cyclin-dependent kinase inhibitor compounds and pharmaceutical composition

专利摘要:
CYCLINE DEPENDENT KINASE INHIBITING COMPOUNDS AND PHARMACEUTICAL COMPOSITION. The present invention relates to compounds of formulas I, II or III, and pharmaceutically acceptable salts thereof, which are useful as inhibitors of cyclin-dependent kinase. In addition, the present invention provides a pharmaceutical composition comprising said compounds.
公开号:BR112013010018B1
申请号:R112013010018-4
申请日:2011-10-25
公开日:2020-11-10
发明作者:Francis X. Tavares；Jay C. Strum
申请人:G1 Therapeutics, Inc.；
IPC主号:

专利说明:

Related Orders Declaration
[001] This order is related to and claims the benefit of provisional United States Order of Copendence No. 61 / 406,498 deposited on October 25, 2010 which is hereby incorporated by reference in its entirety for all purposes. Field of the Invention
[002] The invention relates to compounds useful for inhibiting cyclin-dependent kinase ("CDK"). Background
[003] Cancer remains a challenge for modern medicine. At a basic level, cancer occurs when there is uncontrollable cell division. Uncontrollable cell division is an effect of a breakdown in the natural life cycle of cells. CDK is a family of kinases involved in the cell life cycle. Abnormally high CDK activity is a characteristic of many cancers. There are naturally occurring CDK inhibitor proteins and the abnormally high CDK activity may be due to the malfunction of naturally occurring CDK inhibitors or due to an overabundance of CDK. CDK inhibitors are known in the art but there remains a need for additional CDK inhibitors. summary
[004] The invention is directed to compounds of formula I, II or III:


[005] wherein R, R1, R2, R6, R8, X, X ', X ", Z and y are as defined herein and to pharmaceutically acceptable salts thereof.
[006] The described compounds are useful as CDK inhibitors and may be useful in the treatment of CDK-mediated diseases and disorders such as cancer. Pharmaceutical compositions comprising the compounds and pharmaceutically acceptable salts of the compounds are also described. Brief Description of Drawings
[007] FIGS. 1 to 3 illustrate the R2 modalities of the compounds of the invention.
[008] FIGS. 4 to 8 illustrate the modalities of the core structure of the compounds of the invention. Detailed Description
[009] In one embodiment, compounds of formula I and II are provided:

[0010] where:
[0011] Z is - (CH2) X-, where x is 1,2, 3 or 4 or -O- (CH2) z-, where z is 2, 3 or 4;
[0012] each X is independently CH or N;
[0013] each X 'is independently CH or N;
[0014] X "is CH2, S or NH;
[0015] each of R and R8 are independently H, C1-C3 alkyl or haloalkyl;
[0016] each R1 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes heteroatoms of O or N in place of one carbon in the chain and two R1's in the adjacent ring atoms or in the same ring atom together with the ring atom (s) to which they are optionally attached form a 3-8 membered cycle;
[0017] is 0, 1,2, 3 or 4;
[0018] R2 is - (alkylene) m-heterocycle, - (alkylene) m-heteroaryl, - (alkylene) m-NR3R4, - (alkylene) m-C (O) -NR3R4; - (a | chi | ene) m-C (O) - O-alkyl; - (alkylene) mO-R5, - (alkylene) mS (O) n-R5, or - (alkylene) mS (O) n-NR3R4 any of which can be optionally independently substituted by one or more Rx groups as permitted by valence, and, where two Rx groups attached to the same or adjacent atom, can optionally combine to form a ring and, where m is 0 or 1 and n is 0, 1 or 2;
[0019] R3 and R4 in each occurrence are independently:
[0020] (i) hydrogen or
[0021] (ii) alkyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which can be optionally independently substituted by one or more Rx groups as allowed by valence, and, where two Rx groups attached to the same or adjacent atom, can optionally combine to form a ring; or R3 and R4 together with the nitrogen atom to which they are attached can combine to form the ring heterocycle optionally independently substituted by one or more Rx groups as allowed by valence, and, in which two Rx groups attached to the same atom or adjacent, can optionally combine to form a ring;
[0022] R5 and R5 * in each occurrence is:
[0023] (i) hydrogen or
[0024] (ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted by one or more Rx groups as permitted by valency;
[0025] Rx in each occurrence is independently halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl- - (alkyl) OR5, - (alkylene) mO- alkylene-OR5, - (alkylene) mS (O) n-R5, - (alkylene) m-NR3R4, - (alkylene) m-CN, - (alkylene) mC (O) -R5 , - (alkylene) mC (S) -R5, (alkylene) mC (O) -OR5, - (alkylene) mOC (O) -R5, - (alkylene) mC (S) - OR5, - (alkylene) mC ( O) - (alkylene) m-NR3R4, - (alkylene) mC (S) -NR3R4, - (alkylene) mN (R3) -C (O) -NR3R4, - (alkylene) mN (R3) -C (S) -NR3R4, - (alkylene) mN (R3) -C (O) -R5, - (alkylene) mN (R3) -C (S) -R5, (alkylene) mOC (O) -NR3R4, - (alkylene) mOC (S) -NR3R4, - (alkylene) m-SO2-NR3R4, - (alkylene) mN (R3) -SO2-R5, - (alkylene) mN (R3) - Sθ2-NR3R4, - (alkylene) mN ( R3) -C (O) -OR5) - (alkylene) mN (R3) -C (S) - OR5, or - (alkylene) mN (R3) -SO2-R5; on what:
[0026] said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups can also be independently replaced by one or more - (alkylene) m- CN, - (alkylene) m-OR5 *, - (alkylene) mS (O) n-R5 *, - (alkylene) m-NR3 * R4 *, - (alkylene) mC (O) -R5 *, - (alkylene) mC ( = S) R5 *, - (alkylene) mC (= O) O R5 *, - (alkylene) m-OC (= O) R5 *, - (alkylene) mC (S) -OR5 *, - (alkylene) m - C (O) -NR3 * R4 *, - (alkylene) mC (S) -NR3 * R4 *, - (alkylene) mN (R3 *) - C (O) -NR3 * R4 *, - (alkylene) mN (R3 *) - C (S) -NR3 * R4 *, - (alkylene) m- N (R3 *) - C (O) -R5 *, - (alkylene) mN (R3 *) - C (S) - R5 *, - (alkylene) mO- C (O) -NR3 * R4 *, - (alkylene) mOC (S) -NR3 * R4 *, - (alkylene) m-SO2- NR3 * R4 *, - (alkylene) mN (R3 *) - SO2-R5 *, - (alkylene) mN (R3 *) - SO2-NR3 * R4 *, - (alkylene) mN (R3 *) - C (O) -OR5 *, - (alkylene) mN (R3 *) - C (S) - OR5 *, or - (alkylene) mN (R3 *) - SO2-R5 *,
[0027] n is 0, 1 or 2, and
[0028] m is 0 or 1;
[0029] R3 * and R4 * in each occurrence are independently:
[0030] (i) hydrogen or
[0031] (ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocycle, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted by one or more Rx groups as permitted by valency; or R3 * and R4 * together with the nitrogen atom to which they are attached can combine to form the ring heterocycle optionally independently substituted by one or more Rx groups as allowed by valence; and
[0032] R6 is H or lower alkyl,
[0033] or a pharmaceutically acceptable salt thereof.
[0034] In some respects, the compound is of formula I or formula II and R6 is absent.
[0035] In some respects, the compound is of formula III:
and the variables are as defined for compounds of formulas I and II and pharmaceutically acceptable salts thereof.
[0036] In some respects, Rx is also not replaced.
[0037] In some respects, R2 is - (alkylene) m-heterocycle, - (alkylene) m-heteroaryl, - (alkylene) m-NR3R4, - (alkylene) m-C (O) - NR3R4; - (alkylene) mO-R5, - (alkylene) mS (O) n-R5, or - (alkylene) m- S (O) n-NR3R4 any of which can be optionally independently substituted by one or more Rx groups such as allowed by valence, and, where two Rx groups attached to the same or adjacent atom, can optionally combine to form a ring and, where m is 0 or 1 and n is 0, 1 or 2.
[0038] In some ways, R8 is hydrogen or C1-C3 alkyl.
[0039] In some ways, R is hydrogen or C1-C3 alkyl.
[0040] In some respects, R2 is - (alkylene) m-heterocycle, - (alkylene) m-NR3R4, - (alkylene) mC (O) -NR3R4, - (alkylene) mC (O) -O- alkyl or - (alkylene) m-OR5 any of which can be optionally independently substituted by one or more Rx groups as allowed by valence, and, where two Rx groups attached to the same or adjacent atom, can optionally combine to form one ring.
[0041] In some respects, R2 is - (alkylene) m-heterocycle, - (alkylene) m-NR3R4, - (alkylene) mC (O) -NR3R4, - (alkylene) mC (O) -O- alkyl or - (alkylene) m-OR5 without further substitution.
[0042] In some respects, m in R2 is 1. In another aspect, the alkylene in R2 is methylene.

[0043] In some ways, R2 is where:
[0044] R2 * is a bond, alkylene, - (alkylene) mO- (alkylene) m-, - (alkylene) mC (O) - (alkylene) m-, - (alkylene) mS (O) 2- (alkylene) ) m- and - (alkylene) m-NH- (alkylene) m-, where each m is independently 0 or 1;
[0045] P is a 4- to 8-membered saturated heterocyclyl mono- or bicyclic group;
[0046] each Rx1 is independently - (alkylene) m- (C (O)) m- (alkylene) m- (N (RN)) m- (alkyl) m, where each m is independently 0 or 1 as long as at least one m is 1, - (C (O)) - O-alkyl, - (alkylene) m-cycloalkyl, where m is 0 or 1, -N (RN) -cycloalkyl, -C (O) -cycloalkyl, - (alkylene) m-heterocyclyl, where m is 0 or 1, or -N (RN) -heterocyclyl, - C (O) -heterocyclyl, -S (O) 2- (alkylene) m, where m is 1 or 2, where:
[0047] RN is H, Ci to C4 alkyl or Ci to Ce heteroalkyl, and
[0048] in which two Rx1s, together with the atoms to which they bond to P, which may be the same atoms, form a ring; and
[0049] t is 0, 1 or 2.
[0050] In some respects, each Rx1 is only optionally substituted by unsubstituted alkyl, halogen or hydroxy.
[0051] In some ways, Rx1 is hydrogen or unsubstituted C1-4 alkyl.
[0052] In some respects, at least one Rx1 is - (alkylene) m-heterocyclyl, where m is 0 or 1.
[0053] In some respects, R2 is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.

[0054] In some ways, R2 is ^^ RX1) t.

