution (15 mL) again.
The resulting mixture was stirred for 30 minutes at room temperature.
The aqueous layer was separated and extracted with CH2Cl2 (1 x 10 ml). The combined organic layers were washed with NaHCO; saturated aqueous solution (2 x 10 ml) and brine (1 x 10 ml), dried over MgSO;, filtered, and concentrated under reduced pressure to provide the raw material again, which was purified by flash-column chromatography (1-5% dehydrated). MeOH in CH> 2Cb, gradient). m / z (APCI-pos) M + 1 = 514.3. 'The following example, 116, was prepared by these procedures. using (1E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonylDYphenyl) -3H-benzo [b] azepine-4-carboxylic acid and the appropriate amines (2-methyl - “15 1- (propylamino) propan-2-ol was prepared by the procedure reported in J. 'Am.
Chem.
Soc. 1939, 671, 3562) or hydroxylamine.
Preparation of (1E, 4E) - 4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin-2- "tert-butyl ylcarbonate: A mixture of acid (1E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxylic (200 mg, 0.42 mmol ), HOBt (114 mg, 0.84 mmol), and EDCI (161 mg, 0.84 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature.
To this mixture was added triethylamine (0.12 ml, 0.84 mmol) and propan-1-amine (0.043 ml, 0.53 mmol) at room temperature.
The resulting solution was stirred for an additional 2 hours.
The reaction mixture was diluted with EtO-Ac (5mL) and washed with NH, saturated aqueous CI.
The aqueous layer was separated and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), NaHCO; saturated aqueous (5 ml), and brine (5 ml). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to provide (116.4E) -4- (propylcarbamoyl) -B- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-benzo [b] azepin-2-ylcarbonate - from raw tert-butyl which was used directly without further purification.
Preparation of - (1E, 4E) -2-amino-N-propyl-8B- (4- (pyrrolidine-1-carbonyl) phenyl) -SH-benzo [b]
azepine-4-carboxamide: To a solution of (1E, 4E) -4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin-2-ylcarbonate -butyl (450 mg, 0.87 mmol) in CH2Cl> (5 mL) 2,2,2-trifluoroacetic acid (1.36 mL, 17.4 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide the raw material which was diluted with CHzClz (10 ml) and NaHCO; saturated aqueous solution (15 mL) again. The resulting mixture was stirred for 30 minutes at room temperature. The aqueous layer was separated and extracted with CH2Chb (1 x 10 ml). The combined organic layers were washed with NaHCO; saturated aqueous solution (2 x 10 ml) and brine (1 x 10 ml), dried over MgSO 2, filtered, and concentrated under reduced pressure to provide the raw material again which was purified by flash column chromatography on silica gel ( 1 to 5% MeOH in CHzCL, gradient). “15 Example116, O ss: O Is (1E, 4E) -2-amino-N- (benzyloxy) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4 -Carboxamide TH-NMR (400 MHz, CDCl3) 5 11.59 (br s, 1H), 7.74-7.78 (m, 2H), 7.61-7.65 (m, 2H), 7, 33-7.53 (m, 8H), 4.91 (s, 2H), 3.40-3.53 (m, 4H), 3.03 (s, 2H), 1.80-1.92 ( m, 4H); m / z (APCI-pos) M + 1 = 481.2. Example 118
QO O o
ADA O o (1E, 4E) -2-amino-N- (benzyloxy) -N-propyl-8- (4- (pyrrolidine-1-carbo-
nil) phenyl) -3H-benzo [b] azepine-4-carboxamide Step A: Preparation of O-benzyl-N-propylhydroxylamine: To a solution of propan-1-ol (6.25 mL, 83.2 mmol) and 2,6-dimethylpyridine (11.6 mL, 99.8 mmol) in CH2Cl> (500 mL) under a nitrogen atmosphere at -78 ºC was added in trifluoromethanesulfonic anhydride portion (14.0 mL, 83.2 mmol). After stirring for 30 minutes at -78 ° C, a solution of O-benzylhydroxylamine (10.7 ml, 91.5 mmol) in CH2Cl (10 ml) was added in portions. The resulting mixture was stirred at -78 ° C for 1 hour, then warmed to room temperature, and stirred for an additional 2 hours.
The reaction mixture was diluted with ice water (250 ml) and the organic layer was separated, washed with NaHCO; saturated aqueous (100 ml) and brine (100 ml). The aqueous layers were extracted again with EtOAc (1. x 200 ml). The combined organic layers were dried over MgSO., Filtered, and concentrated under reduced pressure to provide the raw material * 15 which was purified by flash column chromatography on silica gel (CH2Cl2). THE . fraction containing product and 2,6-dimethylpyridine was added 2 M aqueous KOH (100 mL), which was then washed with MTBE. The aqueous layer was brought to a pH of -5 with 1 M aqueous HCI and then extracted: with MTBE (3 x 50 ml). The combined organic layers were dried over MgSO ,,, filtered, and concentrated under reduced pressure to provide 11.2 g (75%) of O-benzyl-N-propylhydroxylamine.
Step B: Preparation of (11, 4E) -4- (benzyloxy (propyl) carbamoyl) -8- (4- (pyrrolidine-1-carbonyl) pheni!) - 3H-benzo [b] azepin-2-ylcarbonate - de tert-butyl: The title compound was prepared by these procedures using (1E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-benzo [b] lazepine-4-carboxylic and O-benzyl-N-propylhydroxylamine. Preparation of tert-butyl (1E, 4E) -4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] Jazepin-2-ylcarbonate: One mixture of (1E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] olive4-carboxylic acid (200 mg, 0.42 mmol), HOBt (114 mg, 0.84 mmol), and EDCI (161 mg, 0.84 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature. To this mixture was added triethylamine (0.12 ml, 0.84 mmol) and propan-1-amine (0.043 ml, 0.53 mmol) at room temperature.
The resulting solution was stirred for an additional 2 hours.
The reaction mixture was diluted with EtOAc (5 ml) and washed with NH, saturated aqueous CI.
The aqueous layer was separated and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), saturated aqueous NaHCO3 (5 ml), and brine (5 ml). The organic layer was dried over Mg-SO ;, filtered, and concentrated under reduced pressure to provide (11.4E) -4-
(raw propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 8H-benzo [b] azepin-2-ylcarbonate which was used directly without further purification Preparation of (1E, 4E ) -2-amino-N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxamide: To a solution of (1E, 4E) -4- ( pro-
'pilcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin-2-ylcarb-. tert-butyl cream (450 mg, 0.87 mmol) in CH2Cl2 (5 mL) 2,2,2-trifluoroacetic acid (1.36 mL, 17.4 mmol) was added at 0 ° C.
The reaction mixture was heated to room temperature and stirred for 2 hours.
The mixture. reaction was concentrated under reduced pressure to provide the raw material which was diluted with CH2Clz (10 mL) and NaHCO; saturated aqueous (15 mL) again.
The resulting mixture was stirred for 30 minutes at room temperature.
The aqueous layer was separated and extracted with CH2Cl (1 x 10 ml). The combined organic layers were washed with NaHCO; saturated aqueous (2 x 10 mL) and brine (1 x 10 mL), dried over MgSO ,,, filtered, and concentrated under reduced pressure to provide the raw material again which was purified by flash column chromatography of silica gel (1 to 5% MeOH in CH> Cl>, gradient). * H-NMR (400 MHz, CDCl3) d 7.67-7.71 (m, 2H), 7.60-7.63 (m, 2H), 7.53-7.55 (m, 1H), 7.29-7.39 (m, 8H), 4.84 (s, 2H), 3.74-3.81 (m, 2H), 3.62-3.71 (m, 2H), 3, 48-3.54 (m, 2H), 2.82 (s, 2H), 1.87-2.01 (m, 4H), 1.74-1.84 (m, 2H), 0.96- 1.02 (m, 3H); m / z (APCI-pos) M + 1 = 523.2.
Example 148 o
EO> Hz 2-amino-8- (benzyloxy) -3H-benzo [b] azepine-4-carboxylate (1E, 4E) -ethyl The title compound was prepared by these procedures using 4- (benzyloxy) - 1-methyl-2-nitrobenzene. Preparation of (E) -1- (4-bromo-2-nitrosteriri) pyrrolidine: A solution of 4-bromo-2-nitrotoluene (100 g, 463 mmol), pyrrolidine (46.2 mL, 565 mmol), and dimethylacetall of NN-. dimethylformamide (75.6 ml, 565 mmol) was refluxed for 4 hours at 110 ° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the raw (E) 1- (4-bromo-2- .- 10 nitro-styripyrrolidine which was used directly without further purification. Preparation of 4-bromo- 2-nitrobenzaldehyde: To a solution of sodium x periodate (298 g, 1.40 mol) in THF-H2O (4 L, 1: 1) at 0ºC was added (E) -1- (4- Y bromo-2 -nitrostyrene) pyrrolidine (138 g, 464 mmol) The mixture was stirred for 15 hours and then filtered to remove solid precipitates. The aqueous layer of the filtrate was separated and extracted with EtOAc (4 x 200 mL) The combined organic layers were washed with HO (2 x 200 mL), dried over MgSO2, filtered, and concentrated under reduced pressure to provide the crude product which was purified by flash column chromatography on silica gel (5% EtOAc in hexanes) Preparation of 2- (cyanomethyl) -3- (3-nitro- 4- (pyrrolidine-1-carbonyl) biphenyl-4yl) (E) -ethyl acrylate: A mixture of 3-nitro-4 ' - (pyrrolidine-1-c arbonyl) biphenyl-4-carbaldehyde (20.0 g, 61.7 mmol) and cyanomethylcarboethoxyethylidene a-triphenylphosphorane (26.3 g, 67.8 mmol) in toluene (200 mL) was gently refluxed for 2.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide 2- (cyanomethyl) -3- (3-nitro-4 '- (pyrrolidine-1-carbonyl) biphenyl-4-yl) acrylate ( E) - raw ethyl that was used directly without further purification. Preparation of 2-amino-8- (4- (pyrrolidine-1-carbonyl) phenyl!) - 3H-benzo [b] Jazepine-4-carboxylate (1E, 4E) -ethyl: To a solution of 2-
(cyanomethyl) -3- (3-nitro-4 "- (pyrrolidine-1-carbonyl) biphenyl-4-yl) crude (E) -ethyl acrylate in AcOH (650 mL) was added iron (29.1 g, 521 mmol) at room temperature The resulting mixture was heated to 85 ° C for 4 hours The reaction mixture was cooled to room temperature and diluted with CHCl) (250 ml) The solids were filtered and washed with CH72Cl> (200 ml The filtrate was concentrated under reduced pressure to provide the raw material which was diluted with CH2Cl> (250 ml) again. To this mixture was slowly added Na2CO; 3 saturated aqueous (-330 ml) with vigorous stirring until it becomes basic (pH —-9-10). The resulting mixture was filtered and washed with CH2Cl; (-250 mL). The aqueous layer was separated and extracted with CHCk (2 x 150 mL). The combined organic layers were washed with brine, dried over MgSO4, and filtered to provide the raw material which: was diluted with EtOAc (70 mL). The mixture was kept for 16 hours at room temperature . The suspension was filtered. The filtered solids were washed with EtOAc (100 mL) to provide the crude product which was washed with a small amount of CH2CL. Example 175 t H N
RE CG (O "NH O (1E, 4E) -2-amino-N-propyl-N- (pyrrolidin-2-ylmethyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxamide Step A: Preparation of pyrrolidin-2-ylmethanol: To a solution of DL-proline (100g, 8689 mmol) in MeOH (1500 mL) was added SOCbk slowly at 0 ° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure to provide the crude material which was dissolved in THF (1700 mL) again. To this mixture was added in portions LiAlH, (132 g, 3.47 mol ) at 0 ° C. The resulting mixture was heated to 60 ° C overnight. The excess LiAlH was quenched with KOH. The reaction mixture was filtered and the solid was washed with MeOH (1000 mL). The combined organic layers were dried, filtered and concentrated under reduced pressure to provide the raw material that was purified by distillation to provide 15.8 g (18%) of pyrrolidin-2-ylmethanol.
Step B: Preparation of tert-butyl 2- (hydroxymethyl) pyrrolidine-1-carboxylate: To a solution of pyrrolidin-2-ylmethane! (505 mg, 4.99 mmol) and TEA (1.0 g, 9.9 mmol) in CH2Cl7 (5 mL) was added a solution of Boc2O (1.31 g, 6 mmol) in CH2Cl> (10 mL) . The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was quenched with water (100 ml) and extracted with CH2 Cl4, the organic layer was washed with brine, dried over Na7zSO2, filtered, and concentrated under pressure. reduced to provide the raw material that was purified by flash column chromatography on silica gel (MeOH: CH2Cl, = 1: 100) to provide 14.2 g (48%) “15 of 2- (hydroxymethyl) pyrrolidine-1-carboxylate tert-butyl. LCMS ESI (+) m / z! 202 (M + 1) detected.
Step C: Preparation of tert-butyl 2 - ((methylsulfonyloxy) methyl) pyrrolidine-1-carboxylate: To a solution of 2- (hydroxymethyl) pyrrolidine-1-. tert-butyl carboxylate (1.0 g, 5.0 mmol) and TEA (1.0 g, 9.9 mmol) in CHCb (40 mL) was added slowly MsC! I (0.63 g, 5.5 mmol). The reaction mixture was stirred for 30 minutes at -20 ° C and then water (60 ml) was added. The aqueous phase was separated and extracted with CH2Cb. The combined organic layers were washed with brine, dried over Na> SO ;, filtered, and concentrated under reduced pressure to provide the raw tert-butyl 2- ((methylsulfonyloxy)) pyrrolidine-1-carboxylate that was used directly without further purification.
Step D: Preparation of tert-butyl 2 - ((propylamino) methyl) pyrrolidine-1-carboxylate: a solution of tert-butyl 2 - ((methylsulfonyloxy) methyl) pyrrolidine-1-carboxylate (5.0 g , 18 mmol) and propan-1-amine (20.0 g, 339 mmol) in toluene (50 mL) was heated to 100 ° C overnight. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the tertiary 2 - ((propylamino) methyl) pyrrolidine-1-carboxylate
raw butyl which was used directly without further purification.
LCMS ESI (+) m / z 243 (M + 1) detected.
Step E: Preparation of (1E, 4E) -2-amino-N-propyl-N- (pyrrolidin-2-ylmethyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxamide: The title compound was prepared by these procedures using (1E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H- benzol [ b] azepine-4-carboxylic and tert-butyl 2 - ((propylamino) methyl) pyrrolidine-1-carboxylate.
Preparation of tert-butyl (1E, 4E) -4- (propylcarbamoyl) -8- (4- (pyrrolidine -1-carbonyl) phenyl) -3H-benzo [b] azepin-2-ylcarbonate: A mixture (16E, 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxylic acid (200 mg, 0.42 mmol ), HOBt (114 mg,] 0.84 mmol), and EDCI (161 mg, 0.84 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature.
To this mixture, triethylamine (0.12 mL, 0.84 mmol) and propan-1-amine (0.043 mL, 0.53 mmol) were added in room temperature.
The resulting solution was stirred for an additional 2 hours.
The reaction mixture was diluted with EtOAc (5 ml) and washed with saturated aqueous NH, CI.