[0055] In some ways, R2 is /

[0056] In some ways, R2 is 'o' where:

[0057] R2 * is a bond, alkylene, - (alkylene) mO- (alkylene) m-, - (alkylene) mC (O) - (alkylene) m-, - (alkylene) mS (O) 2- (alkylene) ) m- and - (alkylene) m-NH- (alkylene) m-, where each m is independently 0 or 1;
[0058] P is a 4- to 8-membered saturated heterocyclyl mono- or bicyclic group;
[0059] P1 is a 4- to 6-membered saturated monocyclic heterocyclyl group;
[0060] each Rx2 is independently hydrogen or alkyl; and
[0061] is 0.1 or 2.
[0062] In some ways, R2 is'

[0063] In some ways, P1 includes at least one nitrogen.
[0064] In some respects, any alkylene in R2 * in any previous aspect is also not substituted.
[0065] In some respects, R2 is selected from the structures represented in FIGS. 1 to 3.
[0066] In some ways, R2 is

[0067] In some respects, the compound has the general formula I and more specifically one of the general structures in FIGS. 4-8, where the variables are as previously defined.
[0068] In some respects, the compound has a general formula la:
where R1, R2, R and y are as previously defined.
[0069] In some embodiments, the compound has the formula la and R is alkyl.
[0070] In some embodiments, the compound has the formula la and R is H.
[0071] In some embodiments, the compound has the formula la and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[0072] In some embodiments, the compound has the formula la and R2
is S, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or unsubstituted C1-C4 alkyl and R2 * is as previously defined.
[0073] In some embodiments, the compound has the formula lb:
where R2 and R are as previously defined.
[0074] In some embodiments, the compound has the formula lb and R is alkyl.
[0075] In some embodiments, the compound has the formula lb and R is H.
[0076] In some embodiments, the compound has the formula lb and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[0077] In some embodiments, the compound has the formula lb and R2
is', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[0078] In some embodiments, the compound has the formula lc:

[0079] where R2 and R are as previously defined.
[0080] In some embodiments, the compound has the formula lc and R is alkyl.
[0081] In some embodiments, the compound has the formula lc and R is H.
[0082] In some embodiments, the compound has the formula lc and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[0083] In some embodiments, the compound has the formula lc and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[0084] In some embodiments, the compound has the formula Id:

[0085] where R2 and R are as previously defined.
[0086] In some embodiments, the compound has the formula Id and R is alkyl.
[0087] In some embodiments, the compound has the formula Id and R is H.
[0088] In some embodiments, the compound has the formula Id and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[0089] In some embodiments, the compound has the formula Id and R2
is', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[0090] In some embodiments, the compound has the formula le:

[0091] In some embodiments, the compound has the formula le and R is alkyl.
[0092] In some embodiments, the compound has the formula le and R is H.
[0093] In some embodiments, the compound has the formula le and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[0094] In some embodiments, the compound has the formula le and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[0095] In some modalities, the compound has the If formula:

[0096] In some embodiments, the compound has the formula If and R is alkyl.
[0097] In some embodiments, the compound has the formula If and R is H.
[0098] In some modalities, the compound has the formula If and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[0099] In some modalities, the compound has the formula If and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[00100] In some embodiments, the compound has the formula lg:

[00101] In some embodiments, the compound has the formula lg and R is alkyl.
[00102] In some embodiments, the compound has the formula lg and R is H.
[00103] In some embodiments, the compound has the formula lg and R2
is ', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2', Rx1 et are as previously defined.
[00104] In some embodiments, the compound has the formula lg and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[00105] In some embodiments, the compound has the formula lh:

[00106] In some embodiments, the compound has the formula 1h and R is alkyl.
[00107] In some embodiments, the compound has the formula lh and R is H.
[00108] In some embodiments, the compound has the formula lh and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[00109] In some embodiments, the compound has the formula lh and R2
is', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[00110] In some embodiments, the compound has the formula li:

[00111] In some embodiments, the compound has the formula li and R is alkyl.
[00112] In some embodiments, the compound has the formula li and R is H.
[00113] In some embodiments, the compound has the formula li and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group and R2 *, Rx1 et are as previously defined.
[00114] In some embodiments, the compound has the formula li and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl and R2 * is as previously defined.
[00115] In some embodiments, the compound has the formula lj:

[00116] In some embodiments, the compound has the formula lj and R is alkyl.
[00117] In some embodiments, the compound has the formula lj and R is H.
[00118] In some embodiments, the compound has the formula lj and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
[00119] In some embodiments, the compound has the formula lj and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl.
[00120] In some embodiments, the compound has the formula lj and R is H, and both X are N.
[00121] In some embodiments, the compound has the formula lk:

[00122] In some embodiments, the compound has the formula Ik and R2 is
, where P * is a 4- to 8-membered saturated heterocyclyl mono- or bicyclic group.
[00123] In some embodiments, the compound has the formula Ik and R2
is —s, where p * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl.
[00124] In some embodiments, the compound has the formula II:

[00125] In some embodiments, the compound has the formula II and R2
is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
[00126] In some embodiments, the compound has the formula II and R2
is', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-4 alkyl.
[00127] In some embodiments, the compound has the formula lm:

[00128] In some embodiments, the compound has the formula lm and
R2 is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
[00129] In some embodiments, the compound has the formula lm and
R2 is', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl.
[00130] In some embodiments, the compound has the formula Ila:

[00131] In some embodiments, the compound has the formula lia and
R2 is', where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
[00132] In some embodiments, the compound has the formula lia and
R2 is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl.
[00133] In some embodiments, the compound has the formula Ilb:

[00134] In some embodiments, the compound has the formula lm and
R2 is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group.
[00135] In some embodiments, the compound has the formula lm and
R2 is, where P * is a 4- to 8-membered mono- or bicyclic saturated heterocyclyl group, Rx1 is hydrogen or C1-C4 alkyl. Definitions
[00136] Unless otherwise stated, the following terms used in this application, including the specification and claims, have the definitions given below. It should be noted that, as used in the specification and the appended claims, the singular forms "one, one (a)," "one, one (an)" and "0, a" include plural referents unless the context is clearly dictate otherwise. The definition of standard chemistry terms can be found in reference works, including Carey and Sundberg (2007) Advanced Organic Chemistry 5th Ed. Vols. A and B, Springer Science + Business Media LLC, New York. The practice of the present invention will employ, unless otherwise indicated, conventional methods of synthetic organic chemistry, mass spectroscopy, preparative and analytical methods of chromatography, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology. Conventional organic chemistry methods include those included in March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Edition, M.B. Smith and J. March, John Wiley & Sons, Inc., Hoboken, NJ, 2007.
[00137] The term "alkyl," either alone or within other terms such as "haloalkyl" and "alkylamino," encompasses linear or branched radicals, having one to about twelve carbon atoms. "Lower alkyl" radicals have one to about six carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and the like. The term "alkylene" embraces divalent linear and branched bridged radicals. Examples include methylene, ethylene, propylene, isopropylene and the like.
[00138] The term "alkenyl" encompasses linear or branched radicals, having at least one carbon-carbon double bond of two to about twelve carbon atoms. "Lower alkenyl" radicals, having two to about six carbon atoms. Examples of alkenyl radicals include ethylene, propenyl, allyl, propenyl, butenyl and 4-methylbutenyl. The terms "alkenyl" and "lower alkenyl," include radicals, having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.
[00139] The term "alkynyl" denotes linear or branched radicals, having at least one carbon-carbon triple bond, and having two to about twelve carbon atoms. "Lower alkynyl" radicals, having two to about six carbon atoms. Examples of such radicals include propargyl, butynyl, and the like.
[00140] Alkyl, alkenyl, and alkynyl radicals can optionally be substituted with one or more functional groups such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle and the like.
[00141] The term "alkylamino" encompasses "N-alkylamino" and "N, N-dialkylamino" in which amino groups are independently substituted with an alkyl radical and with two alkyl radicals, respectively. "Lower alkylamino" radicals have one or two alkyl radicals of one to six carbon atoms attached to a nitrogen atom. Suitable alkylamino radicals can be mono- or dialkylamino such as N-methylamino, N-ethylamino, N.N-dimethylamino, N, N-diethylamino and the like.
[00142] The term "halo" means halogens such as fluorine, chlorine, bromine or iodine atoms.
[00143] The term "haloalkyl" embraces radicals, in which any one or more of the alkyl carbon atoms are replaced with one or more halo as defined above. Examples include monoaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl. A monoaloalkyl radical, for one example, can have an iodine, bromine, chlorine or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals can have two or more of the same halo atoms or a combination of different halo radicals. "Lower haloalkyl" includes radicals, having 1 to 6 carbon atoms. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloroethyl. "Perfluoroalkyl" means an alkyl radical, having all hydrogen atoms replaced with fluorine atoms. Examples include trifluoromethyl and pentafluoroethyl.
[00144] The term "aryl", alone or in combination, means a carbocyclic aromatic system containing one or two rings, in which such rings can be fused together. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronanaftyl, and indanyl. The most preferred aryl is phenyl. Said "aryl" group can have 1 or more substituents, such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino, and the like. An aryl group can be optionally substituted by one or more functional groups, such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle and the like.
[00145] The term "heterocyclyl" (or "heterocycle") encompasses ring radicals containing saturated, and partially saturated, hetero atoms, in which the hetero atoms can be selected from nitrogen, sulfur and oxygen. Heterocyclic rings comprise 6- to 8-membered monocyclic rings, as well as 5- to 16-membered bicyclic ring systems (which may include bridged and spiro-fused bicyclic ring systems). Do not include rings containing -O-O -.- O-S- or -S-S- portions. Said "heterocyclyl" group can have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy, amino, lower alkylamino, and the like.
[00146] Examples of saturated heterocycle groups include 3 to 6 saturated heteromonocyclic groups containing 1 to 4 nitrogen atoms [eg, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated 3 to 6 membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [eg, morpholinyl]; saturated 3 to 6 membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg thiazolidinyl], Examples of partially saturated heterocyclyl radicals include dihydrothienyl, dihydropyranyl, dihydrofuryl, dihydrothiazolyl , and the like.
[00147] Particular examples of partially saturated and saturated heterocycle groups include pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo [l, 4 ] dioxanil, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-d i-hydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a, 9,9a-hexahydro-1 H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4-triazolo [3,4-a ] isoquinolyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, benzo [1,4] dioxanyl, 2,3-dihydro-1H-1À'-benzo [d] isothiazole-6 -ila, dihydropyranyl, dihydrofuryl and dihydrothiazolyl, and the like.
[00148] Heterocycle groups also include radicals in which the heterocyclic radicals are fused / condensed with aryl radicals: unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [e.g., tetrazolo [1,5-b] pyridazinyl]; unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [eg benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg benzothiazolyl, benzothiadiazolyl]; and a saturated, partially unsaturated and unsaturated condensed heterocyclic group containing 1 to 2 oxygen or sulfur atoms [for example, benzofuryl, benzothienyl, 2,3-dihydro-benzo [1,4,] dioxinyl and dihydrobenzofuryl],
[00149] The term "heteroaryl" denotes aryl ring systems that contain one or more heteroatoms selected from the group O, N and S, in which the nitrogen ring and sulfur atom (s) are optionally oxidized, and the atom (s) nitrogen atom (s) are optionally quarternized. Examples include 5- to 6-membered unsaturated heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [for example , 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl]; 5- to 6-membered unsaturated heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc .; 5- to 6-membered unsaturated heteromonocyclic group containing a sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [eg 1,2,4-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated 5- to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, eg thiazolyl, thiadiazolyl [eg 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5- thiadiazolyl].
[00150] The term "heteroarylalkyl" denotes alkyl radicals substituted with a heteroaryl group. Examples include pyridylmethyl and thienylethyl.
[00151] The term "sulfonyl", whether used alone or linked to other terms, such as alkylsulfonyl, denotes respectively divalent radicals -SO2-.
[00152] The terms "carboxy" or "carboxyl", if used alone or with other terms, such as "carboxyalkyl", denotes -C (O) -OH.
[00153] The term "carbonyl", whether used alone or with other terms, such as "aminocarbonyl", denotes -C (O) -.
[00154] The term "aminocarbonyl" denotes an amide group of the formula -C (O) -NH2.
[00155] The terms "heterocycloalkyl" include alkyl radicals substituted by heterocyclic. Examples include piperidylmethyl and morpholinylethyl.
[00156] The term "arylalkyl" encompasses alkyl radicals replaced by aryl. Examples include benzyl, diphenylmethyl and phenylethyl. The aryl in said aralkyl can be further substituted by halo, alkyl, alkoxy, haloalkyl and haloalkoxy.
[00157] The term "cycloalkyl" includes saturated carbocyclic groups of 3 to 10 carbons. Lower cycloalkyl groups include C3-C6 rings. Examples include cyclopentyl, cyclopropyl, and cyclohexyl. Cycloalkyl groups can be optionally substituted with one or more functional groups, such as halo, hydroxy, nitro, amino, cyano, haloalkyl, aryl, heteroaryl, heterocycle and the like.
[00158] The term "cycloalkylalkyl" includes alkyl radicals substituted by cycloalkyl. "Lower cycloalkylalkyl" radicals are cycloalkyl radicals attached to alkyl radicals, having one to six carbon atoms. Examples of include cyclohexylmethyl. The cycloalkyl in said radicals can be further substituted with halo, alkyl, alkoxy and hydroxy.
[00159] The term "cycloalkenyl" includes carbocyclic groups, having one or more carbon-carbon double bonds including "cycloalkylenienyl" compounds. Examples include cyclopentenyl, cyclopentadienyl, cyclohexenyl and cycloheptadienyl.
[00160] The term "comprising" is understood to be open termination, including the indicated component, but not excluding other elements.
[00161] The term "oxo" as used here includes an oxygen atom bonded with a double bond.
[00162] The term “nitro” as used here includes -NO2.
[00163] The term "cyan" as used here includes -CN. Synthesis
[00164] The described compounds can be made by the following general schemes:

[00165] In Scheme 1, Ref-1 is WO 2010/020675 A1; Ref-2 is White, JD; and another. J. Org. Chem. 1995, 60, 3600; and Ref-3 Presser, A. and Hufner, A. Monatshefte fiir Chemie 2004, 135, 1015.

[00166] In Scheme 2, Ref-1 is WO 2010/020675 A1; Ref-4 is WO 2005/040166 A1; and Ref-5 is Schoenauer, K and Zbiral, E. Tetrahedron Letters 1983, 24, 573.
Layout 3
[00167] In Scheme 3, Ref - 1 is WO 2010/020675 A1.

Layout 5
[00168] Scheme 5 illustrates a useful scheme for the synthesis of compounds of formula II. EXAMPLES Example 1
[00169] N- [2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] ethyl] tert-butyl carbamate

[00170] To a solution of 3.2 g of 5-bromo-2,4-dichloropyrimidine (0.0135 mol) in 80 ml of ethanol was added Hunig's base (3.0 ml) followed by the addition of the N solution - (tert-butoxycarbonyl) -1,2-diaminoethane (2.5 g) (0.0156 mol) in 20 ml of ethanol. The contents were stirred overnight for 20 h. The solvent was evaporated in vacuo. Ethyl acetate (200 ml) and water (100 ml) were added and the layers separated. The organic layer was dried over magnesium sulfate and then concentrated in vacuo. Column chromatography on silica gel using hexane / ethyl acetate (0 - 60%) provided N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] ethyl] tert-butyl carbamate . 1HRMN (d6-DMSO) 8.21 (s, 1H), 7.62 (brs, 1H), 7.27 (brs, 1H), 3.39 (m, 2H), 3.12 (m, 2H) , 1.34 (s, 9H). LCMS (ESI) 351 (M + H)
[00171] N- [2 - [[2-Chloro-5- (3,3-diethoxyprop-1-in i I) pyrimid-4-yl] amine- ethyl] tert-butyl carbamate

[00172] The 3.6 mmol (1.265 g) of N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] ethyl] tert-butyl carbamate in THF (10 ml) 0.788 ml of acetal (5.43 mmol), 148 mg of Pd (dppf) CH2Ch, 0.757 ml of triethylamine (5.43 mmol) are added. The contents were degassed and then purged with nitrogen. To this was then added 29 mg of Cul. The reaction mixture was heated to reflux for 48 h. After cooling, the contents were filtered over CELITE ™ and concentrated. Column chromatography of the resulting residue using hexane / ethyl acetate (0 - 30%) provided N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1 -inyl) pyrimidin-4-yl] ami - tert-butyl ethyl] carbamate. 1HRMN (d6-DMSO) 8.18 (s, 1H), 7.63 (brs, 1H), 7.40 (brs, 1H), 5.55 (s, 1H), 3.70 (m, 2H) , 3.60 (m, 2H), 3.42 (m, 2H), 3.15 (m, 2H), 1.19-1.16 (m, 15H). LCMS (ESI) 399 (M + H)
[00173] N- [2- [2-Chloro-6- (dietoxymethyl) pyrrolo [2,3-d] pyrimidin-7-yl] ethyl] tert-butyl carbamate

[00174] To a solution of the coupled product (2.1 g) (0.00526 mol) in THF (30 ml) was added 7.0 g of solid TBAF. The contents were heated to 65 degrees for 2 h. Concentration followed by column chromatography using ethyl acetate / hexane (0 - 50%) gave N- [2- [2-chloro-6- (dietoxymethyl) pyrrolo [2,3-d] pyrimidin-7-yl] ethyl] tert-butyl carbamate as a pale brown liquid (1.1 g). 1HRMN (d6-DMSO) 8.88 (s, 1H), 6.95 (brs, 1H), 6.69 (s, 1H), 5.79 (s, 1H), 4.29 (m, 2H) , 3.59 (m, 4H), 3.34 (m, 1H), 3.18 (m, 1H), 1.19 (m, 9H), 1.17 (m, 6H). LCMS (ESI) 399 (M + H).
[00175] N- [2- (2-Chloro-6-formyl-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] tert-butyl carbamate

[00176] To 900 mg of acetal 8.0 ml of AcOH and 1.0 ml of water were added. This was stirred at room temperature for 16 h. Cone, and ethyl acetate / hexanes column (0 - 60%) provided 0.510 g of N- [2- (2-chloro-6-formyl-pyrrolo [2,3-d] pyrimidin-7-yl) ethyl] carbamate tert-butyl as a foam. 1HRMN (d6-DMSO) 9.98 (s, 1H), 9.18 (s, 1H), 7.66 (s, 1H), 6.80 (brs, 1H), 4.52 (m, 2H) , 4.36 (m, 2H), 1.14 (s, 9H). LCMS (ESI) 325 (M + H)
[00177] 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloro-pyrrole [2,3-d] pyrimidine-6-carboxylic acid

[00178] To the aldehyde 0.940 g in DMF (4 ml) was added oxon (1.95 g, 1.1 eq). The contents were stirred at room temperature for 7 h. Hexane / ethyl acetate column (0 - 100%) gave 0.545 g of 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. 1HRMN (d6-DMSO) 9.11 (s, 1H), 7.39 (s, 1H), 4.38 (m, 2H), 4.15 (m, 2H), 1.48 (m, 9H) . LCMS (ESI) 341 (M + H)
[00179] Methyl 7- [2- (tert-Butoxycarbonylamino) ethyl] -2-chloro-pyrrolo [2,3-d] pyridine-6-carboxylate

[00180] To a solution of 2-chloro-7-propyl-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid (0.545 g) (0.00156 mol) in toluene (3.5 ml) and MeOH ( 1 ml) TMS-diazomethane (1.2 ml) was added. After stirring overnight at room temperature the excess TMS-diazomethane was quenched with acetic acid (3 ml) and then concentrated in vacuo. The residue was columnar with hexane / ethyl acetate (0- 70%) to provide methyl 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylate as a not entirely white solid (0.52 g). 1HRMN (d6-DMSO) 9.10 (s, 1H), 7.45 (s, 1H), 6.81 (brs, 1H) 4.60 (m, 2H), 3.91 (s, 3H), 3.29 (m, 2H), 1.18 (m, 9H) LCMS (ESI) 355 (M + H)
[00181] Tricyclic chlorine amide

[00182] Methyl 7- [2- (tert-butoxycarbonylamino) ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylate (0.50 g) (0.0014 mol) in dichloromethane (2.0 ml) TFA (0.830 ml) was added. The contents were stirred at room temperature for 1 hr. Concentration in vacuo gave the crude amino ester which was suspended in toluene (5 ml) and Hunig's base (0.5 ml). The contents were heated under reflux for 2 h. Concentration followed by column chromatography using hexane / ethyl acetate (0 - 50%) gave the desired chlorinated tricyclic amide (0.260 g). 1HRMN (d6-DMSO) 9.08 (s, 1H), 8.48 (brs, 1H), 7.21 (s, 1H) 4.33 (m, 2H), 3.64 (m, 2H). LCMS (ESI) 223 (M + H)
[00183] Chlorine-N-methyltricyclic amide

[00184] To a solution of the tricycliclactam chlorine (185 mg, 0.00083 mol) in DMF (2.0 ml) was added sodium hydride (55% oil dispersion, 52 mg). After stirring for 15 mins, methyl iodide (62 p, L, 1.2 eq). The contents were stirred at room temperature for 30 mins. After adding methanol (5 mL), sat. was added followed by the addition of ethyl acetate. Separation of the organic layer followed by drying with magnesium sulfate and concentration in vacuo gave the N-methylated amide in quantitative production. 1HRMN (d6-DMSO) 9.05 (s, 1H), 7.17 (s, 1H) 4.38 (m, 2H), 3.80 (m, 2H), 3.05 (s, 3H). LCMS (ESI) 237 (M + H)
[00185] 1 -Meti l-4- (6-n itro-3-pyridine) pi perazine

[00186] To 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) in DMF (20 mL) was added N-methylpiperazine (2.96 g, 1.1 eq) followed by the addition of DIPEA ( 4.65 ml, 26.7 mmol). The contents were heated to 90 degrees for 24 h. After adding ethyl acetate (200 ml), water (100 ml) was added and the layers separated. Drying followed by concentration gave the crude product which was columnar using (0 - 10%) DCM / Methanol. 1HRMN (δ6-DMSO) 8.26 (s, 1H), 8.15 (1H, d, J = 9.3 Hz), 7.49 (1H, d, J = 9.4 Hz), 3.50 (m, 4H), 2.49 (m, 4H), 2.22 (s, 3H).
[00187] 5- (4-Methylpiperazin-1-i) pyrid in-2-amine

[00188] To 1-methyl-4- (6-nitro-3-pyridyl) piperazine (3.4 g) in ethyl acetate (100 ml) and ethanol (100 ml) was added Pd / ca 10% (400 mg ) and then the contents stirred under 0.703 kg / cm2 (10 psi) hydrogen overnight. After filtration through CELITE ™, the solvents were evaporated and the crude product was purified on silica gel using DCM / 7 N Ammonia in MeOH (0 - 5%) to provide 5- (4-methylpiperazin-1-yl) pyridin -2-amine (2.2 g). 1HRMN (d6-DMSO) 7.56 (1H, d, J = 3 Hz), 7.13 (1H, m), 6.36 (1H, d, J = 8.8 Hz), 5.33 (brs , 2H), 2.88 (m, 4H), 2.47 (m, 4H), 2.16 (s, 3H).
[00189] tert-Butyl 4- (6-Amino-3-pyridyl) piperazine-1-carboxylate

[00190] This compound was prepared as described in WO 2010/020675 A1. Example 2 - Synthesis of Additional Intermediates
Layout 4
[00191] Intermediate A: tert-butyl N- [2- (benzyloxycarbonylamino) -3-methyl-butyl] carbamate