The aqueous layer was separated and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), NaH-CO; saturated aqueous (5 ml), and brine (5 ml). The organic layer was dried over MgSO2, filtered, and concentrated under reduced pressure to provide (1E, 4E) -4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl ) -3H-benzo [b] raw tert-butyl azepin-2-ylcarbonate which was used directly without further purification.
Preparation of (1E, 4E) -2-amino-N- (2-amino-2-oxoethyl) -N- propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] Jazepine -4-carboxamide: a solution of (1E, 4E) -4 - ((2-amino-2-oxoethyl) (propyl) carbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H -benzo [b] raw tert-butyl azepin-2-ylcarbonate in anhydrous CH2Ckb (15 mL) was bubbled with HCI (gas) for 4 hours at 0 ° C.
The resulting mixture was warmed to room temperature and stirred until the reaction was complete.
To this mixture was added NaHCO; saturated ab0ºC.
Aqueous layer was separated and extracted with CH2CLI.
The combined organic layers were dried over NazSO;, filtered and concentrated under reduced pressure to provide the crude compound which was purified by flash column chromatography on silica gel (MeOH: CH2 Cl = 1:50). In this case, the product was obtained as an HCl salt. MS APCI (+) m / z 536 (M + 1) detected; 1H-NMR (400 MHz, CDCl3) d 7.80 (s, 1H), 7.62- 7.66 (m, 4H), 7.52 (d, 1H), 7.42 (d, 1H), 6.97 (s, 1H), 4.31 (br s, 1H), 4.08 (br s 1H) 3.86 (brs, 1H), 3.68 (t, 2H), 3.48 (br s, 5H), 3.32 (m, 3H), 2.17 (br s, 2H), 1.92-1.99 (m, 8H), 0.87 (t, 3H). Example 177 o A. 9 = s = O
NR NH a 'o - (1E, 4E) -2-amino-N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -N- (3-sulfamoylpropyl) -3H-benzo [ b] azepine-4-carboxamide “10 MSAPCI (+) m / z538 (M + 1) detected; * H-NMR (400 MHz, CDCl3) 5 7.65 (d,. 2H), 7.59 (d, 2H), 7.45 (s, 1H), 7.32 (d, 1H), 7, 28 (d, 1H), 6.80 (s, 1H), 3.66 (t, 2H), 3.55 (t, 2H), 3.49 (t, 2H), 3.42 (br s, 2H), 3.14 (br s, 2H), 2.80 (s, 2H), Á 2.14 (br s, 2H), 1.87-1.99 (m, 4H), 1.59- 1.64 (m, 2H), 0.87 (t, 3H). - Example 183 os no> NE 2 NH
N (1E, 4E) -2-amino-8- (5- (hydroxymethyl) pyridin-3-yl) -N N-dipropyl-3H-benzo [b] olive-4-carboxamide The title compound was prepared by these procedures using - (1E, 4E) -8-bromo-4- (dipropylcarbamoyl) -3H-benzo [b] azepin-2-ylcarbonate and 3 - ((tert-butyldimethylsilyloxy) acid methyl) phenylboronic. Preparation of 3-nitro-4 '- (pyrrolidine-1-carbonyl) biphenyl-4-carbaldehyde, except in this case, Cs.CO; as a base was used: To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol), 4- (pyrrolidine-1-carbonyl) phenylbo-
ronic (21.2 g, 96.7 mmol), and PAd (PPh3) 4 (508 mg, 0.440 mmol) in toluene (200 mL) were added EtoH (40 mL) followed by Na2CO; (70.0 mL, 140 mmol, 2M aqueous aqueous solution) at room temperature.
The resulting mixture was heated at 100 ° C for 2 hours.
The reaction mixture was cooled to room temperature and the organic layer was separated.
The aqueous layer was extracted with EtOAc (300 ml). The combined organic layers were washed with brine (500 ml), dried over MgSO ,,, filtered, and concentrated under reduced pressure to provide the raw material which was combined with another batch of the raw material obtained from an additional run on the same scale. reaction.
The raw material obtained was purified by silica gel flash column chromatography (1% CH2Cl] MeOH in CH2Clz) to provide 51 g (90%) of 3-nitro-4 '- (pyrrolidine-1-.: Carbonyl) biphenyl-4-carbaldehyde.
Preparation of tert-butyl (1E, 4E) -4- (dipropyl-
carbamoyl) -8- (4 - ((R) -3-hydroxypyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin- “15 2lcarbonate: To a solution of (1E, 4E) -8- (4 - (((R) -3- (tert-butyldimethylsilyloxy)
. pyrrolidine-1-carbonyl) phenyl) -4- (dipropylcarbamoyl) -3H-benzo [b] azepin-2-ylcarbonate (225 mg, 0.327 mmol) in THF (4 ml) at 0 ° C was added A TBAF solution (0.34 mL, 0.34 mmol, 1M THF solution) is added. The resulting mixture was warmed to room temperature and stirred for 1.5 hours.
The reaction mixture was diluted with EtOAc and washed with brine (2x). The organic layer was dried over MgSO2, filtered, and concentrated under reduced pressure to provide (1E, 4E) -4- (dipropylcarbamoyl) - 8- (4 - ((R) -3-hydroxypyrrolidine-1-carbonylNphenyl ) -3H-benzo [b] azepin-2-ylcarbon-
raw tert-butyl cream that was used directly without further purification.
(16.4E) -2-amino-N- (2-amino-2-oxoethyl) -N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b ] azepine-4-carboxamide: a solution of (1E, 4E) -4 - ((2-amino-2-0oxyethyl) (propyl) carbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H -benzo [b] lazepin-2-ylcarbonate of raw tert-butyl in anhydrous CH2 Cl2 (15 mL) was bubbled with HCI (gas) for 4 hours at 0 ° C.
The resulting mixture is heated to room temperature and stirred until the reaction is complete.
To this mixture was added NaHCO; saturated at 0ºC.
The aqueous layer was separated and extracted with CH2Cb.
The combined organic layers were dried over Na2SO2, filtered, and concentrated under reduced pressure to provide the crude compound that was purified by flash column chromatography on silica gel (MeEOH: CH2CI, = 1:50). MS APCI (+) m / z 393 (M + 1) detected; H-NMR (400 MHz, CDCl3) 5 8.77 (d, 1H) 8.55 (d, 1H) 7.95 (s, 1H), 7.41 (d, 1H), 7.36 (d , 1H), 7.25-7.28 (m, 1H), 6.82 (s, 1H), 4.80 (s, 2H), 3.47 (br s, 4H), 2.80 (s , 2H), 1.63-1.72 (m, 4H), 0.94 (t, 6H). Example 184
SO Ao LO O. E NH, & (1E, 4E) -2-amino-8- (3-morpholinopropyl) -N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide Step A: Preparation of 4 - (3- (9-borabicyclo [3,3,1] nonan-9-yl) prop. Pil) morpholine: To a solution of 4-allylmorpholine (2.54 g, 20 mmol) in THF (40 mL) 9-BBN (2.44 g, 10 mmol) was added. The reaction mixture was refluxed until the reaction was complete. After cooling to room temperature, the mixture was concentrated under reduced pressure to provide the raw 4- (3- (9-borabicyclo [3,3,1] Jnonan-9-yl) propyl) morpholine which was used directly without further purification . LCMS ESI (+) m / z 250 (M + 1) detected. Step B: Preparation of (1E, 4E) -2-amino-8- (3-morpholinopropyl) - N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide: The title compound was prepared by these procedures using tert-butyl (1E, 4E) -8-bromo-4- (dipropylcarbamoyl) -3H-benzo [b] azepin-2-ylcarbonate and 4- (3- (9-borabicl ([3, 3.1) Jnonan-g-iNpropyl) morpholine Preparation of 3-nitro-4 '- (pyrrolidine-1-carbonyl) biphenyl-4-carbaldehyde, except in this case, a co-solvent of EtoH / toluene / water (2 : 1: 1) and Cs> CO3 as a base were used: To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol), 4- (pyrrolidine-1-carbonyl) phenylboronic acid ( 21.2 g, 96.7 mmol), and Pd (PPh3) to (508 mg, 0.440 mmol) in toluene (200 mL) was added EtoOH (40 mL) followed by Na> sCO; (70.0 mL, 140 mmol, 2M aqueous solution) at room temperature.
The resulting mixture was heated at 100 ° C for 2 hours.
The reaction mixture was cooled to room temperature and the organic layer was separated.
The aqueous layer was extracted with EtOAc (300 ml). The combined organic layers were washed with brine (500 mL), dried over MgSO2, filtered, and concentrated under reduced pressure to provide the raw material that was combined with another batch of the raw material obtained from an additional run in the same reaction scale.
The raw material obtained was purified by flash column chromatography on silica gel (CH2Cl; to 1% MeOH in CH2Cb). Preparation of (11E, 4E) -2-amino-N- (2-amino-2-oxoethyl) -N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine -4-carboxamide: a solution of (1E, 4E) A4 - ((2-amino-2-0x0ethyl) á (propyl) carbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin-2-. crude tert-butyl ilcarbonate in anhydrous CH2Cl> (15 mL) was bubbled with HCl (gas) for 4 hours at 0 ° C.
The resulting mixture was heated to “15 ° C at room temperature and stirred until the reaction was complete.
To this mixture. NaHCO was added; saturated at 0ºC.
The aqueous layer was separated and extracted with CH2Ckb.
The combined organic layers were dried over Na-> SO2, filtered, and concentrated under reduced pressure to provide the crude compound that was purified by flash column chromatography on silica “20 gel (MeOH: CH2Cb = 1: 50). MS APCI (+) m / z 413 (M + 1) detected; * H-NMR (400 MHz, CDCI; 3) 5 7.20 (d, 1H), 7.07 (br s, 1H), 6.90 (dd, 1H), 6.78 (s, 1H), 3.72 (t, 4H), 345 (br s, 4H), 2.76 (s, 2H), 2.67 (t, 2H), 2.43 (br s, 4H), 2.38 (t , 2H), 1.81-1.89 (m, 2H), 1.60-1.70 (m, 4H), 0.92 (t, 6H). Example185 o as 2 X »Nut
(1E, 4E) -2-amino-8- (benzyloxy) -N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide The title compound was prepared by these procedures using 2-amino-8 - (benzyloxy) -3H-benzo [b] azepine-4-carboxylate (16.4E) -
ethyl and dipropylamine.
Preparation of 2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidone-1-carbonyl) phenyl) - 3H-benzo [b] azepine-4-carboxylate (16, 4E) -ethyl: To a mixture 2-amino-8- (4- (pyrrolidine-1-carbonyl) phenyl) - SH-benzo [b] azepine-4-carboxylate (1E, 4E) -ethyl (9.60 g, 23.8 mmol) in CH2Cl2 (100 mL) Boc2O (5.97 mg, 27.4 mmol) was added at room temperature.
The reaction mixture was stirred for 3 days.
The resulting mixture was washed with NaHCO; saturated aqueous and brine.
The organic layer was separated and dried and dried over MgSO2, filtered, and concentrated under reduced pressure to provide 12.7 g of crude 2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -38H-benzo [b] lazepine-4-carboxylate of (1E, 4E) -ethyl which was used directly without further purification.
Preparation of (112.4E) -2-] (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -38H-benzo [b] aze-. pina-4-carboxylic: To a solution of 1E 4E (2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxylate - Ethyl “15 (12.09.23.8mmoi) in THF-EtoH (60 ml / 60 ml) was added 4 N aqueous LIOH (23.8 ml, 95.3 mmol) at 0ºC.
The reaction mixture was warmed to room temperature and stirred for 21 hours.
An additional 6 mL of 4N aqueous LiOH was added twice after 21 hours and 24 hours.
After stirring for an additional 6 hours, the resulting mixture was concentrated under reduced pressure to provide the raw material which was diluted with water (50 ml) and acidified to a pH of —3.5 with aqueous phosphoric acid to IN (-450 mL). —250 mL of CH2Cl was added during acidification to extract the crude product from the sticky suspension.
The solids formed during acidification were filtered using a glass filter packed with Celite.
The layer — aqueous was separated and extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were dried over MgSO2, filtered, and concentrated under reduced pressure to provide (1E, 4E) -2- (tert-butoxycarbonate)
nilamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-benzo [b] azepine-4-carboxylic acid which was used directly without further purification.
Preparation of (11E, 4E) -
4 (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin-2-
tert-butyl ylcarbonate: A mixture of (1E, 4E) -2- (tert-butoxycarbon-
nylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-benzo [b] azepine-4-carboxylic
(200 mg, 0.42 mmol), HOBt (114 mg, 0.84 mmol), and EDCI (161 mg, 0.84 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature. To this mixture was added triethylamine (0.12 ml, 0.84 mmol) and propan-1-amine (0.043 ml, 0.53 mmol) at room temperature. The resulting solution was stirred for an additional 2 hours. The reaction mixture was diluted with Eto-Ac (5 ml) and washed with NH, saturated aqueous CI. The aqueous layer was separated and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), NaHCO; saturated aqueous (5 ml), and brine (5 ml). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to provide (1E, 4E) -4- (propylcarbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H -benzo [b] raw 'tert-butyl azepin-2-ylcarbonate which was used directly without further purification. Preparation: (1E, 4E) -2-amino-N- (2-amino-2-oxoethyl) -N-propyl-8- (4- (pyrrolidine-1-carbonyl) Yphenyl) -3H-benzo [ b] azepine-4-carboxamide: a solution of (112,4E) -4 - ((2- “15 amino-2-oxoethyl) (propyl) carbamoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl ) -3H-ben-: zo [bJazepin-2-ylcarbonate of raw tert-butyl in anhydrous CH2 Cl2 (15 mL) was bubbled with HCI (gas) for 4 hours at 0 ° C. The resulting mixture was. warmed to room temperature and stirred until the reaction is complete. To this mixture was added NaHCO; saturated at 0ºC. The aqueous layer was separated and extracted with CH2Ck. The combined organic layers were dried over Na7SO4; filtered, and concentrated under reduced pressure to provide the crude compound that was purified by flash column chromatography on silica gel (MeOH: CH2 Cl, = 1:50). MS APCI (+) m / z 392 (M + 1) detected; * H-NMR (400 MHz, CDCl3) 5 7.44- 7.46 (m, 2H), 7.37-7.41 (m, 2H), 7.31-7.34 (m, 1H), 7.19 (d, 1H), 6.83 (d, 1H), 6.73-6.76 (m, 2H), 5.10 (s, 2H), 3.45 (br s, 4H), 2.77 (s, 2H), 1.60-1.70 (m, 4H), 0.92 (t, 6H). Example 191 and
And Ho
2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbamoyl) -3H-benzo [b] azepin-8-yl) phenyl) acetic acid Step A: 2- (4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) benzyl acetate (41%) was prepared according to example 192, Step A described below, benzyl alcohol for ethanol.