[00192] To 11.0 g (0.0464 mol) of benzyl N- [1- (hydroxymethyl) -2-methylpropyl] carbamate in dioxane (100 mL) cooled to 0 ° C, diphenylphosphoryl azide ( 10.99 ml) (1.1 eq) followed by the addition of DBU (8.32 ml) (1.2 eq). The contents were allowed to warm to room temperature and stirred for 16 h. After adding ethyl acetate (300 ml) and water (100 ml), the organic layer was separated and then washed with satd NaHCOs. (100ml). The organic layer was then dried (magnesium sulfate) and then concentrated in vacuo. To this DMSO intermediate (100 ml) was added sodium azide (7.54 g) and the contents were then heated to 90 degrees for 2 h. After adding ethyl acetate and water, the layers were separated. The organic layer was dried with magnesium sulfate followed by concentration in vacuo to provide an oil that was columnar using hexane / ethyl acetate (0 - 70%) to provide N- [1- (azidomethyl) -2-methyl-propyl] benzyl carbamate (6.9 g) as a colorless oil.
[00193] To benzyl N- [1- (azidomethyl) -2-methyl-propyl] carbamate (6.9 g) (0.0263 mol) in THF (100 mL) was added triphenyl phosphine (7.59 g) (1.1 eq). The contents were stirred for 20 h. After adding water (10 mL), and stirring for an additional 6 h, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columnar using DCM / MeOH (0 - 10%) to provide benzyl N- [1- (aminomethyl) -2-methyl-propyl] carbamate as a yellow oil .
[00194] To benzyl N- [1- (aminomethyl) -2-methyl-propyl] carbamate (4.65 g) (0.019 mol) in THF (70 mL) was added 2 N NaOH (20 mL) followed by addition of di-tert-butyl dicarbonate (5.15 g) (1.2 eq). After stirring for 16 h, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was purified using hexane / ethyl acetate (0 - 40%) on a silica gel column to provide intermediate A, N- [2- (benzyloxycarbonylamino) -3 tert-butyl methyl-butyl] carbamate, (6.1 g). 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.89 (d, J = 6.73 Hz, 3 H) 0.92 (d, J = 6.73 Hz, 3 H) 1.38 (s, 9 H) 1.70-1.81 (m, 1 H) 3.18 (d, J = 5.56 Hz, 2 H) 3.47 - 3.60 (m, 1 H) 4.76 (s , 1 H) 4.89 (d, J = 7.90 Hz, 1 H) 5.07 (s, 2 H) 7.25 - 7.36 (m, 5 H). LCMS (ESI) 337 (M + H).
[00195] Intermediate B: tert-butyl N- [2- (benzyloxycarbonylamino) -4-methyl-pentyl] carbamate

[00196] To a solution of benzyl N- [1 - (hydroxymethyl) -3-methyl-butyl] carbamate (6.3 g) (0.025 mol) in DCM (100 ml) was added 5.25 ml diisopropylethyl amine ( 1.2 eq) followed by the addition of methane sulfonylchloride (2.13 ml) (1.1 eq) at 0 degrees. After stirring for 3 h, water (100 ml) was added and the organic layer separated. After drying with magnesium sulfate and concentration under vacuum, the crude [2- (benzyloxycarbonylamino) -4-methylpentyl] methanesulfonate which was taken directly to the next step.
[00197] To the crude [2- (benzyloxycarbonylamino) -4-methylpentyl] methanesulfonate from the above reaction in DMF (50 ml), sodium azide (2.43 g) was added. The reaction mixture was then heated to 85 degrees for 3 h. After cooling, ethyl acetate (300 mL) and water were added. The organic layer was separated, dried with magnesium sulfate and then concentrated in vacuo to provide the crude benzyl N- [1- (azidomethyl) -3-methyl-butyl] carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine (7.21 g) and stirred under nitrogen for 16 h. After adding water (10 mL), and stirring for an additional 6 h, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columnar using DCM / MeOH (0 - 10%) to provide benzyl N- [1- (aminomethyl) -3-methyl-butyl] carbamate (4,5 g).
[00198] To N- [1- (aminomethyl) -3-methyl-butyl] benzyl carbamate (4.5 g) (0.018 mol) in THF (60 ml) was added 2N NaOH (18 ml) followed by addition of di-tert-butyl dicarbonate (4.19 g) (1.07 eq). After stirring for 16 h, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentrating under vacuum, the crude product was taken to the next step. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.89 (d, J = 6.73 Hz, 6 H) 1.25 - 1.34 (m, 1 H) 1.39 (s, 9 H) 1.57 -1.71 (m, 2 H) 3.04 - 3.26 (m, 2 H) 3.68 - 3.80 (m, 1 H) 4.72 - 4.89 (m, 2 H) 5.06 (s, 2 H) 7.25 - 7.38 (m, 5 H). LCMS (ESI) 351 (M + H).
[00199] Intermediate C: N - [(2R) -2- (benzyloxycarbonylamino) -3-methyl-butyl] tert-butyl carbamate

[00200] Intermediate C was synthesized from N - [(1R) -1- (hydroxymethyl) -2-methyl-propyl] benzyl carbamate using similar synthetic steps as those described for intermediate B. The analytical data (mass spectrometry and NMR) were consistent with that for intermediate A.
[00201] Intermediate D: - N - [(2S) -2- (benzyloxycarbonylamino) -3-methyl-butyl] tert-butyl carbamate

[00202] Intermediate D was synthesized from N - [(1S) -1- (hydroxymethyl) -2-methyl-propyl] benzyl carbamate using similar synthetic steps as those described for intermediate B. The analytical data (mass spectrometry and NMR) were consistent with that for intermediate A.
[00203] Intermediate E: N - [(1S) -1- (aminomethyl) -2-methyl-propyl] tert-butyl carbamate

[00204] To a solution of N - [(1S) -1- (hydroxymethyl) -2-methyl-propyl] tert-butyl carbamate (6.3 g) (0.025 mol) in THF (100 mL) diisopropylethyl amine (5.25 ml) (1.2 eq) is added followed by the addition of methane sulfonyl chloride (2.13 ml) (1.1 eq) at 0 degrees. After stirring for 3 h, water (100 ml) was added and the organic layer separated. After drying with magnesium sulfate and concentration under vacuum, the crude [(2S) -2- (tert-butoxycarbonylamino) -3-methyl-butyl] methanesulfonate which was taken directly to the next step.
[00205] Crude [(2S) -2- (tert-butoxycarbonylamino) -3-methyl-butyl] methanesulfonate, the above reaction in DMSO (50 ml), sodium azide (2.43 g) was added. The reaction mixture was then heated to 85 degrees for 3 h. After cooling, ethyl acetate (300 mL) and water were added. The organic layer was separated, dried with magnesium sulfate and then concentrated in vacuo to provide the crude benzyl N- [1- (azidomethyl) -3-methyl-butyl] carbamate. To this crude intermediate was added THF (100 mL) followed by triphenylphosphine (7.21 g) and stirred under nitrogen for 16 h. After adding water (10 mL), and stirring for an additional 6 h, ethyl acetate was added and the layers separated. After drying with magnesium sulfate and concentration under vacuum, the crude product was columnar using DCM / MeOH (0 - 10%) to provide benzyl N- [1- (aminomethyl) -3-methyl-butyl] carbamate (4,5 g). LCMS (ESI) 203 (M + H).
[00206] Intermediate F: N - [(1 R) -1- (aminomethyl) -2-methyl-propyl] tert-butyl carbamate

[00207] Intermediate F was synthesized from N - [(1R) -1- (hydroxymethyl) -2-methyl-propyl] tert-butyl carbamate using a similar synthetic sequence as described for intermediate E. The analytical data (spectrometry of mass and NMR) were consistent with intermediate E.
[00208] Intermediate G: N - [(2S) -2- (benzyloxycarbonylamino) -4-methyl-pentyl] tert-butyl carbamate

[00209] Intermediate G was synthesized from N - [(1S) -1- (hydroxymethyl) -3-methyl-butyl] benzyl carbamate using a similar synthetic sequence as described for intermediate B. The analytical data (mass spectrometry and NMR) were consistent with intermediate B.
[00210] Intermediate H: N - [(2S) -2- (benzyloxycarbonylamino) -2-phenyl-ethyl] tert-butyl carbamate

[00211] Intermediate H was synthesized from benzyl N - [(1 S) -2-hydroxy-1-phenyl-ethyl] carbamate using a similar synthetic sequence as described for intermediate B. 1H NMR (600 MHz, DMSO-de ) δ ppm 1.20 - 1.33 (m, 9 H) 3.11 (t, J = 6.29 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 4.88 - 5 , 01 (m, 2 H) 6.81 (t, J = 5.42 Hz, 1 H) 7.14 - 7.35 (m, 10 H) 7.69 (d, J = 8.49 Hz, 1 H). LCMS (ESI) 371 (M + H).
[00212] Intermediate I: N - [(2S) -2- (benzyloxycarbonylamino) -3-methyl-pentyl] tert-butyl carbamate

[00213] Intermediate I was synthesized from N - [(1S) -1- (hydroxymethyl) -2-methyl-butyl] benzyl carbamate using a similar synthetic sequence as described for intermediate B. 1H NMR (600 MHz, CHLOROPHORM) d) δ ppm 0.85 - 0.92 (m, 6 H) 1.05 -1.15 (m, 1 H) 1.35 - 1.41 (m, 9 H) 1.45 - 1.56 (m, 2 H) 3.14 - 3.24 (m, 2 H) 3.54 - 3.64 (m, 1 H) 4.78 (s, 1 H) 4.96 (d, J = 7 , 91 Hz, 1 H) 5.06 (s, 2 H) 7.27 - 7.37 (m, 5 H). LCMS (ESI) 351 (M + H).
[00214] Intermediate J: N - [(2S) -2- (benzyloxycarbonylamino) -3,3-dimethyl-butyl] tert-butyl carbamate

[00215] Intermediate J was synthesized from N - [(1 S) -1 - (hydroxymethyl) -2,2-dimethyl-propyl] benzyl carbamate using a similar synthetic sequence as described for intermediate B. LCMS (ESI) 351 .
[00216] Intermediate K: N - [[1- (benzyloxycarbonylamino) cyclohexyl] methyl] tert-butyl carbamate

[00217] To a solution of benzyl N- [1- (aminomethyl) cyclohexyl] carbamate 10.0 g (0.0381 mol) in THF (150 mL) was added di-tert-butyl dicarbonate (9, 15 g, 1.1 eq) and the contents stirred at room temperature for 16 h. Ethyl acetate and water were then added. The organic layer was separated, dried over magnesium sulfate and then concentrated in vacuo to provide tert-butyl N - [[1 - (benzyloxycarbonylamino) cyclohexyl] methyl] carbamate (13.1 g). 1H NMR (600 MHz, DMSO-d6) δ ppm 0.92-1.54 (m, 17H) 1.76 - 2.06 (m, 2 H) 3.09 (d, J = 6.15 Hz, 2 H) 4.92 (s, 2 H) 6.63 (d, J = 17.27 Hz, 1 H) 7.16 - 7.49 (m, 6 H). LCMS (ESI) 363 (M + H).
[00218] Intermediate L: N - [[1- (benzyloxycarbonylamino) cyclopentyl] methyl] tert-butyl carbamate

[00219] N - [[1- (Benzyloxycarbonylamino) cyclopentyl] methyl] tert-butyl carbamate was synthesized in a manner analogous to N - [[1- (benzyloxycarbonylamino) cyclohexyl] methyl] tert-butyl carbamate . LCMS (ESI) 349 (M + H). Example 3 - Synthesis of substituted 2-aminopyridines

[00220] To 5-bromo-2-nitropyridine (1.2 g, 5.9 mmol) in DMSO (4 mL) were added 1- (4-piperidyl) piperidine (1.0 g, 5.9 mmol) and triethyl amine (0.99 ml, 7.1 mmol). The contents were heated to 120 degrees in a CEM Discovery microwave system for 3 hours. The crude reaction was then loaded onto a silica gel column and eluted with DCM / methanol (0 - 20%) to provide 2-nitro-5- [4- (1-piperidyl) -1-piperidyl] pyridine as a oil (457 mg). 1H NMR (600 MHz, DMSO-dθ) δ ppm 1.26 - 1.36 (m, 2 H) 1.43 (m, 6 H) 1.76 (m, 2 H) 2.37 (m, 5 H) 2.94 (t, J = 12.74 Hz, 2 H) 4.06 (d, J = 13.47 Hz, 2 H) 7.41 (dd, J = 9.37, 2.64 Hz , 1 H) 8.08 (d, J = 9.37 Hz, 1 H) 8.20 (d, J = 2.64 Hz, 1 H).
[00221] 5- [4- (1-Piperidyl) -1-piperidyl] pyridin-2-amine

[00222] 5- [4- (1-Piperidyl) -1-piperidyl] pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine . 1H NMR (600 MHz, DMSO-de) δ ppm 1.13 - 1.37 (m, 6 H) 1.40 - 1.63 (m, 6 H) 1.71 (m, 2 H), 2, 24 (m, 1H) 2.43 (m, 2 H) 3.33 (d, J = 12.30 Hz, 2 H) 5.31 (s, 2 H) 6.33 (d, J = 8, 78 Hz, 1 H) 7.10 (dd, J = 8.78, 2.93 Hz, 1 H) 7.55 (d, J = 2.64 Hz, 1 H). LCMS (ESI) 261 (M + H).
[00223] 4- [1 - (6-N itro-3-pyridyl) -4-pi peridyl] morpholine

[00224] 4- [1- (6-Nitro-3-pyridyl) -4-piperidyl] morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1- piperidyl) -1 -piperidyl] pyridine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.41 (m, 2 H) 1.82 (m, 2 H) 2.42 (m, 5 H) 2.98 (t, J = 12.44 Hz, 2 H) 3.52 (s, 4 H) 4.04 (d, J = 12.88 Hz, 2 H) 7.42 (d, J = 9.37 Hz, 1 H) 8.08 ( d, J = 9.08 Hz, 1 H) 8.21 (s, 1 H).
[00225] 5- (4-Morpholino-1-piperidyl) pyridin-2-amine

[00226] 5- (4-Morpholino-1-piperidyl) pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.34 - 1.52 (m, 2 H) 1.78 (m, 2 H) 2.14 (m, 1 H) 2.43 (m, 4 H) 3.32 (d, J = 12.30 Hz, 4 H) 3.47 - 3.59 (m, 4 H) 5.32 (s, 2 H) 6.34 (d, J = 8, 78 Hz, 1 H) 7.11 (dd, J = 8.93, 2.78 Hz, 1 H) 7.47 - 7.62 (m, 1 H). LCMS (ESI) 263 (M + H).
[00227] 4- [1 - (6-N itro-3-pyridyl) -4-pi peridyl] thiomorphine

[00228] 4- [1- (6-Nitro-3-pyridyl) -4-piperidyl] thiomorpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1- piperidyl) -1 -piperidyl] pyridine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.40 - 1.52 (m, 2 H) 1.71 (m, 2 H) 2.49 - 2.55 (m, 4 H) 2.56 - 2.63 (m, 1 H) 2.68 - 2.75 (m, 4 H) 2.88 - 2.98 (m, 2 H) 4.09 (d, J = 13.18 Hz, 2 H) 7.42 (dd, J = 9.22, 3.07 Hz, 1 H) 8.08 (d, J = 9.37 Hz, 1 H) 8.20 (d, J = 3.22 Hz , 1 H).
[00229] 5- (4-Thiomorpholino-1-pi perid i I) pyrid in-2-amine

[00230] 5- (4-Thiomorpholino-1-piperidyl) pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-dβ) δ ppm 1.47 - 1.59 (m, 2 H) 1.65 (m, 2 H) 2.22 - 2.38 (m, 1 H) 2.50 - 2.59 (m, 6 H) 2.68 - 2.82 (m, 4 H) 3.33 (d, J = 12.00 Hz, 2 H) 5.31 (s, 2 H) 6, 33 (d, J = 9.08 Hz, 1 H) 7.10 (dd, J = 8.78, 2.93 Hz, 1 H) 7.55 (d, J = 2.64 Hz, 1 H) . LCMS (ESI) 279 (M + H).
[00231] 2-Nitro-5- (1-pi perid i I) pyridine

[00232] 2-Nitro-5- (1-piperidyl) pyridine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl) -1 - piperidyl] pyridine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.56 (m, 6 H) 3.49 (d, J = 4.39 Hz, 4 H) 7.30 - 7.47 (m, 1 H) 8.02 - 8.12 (m, 1 H) 8.15 -8.26 (m, 1 H).
[00233] 5- (1 -P i perid i I) pyrid in-2-amine

[00234] 5- (1-Piperidyl) pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.39 - 1.46 (m, 2 H) 1.51 - 1.62 (m, 4 H) 2.75 - 2.92 (m, 4 H ) 5.30 (s, 2 H) 6.34 (d, J = 8.78 Hz, 1 H) 7.09 (dd, J = 8.78, 2.93 Hz, 1 H) 7.54 ( d, J = 2.93 Hz, 1 H). LCMS (ESI) 178 (M + H).
[00235] 4- (6-Nitro-3-pyridyl) thiomorpholine

[00236] 4- (6-Nitro-3-pyridyl) thiomorpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl) -1 - piperidyl] pyridine. 1H NMR (600 MHz, DMSO-de) δ ppm 2.56 - 2.69 (m, 4 H) 3.79 - 3.92 (m, 4 H) 7.43 (dd, J = 9.22, 3.07 Hz, 1 H) 8.10 (d, J = 9.37 Hz, 1 H) 8.20 (d, J = 2.93 Hz, 1 H).
[00237] 5-Tiomorfolinopyridin-2-amine

[00238] 5-Tiomorfolinopyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-de) δ ppm 2.59 - 2.73 (m, 4 H) 3.04 - 3.20 (m, 4 H) 5.41 (s, 2 H) 6.35 (d, J = 8.78 Hz, 1 H) 7.10 (dd, J = 8.78, 2.93 Hz, 1 H) 7.57 (d, J = 2.64 Hz, 1 H). LCMS (ESI) 196 (M + H).
[00239] (4R) -5- (6-Nitro-3-pyridyl) -2,5-diazabicyclo [2,2,1] heptane-2-tert-butyl carboxylate

[00240] (4R) -5- (6-Nitro-3-pyridyl) -2,5-diazabicyclo [2,2,1] heptane-2-tert-butyl carboxylate was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl) -1-piperidyl] pyridine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.33 (d, J = 32.21 Hz, 11 H) 1.91 (m, 2 H) 3.15 (d, J = 10.25 Hz, 1 H) 3.58 (m, 1 H) 4.46 (m, 1 H) 4.83 (s, 1 H) 7.16 (s, 1 H) 7.94 (s, 1 H) 8, 05 - 8.16 (m, 1 H).
[00241] (4R) -5- (6-Amino-3-pyridyl) -2,5-diazabicyclo [2,2,1] tert-butyl heptane-2-carboxylate

[00242] (4R) -5- (6-Amino-3-pyridyl) -2,5-diazabicyclo [2,2,1] heptane-2-tert-butyl carboxylate was prepared in a manner similar to that used in the synthesis 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.31 (d, J = 31.91 Hz, 11 H) 1.83 (m, 2 H) 2.71 - 2.82 (m, 1 H) 3.44 (m, 1 H) 4.30 (d, 2H) 5.08 (s, 2 H) 6.35 (d, J = 8.78 Hz, 1 H) 6.77 - 6.91 ( m, 1 H) 7.33 (s, 1 H). LCMS (ESI) 291 (M + H).
[00243] N, N-Dimethyl-1- (6-nitro-3-pyridyl) piperidin-4-amine

[00244] N, N-Dimethyl-1- (6-nitro-3-pyridyl) piperidin-4-amine was synthesized in a manner similar to that used in the synthesis of 2-nitro- 5- [4- (1-piperidyl) -1 -piperidyl] pyridine. 1H NMR (600 MHz, DMSO-dθ) δ ppm 1.30 - 1.45 (m, 2 H) 1.79 (m, 2 H) 2.14 (s, 6 H) 2.33 (m, 1 H) 2.92 - 3.04 (m, 2 H) 4.03 (d, J = 13.76 Hz, 2 H) 7.42 (dd, J = 9.22, 3.07 Hz, 1 H ) 8.04 - 8.11 (m, 1 H) 8.21 (d, J = 2.93 Hz, 1 H).
[00245] 5- [4- (Dimethylamino) -1-pi perid i I] pyrid in-2-amine

[00246] 5- [4- (Dimethylamino) -1-piperidyl] pyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.35-1.50 (m, 2 H) 1.69 - 1.81 (m, 2 H) 2.00 - 2.10 (m, 1 H ) 2.11 - 2.22 (s, 6 H) 3.17 - 3.36 (m, 4 H) 5.19 - 5.38 (s, 2 H) 6.34 (d, J = 8, 78 Hz, 1 H) 7.10 (dd, J = 8.78, 2.93 Hz, 1 H) 7.55 (d, J = 2.63 Hz, 1 H). LCMS (ESI) 221 (M + H).
[00247] 4- (6-Nitro-3-pyridyl) morpholine

[00248] 4- (6-Nitro-3-pyridyl) morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl) -1- piperidyl] pyridine.
[00249] 5-Morpholinopyridin-2-amine

[00250] 5-Morpholinopyridin-2-amine was prepared in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 2.91 - 3.00 (m, 4 H) 3.76 - 3.84 (m, 4 H) 4.19 (br. S., 2 H) 6.45 (d, J = 8.78 Hz, 1 H) 7.12 (dd, J = 8.78, 2.93 Hz, 1 H) 7.72 (d, J = 2.93 Hz, 1 H).
[00251] 5- (4-lsobutylpiperazin-1-i) pyrid in-2-amine

[00252] 1 -1 sobuti l-4- (6-n itro-3-pyridine) pi perazin was synthesized in a similar manner to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl ) -1 - piperidyl] pyridine which was then converted to 5- (4-isobutylpiperazin-1-yl) pyridin-2-amine in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridine -2-amine. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.88 (d, J = 6.73 Hz, 6 H) 1.71 - 1.84 (m, 1 H) 2.10 (d, J = 7 , 32 Hz, 2 H) 2.46 - 2.58 (m, 4 H) 2.97 - 3.07 (m, 4 H) 4.12 (s, 2 H) 6.45 (d, J = 8.78 Hz, 1 H) 7.14 (dd, J = 8.78, 2.93 Hz, 1 H) 7.75 (d, J = 2.93 Hz, 1 H). LCMS (ESI) 235 (M + H).
[00253] 5- (4-lsopropylpiperazin-1-i) pyridin-2-amine

[00254] 1-lsopropyl-4- (6-nitro-3-pyridyl) piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro-5- [4- (1-piperidyl) -1-piperidyl] pyridine which was then converted to 5- (4-isopropylpiperazin-1-yl) pyridin-2-amine in a manner similar to that used in the synthesis of 5- (4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 1.06 (d, J = 6.44 Hz, 6 H) 2.59 - 2.75 (m, 5 H) 2.97 - 3.10 (m , 4 H) 4.13 (s, 2 H) 6.45 (d, J = 8.78 Hz, 1 H) 7.15 (dd, J = 9.08, 2.93 Hz, 1 H) 7 , 76 (d, J = 2.93 Hz, 1 H). LCMS (ESI) 221 (M + H).
[00255] 5 - [(2R, 6S) -2,6-Dimethylmorpholin-4-yl] pyridin-2-amine