Step B: 2- (4 - ((11E, 4E) -2-amino-4- (dipropylcarbamoyl) -3H-benzo blazepin-8-yl) phenyl) benzyl acetate (33%) was prepared as follows, replacing 2 - (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) benzyl acetate by 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo- NN-dipropyl-3H-benzo [b] lazepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55.6 mgs, 0.309 mmol, tetracis (tri-phenylphosphine) palladium (0) (23.8 but, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial This mixture was heated in “15 microwaves to 100 ° C for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. M / z (APCI-pos) M + 1 = 510.3. Step C: 2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbamoyl) -3H-benzo b] lazepin-8-yl) phenyl) acetic acid (28%) was prepared as follows, replacing 2 - (4 - ((1E, 4E) -2-amino-4- (dipropylcarbamoyl) -3H-benzo [b] azepin-8-yl) phenyl) benzyl acetate for 4 - (((1E, 4E) -2- amino-4- (dipropyl carbamoyl) -3H-benzo [b] azepin-8-yl) benzyl benzoate. 4 - ((1E, 4E) -2-amino-4- (dipropylcarbamoyl) - 3H-benzo [bjlazepin-8-yl) benzyl benzoate (0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol , and 25 mg of 10% Pd / C (Degussa type) were added and the mixture was hydrogenated under a hydrogen balloon for one hour. This mixture was then filtered through GFTF filter paper, and the filtrate was concentrated. m / z (APCI-pos) M + 1 = 420.2.
Example 192 Q
IF CA TO NHa 2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbamoyl) -3H-benzo [b] azepin-8-yl) phenyl) ethyl acetate Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylacetic acid (0.18 mg, 0.67 mmol) was dissolved in dry THF (7 mls) To this solution was added ethanol (0.037 mis, 0.81 mmol) and triphenylphosphine. Bonded to the resin (0.93 g, 2.014 mmol, 2.16 mmol / g). This mixture was gently stirred at room temperature for 20 minutes. Diisopro-pylazidodicarboxylate (0.34 mis, 1.68 mmol) was then added and the mixture was stirred at room temperature for one hour, then filtered, and the resin rinsed several times with EtOAc. was concentrated and the resulting material was purified by Flash 40 Biotage (40M cartrid- ge, 30% EtOAc / Hexanes) to provide 137 mg (70%) of 2- (4- (4,4,5,5) - tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethyl acetate as an orange oil.
* A5 Step B: 2- (4 - ((11E, 4E) -2-amino-4- (dipropylcarbamoyl) -3H-benzo blazepin-8-yl) phenyl) ethyl acetate (20%) was prepared as follows, replacing 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethyl acetate with 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] lazepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonylphenylboronic acid) (55, 6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a vial- This reaction mixture was heated in a microwave to 100 ° C for 30 minutes The mixture was then diluted with EtO-Ac, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. * H NMR (400 MHz, CDCI; 3) 5 7.59-7.65 ( m, 2H), 7.48-7.53 (m, 1H), 7.30-7.39
(m, 4H), 6.84 (s, 1H), 5.50 (very broad s, 1H), 4.14-4.23 (m, 2H), 3.66 (s, 2H), 3, 38 -3.52 (m, 4H), 2.86 (m, 2H), 1.59-1.72 (m, 4H), 1.22-1.32 (m, 3H), 0.88- 0.97 (m, 6H); m / z (APCI-pos) M + 1 = 448.2. Example 193 q
N Nes = and SO. NH> o 3- (4 - ((1E, 4E) -2-amino4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) pro- is ethyl panoate Step A: 3- (4 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-i) phenyl) pro-. ethyl panoate (24%) was prepared according to Example 192, Step A: described above, replacing 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2Dphenyl) acid) propanoic acid 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-phenyl) acetic acid.
Step B: Ethyl 3- (4 - ((11E 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo blazepin-8-yl) phenyl) propanoate (27%) was prepared as follows, + replacing - Ethyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanoate 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo- N N-dipropyl-3H-benzo [b] Jazepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55, 6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a vial of microwave reaction This mixture was heated in a microwave to 100 ° C for 30 minutes The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. 'H NMR (400 MHz, CDCl3) 5 7.57-7.60 (m , 2H), 7.49-7.51 (m, 1H), 7.25-7.35 (m, 4H), 6.84 (s, 1H), 5.22 (very broad singlet, 1H), 4.11 - 4.17 (m, 2H), 3.41 - 3.51 (m, 4H), 2.95-3.04 (m, 2H), 2.83 (s, 2H), 2, 64-2.69
(m, 2H), 1.58-1.72 (m, 4H), 1.20-1.30 (m, 3H), 0.88-0.99 (m, 6H); m / z (APCI-pos) M + 1 = 462.3. Example 196
JA oo Acid - 2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-ifenoxy) acetic Step A: (11E, 4E) -2- amino-8- (4- (benzyloxy) phenyl) -N, N-dipropyl-3H-benzo [b] a- Zepine-4-carboxamide (36%) was prepared as follows, replacing acid. 4- (benzyloxy) phenylboronic acid 4- (methoxycarbonyl) phenylboronic acid. (116.4E) - 2-amino-8-bromo-N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol) , 4- (methoxycarbonyl) phenylboronic acid (55.6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) combined in 2 ml of acetonitrile in a microwave reaction vial This mixture was heated in a microwave to 100 ° C for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% Me-OH / DCM) was then used. m / z (APCI-pos) M + 1 = 468.2. Step B: (115E, 4E) -2-amino-8- (4- (benzyloxy) phenyl) -N, N-dipropyl-3H-benzolbjazepine-4-carboxamide (0.100 g, 0.214 mmol), di-tert-butyl -dicarbonate (0.117 g, 0.535 mmol), and dimethylaminopyridine (0.026 g, 0.214 mmol) were combined in 3 mls of dry dichloromethane and stirred at room temperature for 16 hours. The mixture was then placed directly on a Flash 40 Biotage column (40M, 3: 1 Hexane: EtOAc) to provide 0.056g (40%) of product. m / z (APCI-pos) M + 1 = 667.9. Step C: The product from step B (0.050 g, 0.075 mmol) was dissolved in 1 ml of RtOAc, and 0.050 g of 10% Pd / C was dissolved. The mixture was hydrogenated under a hydrogen balloon for 1 hour. Another 0.050 g of catalyst was added and the mixture hydrogenated for an additional 1.5 hour, then filtered through GF / F paper. The filter was concentrated under reduced pressure to provide 37 mas (87%) of product. m / z (APCI-pos) M + 1 =
5779.
Step D: The product from step C (0.030 g, 0.519 mmol) was dissolved in 1 ml of dry DMF. To this was added cesium carbonate (0.051 g, 0.156 mmol) and benzyl-2-bromoacetate (0.012 mis, 0.078 mmol) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then diluted with EtOAc, washed several times with brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was then dissolved in 1 ml of dichloromethane and 1 ml. ml of TFA was then added. After 1 hour, the mixture was concentrated under reduced pressure and the resulting residue neutralized with concentrated 15 ammonium hydroxide and water, extracted with dichloromethane, the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% Me-, OH / DCM) gave 0.015 g (55%) of 2- (4 - ((1E, 4E) -2- amino-4- (dipropylcarbonyl) -3H-benzo [b] azepin-8-yl) phenoxy) benzyl acetate. m / z (APCI-pos) M + 1 “20 = 5262.
Step E: 2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzol [b] azepin-8-yl) phenoxy) acetic acid (46%) was prepared as follows, replacing 2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) pheoxy) benzyl acetate with 4 - ((1E , 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [blazepin-8-yl) benzyl benzoate. 4 - ((11E, 4E) -2-amino-4- (dipropylcar-bomoyl) -3H-benzo [b] azepin-8-yl) benzyl benzoate (0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol, and 25 mg of 10% Pd / C (Degussa type) were added and the mixture was hydrogenated under a hydrogen balloon for one hour. This mixture was then filtered through GF / F filter paper, and the filter was concentrated. * H NMR (400 MHz, DMSO-ds) 5 7.48- 7.56 (m, 2H), 7.33-7.42 (m, 1H), 7.21-7.30 (m, 3H) , 6.93-7.00 (m, 3H), 6.77 (s, 1H), 4.43 (s, 2H), 2.87 (s, 2H), 1.45-1.61 (m , 4H), 0.74-0.92 (m, 6H); m / z
(APCI-neg) M-1 = 434.0. Example 197
And Cs
OO A IV o 2- (4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) phenoxy) ethyl acetate Step A: 2- (4 - Ethyl ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo Iblazepin-8-ifenoxy) acetate (21%) was prepared as follows, replacing 2- (4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-i) phenoxy) ethyl acetate. By 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N , N-i dipropyl-38H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4 (methoxycarbonyl) phenylboronic acid (55.6 mg, 0.309 mmol, tetracis (triphenylphos- - thin) palladium (0) (23.8 mas, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in one ml - .chroma to 100ºC for 30 minutes The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography va (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. * H NMR (400 MHz, DMSO-ds) 5 7.58-7.63 (m, 2H), 7.33-7.37 (m, 1H), 7.19-7.26 (m, 2H) , 6.98-7.03 (m, 2H), 6.75 (s, 1H), 4.82 (s, 2H), 4.15- 4.22 (m, 2H), 3.25-3 , 34 (m, 4H), 2.76 (s, 2H), 1.50-1.61 (m, 4H), 1.19-1.26 (m, 3H), 0.73-0.90 (m, 6H); m / z (APCI-pos) M + 1 = 464.3. Example 198 q = N so O, (O N NH2 o
(1E, 4E) -2-amino-8- (1-0x0-1,3-dihydroisobenzofuran-S-yl) -N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide Step A: 5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) isobenzo-furan-1- (3H) -one (57%) was prepared according to Example 224/225, StepC described below. Step B: (11E, 4E) -2-amino-8- (1-0x0-1,3-dihydroisobenzofuran-5S-yl) - N N-dipropyl-3H-benzo [b] azepine-4-carboxamide was prepared as follows, replacing 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) isobenzofuran-1- (3H) -one with 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] lazepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55, 6 mg, 0.309 mmol, tetra- 'cis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 ml of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100 ° C for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate , and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. * H NMR (400 MHz, CDCl3) 5 7, 96-8.00 (m, 1H), 7.78- '20 7.82 (m, 1H), 7.72-7.74 (m, 1H), 7.52-7.55 (m, 1H ), 7.38-7.42 (m, 1H), 7.30- 7.35 (m, 1H), 6.85 (s, 1H), 5.37 (s, 2H), 3.60- 3.71 (m, 2H), 3.39-3.53 (m, 4H), 2.85 (m, 2H), 1.59-1.75 (m, 4H), 0.90-0, 99 (m, 6H); m / z (APCI-pos) M + 1 = 418.2. example 199 o - / OEt EA,
N 2-amino-8- (5- (hydroxymethyl) pyridin-3-yl) -3H-benzo [b] azepine-4-carboxylate - de (1E 4E) -ethyl The title compound was prepared by these procedures u- sando (1E, 4E) -ethyl 8-bromo-2- (tert-butoxycarbonylamino) -3H-benzo [b] aze-
pina-4-carboxylate and 3 - ((tert-butyldimethylsilyloxy) methylphenylboronic acid.
Preparation of 3-nitro-4 '- (pyrrolidine-1-carbonyl) biphenyl-4-carbaldehyde, except in this case CsxCO; was used: To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol), 4- (pyrrolidine-1-carbonyl) phenylboronic acid (21.2 9, 96.7 mmol), ePd (PPhz3) s (508 mg, 0.440 mmol) in toluene (200 mL) was added EtOH (40 mL) followed by Na2CO; (70.0 mL, 140 mmol, 2M aqueous solution) at room temperature.
The resulting mixture was heated at 100 ° C for 18 hours.
The reaction mixture was cooled to room temperature and the organic layer separated.
The aqueous layer was extracted with EtOAc (300 ml). The combined organic layers were washed with brine (500 mL), dried over MgSO;, filtered, and concentrated under reduced pressure to provide the raw material that was combined with another batch of. raw material obtained from an additional run on the same reaction scale.
The raw material obtained was purified by flash column chromatography "15 silica gel (CHXCl; for 1% MeOH in CH2Ch2). Preparation of (1E, 4E) -. 4- (dipropylcarbomoyl) -8- (4 - ((R ) -3-hydroxypyrrolidine-1-carbonyl) phenyl) -3H-benzol [b] ter-butyl azepin-2-ylcarbamate: To a solution of (1E, 4E) -8- (4- f ((R) - 3- (tert-butyldimethylsilyloxy) pyrrolidine-1-carbonyl) phenyl) -4-
(terpropylbutyl-3H-benzo [b] azepin-2-ylcarbamate (225 mg, 0.327 mmol) in THF (4 mL) at 0 ° C a solution of TBAF (0.34 mL, 0.34 mmo) was added 1 M solution in THF). The resulting mixture was warmed to room temperature and stirred for 1.5 hours.
The reaction mixture was diluted with EtOAc and washed with brine (2x). The organic layer was dried over MgSO2, filtered, and concentrated under reduced pressure to provide (1E, 4E) -4- (dipropylcarbomoyl) -8- (4 - ((R) -3-hydroxypyrrolidine-1-carbonyl ) phenyl) -3H-benzo [b] raw tert-butyl azepin-2-ylcarbamate which was used directly without further purification.
Preparation of (1E, 4E) -2-amino-N-
(2-amino-2-oxoethyl) -N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzol [b] azepine-4-carboxamide: a solution of (1E, 4E) - 4 - ((2-amino-2-
- oxoethyl (propyl) carbomoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-
raw tert-butyl benzo [b] azepin-2-ylcarbamate in anhydrous CH2Clz (15 mL) was bubbled with HCI (gas) for 4 hours at 0 ° C.
The resulting mixture was warmed to room temperature and stirred until the reaction was complete.
To this mixture was added NaHCO; saturated at 0ºC.
The aqueous layer was separated and extracted with CH2Cl2. The combined organic layers were dried over NazSO;, filtered, and concentrated under reduced pressure to provide the crude compound that was purified by flash column chromatography on silica gel (MeOH: CH2Ckb = 1:50). MS APCI (+) m / z 338 (M + 1) detected; * H-NMR (400 MHz, CDCl3) 5 8.78 (s, 1H), 8.57 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.49 (d, 1H), 7.42 (s, 1H), 7.31 (d, 1H), 4.80 (s, 2H), 4.33 (q, 2H), 3.00 (s, 2H) , 1.40 (t, 3H). Example200 o - / OEt | AA NH, '2-amino-8- (3-morpholinopropyl) -3H-benzo [b] azepine-4-carboxylate (1E, 4E) -ethyl. The title compound was prepared by these procedures using 8-bromo-2- (tert-butoxycarbonylamino) -3H-benzo [b] azepine-4-carboxy (11E, 4E) -ethyl and 4- ( 3- (9-borabicyclo [3,3,1] nonan-9-yl) propyl)] morpholine. .— 15 Preparation of 3-nitro-4 '- (pyrrolidine-1-carbonyl) biphenyl-4-carbaldehyde, except in this case a co-solvent of EtoH / toluene / water (2: 1: 1) and CsxCO; 3 were used: To a solution of 4-bromo-2-nitrobenzaldehyde (20.2 g, 87.9 mmol), 4- (pyrrolidine-1-carbonyl) phenylboronic acid (21.2 g, 96.7 mmol), and PAd (PPh3) to (508 mg, 0.440 mmol) in toluene (200 mL) was added EtOH (40 mL) if- guidoporNa; CO; (70.0 mL, 140 mmol, 2 M aqueous solution) at room temperature.
The resulting mixture was heated at 100 ° C for 18 hours.
The reaction mixture was cooled to room temperature and the organic layer separated.
The aqueous layer was extracted with EtOAc (300 ml). The combined organic layers were washed with brine (500 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to provide the raw material that was combined with another batch of the raw material obtained from a additional execution on the same reaction scale.
The raw material obtained was purified by flash column chromatography on silica gel (CH2Cl; for 1% MeOH in CH2Cl2). Preparation of (11E, 4E) -2-amino- N- (2-amino-2-oxoethyl) -N-propyl-8- (4- (pyrrolidine-1-carbonylN) phenyl) -3H-benzo [b] azepine -4-carboxamide: a solution of (1E, 4E) -4 - ((2-amino-2-oxoethyl) (propyl) carbomoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H -benzo [b] azepin-2-ylcarba-matodeterc-butyl crude in CH> Cl; anhydrous (15 mL) was bubbled with HCI (gas) for 4 hours at 0ºC. The resulting mixture was warmed to room temperature and stirred until the reaction was complete. To this mixture was added NaHCO; saturated at 0ºC. The aqueous layer was separated and extracted with CH; Cl. The combined organic layers were dried over Na-SO, filtered, and concentrated under reduced pressure to provide the crude compound which was purified by flash column chromatography on silica gel (MeOH: CH2Ck = 1:50). D MS APCI (+) m / z 358 (M + 1) detected; * H-NMR (400 MHz, CDCIz) 5 7.78 (s, 1H), 7.30 (d, 1H), 7.06 (s, 1H), 6.92 (d, 1H), 4.30 (q, 2H), 3.72 (t, 4H), 2.94 "15 (s, 2H) 2.67 (t 2H), 2.43 (brs, 4H), 2.38 (t, 2H) , 1.81-1.89 (m, 2H), 1.37 (t, .3H). Example 201 os
STEEL A o 4- (4 - ((1E, 4E) -2-amino4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) benzazide) benzyl butanoate Step A: Preparation of 4- Benzyl (4- (4,4,5,5-tetramethyl-1,3,2-dioxaboro-lan-2-yl) benzamido) butanoate: The title compound was prepared by these procedures using 4- (4, 4,5,5-tetramethyl-1,3,2-dioxaboran-lan-2-yl) benzoic and benzyl 4-aminobutanoate 4-methylbenzenesulfonate. Preparation of (1E, 4E) 4- (propylcarbomoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] tert-butyl lazepin-2-ylcarbamate: A mixture of acid (1E , 4E) -2- (tert-butoxycarbonylamino) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxylic (200 mg, 0.42 mmol), HOBt ( 114 mg, 0.84 mmol), and EDCI (161 mg, 0.84 mmol) in DMF (5 mL) was stirred for 1 hour at room temperature.
To this mixture, triethylamine (0.12 mL, 0.84 mmol) and propan-1-amine (0.043 mL, 0.53 mmol) were added at room temperature.
The resulting solution was stirred for an additional 2 hours.
The mixed mixture was diluted with EtOAc (5 mL) and washed with NH, saturated aqueous CI.
The aqueous layer was separated and extracted with EtOAc (3 x 5 ml). The combined organic layers were washed with brine (5 ml), NaH-CO; saturated aqueous (5 ml), and brine (5 ml). The organic layer was dried over MgSOA4, filtered, and concentrated under reduced pressure to provide (1E, 4E) 4- (propylcarbomoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] Raw tert-butyl jazepin-2-ylcarbamate that was used directly without other-
'tra purification.
MS APCI (+) m / z 424 (M + 1) detected. . Step B: Preparation of benzyl 4- (4 - ((11E, 4E) -2-aminoH4- (dipropylcarbonooyl) -3H-benzo [b] azepin-8-yl) benzamido) butanoate: The compos- “15 the entire title was prepared by these procedures using tert-butyl (1E, 4E) -8-bromo-) 4- (dipropylcarbomoyl) -3H-benzo [b] azepin-2-ylcarbamate and 4- (4- (4.4 , 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamido) benzyl butanoate. "Preparation of tert-butyl (1E, 4E) -8- (4- (dimethylcarbomoyl) phenyl) -4- (dipropylcarborooyl) -3H-benzo [b] azepin-2-ylcarbamate, except in this case a co-solvent of MeCN-water (1.5: 1) was used: To NazCO; z (129 mg, 1.214 mmol) in a 50 mL round-bottom flask water (3.7 mL) was added and bubbled with N> for 10 minutes.
To this mixture was added (11E, 4E) -8-bromo-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-2-ylcarbamate (200 mg, 0.40 mmol) in EtOH (4, 9 mL) at room temperature.
The resulting mixture was bubbled with N> for 10 minutes.
Pd (OAc)> (9.3 mg, 0.040 mmol) and 4,4 '- diphenium acid (phenylphosfinidene) bisbenzenesulfonic acid (45 mg, 0.081 mmol) were added.
The resulting mixture was heated to 65 ° C with bubbling with N ,. To this mixture, a solution of 4- (dimethylcarbomoyl) phenylboronic acid (97 mg, 0.49 mmol) in EtOH (0.6 mL) was added. The resulting mixture was stirred at 65 ° C for 1 hour.
The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the raw material which was diluted with water (5 ml) and EtOAc (10 ml). The mixture was filtered through a GF / F filter. The aqueous layer was separated and extracted with EtOAc (10 ml). The combined organic layers were washed with brine (10 ml), dried over MgSO:, filtered, and concentrated under reduced pressure to provide the crude product which was purified by flash column chromatography on silica gel (CH2Cl, for MeOH at 2 % in CHz2Cl2). Preparation of (11.4E) -2-amino-N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine-4-carboxamide: To a solution of (1E, 4E) -4- (propylcarbomoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) - 3H-benzo [b] azepin-2-ylcarbamate tert-butyl (450 mg, 0.87 mmol) in CH2Cl (5 ml) 2,2,2-trifluoroacetic acid (1,368 ml, 17.4 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure. to supply the raw material which was diluted with CH2Ch (10 ml) and saturated aqueous NaH-CO3 (15 ml) again. The resulting mixture was stirred "15 ° C for 30 minutes at room temperature. The aqueous layer was separated and extracted with CH2 Cl2 (1 x 10 mL). The combined organic layers were washed with NaHCO; saturated aqueous (2 x 10 mL) and brine (1 x 10 ml), dried over MgSOSO, filtered, and concentrated under reduced pressure to provide the crude material again which was purified by flash column chromatography on silica gel (1 to 5% MeOH in CH72CL, gradient). MS APCI (+) m / z 581 (M + 1) detected; * H-NMR (400 MHz, CDCI;) δ 7.82- 7.84 (m, 2H), 7.70-7.72 (m , 2H), 7.51 (d, 1H), 7.30-7.38 (m, 7H), 6.83 (s, 1H), 6.53 (t, 1H), 5.13 (s, 2H), 3.54 (q, 2H), 3.47 (br s, 4H), 2.81 (s, 2H), 2.52 (t, 2H), 1.98-2.04 (m, 2H), 1.62-1.72 (m, 4H), 0.93 (t, 6H). N
COS o. - = Ds o NH NH 2- 2- (3 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) ethyl acetate Step A: To 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
iNphenyl) acetic (0.509, 1.91 mmol) in 20 mls of dry DMF was added cesium carbonate (1.24 g, 3.82 mmol) and iodoethane (0.20 mis, 2.48 mmol). This mixture was stirred at room temperature for 16 hours, then diluted with brine, extracted twice with EtOAc, the extracts washed with brine (2X), dried over sodium sulfate and concentrated under reduced pressure to provide 360 mg (65 %) of 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethyl acetate as a clear oil. Step B: 2- (3 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -38H-benzo blazepin-8-yl) phenyl) ethyl acetate was prepared as follows, replacing 2- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethyl acetate by 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H- "benzolb] azepine-4-carboxamide (75.0 mas, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid ( 55.6 but, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, “15 0.618 mmol) were combined in 2 mls of acetonitrile in one frasconette y microwave reaction This mixture was heated in a microwave to 100ºC for 30 minutes.The mixture was then diluted with EtO-7 Ac, washed twice with brine, dried over sodium sulfate, and - centered under reduced pressure. Preparative tin layer chromatography (20 x 2 x 0.5 mm plates, 7% MeOH / DCM) was then used. H NMR (400 MHz, CDCI3) 5 7,49-7 , 60 (m, 3H), 7.26-7.42 (m, 4H), 6.83 (s, 1H), 5.20 (br s, 1H), 4.12-4.21 (m, 2H), 3.67 (s, 2H), 3.42-3.52 (m, 4H), 2.83 (s, 2H), 1.56-1.74 (m, 4H), 1.23 -1.30 (m, 3H), 0.90-0.97 (m, 6H); m / z (APCI-pos) M + 1 = 448.3.
OH o É O Ds SO Pe NH2 o 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] aze- pin-8 -ylphenyl) methyl acetate
Step A: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) phenyl) acetate methyl was prepared as follows, replacing 4- (2-methoxy-2-oxoethyl) phenylboronic acid with 4- (ethoxycarbonyl) phenylboronic acid. - 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) ben - ethyl zoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] a - tert-butyl zepin-2-ylcarbamate by (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide and 4- (ethoxycarbonyl) phenylboronic acid by phenylboronic acid4- (methoxycarbonyl). (1E, 4E) -2-amino-8-bromo-N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (metho- "xicarbonyl) acid phenylboronic (55.6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 but, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a flask- “15 micron reaction nets.
This mixture was heated in a micro-. waves to 100ºC for 30 minutes.
The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - (( Ethyl 3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) benzoate (0.050 9, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) was used. 1 H NMR (400 MHz, CDCI; 3) 5 7.59-7.66 (m, 2H), 7.48-7.51 (m, 1H), 7.28-7.39 (m, 4H) , 6.87 (s, 1H), 3.72 (s, 3H), 3.57-3.70 (m, 6H), 3.45-3.53 (m, 2H), 2.83 (s , 2H), 1.79-1.88 (m, 2H), 1.65-1.75 (m, 2H), 0.90-0.96 (m,
3H); m / z (APCI-pos) M + 1 = 450.2. Example 214 Q / ToH
N 1 ...
NH o 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azeprix-8-yl) phenyl) ethyl acetate Step A: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) phenyl) acetate of ethyl (40%) was prepared as follows, replacing 4- (2-ethoxy-2-oxoethyl) phenylboronic acid with 4- (ethoxycarbonyl) phenylboronic acid. - 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) ben - * 10 ethyl zoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b ] tert-butyl a-zepin-2-ylcarbamate by (1E, 4E) -2-amino-8-bromo-N N-dipropyl- - 3H-benzo [b] azepine-4-carboxamide and 4- (ethoxycarbonyl) acid ) phenylboronic acid with 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl- * 15 3H-benzo [blazepine4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55, 6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 ml of acetonitrile in a vial- This reaction mixture was heated in a microwave to 100 ° C for 30 minutes The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4- ( Ethyl (3- (tert-butyldimethylsilyloxy) propyl (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) benzoate (0.050 9, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.After about an hour, the mixture was concentrated under reduced pressure and the i-
The resulting duo was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) was used. '* H NMR (400 MHz, DMSO-ds) 5 7.60-7.68 (m, 2H), 7.20-7.41 (m, 5H), 6.73-6.85 (m, 3H ), 4.42-4.52 (m, 1H), 4.05-4.16 (m, 2H), 3.71 (s, 2H), 3.24-3.52 (m, 6H, partially obscured by peak water), 2.75 (s, 2H), 1.66-1.78 (m, 2H), 1.50-1.65 (m, 2H), 1.15-1.23 ( m, 3H), 0.75-0.92 (m, 3H); m / z (APCI-pos) M + 1 = 464.2. f Example 215 oH 'q Vad: SA À o NH,' o. 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) isopropyl acetate Na E) Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) Isopropyl acetate (59%) was prepared according to Example 192, E-cap A described above, replacing 2-propanol with ethanol.
Step B: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbooyl) -3H-benzo [b] azepin-8-i) phenyl) acetate of isopropyl (42%) was prepared as follows, replacing 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-phenyl) isopropyl acetate with 4- ( ethoxycarbonyl) phenylboronic 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8- il) ethyl benzoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) pro- - pill (propyl) carbomoyl) -3H-benzo [ b] tert-butyl azepin-2-ylcarbamate by (1E, 4E) -2-amino-8-bromo-N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide and 4- (ethoxycarbonyl) acid phenylboronic acid with 4- (methoxycarbonyl) phenylboronic acid.
(1E, 4E) -2-amino-8-bromo-N, N-dipropyl-3H-benzo [b] Jazepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55 , 6 mas, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mas, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a reaction vial This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) - 4- ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8- 'i) ethyl benzoate (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloro-methane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the residue The resulting duo was then redissolved in “15 dichloromethane and 1 ml of concentrated ammonium hydroxide added and the EF mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, CDCl3) 5 7.58- 7.64 (m, 2H), 7.48-7.52 (m, 1H), 7.31-7.39 (m, 4H), 6 .88 (s, 1H), 5.00-5.08 (m, 1H), 3.58-3.69 (m 6H), 3.44-3.51 (m, 2H), 2.85 ( m, 2H), 1.79-1.88 (m, 2H), 1.65-1.75 (m, 2H), 1.23-1.28 (m, 6H), 0.90-0, 97 (m, 3H); m / z (APCI-pos) M + 1 = 478.3. Example216 oH Q Y / ”
COS VASE Au o 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azeprix-8-i) phenyl) isobutyl acetate
Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) isobutyl acetate (54%) was prepared according to Example 192 , Step A described above, replacing 2-methylpropan-1-ol with ethanol.
Step B: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [blazepin-8-yl) phenyl) isobutyl acetate (40%) was prepared as follows, replacing 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) isobutyl acetate with 4- ( ethoxycarbonyl) phenylboronic. 4 - (((11E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) ethyl benzoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - (((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] tert-butyl azepin-2-ylcarbamate by (11.4E) -2- To amino-8-bromo-N N-dipropyl-38H-benzo [b] azepine-4-carboxamide and 4- F (ethoxycarbonyl) phenylboronic acid 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide (75.0 “15 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55.6 mg, 0.309 i mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 ml of acetonitrile in a microwave reaction flask.
This mixture was heated in a microwave to 100ºC for 30 minutes.