[00256] (2S, 6R) -2,6-Dimethyl-4- (6-nitro-3-pyridyl) morpholine was synthesized in a manner similar to that used in the synthesis of 2-nitro- 5- [4- (1 - piperidyl) -1-piperidyl] pyridine which was then converted to 5 - [(2R, 6S) -2,6-dimethylmorpholin-4-yl] pyridin-2-amine in a manner similar to that used in the synthesis of 5- ( 4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 1.20 (d, J = 6.44 Hz, 6 H) 2.27 - 2.39 (m, 2 H) 3.11 - 3.21 (m , 2 H) 3.70 - 3.84 (m, 2 H) 4.15 (s, 2 H) 6.45 (d, J = 8.78 Hz, 1 H) 7.12 (dd, J = 8.78, 2.93 Hz, 1 H) 7.72 (d, J = 2.63 Hz, 1 H). LCMS (ESI) 208 (M + H).
[00257] 5 - [(3R, 5S) -3,5-Dimethylpiperazin-1-i] pyridin-2-amine

[00258] (3S, 5R) -3,5-Dimethyl-1- (6-nitro-3-pyridyl) piperazine was synthesized in a manner similar to that used in the synthesis of 2-nitro- 5- [4- (1- piperidyl) -1-piperidyl] pyridine which was then converted to 5 - [(3R, 5S) -3,5-dimethylpiperazin-1-yl] pyridin-2-amine in a manner similar to that used in the synthesis of 5- ( 4-methylpiperazin-1-yl) pyridin-2-amine. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 1.09 (d, J = 6.44 Hz, 6 H) 2.20 (t, J = 10.83 Hz, 2 H) 2.95 - 3, 08 (m, 2 H) 3.23 (dd, J = 11.71, 2.05 Hz, 2 H) 4.13 (s, 2 H) 6.45 (d, J = 8.78 Hz, 1 H) 7.14 (dd, J = 8.78, 2.93 Hz, 1 H) 7.73 (d, J = 2.63 Hz, 1 H). LCMS (ESI) 207 (M + H). Intermediate 1A:
Tert-butyl N- [2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) aminol-3-methyl-butylcarbamate

[00259] The solution of intermediate A in ethanol (100 mL) was hydrogenated under 2.10 kg / cm2 (30 psi) of hydrogen using 10% Pd / C (0.7 g) in a pressure pump for 7 h . After filtering the reaction mixture through CELITE ™, the organic layer was concentrated in vacuo to provide tert-butyl N- (2-amino-3-methyl-butyl) carbamate (3.8 g).
[00260] To a solution of 5-bromo-2,4-dichloro-pyrimidine (7.11 g) (0.0312 mol) in ethanol (100 ml) was added diisopropylethyl amine (5.45 ml) (1.0 eq) and tert-butyl N- (2-amino-3-methyl-butyl) carbamate (6.31 g) (0.0312 mol). The reaction mixture was stirred at room temperature for 20 h. After concentration in vacuo, ethyl acetate and water were added. The organic layer was separated, dried with magnesium sulfate and then concentrated in vacuo. The crude product was purified by column chromatography using hexane / ethyl acetate (0 - 30%) on silica gel to provide N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] tert-butyl carbamate. 1H NMR (600 MHz, DMSO-de) δ ppm 0.77 - 0.85 (d, J = 6.5 Hz, 3 H) 0.87 (d, J = 6.73 Hz, 3 H) 1, 31 - 1.39 (m, 9 H) 1.82 - 1.93 (m, 1 H) 2.94 (d, J = 5.56 Hz, 1 H) 3.08 - 3.22 (m, 2 H) 3.98 (d, J = 8.20 Hz, 1 H) 6.96 (d, J = 8.78 Hz, 1 H) 8.21 (s, 1 H). LCMS (ESI) 393 (M + H). Tert-butyl N- [2- [2-Chloro-6- (dietoxymethyl) pyrrolo [2,3-dlpyrimidin-7-ill-3-methyl-butylcarbamate

[00261] N- [2- [2-Chloro-6- (dietoxymethyl) pyrrolo [2,3-d] pyrimidin-7-yl] -3-methyl-butyl] carbamate was synthesized by subjecting N- [ 2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] tert-butyl carbamate to Sonogoshira conditions as described for N- [2 - [[2-chloro-5 - tert-Butyl (3,3-dietoxyprop-1 -inyl) pyrimidin-4-yl] amino] ethyl] carbamate followed by subsequent treatment with TBAF as described in the synthesis of N- [2- [2-chloro-6- (dietoxymethyl) pyrrolo [2,3-d] pyrimidin-7-yl] ethyl] tert-butyl carbamate. 1H NMR (600 MHz, DMSO-de) δ ppm 1.11 (d, J = 6.44 Hz, 3 H) 1.18 (t, J = 7.03 Hz, 6 H) 1.21 -1, 26 (m, 12 H) 2.88 (br. S, 1 H) 3.43 - 3.78 (m, 6 H) 3.97 - 4.08 (m, 1 H) 5.61 (s , 1 H) 6.65 (s, 1 H) 6.71 - 6.78 (m, 1 H) 8.87 (s, 1 H). LCMS (ESI) 441 (M + H). 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propill-2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00262] To the solution N- [2 - [[2-chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] ethyl] tert-butyl carbamate in THF was added TBAF and the contents refluxed for 3 h. Ethyl acetate and water were then added and the organic layer separated, dried over magnesium sulfate and then concentrated in vacuo. To this crude reaction was added acetic acid / water (9: 1) and then the contents stirred for 12 h at room temperature. After concentration in vacuo, NaHCCh sat. and ethyl acetate were then added. The organic layer was separated, dried and then concentrated in vacuo. The crude reaction product thus obtained was dissolved in DMF, oxon was then added and the contents stirred for 3 h. After adding ethyl acetate, the reaction mixture was filtered through CELITE ™ and concentrated in vacuo. Column chromatography of the crude product over silica gel using hexane / ethyl acetate (0 - 100%) provided 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrole acid [2,3-d] pyrimidine-6-carboxylic. 1H NMR (600 MHz, DMSO-de) δ ppm 0.85 (d, J = 7.03 Hz, 3 H) 0.97 (d, J = 6.73 Hz, 3 H) 1.52 (s, 9 H) 1.99 - 2.23 (m, 1 H) 3.98 (dd, J = 14.05, 3.51 Hz, 1 H) 4.47 - 4.71 (m, 2 H) 7 , 47 (s, 1 H) 9.17 (s, 1 H). LCMS (ESI) 383 (M + H). Intermediate 1A
[00263] 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid (0.050 g) (0, 00013 mol) in DCM (1.5 ml) DIC (32.7 mg) and DMAP (10 mg) were added. The contents were stirred for 2 h. Trifluoroacetic acid (0.4 ml) was then added and stirring continued for an additional 30 minutes. After adding NaHCO3 satd to neutralize the excess acid, ethyl acetate was then added and the organic layer separated, dried using magnesium sulfate and then concentrated in vacuo. The crude product was column chromatographed on silica gel using hexane / ethyl acetate (0 - 100%) to provide Intermediate 1A. 1H NMR (600 MHz, DMSO-de) δ ppm 0.72 (d, J = 6.73 Hz, 3 H) 0.97 (d, J = 6.73 Hz, 3 H) 2.09 - 2, 22 (m, 1 H) 3.57 (dd, J = 13.18, 4.98 Hz, 1 H) 3.72 (dd, J = 13.61.4.25 Hz, 1 H) 4.53 (dd, J = 8.05, 3.95 Hz, 1 H) 7.20 (s, 1 H) 8.34 (d, J = 4.98 Hz, 1 H) 9.08 (s, 1 H ). LCMS (ESI) 265 (M + H). Intermediate 1B:

[00264] Intermediate C was hydrogenated with 10% Pd / C to provide tert-butyl N - [(2R) -2-amino-3-methyl-butyl] carbamate, which was then treated with 5-bromine -2,4-dichloro-pyrimidine using analogous reaction conditions as described for intermediate 1A to provide intermediate 1B. The analytical data are consistent with that reported for the racemate (Intermediate 1A). Intermediate 1C:
D was hydrogenated with 10% Pd / C to
[00265] Intermediate provide tert-butyl N - [(2S) -2-amino-3-methyl-butyl] carbamate, which was then treated with 5-bromo-2,4-dichloro-pyrimidine using conditions analogous reactions as described for intermediate 1A to provide intermediate 1C. The analytical data (NMR and LCMS) were consistent with that reported for the racemate (intermediate 1A). Intermediate 1CA:

[00266] To a solution of Intermediate 1A (80 mg, 0.00030 mol) in DMF (3 ml) was added a 60% dispersion of sodium hydride in oil (40 mg). After stirring for 15 minutes, methyl iodide (37 pL, 2 eq) was added. The contents were stirred at room temperature for 30 minutes. NaHCO3 satd was then added followed by ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated in vacuo to provide intermediate 1AA. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.74 (d, J = 6.73 Hz, 3 H) 0.91 (d, J = 6.73 Hz, 3 H) 2.04 - 2, 20 (m, 1 H) 3.04 (s, 3 H) 3.69 (dd, J = 13.76, 1.17 Hz, 1 H) 3.96 (dd, J = 13.76, 4, 68 Hz, 1 H) 4.58 (dd, J = 7.32, 3.51 Hz, 1 H) 7.16 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H). Intermediate 1D

Tert-butyl N - [(2S) -2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -4-methyl-pentylcarbamate
[00267] Intermediate G was hydrogenated with 10% Pd / C in ethanol under a hydrogen blanket at 3.51 kg / cm2 (50 psi) in a pressure pump to provide N - [(2S) -2-amino- Tert-butyl 4-methyl-pentyl] carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using similar reaction conditions as described for N- [2 - [(5-bromo-2-chloro -pyrimidin-4-yl) amino] -3-methyl-butyl] tert-butyl carbamate to provide N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -4-tert-butyl methyl pentyl] carbamate. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.91 (d, J = 6.44 Hz, 3 H) 0.94 (d, J = 6.44 Hz, 3 H) 1.32 - 1, 51 (m, 11 H) 1.55 - 1.67 (m, 1 H) 3.28 (t, J = 5.86 Hz, 2 H) 4.21 - 4.42 (m, 1 H) 4 , 84 (s, 1 H) 5.84 (d, J = 7.32 Hz, 1 H) 8.07 (s, 1 H). LCMS (ESI) 407 (M + H). OEt

[00268] To a solution of tert-butyl N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -4-methyl-pentyl] carbamate (5.0 g) (12.3 mmol) in toluene (36 mL) and triethyl amine (7.2 mL) were added under nitrogen, 3,3-diethoxyprop-1-ino (2.8 mL) (19.7 mmol), Pd2 (dba) 3 (1.1 g) (1.23 mmol), and triphenylarsine (3.8 g) (12.3 mmol). The contents were heated to 70 degrees for 24 h. After cooling to room temperature, the reaction mixture was filtered through CELITE ™ and then concentrated in vacuo. The crude product was columnated on silica gel using hexane / ethyl acetate (0 - 30%) to provide (2S) -N2- [2-chloro-5- (3,3-diethoxyprop-1-yl) pyrimidin-4 -yl] -4-methyl-pentane-1,2-diamine. LCMS (ESI) 455 (M + H).