The mixture was Ê20 then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 7% Me-OH / DCM) was then used. 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4- ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) —benzoate of ethyl (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10%
MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, CDCl3) 57.59- 7.65 (m, 2H), 7.48-7.51 (m, 1H), 7.29-7.39 (m, 4H), 6, 87 (s, 1H), 5.08 (br s, 1H), 3.87-3.92 (m, 2H), 3.58-3.71 (m, 6H), 3.45-3.52 (m, 2H), 2.82 (s, 2H), 1.78-1.99 (m, 3H), 1.64-1.77 (m, 2H), 0.87-0.97 (m , 9H); m / z (APCI-pos) M + 1 = 4922. Example 217 Q 2 / 7ToH
N. o N So GO NH, 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-iDphenyl) cyclopropylmethyl acetate Step A: Cyclopropylmethyl 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxabo-. 10 rolan-2ylpheni) acetate (47%) was prepared according to the Example 192, Step A described above, replacing cyclopropylmethane! With ethanol ã Step B: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbo-: moil) - 3H-benzo [b] azepin-8-yl) phenyl) cyclopropylmethyl acetate (31%) was prepared as follows, replacing 2- (4- (4,4,5,5-tetramethyl-1,3,2) -dioxaborolan- * 15 2Dphenyl cyclopropylmethyl acetate by 4- (ethoxycarbonyl) phenylboronic acid. 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) ethyl benzoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy ) teryl-butyl propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-2-ylcarbamate by (1E, 4E) -2-amino-8-bromo-N N-dipropyl-38H-benzo [b] azepine-4-carboxamide and 4- (ethoxycarbonyl) phenylboronic acid by 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonylN-phenylboronic acid (55.6 mg , 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine,
dried over sodium sulfate, and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) - 4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-
ethyl ilbenzoate (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was
diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10%: MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, CDCI; 3) 5 7.59- 7.65 (m, 2H), 7.47-7.51 (m, 1H), 7.28-7.40 (m, 4H) , 6.88 (s, 1H), 5.18 (br s, "15 1H) 3.92-3.99 (m, 2H), 3.58-3.72 (m, 6H), 3.43 -3.53 (m, 2H), 2.83 (s, 2H),. 1.79-1.88 (m, 2H), 1.65-1.77 (m, 2H), 1.08- 1.20 (m, 1H), 0.90-0.98 (m, 3H), 0.53-0.60 (m, 2H), 0.24-0.31 (m, 2H); m / z (APCI-pos) M + 1 = 490.2. f Example 218 q OH | already PROTO À O "e 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-i) phenyl) benzyl acetate Step A: 2- (4 - ((11.4E) -2-amino-4 - ((3- hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) phenyl) benzyl acetate (31%) was prepared as follows, replacing 2- (4- (4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) benzyl acetate by 4- (ethoxycarbonyl) phenylboronic acid. 4 - ((11,4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) ethyl benzoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilitoxy) propyl) (propyl) carbomoyl) -3H-benzo [b] tert-butyl azepin-2-ylcarbamate by (115.4E) -2-
amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide and 4- (ethoxycarbonyl) phenylboronic acid by 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-38H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55, 6 mg, 0.309 mmol tetracis (triphenylphosphine) palladium (O0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a micro reaction vial This mixture was heated in a microwave to 100ºC for 30 minutes The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Tin layer chromatography (2 x 0.5 mm plates, 7% Me-OH / DCM) was then used. 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4- ((3- (tert -butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8- i) ethyl benzoate (0.050 g, 0.075 mmol) was dissolved in 2 mls of dichloro- “15 methane and 0.5 ml of TFA. one hour, the mixture was concentrated i under reduced pressure and the residue was Then it was redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, CDCl3) 5 7.59- 7.64 (m, 2H), 7.49-7.51 (m, 1H), 7.29-7.39 (m, 9H), 6 , 88 (s, 1H), 5.16 (s, 2H), 3.70 (s, 2H), 3.58-3.69 (m, 4H), 3.45-3.52 (m, 2H ), 2.84 (s, 2H), 1.79-1.88 (m, 2H), 1.66-1.77 (m, 2H), 0.90-0.97 (m, 3H); m / z (APCI-pos) M + 1 = 526.2.
Example 219 o o N
CO AÀv-o The NH2 o 3- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-
benzolb] azepin-8-yl) isobutyl phenyl) propanoate Step A: isobutyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propanoate ( 67%) was prepared according to Example 192, Step A described above, replacing 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenylpropanoic acid) with acid 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-phenyl) acetic and 2-methylpropan-1-ol by ethanol.
Step B Isobutyl 3- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzol [b] azepin-8-yl) phenyl) propanoate ( 31%) was prepared as follows, replacing isobutyl 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ylphenyl) propanoate with 4- (ethoxycarbonyl) phenylboronic acid. 4- ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) - 3H-benzo [b] azepin-8-yl) ethyl benzoate ( 44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - (((3- (tert-butyldimethylsilyloxy) propyl) (propyl) car-bomoyl) -3H-benzo [b] azepin-2- tert-butyl ilcarbamate by (1E, 4E) -2-amino- “15 8bromo-N, N-dipropyl-3SH-benzo [b] lazepine4-carboxamide and 4- (ethoxy-: carbonyl) phenylboronic acid 4- (methoxycarbonyl) phenylboronic. (11.4E) -2-amino-8-bromo-N N-dipropyl-3 H-benzo [b] azepine-4-carboxamide (75.0 mg, It is 0.206 mmol), acid 4 - (methoxycarbonyl) phenylboronic (55.6 mg, 0.309 mmol,: tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), powdered carbonate 2M aqueous tassium (0.309 ml, 0.618 mmol) were combined in 2 ml of acetonitrile in a microwave reaction flask.
This mixture was heated in a microwave to 100ºC for 30 minutes.
The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 7% Me-OH / DCM) was then used. 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) -4- ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) benzoate ethyl (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml! of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml! of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was
diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, CDCI;) 5 7.56- 7.60 (m, 2H), 7.47-7.50 (m, 1H), 7.26-7.36 (m, 4H), 6.87 (s, 1H), 5.08 (br s, 2H), 3.85-3.89 (m, 2H), 3.58-3.69 (m, 5H), 3.45-3 , 52 (m, 2H), 2.97-3.03 (m, 2H), 2.82 (s, 2H), 2.65-2.71 (m, 2H), 1.79-1.95 (m, 3H), 1.66-1.76 (m, 2H), 0.88-0.97 (m, 9H); m / z (APCI-pos) M + 1 = 506.3.
Example 221 oH O NE NH O . o (1E, 4E) -2-amino-N- (3-hydroxypropyl) -8- (1-0x0-1,3-dihydroisobenzofuran-5-yl) -N-, propyl-3H-benzo [b] azepine- 4-carboxamide v Step A: 5- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) isobenzo-furan-1- (38H) -one (57%) was prepared from according to Example 224/225, "Step C described below, replacing 5-bromoisobenzofuran-1- (3H) -one with 4 (4-bromophenyl) -1,3-dioxolan-2-one.
Step B: (11E, 4E) -2-amino-N- (3-hydroxypropyl) -8- (1-0x0-1,3-dihydro-isobenzofuran-5-yl) -N-propyl-3H-benzo [b ] lazepine-4-carboxamide (33%) was prepared as follows, replacing 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iisobenzofuran-1- (3H) -one with acid 4- (ethoxycarbonyl) phenylboronic 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin -8-yl) ethyl benzoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H -benzo [b] tert-butyl azepin-2-ylcarbamate by (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide and 4- ( ethoxycarbonyl) phenylboronic acid 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol ), 4- (methoxycarbonyl) phenylboronic acid (55.6 but,
0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a micro reaction vial -waves.
This mixture was heated in a microwave to 100ºC for 30 minutes.
The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. Ethyl 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) - 4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-ylbenzoate ( 0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10% i MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, CDCl3) 5 7.95-. 8.00 (m, 1H), 7.78-7.82 (m, 1H), 7.70-7.73 (m, 1H), 7.50-7.53 (m, 1H), 7, 37- 7.42 (m, 1H) 7.28-7.33 (m, 1H), 6.89 (s, 1H), 5.37 (s, 2H), 5.12 (br s, 1H) , 3.58-3.71 (m, 4H), 3.43-3.55 (m, 3H), 2.82 (m, 2H), 1.79-1.88 (m, 2H), 1 , 64 - 1.77 (m, 2H), 0.90-0.99 (m, 3H); m / z (APCI-pos) M + 1 = 434.2. Example 222 oH Q “x OO o O Am O, O n NH, (1E, 4E) -2-amino-N- (3-hydroxypropyl) -8- (3-0x0-1,3-dihydroisobenzofuran-5-yl ) -N- propyl-3H-benzo [blazepine-4-carboxamide Step A: 6- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) isobenzzofuran-1- ( 3H) -one (67%) was prepared according to Example 224/225, Step C described below, replacing 6-bromoisobenzofuran-1- (3H) -one with
4- (4-bromophenyl) -1,3-dioxolan-2-one.
Step B: (11E, 4E) -2-amino-N- (3-hydroxypropyl) -8- (3-0x0-1,3-dihydro-isobenzofuran-5-yl) - N-propyl-38H-benzo [b ] lazepine-4-carboxamide (36%) was prepared as follows, replacing 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2ylisobenzofuran-1- (3H) -one with 4- (ethoxycarbonyl) phenylboronic. 4- ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8 -yl) ethyl benzoate (44%) was prepared as follows, replacing (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] tert-butyl azepin-2-ylcarbamate by (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide and 4- (ethoxycarbonyl) acid phenylboronic acid 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N N-dipropyl-38H-benzo [b] azepine-4-carboxamide - (75.0 mg, 0.206 mmol) , 4- (methoxycarbonyl) phenylboronic acid (55.8 but, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), carbo- “15 potassium natode 2M aqueous (0.309 ml, 0.618 mmol) were combined in. 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine. dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) - 4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8- i) benzoate ethyl (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) was used. * H NMR (400 MHz, DMSO-ds) at 8.08-8.13 (m, 1H), 8.03-8.06 (m, 1H), 7.74-7.78 (m, 1H) , 7.41-7.45 (m, 1H),
7.32-7.36 (m, 2H), 6.91 (br s, 2H), 6.80 (s, 1H), 5.47 (s, 2H), 4.45-4.50 (m , 1H), 53.37-3.48 (m, 2H), 3.28-3.37 (m, 4H, obscured by water spike), 2.75 (s, 2H), 1.66-1 , 77 (m, 2H), 1.51-1.62 (m, 2H), 0.72-0.91 (m, 3H); m / z (APCI-pos) M + 1 = 434.2. Example 223 and Os LI Eu, o (1E, 4E) -2-amino-8- (4- (2-oxotetrahydrofuran-3-iN) phenyl) -N N-dipropyl-3H-benzo [b] Jazepine4-carboxamide Step A: 4-bromophenylacetic acid (1.00 g, 4.65 mmol) was dissolved in 45 mls of dry THF and cooled to -78ºC. To this was added Õ 10 LDA (9.30 mis, 18.8 mmol, 2M in THF / heptane), resulting in a dark color, and this mixture was stirred at -78ºC for 20 minutes. (2-bromo-ethoxy) (tert-butyl) dimethylsilane (1.20 mls, 5.58 mmol) was then added via syringe, and then the cooling bath was removed to allow the reaction to warm up to room temperature. Under heating, the blend became an amber color. As soon as at room temperature, 50 mils of 1N aqueous HCI were then added and the mixture was vigorously stirred for 16 hours, then extracted with EtOAc (2X), the extracts washed with 2M aqueous sodium carbonate, dried over sodium sulfate and concentrated to an orange oil. Flash 40 Biotage (40M cartridge, 3: 1Hexane: EtOAc) provided 211 mg (19%) of 3- (4-bromo-phenyl) dihydrofuran-2 (3H) -one as an orange oil.
Step B: 3- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) dihydrofuran-2 (3H) -one (40%) was prepared according to Example 224/225, Step C described below.
Step C: (1E, 4E) -2-amino-8- (4- (2-oxotetrahydrofuran-3-yl) phenyl) - N N-dipropyl-38H-benzo [b] azepine-4-carboxamide (9%) was prepared as follows, replacing 3- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) diyl
drofuran-2 (3H) -one by 4- (methoxycarbonyl) phenylboronic acid. (1E, 4E) -2-amino-8-bromo-N, N-dipropyl-3H-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55 , 6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 but, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a vial microwave reaction This mixture was heated in a microwave to 100ºC for 30 minutes The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. of preparative tin layer (2 x 0.5 mm plates, 7% Me-OH / DCM) was then used. * H NMR (400 MHz, CDCl3) 5 7.64-7.68 (m, 2H ), 7.51-7.54 (m, 1H), 7.32-7.39 (m, 4H), 6.84 (s, 1H), 4.48-4.55 (m, 1H), 4.33-4.42 (m, 1H), 3.83-3.90 (m, 1H), 3.41-3.50 (m, 4H), 2.89 (s, 2H), 2, 70-2.81 (m, 1H), 2.44-2.56 (m, 1H), 1.59-1.72 (m, 4H), 0.88-0.98 (m, 6H); m / z "15 (APCI-pos) M + 1 = 446.2. - Example 224 o P SA es 5 - O O Ns NH,
HO Ho (1E, 4E) -2-amino-8- (4- (1,2-dihydroxyethyl) phenyl) -N N-dipropyl-8H-benzo [b] azepine-4-carboxamide Example 225 oO A As
ÇX NH, ooo (1E, 4E) -2-amino-8- (4- (2-0x0-1,3-dioxolan-4-yl) phenyl) -N N-dipropyl-3H-benzo [b] azepine- 4-carboxamide
(1E, 4E) -2-amino-8- (4- (1,2-dihydroxyethyl) phenyl) -N, N-dipropyl-8H-benzo [b] azepine-4-carboxamide Step A: 4-bromo-styrene (1 .00 g, 5.46 mmol) was dissolved in 25 ml of 2: 1 water: acetone. To this was added 4-methylmorpholine N-oxide (0.704 g, 6.01 mmol) and osmium tetroxide (0.167 g, 0.061 mmol, 2.5% in t-BuOH). This mixture was stirred at room temperature for 16 hours, then diluted with EtOAc, washed once with 1N aqueous HCI, once with saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product was purified by Flash 40 Biotage (40 M cartridge, 100% EtOAc as the eluent) to provide 335 mg (28%) of 1- (4-bromophenyl) ethane-1,2-diol as a white solid . Step B: 1- (4-bromophenyl) ethane-1,2-diol (0.15 g, 0.689 mmol) was dissolved in 7 mls of acetonitrile seci, followed by the addition of carbonyldii- “15 midazole (0.179, 1.04 mmol). This mixture was heated to 40 ° C for 1.5 - hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride solution, water, dried over sodium sulfate and concentrated under reduced pressure. y Purification of 10 g Sep Pak (1: 1 EtOAc: Hexanes) gave 0.095 g of 4- (4-bromophenyl) -1,3-dioxolan-2-one (57%) as a white solid. Step C: 4- (4-bromophenyl) -1,3-dioxolan-2-one (0.093 g, 0.383 mmol), 4.4.4'4 ', 5.5.5', 5'-octamethyl-2 , 2'-bi (1,3,2-dioxaborolane) (0.117 g,
0.459 mmol), potassium acetate (0.113 g, 1.45 mmol) and 1.1 "-bis (diphenylphosphine) ferrocene palladium (II) dichloromethane (0.0094 9, 0.012 mmol) adduct were combined in dioxane and heated to 100ºC for 3 hours, the mixture was then diluted with water, extracted twice with EtOAc, the extracts dried over sodium sulfate and concentrated under reduced pressure. Purification of 10 g Sep Pak (100% DCM as the eluent ) provided 0.070 g of 4- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) -1,3-dioxolan-2-one (63%) as a white solid Step D: Reaction of (1E, 4E) -2-amino-8-bromo-N N-dipropyl-3H-benzo [b] azepine-4-carboxamide and 4- (4- (4.4, 5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-iN) Yphenyl) -1,3-dioxolan-2-o0na as follows provided (1E, 4E) -2-amino-8- (4- (2-0x0-1,3-dioxolan-4-yl ) phenyl) -N N-dipropyl-38H-benzo [b] azepine-4-carboxamide (9%). (1E, 4E) -2-amino-8-bromo-N, N-dipropyl-3SH-benzo [b] azepine-4-carboxamide (75.0 mg, 0.206 mmol), 4- (methoxycarbonyl) phenylboronic acid (55 , 6 mg, 0.309 mmol, tetracis (triphenylphosphine) palladium (0) (23.8 mg, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a reaction vial This mixture was heated in a microwave to 100ºC for 30 minutes The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. preparative tin (2 x 0.5 mm plates, 7% MeOH / DCM) was then used. * H NMR (400 MHz, DM-SO-ds) 5 7.74-7.80 (m, 2H ), 7.55-7.60 (m, 2H), 7.26-7.42 (m, 3H), 6.78 (s, 1H), 5.89-5.96 (m, 1H), 4.88-4.95 (m, 1H), 4.45-4.52 (m, 1H), 2.78 (s, 2H), 1.50-1.63 (m, 4H), 0, 71-0.93 (m, 6H); m / z (APCI-pos) M + 1 = 448.2. (1E, 4E) -. 2-amino-8- (4- (1,2-dihydroxyethyl) phenyl) -N, N-dipropyl-38H-benzo [b] azepine-4-carboxamide (19%) was obtained as the most polar product. (19%). * H NMR (400 "MHz, DMSO-ds) 5 7.59-7.64 (m, 2H), 7.39-7.44 (m, 2H), 7.33-7.38 (m, 1H ),: 7.26-7.28 (m, 1H), 7.20-7.24 (m, 1H), 6.84 (br s, 1H), 6.74 (s, 1H), 5, 23-5.27 (m, 1H), 4.71 to 4.75 (m, 1H), 4.54-4.62 (m, 1H), 3.44-3.50 (m, 2H), 3.28-3.35 (m, 4H), 2.74 (s, 2H), 1.51-1.61 (m, 4H), 0.73-0.90 (m, 6H); m / z (APCI-pos) M + 1 = 422.2 Example 226 O
XX no O 'ne 4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) phenyl trifluoro- —methanesulfonate Step A: Preparation of (1E, 4E ) Tert-butyl -4- (dipropylcarbomoyl) -8- (4-hydroxyphenyl) -3H-benzo [b] azepin-2-ylcarbamate: The title compound was prepared by these procedures using (1E, 4E) - 8-bromo-4- (dipro-
pilcarbomoil) -3H-benzo [b] azepin-2-ylcarbamate of tert-butyl and 4-hydroxyphenylboronic acid. Preparation of (1E, 4E) -8- (4- (dimethylcarbomoyl) phenyl) -4- (dipropylcarbomoyl) -3H-benzo [b] azepin-2-ylcarbamate = from tert-butyl Ao NasCO; (129 mg, 1.214 mmol) in a 50 ml round bottom flask water (3.7 ml) was added, bubbled with N for 10 minutes. To this mixture was added tert-butyl (1E, 4E) -8-bromo-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-2-ylcarbamate (200 mg, 0.40 mmol) in EtOH (4.9 mL ) at room temperature. The resulting mixture was bubbled with N for 10 minutes. Pd (OAc) 2 (9.3 mg, 0.040 mmol) and 4/4 '(phenylphosfinidene) bisbenzenesulfonic acid dipotassium hydrate (45 mg, 0.081 mmol) were added. The resulting mixture was heated to 65ºC with bubbling of N2. To this mixture was added a solution of 4- (dimethyl-carbomoyl) phenylboronic acid (97 mg, 0.49 mmol) in EtOH (0.6 mL). The resulting mixture was stirred at 65 ° C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to provide the crude material which was diluted with water (5 ml) and EtOAc (10 ml). The mixture was filtered through a GF / F filter. The aqueous layer was separated and extracted with EtOAc (10 ml). The combined organic layers were washed E with brine (10 ml), dried over MgSO;, filtered, and concentrated under reduced pressure to provide the crude product which was purified by flash column chromatography on silica gel (CH2Clz for MeOH 2 % in CH2Cb). MS APCI (+) m / z 478 (M + 1) detected.
Step B: Preparation of 4 - ((11E, 4E) - 2- (tert-butoxycarbonylamino) -4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) phenyl trifluoromethanesulfonate: To a solution of (1E , 4E) -4- (dipropylcarbomoyl) -8- (4-hydroxyphenyl) -3H-benzo [b] tert-butyl azepin-2-ylcarbamate (6899 mg, 1.30 mmol) and 1,1,1-trifluoro -N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (698 mg, 1.95 mmol) in CH2Cl2 (7 mL) TEA (0.27 mL, 1.95 mmol) was added at room temperature. After stirring for 23 hours at room temperature, the reaction mixture was diluted with CH2Cl; (25 mL) and washed with NaHCO; saturated aqueous (15 ml) followed by brine (15 ml). The organic layer was dried over MgSO:, filtered, and concentrated under reduced pressure to provide the raw material which was purified by flash column chromatography on silica gel (10 to 30% EtOAc in hexanes, gradient) to provide 526 mg (66% ) 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-yl) Yfenyl trifluoromethanesulfonate. MS APCI (+) m / z 610 (M + 1) detected.
Step C: Preparation of 4 - ((1E, 4E) - 2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8-i) phenyl trifluoromethanesulfonate: The title compound was prepared by these procedures. Preparation of (115.4E) -2-amino-N-propyl-8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepine4-carboxamide: To a solution of (1E, 4E) tert-butyl -4- (propylcarbomoyl) -8- (4- (pyrrolidine-1-carbonyl) phenyl) -3H-benzo [b] azepin-2-ylcarbamate (450 mg, 0.87 mmol) in CH2Clk (5 ml) 2,2,2-trifluoroacetic acid (1.36 ml, 17.4 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide the crude material which was diluted with CH2 Cl2 (10 ml) and NaHCO; saturated aqueous solution (15 mL) again. The resulting mixture was stirred for 30 minutes at room temperature. The aqueous layer was: separated and extracted with CH2Cl2 (1 x 10 ml). The combined organic layers were washed with NaHCO; saturated aqueous solution (2 x 10 ml) and brine (1x10 ml), dried over MgSO;, filtered, and concentrated under reduced pressure to provide the raw material again which was purified by silica gel flash column chromatography (1 to 5 % MeOH in CH2CL, gradient). MS APCI (+) m / z 510 (M + 1) detected; * H-NMR (400 MHz, CDCl3) 7.69-7.72 (m, 2H), 7.45 (d, 1H), 7.33-7.37 (m, 3H), 7.24-7 , 26 (m, 1H), 6.83 (s 1H), 3.47 (brs, 4H), 2.81 (s, 2H), 1.62-1.72 (m, 4H), 0.94 (t, 6H); * F-NMR (376 MHz, CDCl3) d-73.2.
Example 227 Q - / 7ToH
N Ro NON O (O Nn = NH> 2 o
| 110/134 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] a-zepin-8-yl) phenyl) acetate propyl phase A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propyl acetate (43%) was prepared according to Example 192, Step A, replacing propanol with ethanol.
Step B: 2- (4 - ((11E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) pheni) acetate propyl (10%) was prepared as follows: Step 1: (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3SH-benzo [b] lazepin Tert-butyl -2-ylcarbamate, 2- (4- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propyl acetate (1.5 equivalents) , tetracis (triphenylphosphine) palladium (0), 2M aqueous potassium carbonate (3 equivalents) were combined in 2 ml of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave 5 to 100ºC for 30 minutes. The mixture was then diluted with EtO- "Ac, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates , 7% MeOH / DCM) provided 2- (4 - ((1E, 4E) -2- '(tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbon) -3H-benzo [b] lazepin-8-yl) phenyl) propyl acetate.
Step 2: 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin- 8-yl) phenyl) propyl acetate was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH.OH) gave 2- (4 - ((1E, 4E) -2-amino-4- Propyl ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzol [b] azepin-8-yl) phenyl) acetate. 1H NMR (400 MHz, DMSO-d6) at
7.60-7.68 (m, 2H), 7.20-7.41 (m, 5H), 6.73-6.85 (m, 3H), 4.42-4.52 (m, 1H ), 4.05-4.16 (m, 2H), 3.71 (s, 2H), 3.24-3.52 (m, 6H, partially obscured by peak water), 2.75 (s, 2H), 1.66-1.78 (m, 2H), 1.50-1.65 (m, 2H), 1.15-1.23 (m, 3H), 0.75-0.92 ( m, 3H); m / z (APCI-pos) M + 1 = 464.2. Example228
OH ”area, - NH o 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azeprix-8-yl) phenyl) butyl acetate Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) butyl acetate (40%) was prepared according to Example 192 , Step A, * 10 replacing 1-butanol with ethanol. Step B: 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) phenyl) butyl acetate (8%) was prepared as - follows: Step 1: (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl)] 15 (propyl) carbomoyl) -3H-benzo [b] tert-butyl azepin-2-ylcarbamate, 2- (4- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) butyl acetate (1,5 equivalents), tetracis (triphenylphosphine) palladium (O0), 2M aqueous potassium carbonate (3 equivalents) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtO-Ac, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - (( 3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbo- —moyl) -3BH-benzo [blazepin-8-yl) phenyl) butyl acetate. Step 2: 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] Jazepin- 8-yl) phenyl) ace-
Butyl tact was dissolved in 2 ml of dichloromethane and 0.5 ml! of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) gave 2- (4 - ((1E, 4E) -2-amino-4 - butyl ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzol [bjazepin-8-yl) phenyl) acetate. 1H NMR (400 MHz, CDCl3) at 7.59-7.63 (m, 2H), 7.50-7.51 (m, 1H), 7.34-7.38 (m 2H), 7.32 -7.34 (m, 2H), 6.88 (s, 2H), 4.09-4.14 (m, 2H), 3.58-3.68 (m, 6H), 3.45-3 , 51 (m, 2H), 2.87 (s, 2H), 1.79-1.88 (m, 2H), 1.57-1.76 (m, 4H), 1.30-1.42 (m, 2H), 0.89-0.96 (m, 6H); m / z (APCI-pos) M + 1 = 492.2. “15 Example229: x Q“ OO oH. the GO Sm DO. 2- (2 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azeprix-8-ylphenyl) isobutyl acetate Step A: 2- (2-bromophenyl) acetic acid (1.00 g, 4.65 mmol) was dissolved in 45 mls of dry dichloromethane.
To this solution was added oxalyl chloride (0.609 ml, 6.98 mmol), followed by a drop of DMF.
This mixture was stirred for two hours at room temperature, then concentrated under reduced pressure.
The resulting residue was then redissolved in dry dichloromethane (45 ml), and 2 mls of 2-methylpropan-1-ol were then added and the mixture stirred at room temperature for 1.5 hours, then concentrated to 2- ( 2-bromophenyl) isobutyl acetate (100%). Step B: 2- (2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) isobutyl acetate (49%) was prepared according to Example 224 / 225, E-
slap C, replacing 2- (2-bromophenyl) isobutyl acetate with 4- (4-bromophenyl) -1,3-dioxolan-2-one.
Step C: 2- (2 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) phenyl) acetate of isobutyl (30%) was prepared as follows: Step 1: (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin Tert-butyl -2-ylcarbamate, 2- (2-bromophenyl) isobutyl acetate (1.5 equivalents), tetracis (triphenylphosphine) palladium (O0), 2M aqueous potassium carbonate (3 equivalents) were combined 2mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4-. ((3 - (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) isobutyl acetate. Step 2: 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-. Butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) acetate) of isobutyl was dissolved in 2 mls of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH.OH) provided isobutyl 2- (4 - ((15.4E) -2-amino- 4 - (((3-hydroxypropyl) (propyl) carbonyl) -3H-benzo [b] azepin-8-iNphenyl) acetate.1H NMR (400 MHz, CDCl3) at 7.27-7.39 (m, 5H ), 7.19-7.21 (m, 1H), 7.01-7.06 (m, 1H), 6.87 (s, 1H), 3.80-3.85 (m, 2H), 3.58-3.69 (m, 6H), 3.46-3.53 (m, 2H), 2.82 (s, 2H), 1.80-1.89 (m, 3H), 1, 66-1.75 (m, 2H), 0.90-0.98 (m, 3H), 0.81-0.87 (m, 6H); m / z (APCI-
pos) M + 1 = 492.3. Example 230 oH o “x O Ss
The NH PO, To. 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azeprix-8-yl) phenyl) cyclobutylmethyl acetate Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclobutylmethyl acetate (100%) was prepared according to Example 192, Step A, replacing cyclobutylmethane! by ethanol. Step B: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) car-: bomoi! 1) -3H-benzo [b] azepin-8-yl) phenyl) cyclobutylmethyl acetate (10%) was prepared as follows: - Step 1: (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H- tert-butyl benzo [b] azepin-2-ylcarbamate, 2- (4- (4.4, É 5.5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) cyclobutylmethyl acetate (1 , 5 equivalents), tetracis (triphenylphosphine) palladium (0), a2M aqueous potassium carbonate (3 equivalents) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 2- (4- ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - (( 3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) cyclobutylmethyl benzoate Step 2: 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyl-dimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) cyclobutylmethyl acetate was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) provided cyclobutylmethyl 2- (4 - (((1E, 4E) -2-amino- 4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) acetate. 1H NMR (400 MHz, CDCl3) 5 7.59-7.64 (m, 2H), 7.49-7.51 (m, 1H), 7.29-7.39 (m, 4H), 6, 87 (s, 1H), 4.06 - 4.12 (m, 2H), 3.57-3.70 (m, 6H), 3.44-3.53 (m, 2H), 2.83 ( s, 2H), 2.56-2.67 (m, 1H), 1.96-2.07 (m, 2H), 1.66-1.92 (m, 8H), 0.91-0, 97 (m, 3H); m / z (APCI-pos) M + 1 = 504.2. Example 231 The OH
O o O CO NE y Fo NH - 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] olive-8-yl) phenyl) 2-acetate -fluoroethyl '15 Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) 2-fluoroethyl acetate (35%) was prepared according to Example 192, Step A, replacing 2-fluoroethane! by ethanol.
Step B: 2- (4 ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbooyl) -3H-benzo [b] azepin-8-yl) phenyl) acetate 2-fluoroethyl (25%) was prepared according to the following: Step 1: (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H- tert-butyl benzo [b] azepin-2-ylcarbamate, 2-fluoroethyl 2- (4- (4,4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetate ( 1.5 equivalents), tetracis (triphenylphosphine) palladium (O0), 2M aqueous potassium carbonate (3 equivalents) were combined in 2 mls of acetonitrile in a microwave reaction flask. This mixture was heated in a microwave to 100 ° C for 30 minutes. The mixture was then diluted with
EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 2- (4- ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] lazepin-8-yl) phenyl) 2-fluoroethyl acetate.