[00269] 7 - [(1S) -1 - [(tert-butoxycarbonylamino) methyl] -3-methyl-butyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using sequence analogous synthetic as those described for 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-de) δ ppm 0.88 (d, J = 6.44 Hz, 3 H) 0.97 (d, J = 6.44 Hz, 3 H) 1.47 (s, 9 H) 1.49 - 1.54 (m, 1 H) 1.56 (t, J = 7.17 Hz, 2 H) 3.98 (dd, J = 13.91, 3.07 Hz, 1 H) 3.76 (dd, J = 13.31.4.13 Hz, 1 H) 4.38 (d, J = 14.05 Hz, 1 H) 4.90 (t, J = 7.17 Hz , 1 H) 7.41 (s, 1 H) 9.11 (s, 1 H). LCMS (M + H) 397.
[00270] Intermediate 1D was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.82 (d, J = 6.73 Hz, 3 H) 0.97 (d, J = 6.44 Hz, 3 H) 1.34 - 1, 46 (m, 1 H) 1.48 - 1.65 (m, 2 H) 3.40 (dd, J = 13.32, 5.42 Hz, 1 H) 3.76 (dd, J = 13, 47, 4.10 Hz, 1 H) 4.76 - 4.92 (m, 1 H) 7.17 (s, 1 H) 8.34 (d, J = 5.27 Hz, 1 H) 9, 04 (s, 1 H). LCMS (ESI) 279 (M + H). Intermediate 1DA:

[00271] Intermediate 1DA was synthesized in a similar way to that described for 1CA. 1H NMR (600 MHz, DMSO-de) δ ppm 0.82 (d, J = 6.44 Hz, 3 H) 0.97 (d, J = 6.44 Hz, 3 H) 1.37 - 1, 68 (m, 3 H) 3.04 (s, 3 H) 3.56 (d, J = 13.47 Hz, 1 H) 4.00 (dd, J = 13.32, 4.25 Hz, 1 H) 4.82 - 4.94 (m, 1 H) 7.16 (s, 1 H) 9.03 (s, 1 H). LCMS (ESI) 293 (M + H) Intermediate 1E: N - [(2S) -2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-pentylcarbamate of tert-butyl


[00272] Intermediate I was hydrogenated using 10% Pd / C under 3.51 kg / cm2 (50 psi) hydrogen in a pressure vessel to provide N - [(2S) -2-amino-3-methyl-pentyl ] tert-butyl carbamate which was reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] tert-butyl carbamate to provide N - [(2S) -2- [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-pentyl] tert-butyl carbamate. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.88 - 0.95 (m, 6 H) 1.11 - 1.20 (m, 1 H) 1.34 (s, 9 H) 1.44 - 1.54 (m, 1 H) 1.64 - 1.72 (m, 1 H) 3.17 - 3.27 (m, 1 H) 3.33 - 3.43 (m, 1 H) 4 , 11 - 4.21 (m, 1 H) 4.81 (s, 1 H) 5.92 (d, J = 8.20 Hz, 1 H) 8.05 (s, 1 H). LCMS (ESI) 407. N - [(2S) -2 - [[2-Chloro-5- (3,3-diethoxyprop-1-inyl) pyrimidin-4-illaminol-3-methyl-pentylcarbamate of tert-butyl

[00273] N - [(2S) -2 - [[2-Chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4-yl] amino] -3-methyl-pentyl] tert-carbamate butyl was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4-yl] -4-methyl-pentane-1 , 2- diamine. 1H NMR (600 MHz, DMSO-de) δ ppm 0.76 - 0.89 (m, 6 H) 1.03 (q, J = 7.22 Hz, 3 H) 1.10 - 1.17 (m , 3 H) 1.25 - 1.42 (m, 11 H) 1.59 - 1.73 (m, 1 H) 3.35 - 3.47 (m, 4 H) 3.51 - 3.73 (m, 2 H) 3.99 - 4.11 (m, 1 H) 5.52 - 5.56 (m, 1 H) 6.76 - 7.03 (m, 2 H) 8.12 - 8 , 23 (m, 1 H). LCMS (ESI) 455 (M + H). 7 - [(1 S) -1 -i (tert-butoxycarbonylamino) methyl1-2-methyl-butyl1-2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00274] 7 - [(1S) -1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-butyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using sequence analogous synthetic as those described for 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-de) δ ppm 0.80 (t, J = 7.47 Hz, 3 H) 0.86 (d, J = 7.03 Hz, 3 H) 1.06 - 1, 30 (m, 2 H) 1.48 (s, 9 H) 1.79 - 1.96 (m, 1 H) 3.95 (dd, J = 14.05, 3.22 Hz, 1 H) 4 , 52 (d, J = 14.35 Hz, 1 H) 4.61 - 4.73 (m, 1 H) 7.43 (s, 1 H) 9.13 (s, 1 H). LCMS (ESI) 397 (M + H).
[00275] Intermediate 1E was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.74 (t, J = 7.32 Hz, 3 H) 0.89 (d, J = 6.73 Hz, 3 H) 1.00 - 1, 12 (m, 2 H) 1.82 - 1.94 (m, 1 H) 3.55 (dd, J = 13.91.4.83 Hz, 1 H) 3.70 (dd, J = 13, 61.4.25 Hz, 1 H) 4.57 (dd, J = 7.91, 4.10 Hz, 1 H) 7.17 (s, 1 H) 8.31 (d, J = 5.27 Hz, 1 H) 9.05 (s, 1 H). LCMS (ESI) 279 (M + H). Intermediate 1EA:

[00276] Intermediate 1 EA was synthesized in a similar way to Intermediate 1CA. 1H NMR (600 MHz, DMSO-de) δ ppm 0.77 (t, J = 7.47 Hz, 3 H) 0.84 (d, J = 6.73 Hz, 3 H) 1.07 - 1, 16 (m, 2 H) 1.82 - 1.95 (m, 1 H) 3.03 (s, 3 H) 3.68 (d, J = 13.76 Hz, 1 H) 3.96 (dd , J = 13.76, 4.39 Hz, 1 H) 4.59 - 4.70 (m, 1 H) 7.16 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 293 (M + H). Intermediate 1F
Tert-butyl N - [(2S) -2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -3,3-dimethyl-butyl] carbamate

[00277] Intermediate J was hydrogenated using 10% Pd / C under 3.51 kg / cm2 (50 psi) hydrogen in a pressure vessel to provide N - [(2S) -2-amino-3,3-dimethyl -butyl] tert-butyl carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for N- [2 - [(5-bromine Tert-butyl -2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate to provide N - [(2S) -2- [(5-bromo-2-chloro-pyrimidin-4- il) tert-butyl amino] -3,3-dimethyl-butyl] carbamate. LCMS (ESI) 407 (M + H). Tert-butyl N - [(2S) -2 - [[2-Chloro-5- (313-diethoxyprop-1-ynyl) pyrimidin-4-yl] amino] -3l3-dimethyl-butylcarbamate

[00278] N - [(2S) -2 - [[2-Chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] -3,3-dimethyl-butyl] carbamate tert-butyl was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] -4-methyl-pentane -1,2-diamine. LCMS (ESI) 455 (M + H). 7 - [(1 S) -1-i (tert-butoxycarbonylamino) methyl1-2,2-dimethyl-propyl1-2-chloro-pyrrolo [2,3-dlpyrimidine-6-carboxylic acid

[00279] 7 - [(1S) -1 - [(tert-butoxycarbonylamino) methyl] -2,2-dimethyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using a similar synthetic sequence as those described for 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. LCMS (ESI) 397 (M + H).
[00280] Intermediate 1F was synthesized using a synthetic sequence analogous to those described for intermediate 1A. LCMS (ESI) 279 (M + H). Intermediate 1FA

[00281] Intermediate 1FA was synthesized in a similar way to that described for intermediate 1CA. LCMS (ESI) 293 (M + H). Intermediate 1G
Tert-butyl N - [(2S) -2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -2-phenyl-ethyl] carbamate

[00282] Intermediate J was hydrogenated using 10% Pd / C under 3.51 kg / cm2 (50 psi) hydrogen in a pressure vessel to provide N - [(2S) -2-amino-2-phenyl-ethyl ] tert-butyl carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described as described for N- [2 - [(5-bromo-2-chloro-pyrimidin- 4-yl) amino] -3-methyl-butyl] tert-butyl carbamate to provide N - [(2S) -2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -2- phenylethyl] tert-butyl carbamate. 1H NMR (600 MHz, DMSO-de) δ ppm 1.32 (s, 9 H) 3.29 - 3.50 (m, 2 H) 5.12 - 5.24 (m, 1 H) 7.10 (t, J = 5.27 Hz, 1 H) 7.21 (t, J = 6.88 Hz, 1 H) 7.26 - 7.34 (m, 4 H) 7.89 (d, J = 7.32 Hz, 1 H) 8.24 (s, 1 H). LCMS (ESI) 427 (M + H). Tert-butyl N - [(2S) -2 - [[2-Chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4-yl] amino] -2-phenylethylcarbamate

[00283] N - [(2S) -2 - [[2-Chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] -2-phenyl-ethyl] tert-carbamate butyl was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxyprop-1 -inyl) pyrimidin-4-yl] -4-methyl-pentane-1 , 2- diamine. 1H NMR (600 MHz, DMSO-de) δ ppm 1.14 (t, J = 7.03 Hz, 6 H) 1.32 (s, 9 H) 3.39 (s, 2 H) 3.52 - 3.61 (m, 2 H) 3.64 - 3.73 (m, 2 H) 5.17 - 5.26 (m, 1 H) 5.57 (s, 1 H) 7.07 - 7, 14 (m, 1 H) 7.20 - 7.25 (m, 1 H) 7.26 - 7.33 (m, 4 H) 7.90 (d, J = 7.61 Hz, 1 H) 8 , 19 (s, 1 H). LCMS (ESI) 475 (M + H). 7 - [(1 S) -2- (tert-butoxycarbonylamino) -1 -phenyl-ethyl-2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00284] 7 - [(1S) -2- (tert-butoxycarbonylamino) -1-phenyl-ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using analogous synthetic sequence as those described for 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. LCMS (ESI) 417 (M + H). Intermediate 1G
[00285] Intermediate 1G was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-d6) δ ppm 3.58 - 3.69 (m, 1 H) 4.13 (dd, J = 13.47, 4.39 Hz, 1 H) 6.07 (d , J = 3.81 Hz, 1 H) 6.85 (d, J = 7.32 Hz, 2 H) 7.19 - 7.31 (m, 3 H) 7.34 (s, 1 H) 8 , 27 (d, J = 5.27 Hz, 1 H) 9.13 (s, 1 H). LCMS (ESI) 299 (M + H). Intermediate 1H
Tert-Butyl N - [(1S) -1 - [[(5-Bromo-2-chloro-pyrimidin-4-yl) amino] methyl1-2-methyl-propyl] carbamate

[00286] N - [(1 S) -1 - [[((5-Bromo-2-chloro-pyrimidin-4-yl) amino] methyl] -2-methyl-propyl] tert-butyl carbamate was synthesized using 5 -bromo-2,4- dichloro-pyrimidine and Intermediate E using analogous reaction conditions as described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl ] tert-butyl carbamate. 1H NMR (600 MHz, CHLOROPHORUM-d) δ ppm 0.95 - 1.02 (m, 6 H) 1.35 - 1.45 (m, 9 H) 1.75 - 1.90 (m, 1 H ) 3.35 - 3.48 (m, 1 H) 3.52 - 3.61 (m, 1 H) 3.64 - 3.76 (m, 1 H) 4.56 (d, J = 8, 49 Hz, 1 H) 6.47 (s, 1 H) 8.07 (s, 1 H). LCMS (ESI) 393 (M + H). N - [(1S) -1 - [[[2-Chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] methyl] - tert-butyl 2-methyl-propylcarbamate