Step 2: 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin- 8-yl) 2-fluoroethyl phenyl) acetate was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. "15 preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5%: NH, OH) gave 0.012 g (35%) of 2- (4 - (( 1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) 2-fluoroethyl acetate. 1H 'NMR (400 MHz, CDCl3) 5 7.60-7.65 (m, 2H), 7.49-7.51 (m, 1H), 7.29-7.39' (m, 4H), 6, 87 (s, 1H), 4.66-4.69 (m, 1H), 4.54-4.58 (m, 1H), 4.39-4.43 (m, 1H), 4.32- 4.36 (m, 1H), 3.73 (s, 2H), 3.58-3.68 (m, 4H), 3.43-3.52 (m, 2H), 1.78-1, 87 (m, 2H), 1.65-1.75 (m, 2H), 0.90-0.96 (m, 3H); m / z (APCI-pos) M + 1 = 482.2. Example 232 the JU TOH
N CO 5! À O n NH: AND 2 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepino-Bi) phenyl ) 2- (dimethylamino) ethyl acetate Step A: 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-iN) phenyl) 2- (dimethylamino) acetate ) ethyl (60%) was prepared according to the
example 192, Step A, replacing 2- (dimethylamino) ethanol with ethanol.
Step B: 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbo-moil) -3H-benzo [b] azepin-8-yl) phenyl) acetate 2- (dimethylamino) ethyl (5%) was prepared according to the following: Step 1: (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) - Tert-butyl 3H-benzo [b] azepin-2-ylcarbamate, 2- (4- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) acetate 2- (dimethylamino) ethyl (1.5 equivalents), tetracis (triphenylphosphine) palladium (0), 2M aqueous potassium carbonate (3 equivalents) were combined in 2 ml of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 2- (dimethylamino) ethyl-2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyl- - dimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) acetate. Step 2: 2- (dimethylamino) ethyl-2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- Ú (tert-butyldimethylsilitoxy) propyl) (propyl) carbomoyl) - 3H-benzo [b] azepin-8-yl) - fe-: nil) acetate was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about one hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) provided —2- (dimethylamino) ethyl-2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) acetate. 1H NMR (400 MHz, CD-CI3) 5 7.59-7.64 (m, 2H), 7.48-7.51 (m, 1H), 7.28-7.38 (m, 4H), 6.87 (s, 1H), 4.194.24 (m, 2H), 3.58-3.74 (m, 6H), 3.44-3.52 (m, 2H), 2.84 (s, 2H), 2.54-2.61 (m, 2H), 2.27 (s, 6H), 1.79-1.86 (m, 2H), 1.65-1.76 (m, 2H) , 0.89-0.97 (m, 3H); m / z (APCI-pos) M + 1 = 507.2.
Example 233
OH Vad O CC.
WOo Nha 3- (dimethylamino) 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) - 3H-benzo [b] azepin-8-yl) phenyl ) propyl acetate Step A: 3- (dimethylamino) 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxabo-5 rolan-2ylphenyl) propyl acetate (45%) was prepared according to Example 192, Step A, replacing 3- (dimethylamino) propan-1-ol with ethanol Step B: 3- (dimethylamino) 2- (4 - ((1E, 4E) -2-amino- 4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) propyl acetate (6%) was prepared as follows: Step 1: (1E , 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl). (Propyl) carbomoyl) -3H-benzo tert-butyl azepin-2-ylcarbamate, 3- (dimethylamino ) 2- (4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) propyl acetate i (1.5 equivalents), tetracis (triphenylphosphine) palladium (O0) , 2M aqueous potassium carbonate (3 equivalents) were combined in 2 mls of acetonitrile in a microwave reaction vial This mixture was heated in a microwave to 100º C for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 2- (4 ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- ( tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] jazepin- & 8-yl) phenyl) 3- (dimethylamino) propyl acetate. Step 2: 2- (4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin- 8-yl) phenyl) acetate 3- (dimethylamino) propyl was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane.
no and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% NH, OH) gave 3- (dimethylamino) 2- (4 - ((1E, 4E) -2-amino-4 - ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) propyl acetate. 1H NMR (400 MHz, CDCl3) 5 7.57-7.65 (m, 2H), 7.46-7.51 (m, 1H), 7.28- 7.40 (m, 4H), 6, 87 (s, 2H), 4.07-4.21 (m, 2H), 3.56-3.71 (m, 6H), 3.40-3.54 (m, 2H), 2.82 ( s, 2H), 2.26-2.36 (m, 2H), 2.20 (s, 6H), 1.59-1.87 (m, 6H), 0.86-0.99 (m, 3H); m / z (APCI-pos) M + 1 = 521.3. Example 234 NH,
Is it the NH : 2- (4 - ((1E, 4E) -2-amino4 - ((2-amino-2-oxoethyl) (propyl) carbomoyl) -3H-benzo [b] - azepin-8-yl) phenyl) acetate isobutyl Step A: 2- (4 - ((1E, 4E) -2-amino-4 - (((2-amino-2-oxoethyl) (propyl) car-bomoyl) -3H-benzo [b] azepin-8- il) Yfenyl) isopropyl acetate (23%) was prepared as described below in steps 1 and 2, except for substitution of 2- (4- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) phenyl) isobutyl acetate by 4- (ethoxycarbonyl) phenylboronic acid and (1E, 4E) -4 - ((2-amino-2-oxoethyl) (propyl) carbo- —moil) -8-bromine -3H-benzo [b] tert-butyl azepin-2-ylcarbamate by (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [ b] tert-butyl α-zepin-2-ylcarbamate. Step 1: tert-butyl acid (4E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-2-ylcarbamate, acid 4 - (ethoxycarbonyl) phenylboronic (1.5 equivalents), tetracis (triphenylphosphine) palladium (O0), 2M aqueous potassium carbonate (3 equivalents) were combined in 2 ml of acetonitrile in a micro-reaction vial waves.
This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) provided 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4- ((3- (tert -butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] Jazepin-8-yl) ethyl benzoate. Step 2: 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyl-dimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] Jazepin-8 -yl) benzoate - ethyl (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted
415. with water, extracted with dichloromethane (2X), the extracts dried over sul-. fact of sodium and concentrates under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5% 'NH, OH) gave 0.012 g (35%) of 4 - ((1E, 4E ) Ethyl -2-amino-4 - ethyl ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) benzoate. 1H NMR (400 MHz, DMSO-d6) 5 7.59-7.66 (m, 2H), 7.32-7.38 (m, 2H), 7.22- 7.30 (m, 2H), 7.07-7.13 (m, 1H), 3.92-4.00 (m, 2H), 3.83-3.87 (m, 2H), 3.73 (s, 2H), 2, 75 (s, 2H), 1.82-1.92 (m, 1H), 1.51-1.61 (m, 2H), 0.84-0.89 (m, 9H); m / z (APCI-pos) M + 1 = 491.2. Example 235 Oo NH2 and LAST Sum o 2 - ((((1E, 4E) -2-amino4 - ((2-amino-2-0x0ethyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) tert-butyl acetate Step A: 2- (4- (4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl) acid
phenyl) acetic acid (0.250 g, 0.954 mmol) was dissolved in 10 ml of dry THF.
To this solution was added (Z) -tert-butyl N, N'-diisopropylcarbamimidate (3.82 g, 19.08 mmol) and the mixture was allowed to stir at room temperature for 16 hours.
The mixture was then filtered, the filtrate concentrated under reduced pressure and purified by a 50 g Snap cartridge (Biota, 10% EtOAc / Hexanes) to provide 280 mg (92%) of 2- (4- ( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) tert-butyl acetate as a coarse oil.
Step B: 2- (4 - ((1E, 4E) -2-amino-4 - ((2-amino-2-oxoethyl) (propyl) car-bomoyl) -3H-benzo [b] azepin-8-yl ) phenyl) tert-butyl acetate (32%) was prepared as described below in steps 1 and 2, except for the replacement of 2- (4- (4,4,5,5-tetramethyl-1,3,2) -dioxaborolan-2-yl) phenyl) isobutyl tert-butyl acetate by 4- (ethoxycarbonyl) phenylboronic acid and (1E, 4E) -2-amino-N- (2-amino-2-oxoethyl) -8-bromo- N-propyl-3H-benzo [b] Jazepine-4-carboxamide by (11E, 4E) -8- A5 bromo-4 - (((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [ b] aze-. tert-butyl pin-2-ylcarbamate.
Step 1: tert-Butyl (1E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) Ú (propyl) carbomoyl) -3H-benzo [b] azepin-2-ylcarbamate, acid 4- '(ethoxycarbonyl) phenylboronic (1.5 equivalents), tetracis (triphenylphosphine) palladium (O), 2M aqueous potassium carbonate (3 equivalents) were combined in 2 mls of acetonitrile in a reaction vial. microwave.
This mixture was heated in a microwave to 100ºC for 30 minutes.
The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeOH / DCM) gave 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert- butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) ethyl benzoate.
Step 2: 4 - (((1E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyl-dimethylsilloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8 -i) ethyl benzoate (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA.
After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes.
This mixture was then diluted with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure.
Preparative tin layer chromatography (2 x 0.5 mm plates, 10% MeO0H / DCM / 0.5% NH.OH) gave 0.012 g (35%) of 4 - ((1E, 4E) -2-amino-4 - ethyl ((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) benzoate. 1H NMR (400 MHz, DMSO-d6) 5 7.50-7.65 (m, 2H), 7.23-7.36 (m, 5H), 7.09- 7.14 (brs, 1H), 6.84-6.91 (br s, 1H), 3.92-4.00 (br s, 2H), 3.61 (s, 2H), 3.51 (s, 1H), 2.77 ( br s, 2H), 1.51-1.61 (m, 2H), 1.42 (s, 9H), 0.73-0.91 (m, 3H); m / z (APCI-pos) M + 1 = 491.2. Example 236 NH> 2 J A v O R NH 2- (4 - ((1E, 4E) -2-amino-4 - (((2-amino-2-oxoethyl) (propyl) carbomoyl) -3H-benzo [b] 5 azepin-8-yl) phenyl) acetate 2- (dimethylamino) ethyl Step A: 2- (4 - ((1E, 4E) -2-amino-4 - (((2-amino-2-oxoethyl) (propyl) car-bomoyl) -3H-benzo [ b] azepin-8-yl) phenyl) 2- (dimethylamino) ethyl acetate (19%) was prepared as described below in steps 1 and 2, except for the replacement of 2- (4- (4.4.5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) 2- (dimethylamino) ethyl acetate by 4- (ethoxycarbonyl) phenylboronic acid and (11E, 4E) -2-amino-N- (2 -amino-2-oxoethyl) -8-bromo-N-propyl-38H-benzo [b] azepine-4-carbo-xamide by (1E, 4E) -8-bromo-4 - (((3- (tert-butyldimethylsilyloxy ) tert-butyl propyl) (propyl) carbonoyl) -3H-benzo [b] azepin-2-ylcarbamate.
Step 1: tert-butyl acid (4E, 4E) -8-bromo-4 - ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-2-ylcarbamate, acid 4 - (ethoxycarbonyl) phenylboronic (1.5 equivalents), tetracis (triphenylphosphine) palladium (O), 2M aqueous potassium carbonate (3 equivalents) were combined
in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100ºC for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative tin layer chromatography (2 x 0.5 mm plates, 7% MeO0H / DCM) provided 4 - ((1E, 4E) -2- (tert-butoxycarbonylamino) -4- ((3- (tert-butyldimethylsilyloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8- il) ethyl benzoate. Step 2: 4 - (((11E, 4E) -2- (tert-butoxycarbonylamino) -4 - ((3- (tert-butyl-dimethylsilloxy) propyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8 -yl) benzoate - ethyl (0.050 g, 0.075 mmol) was dissolved in 2 ml of dichloromethane and 0.5 ml of TFA. After about an hour, the mixture was concentrated under reduced pressure and the resulting residue was then redissolved in dichloromethane and 1 ml of concentrated ammonium hydroxide added and the mixture vigorously stirred for 15 minutes. This mixture was then diluted -. with water, extracted with dichloromethane (2X), the extracts dried over sodium sulfate and concentrated under reduced pressure. Preparative tin bed chromatography (2 x 0.5 mm plates, 10% MeOH / DCM / 0.5%: NH.OH) gave 0.012 g (35%) of 4 - ((11E, 4E) -2-amino-4 - ((3-hydroxypropyl (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) ethyl benzoate.1H NMR (400 MHz, DMSO-d6) 5 7 , 60-7.64 (m, 2H), 7.33-7.37 (m, 2H), 7.26- 7.28 (m, 1H), 7.21-7.25 (m, 1H) , 7.11 (br s, 1H), 6.75-6.90 (br m, 3H), 4.11 - 4.16 (m, 2H), 3.96 (br s, 2H), 3, 71 (s, 2H), 3.51 (s, 2H), 2.73 (s, 2H), 2.16 (s, 6H), 1.50-1.62 (m, 2H), 0.75 -0.91 (m, 3H); m / z (APCI-pos) M + 1 = 506.2 Example 237 NH> O v NS
CO 1 O NH, HCl
HO 2- (4 - ((1E, 4E) -2-amino-4 - (((2-amino-2-0x0-ethyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8- hydrochloride il) phenyl) acetic
Step A: 2- (4 - ((1E, 4E) -2-amino-4 - ((2-amino-2-oxoethyl) (propyl) car-bomoyl) -3H-benzo [b] azepin-8-yl ) phenyl) tert-butyl acetate (0.037 g, 0.0754 mmol) was dissolved in 1 ml! dioxane and cooled to 0 ºC. HCI gas was bubbled in for another 15 minutes, the reaction vessel tightly sealed and the mixture was allowed to warm to room temperature overnight. The gas pressure was carefully released and the mixture was concentrated to 2- (4 - ((1E, 4E) -2-amino-4 - ((2-amino-2-0xo0ethyl) (propyl) carbomoyl) - hydrochloride 3H-benzo [b] azepin-8-i) phenyl) acetic (100%). m / z (APCI-pos) M + 1 = 435.1. Example238 the Z // ToH
CO o - HO 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomo- i) -3H-benzo [b] Jazepin-8-ylphenyl) acetic acid - Step A: 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl acid ) acetic (8%) was prepared as] 15 described below in Step 1, except for substitution of 2- (4 - ((1E, 4E) -2-amino-4 - (((3-hydroxypropyl) (propyl) carbomoyl) -3H-benzo [b] azepin-8-yl) phenyl) benzyl acetate for 4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] aze- pin- Benzyl benzoate 8-yl Step 1: 4 - ((11E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzo [b] azepin-8yl) benzyl benzoate (0.025 g, 0.0504 mmol) was suspended in 1 ml of methanol, and 25 mg of 10% Pd / C (Degussa type) was added and the mixture was hydrogenated under a hydrogen balloon for one hour, which was then filtered through GF / F filter paper, and the filter was concentrated to 16 mg of 4 - ((1E, 4E) -2-amino-4- (dipropylcarbomoyl) -3H-benzol [bjazepin-8-yl) benzoic acid (78% ). m / z (APCI-pos) M + 1 = 436.2.
Example 2 HEK / TLR assays The activity of the compounds of this invention can be determined by the following assays.
The HEK-293 hTLR transfectant assay employs HEK293 cells stably transfected with several hTLRs and transiently cotransfected with a plasmid containing a secreted embryonic alkaline phosphate reporter (SEAP) gene directed to NF-kB. The stimulation of TLRs activates its signaling reaction series downstream and induces nuclear translocation of the transcription factor NF- «B. The reporter gene activity is then measured using a spectrophotometric assay.
To assess agonist activity, human embryonic kidney cells (HEK) that stably express several human TLR genes, including TLR7 and TLR8, and an NFKB-luciferase reporter gene (for example, 293XL-hTLR8 cells available from InvivoGen , San Diego, CA) are. prepared according to the supplier's instructions and incubated with various concentrations of test compound overnight. The amount of É luciferase induced is measured by reading the absorption at 650 mu. Agonist compounds of the invention have an MCrs9 of 25 µM or less, where MCs are defined as the concentration at which 50% maximum induction is observed. Example 3 PBMC assays for TLR7 and TLR8. Peripheral blood mononuclear cells (PBMCs) from human blood were isolated using BD Vacutainer cell preparation tubes with sodium citrate. The cells were incubated with the compound overnight. TLR8 activity was assayed by measuring the amount of TNFα in supernatants by ELISA. TLR7 activity was tested by measuring the amount of IFNa in supernatants by ELISA (R&D Systems). The compounds of this invention had an MCrs, 9 of 25,000 (nM) or less, where MCs are the concentration at which 50% of the maximum induction is observed. The results of this test are shown below in tables 2 and 3.
The numbers of MCs, are represented as tens factors, for example, + indicates an MCs9 value of X 10º, or a value in tens of thousands of nanomolar (nM range); ++ indicates an MCs59 value of X 10º, or a value in thousands; +++ indicates an MCso value of X 10º, or a —value hundreds; e ++++ indicates an MCso value of X 10º or 10º, or a value in tens or units. Table 2. E. MCs5o o 113 oO CO +++ Q O s NO 175 N ++ o. (D NÔ NH AS : O | 116 o RS + ” N
KA o 118 o RS ++++ Oq
OI É Oo o 1177 o, vw A / TS-NH2 +++ o = A ”NO NH
GSI o e. .. MC50 or 148 cs ”+++
ST 185 o A +++ NR NO NH
The f ”+
NR. (7 NO NH, 'the rox: the 197 to À "+ N
OJ o eo 184 o A ++++ E) TA NO NH, to 200 R OEt ++++ TA NO NH ON
NEN) and MC50 183 o A ++++ N NH NODE HO VAZ
N 191 o +
NR (D NODE NH 3 (DZ
HO 192 o> +++. AT "
NH NODE | SO Eto 193 o A ++
N Fº NÓ NH Eto- o 198 o Á +++ E 'De
NH NODE: o
Compound * Structure TLR8 MC5o O, 199 OEt ++++ NÔ NH, Ho 6 201 fe +++ ”No It o o. 205 g nO +++
The AL. Eto. ”> NH
213 is nOTMOH +++. A LL is not NH in o 214 = is; ++++ o O / No Eto ”215 5 NT / MTOoH ++++ The AL
SS At 216 Nor ++++
AL: No O
—— MCs5o 217 SEE 'oH ++++ If NHz
AO 218 O NO +++ o NH
PKTO O o 219 - OO + ”” NNNHo Ae o q 221 Swim | +++
O A WS SO. ”O: o o. 222 EO ++
WS e 'DESTA <TD q 223 N O q ++ De Tosta, o 224 R: +++ O er, Ho dy
MC50 Table 226 o = 4 N
NO FS. The He o the 225 OS e. () = WS
E o o Table 3. O A and E MCso 116 So e + E N
KA: Pest (e) 197 o. A ++ N
JO o Box o À ++ &
TA NÓ NH NaN
Composite Structure TLR7 MC5o 183 o A +
NR 2 NÔDNHZ HO N Z
N 191 b A +
NR From
NH NODE 3 (2
HO 192 ê À + - À: () ã
NODE NH o SD Eto 193 o À. NW & Fº NÓ NH Eto- o
OEt p + NH NODE HO N
No. 213 Nou ”
O A LL nº o NH ed
MCso the A ++ at NH,
LO Eto ”the ADO + tact A Ne NNH
ALT o $ NOR + 216 AO o SE NAN, x [F Pon 2 219 SO Le oo '+++ 222 ”NODE: TS NO NH, <A b AE ++ 223 O Je 9 THIS f' AD + 224" ”Sos no dy
MCs5o 225 b EA: The WS
NH do o The above description is considered to be illustrative only of the principles of the invention. Furthermore, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not desired to limit the invention to the exact construction and process shown as described above. Consequently, all suitable modifications and equivalents can be reclassified to fall within the scope of the invention as defined by the following claims.
. The words "understand," "comprising," "include," "including," and "include" when used in this specification and in the following claims * 10 cations are intended to specify the presence of established characteristics, numbers integers, components, or steps, but they do not exclude the presence or addition of one or more other characteristics, integers, components, steps, or groups thereof. Unless otherwise noted, all references listed here are specifically incorporated by reference.

权利要求:
Claims (19)
[1]
1. A compound having the formula |: o = Rs en i N NH> 2 0) or a tautomer, enantiomer or salt thereof, where: Y is (O) CH2), R "'; x is selected from 0 and 1; y is selected from 0, 1,2, and 3; R * 'is selected from aryl, heteroaryl, and saturated or partially saturated heterocycle, where when x is O, said aryl or heteroaryl is replaced with -C ( O) NR'R 'or T; R' and R 'are independently selected from hydrogen and alkyl, wherein said alkyl is optionally substituted with -C (O0) O: (CHo) .R' or R 'and R together with the nitrogen atom to which they are attached, form a saturated heterocyclic ring; | t is selected from 0, 1,2, and 3; - As R ' is selected from cycloalkyl and aryl; T is selected from heterocycle, - ( CHR ”) - ORº, - (O) u (CH2): - C (O) R, -OSO2R" , and -CH (OH) CH2OH; R ”is selected from H or -OH; R $ is selected from -OR "º and alkyl; Rº is selected from alkyl and H; R'º is selected from alkyl, - (CH2) R" , and hydrogen, where said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine; R * is selected from -OH, alkyl, CF3, cycloalkyl, heterocycle, aryl, heteroaryl; u is selected from 0 and 1; z is selected from 1,2, and 3; s is selected from 1 and 2;
[2]
Rº is selected from -NRºRº and -OR "º; R And Rº are independently selected from H, alkyl, - (O) (CH2) .P; wherein said alkyl is optionally substituted with one or more -OH; q is selected from 0 and 1; r is selected from 0, 1,2, and 3; P is selected from aryl, -SO-Rº, -C (O) NH ,, and heterocycle; and R $ is selected from -NH > 2, -NH (alkyl), -N (alkyl) 2, provided that when R '' is aryl or heteroaryl, then a) Kx + y> 1; or b) R ** will be replaced with T; or co) Rº will be NRºRº and at least one of Rº Or Rº is [(O) (CH> 2), P] and q + r> 1; or. D) at least one of R 'or R Is alkyl substituted with -C (O) O (CHa) R . h 2. A compound according to claim 1, having the formula | l: yo = Rs | 1TÊ> No. NHo w (1) or a tautomer, enantiomer or salt thereof in which : W is selected from N, CT and CH.
[3]
A compound according to claim 2, having the formula 1a:
O = Rs "Í wW (Ila) or a tautomer, enantiomer or salt thereof.
[4]
A compound according to claim 2, having the formula Ilb: oO = Rs | y = [NO NHZ TOW (Ilb) or a tautomer, enantiomer or salt thereof.
[5]
A compound according to claim 1, having the formula 1 o = Rs | RICH), (O), N = NH (al) or a tautomer, enantiomer or salt thereof, provided that when; R'for aryl or heteroaryl, then x + y> 1.
[6]
6. Compound according to claim 1, the formula having Wv: "nOMICHIIP
E Y N = NH, (IV) —or a tautomer, enantiomer or salt thereof, where q + r> 1.
[7]
A compound according to claim 1, having the formula v: o = Rs EA.
SAS
RÓ D V) or a tautomer, enantiomer or salt thereof, in which at least one of R 'or R is alkyl substituted with -C (O) O (CH2) R ' .
[8]
A compound according to claim 1, having the formula
VIE
O = NRºRº NH, VI) or a tautomer, enantiomer or salt thereof, where: R '' is selected from aryl and saturated or partially saturated heterocycle, in which the said aryl is replaced with T; T is selected from heterocycle, - (O) U (CH2), C (O) R ', and -CH (OH) CH2OH; R $ is selected from -OR "º and alkyl; R'º is selected from alkyl, - (CHo) R ' , and hydrogen, in which said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine ; 'R *' is selected from cycloalkyl and aryl; u is selected from 0 and 1; s is selected from 1 and 2; e - 15 R 'and Rº are independently alkyl; wherein said alkyl is optionally substituted with one or more -Oh.
[9]
A compound according to claim 8, wherein: R * '! it is selected from aryl and saturated or partially saturated heterocycle, in which said aryl is replaced with T; T is selected from heterocycle and - (O) L (CH2); C (O) Rº; R $ is selected from -OR "* and alkyl; R'º is selected from alkyl, - (CH2a) R” , and hydrogen, since said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine ; R " is selected from cycloalkyl and aryl; u is selected from 0 and 1; s is selected from 1 and 2; and Rº and Rs are independently alkyl; wherein said alkyl is optionally substituted with one or more -OH.
[10]
A compound according to claim 8, wherein: R "'is T-substituted aryl; T is selected from - (O) (CH2) .C (O) Rº, and -CH (OH) CH; OH; R $ is selected from -OR ** and alkyl; R'º is selected from alkyl, - (CH2a) R " , and hydrogen, where said alkyl is optionally substituted with halogen, amine, alkylamine, or dialkylamine ; R * is selected from cycloalkyl and aryl; u is selected from O and 1; s is selected from 1 and 2; and R and Rision independently alkyl; wherein said alkyl is optionally substituted with one or more -OH.
[11]
A compound according to claim 1, selected from the group consisting of: 113 & o CO 116 o O: a 'o. OQ O IN ANH o 148 o ”118 3 O nº CS” No Ss [8 O NH o 175 o Ps 177 Q tn N = - 9 () ”E FO
NODE NH ASI ds o
183 q 18 o
N N "NÔ NH OT NÔ NH HO” ty has 185 o E 225 »NO So Sd Ss NÔ NH O NNNH) O <S
S 191 or 192 a
N N << X ÁR (D NH NODE (> 2 | is O: The NH NODE,
HO Y Eto 193 q 7 196 = p E o Se A (DZ NÔ NH () 2 C NÓ NH, Eto- *> to 197 o E o A = <a. ”NÔ NH () En. (DS NO NH oo ”o: o
199 oe | 200 No NO NHo ST NO NH no é E earai 205 dr 213 À TOR O PL O this Eto, nº No O NH Meo o o 214 = ada 215 is not O * No o (DJ Nº NH "AA 216 s LdfoafEia: 217 s NO unio Se. CG o O NO NH Y gos 218 e NT: [219 O.
OO: o ”Nua o DESTA ari Ao O, 221 of [222 For - O Ã NA = fisaP O NO NH Q” nº Sr O: O (O 2 Oo 223 NT | 224 NO = X ima QEEÍ SAR C: SO NÃo SK NO NH Q Ho dy 226 3X 201 8 << SHE Tede FC So, O "and AA" o (J q É q To 227 & 228 AX os Flioeas | E; á CG Nãz
229 | TX AA 280 do
SEA SA v 1 NH. Q o Dao TFT Q TON = N N, A. FR, O Ne | o N = o ASAS - ”. 233 SERUM 2 3 E on O “If GO Ç NA o 1 NH q No q à 235 OS 236 a SS fe ALLT us A ALT ru 237 SS ess Er
CS CS ”. The NH, HC! P Nu and tautomers, enantiomers and salts thereof.
[12]
A compound according to claim 11, selected from the group consisting of: r 198 Q C 225 ia. ro: SA AA,
O NÔ NH OG À oov 191% O 192 RS C = “= <o N NHa (o NÔ NH o (O o (SD no eo 193 o C 196 F = 4 dn O NÔ NH) ͺ NÔ NH, so Ho: <SO
P q 197% 221 nO MOoH = “O W (D NÔ NH Nº NH>
P A and o o o 205. SE 213 = e so ”nº NH o” NNH O ne oo 214 = x Ss 215 = PERO x ST o DA, so AA oo 216 E Cm until NO "LO ha DA,. EO vv õ õ | a É E no HH aí OAY oo 223 - CÍ 224 - O 3 SS and Dee, - À O Ho OH o AX> oH 222 NO 8 From NH
TO and tautomers, enantiomers and salts thereof.
[13]
13. Compound according to claim 11, selected from the group consisting of: o o = 225 NO NR Te sá
NANA
SO ST
Oo o É
193 Q = 192 o A
MN SA Pia O NÓ NH (> NO NH 3 SD Eto- o Eto o 197 o | 221 nTTNMOH ”» N & q Ms ”NÔ NH O CD Nº NH> (DS ooo and * CS of * OO Eto, (S = ( 7 ne NO NH o NH É Meo ”214 s DE 215 o O o $) Nu o O z NA EtO O Ao ook 216 - TO 217 = OO | De De
À o O NHz o O NH: "Yo e 218 O 219 O NO De, O LO b Na, PO Ao O o 223 IO 222 Lo
O AM O A WS o N NH k No. NH
TO and tautomers, enantiomers and salts thereof.
[14]
14. A compound according to claim 11, selected from the group consisting of:
191 o To 196 o. > ”= NR and NR” N NH (> NÔ NH o (DD O Ho ox o 224 s NO O) NO NH>
HO OH and tautomers, enantiomers and salts thereof.
[15]
A compound according to claim 1, wherein the salt is a pharmaceutically acceptable salt.
[16]
A kit for treating a condition mediated by TLR7 and / or TLR8, comprising: a) a pharmaceutical composition comprising a compound as defined in claim 1, or a tautomer, enantiomer or salt thereof; and, b) optionally instructions for use.
[17]
17. A pharmaceutical composition, comprising a compound as defined in claim 1 or a tautomer, enantiomer or salt thereof together with a pharmaceutically acceptable diluent or carrier.
[18]
18. A method of treating a condition mediated by TLR7 and / or TLR8, comprising administering to a patient in need of the patient an amount of a compound as defined in claim 1, or a tautomer, enantiomer or salt thereof.
[19]
19. A method of modulating the patient's immune system, comprising administering to a patient in need of the patient an amount of a compound as defined in claim 1 or a tautomer, enantiomer or salt thereof.

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法律状态:
2020-08-25| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-09-15| 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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2021-04-20| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-05-04| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-06-22| B08F| Application dismissed because of non-payment of annual fees [chapter 8.6 patent gazette]|Free format text: REFERENTE A 11A ANUIDADE. |

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2021-08-17| B11B| Dismissal acc. art. 36, par 1 of ipl - no reply within 90 days to fullfil the necessary requirements|

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2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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US23496909P| true| 2009-08-18|2009-08-18|

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US61/234,969|2009-08-18|

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US23558609P| true| 2009-08-20|2009-08-20|

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US61/235,586|2009-08-20|

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