[00287] N - [(1 S) -1 - [[[2-Chloro-5- (3,3-diethoxyprop-1-in I) pyrim id i n-4-yl] amino] methyl] -2- methyl-propyl] tert-butyl carbamate was synthesized using experimental conditions similar to that used in the synthesis (2S) -N2- [2-chloro-5- (3,3-dietoxyprop-1-inyl) pyrimidin-4-yl] - 4-methyl-pentane-1,2-diamine. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.90 - 1.00 (m, 6 H) 1.18 - 1.25 (m, 6 H) 1.34 - 1.36 (m, 9 H ) 1.69 - 1.90 (m, 1 H) 3.34 - 3.82 (m, 6 H) 4.53 - 4.77 (m, 1 H) 5.45 - 5.55 (m, 1 H) 6.37 (dd, J = 15.37, 6.59 Hz, 1 H) 6.56 (s, 1 H) 8.05 (s, 1 H). LCMS (ESI) 441 (M + H). 7 - [(2S) -2- (tert-butoxycarbonylamino) -3-methyl-butyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00288] 7 - [(2S) -2- (tert-butoxycarbonylamino) -3-methyl-butyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using a similar synthetic sequence as those described for 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 0.90 (d, J = 6.73 Hz, 3 H) 0.96 (d, J = 7.03 Hz, 3 H) 1.55 - 1, 66 (m, 10 H) 4.14 (dd, J = 13.61, 3.95 Hz, 1 H) 4.52 - 4.63 (m, 1 H) 4.84 (dd, J = 13, 61, 1.32 Hz, 1 H) 7.37 (s, 1 H) 8.95 (s, 1 H). LCMS (ESI) 383 (M + H). Intermediate H
[00289] Intermediate 1H was synthesized using a synthetic sequence analogous to those described for intermediate 1A. LCMS (ESI) 265 (M + H). Intermediate 11

[00290] Intermediate 11 was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate F as starting materials, and following a similar sequence of synthetic steps as for intermediate 1H. The analytical data were consistent with that described for its antipode (intermediate 1H). 1H NMR (600 MHz, DMSO-de) δ ppm 0.88 (d, J = 6.44 Hz, 6 H) 1.73 - 1.86 (m, 1 H) 3.67 - 3.76 (m , 2 H) 4.11 - 4.21 (m, 1 H) 7.13 - 7.19 (m, 1 H) 8.56 (s, 1 H) 9.05 (s, 1 H). LCMS (ESI) 265 (M + H). Intermediate 1J
Tert-butyl N- [2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -2-methyl-propyl] carbamate

[00291] N- [2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -2-methyl-propyl] tert-butyl carbamate was synthesized using 5-bromo-2,4 -dichloro-pyrimidine and tert-butyl N- (2-amino-2-methyl-propyl) carbamate using analogous reaction conditions as described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4- il) tert-butyl amino] -3-methyl-butyl] carbamate. LCMS (ESI) 379 (M + H). Tert-butyl N- [2 - chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4-yl] amino] -2-methylpropylcarbamate

[00292] tert-butyl N- [2 - [[2-Chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] - 2-methyl-propyl] carbamate was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxyprop-1-yl) pyrimid in-4-yl] -4-methyl-pentane-1,2- diamine. 1H NMR (600 MHz, DMSO-de) d ppm 1.11 - 1.22 (m, 6 H) 1.31 - 1.45 (m, 15 H) 3.10 - 3.24 (m, 2 H ) 3.51 - 3.76 (m, 4 H) 5.60 (s, 1 H) 6.94 (s, 1 H) 7.33 (t, J = 6.44 Hz, 1 H) 8, 18 (s, 1 H). LCMS (ESI) 427 (M + H). 7- [2- (tert-butoxycarbonylamino) -1,1-dimethyl-ethyl-2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00293] 7- [2- (tert-butoxycarbonylamino) -1,1-dimethyl-ethyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid using a similar synthetic sequence as those described for acid 7- [1 - [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic. 1H NMR (600 MHz, DMSO-de) δ ppm 1.43 (s, 9H) 1.73 (s, 6 H) 4.06 (s, 2 H) 7.46 (s, 1 H) 9.23 (s, 1H). LCMS (ESI) 369 (M + H). Intermediate 1J
[00294] Intermediate 1J was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-de) δ ppm 1.73 (s, 6 H) 3.50 (d, J = 2.93 Hz, 2 H) 7.25 (s, 1 H) 8.46 - 8.55 (m, 1 H) 9.07 (s, 1 H). LCMS (ESI) 251 (M + H). Intermediate 1K
Tert-butyl N - [[i - [(5-Bromo-2-chloro-pyrimidin-4-yl) aminolcyclohexylmethylcarbamate

[00295] N - [[1 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] cyclohexyl] methyl] tert-butyl carbamate was synthesized using 5-bromo-2,4-dichloro - pyrimidine and Intermediate K using analogous reaction conditions as described for tert-butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate. 1H NMR (600 MHz, DMSO-de) δ ppm 1.18 - 1.54 (m, 17 H) 2.23 (d, J = 14.35 Hz, 2 H) 3.36 (d, J = 6 , 44 Hz, 2 H) 5.82 (s, 1 H) 6.93 (s, 1 H) 8.22 (s, 1 H). LCMS (ESI) 419 (M + H). N - [[1 - [[2-Chloro-5- (3,3-diethoxyprop-1-inyl) pyrimidin-4-yl] amino] cyclohexyl] tert-butyl methylcarbamate

[00296] N - [[1 - [[2-Chloro-5- (3,3-diethoxyprop-1-in i I) pyrim id in-4-yl] amino] cyclohexyl] methyl] tert-carbamate butyl was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4-yl] -4-methyl-pentane-1 , 2- diamine. 1H NMR (600 MHz, DMSO-de) d ppm 1.08-1.16 (m, 6 H) 1.17 - 1.54 (m, 17 H) 2.13 (br. S., 2 H) 3.36 (d, J = 6.73 Hz, 2 H) 3.50 - 3.69 (m, 4 H) 5.72 (s, 1 H) 6.94 (s, 1 H) 5.72 (br. s., 1H) 8.17 (s, 1 H). LCMS (ESI) 467 (M + H). 7- [1 - [(tert-butoxycarbonylamino) methyl] cyclohexyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00297] 7- [1 - [(tert-butoxycarbonylamino) methyl] cyclohexyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using synthetic sequence analogous to those described for acid 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic. 1H NMR (600 MHz, DMSO-de) δ ppm 1.37 - 1.54 (m, 13 H) 1.75 (br. S „4 H) 2.74 (br. S., 2 H) 3, 78 - 3.84 (m, 2 H) 7.44 - 7.51 (m, 1 H) 8.23 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 409 (M + H). Intermediate K
[00298] Intermediate 1K was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.28 (br. S., 2 H) 1.42 (br. S., 2 H) 1.70 (br. S., 4 H) 1, 85 - 1.95 (m, 2 H) 2.69 (m, 2 H) 7.16 - 7.25 (m, 1 H) 8.41 (br. S, 1 H) 9.04 (s , 1 H). LCMS 291 (M + H). Intermediate 1L
Tert-butyl N - [[1 - [(5-Bromo-2-chloro-pyrimidin-4-yl) aminolcyclopentillmetillcarbamate

[00299] N - [[1 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] cyclopentyl] methyl] tert-butyl carbamate was synthesized using 5-bromo-2,4-dichloro-pyrimidine and Intermediate L using analogous reaction conditions as described for tert-butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate. 1H NMR (600 MHz, DMSO-de) δ ppm 1.34 (s, 9 H) 1.50 - 1.58 (m, 2 H) 1.63 - 1.78 (m, 4 H) 1.96 - 2.06 (m, 2 H) 3.25 (d, J = 6.15 Hz, 2 H) 6.71 (s, 1 H) 7.18 (t, J = 6.29 Hz, 1 H ) 8.20 (s, 1 H). LCMS (ESI) 405 (M + H). N - [[1 - [[2-Chloro-5- (3,3-diethoxyprop-1-yl) pyrimidin-4-yl] amino] cyclopentyl] tert-butyl methylcarbamate

[00300] N - [[1 - [[2-Chloro-5- (3,3-dietoxyprop-1-in i I) pyrim id in-4-yl] amino] cyclopentyl] methyl] tert-butyl carbamate was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] -4-methyl-pentane-1,2 - diamine. LCMS (ESI) 453 (M + H). 7- [1 - [(tert-butoxycarbonylamino) methyl-cyclopentill-2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00301] 7- [1 - [(tert-butoxycarbonylamino) methyl] cyclopentyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using synthetic sequence analogous to those described for 7- acid [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic. 1H NMR (600 MHz, DMSO-de) δ ppm 1.47 (s, 9 H) 1.74 (br. S., 2 H) 1.88 (br. S., 2 H) 2.04 (br s., 2 H) 2.41 - 2.45 (m, 2 H) 4.06 (s, 2 H) 7.45 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 395 (M + H). Intermediate 1L
[00302] Intermediate 1L was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.72 (br. S., 2 H) 1.86 - 1.93 (m, 2 H) 1.99 (d, J = 3.81 Hz, 2 H) 2.40 (br. S., 2 H) 3.48 (d, J = 2.34 Hz, 2 H) 7.22 (s, 1 H) 8.53 (br. S „1 H ) 9.05 (s, 1 H). LCMS (ESI) 277 (M + H). Intermediate 1M
Tert-butyl N- [2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) aminol-4-methyl-pentyl] carbamate

[00303] N- [2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] -4-methyl-pentyl] tert-butyl carbamate was synthesized using 5-bromo-2,4-dichloro -pyrimidine and Intermediate B using analogous reaction conditions as described for tert-butyl N- [2 - [(5-bromo-2-chloro-pyrimidin-4-yl) amino] -3-methyl-butyl] carbamate. The analytical data are consistent with that described for the L enantiomer. N- [2 - [[2-Chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] -4-methyl- tert-butyl pentillcarbamate

[00304] N tert-butyl N- [2 - [[2-Chloro-5- (3,3-dietoxyprop-1-ynyl) pyrimidin-4-yl] amino] - 4-methyl-pentyl] carbamate was synthesized using experimental conditions similar to that used in the synthesis of tert-butyl N- [2 - [[2-chloro-5- (3,3-diethoxyprop-1-ynyl) pyrimidin-4-yl] amino] ethyl] carbamate. 1H NMR (600 MHz, CHLOROPHORMUM-d) δ ppm 1.21 - 1.31 (m, 12 H) 1.38 - 1.46 (m, 11 H) 1.70 (m, 1H) 3.24 ( m, 2 H) 3.65 - 3.82 (m, 4 H) 4.86 (brs., 1H), 5.65 (s, 1 H) 5.85 (brs., 1H) 6.94 ( s, 1 H) 8.21 (s, 1 H). LCMS (ESI) 455 (M + H). 7- [1 - [(tert-butoxycarbonylamino) methyl-3-methyl-butyl-2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00305] 7- [1 - [(tert-butoxycarbonylamino) methyl] -3-methyl-butyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using a similar synthetic sequence as those described for 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. The analytical data were consistent with that described for the L isomer. Intermediate 1M
[00306] Intermediate 1M was synthesized using a synthetic sequence analogous to those described for intermediate 1A. The analytical data were consistent with that described for the L isomer. Intermediate 1MA

[00307] To a solution of Intermediate 1M (100 mg, 0.00024 mol) in DMF (3.0 mL) was added sodium hydride (60% oil dispersion), (27.6 mg, 3 eq). After stirring for 15 mins, methyl iodide (30, 2 eq) was added. The contents were stirred at room temperature for 30 mins. After adding NaHCOs salt, ethyl acetate was added. Separation of the organic layer followed by drying with magnesium sulfate and concentration in vacuo gave intermediate 1MA. The analytical data were similar to Intermediate 1DA. Intermediate 1N
N - [(1 S, 2S) -2 - [(5-Bromo-2-chloro-pyrimidin-4-tert-butylaminolcyclopentillcarbamate

[00308] N - [(1S, 2S) -2 - [(5-Bromo-2-chloro-pyrimidin-4-yl) amino] cyclopentyl] tert-butyl carbamate was synthesized by treating N - [(1S, 2S) -2-aminocyclopentyl] tert-butyl carbamate with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described for N- [2 - [(5-bromo-2-chloro-pyrimidin-4 -yl) amino] -3-methyl-butyl] tert-butyl carbamate. 1H NMR (600 MHz, DMSO-de) δ ppm 1.27 (s, 9 H) 1.42 -1.54 (m, 2 H) 1.56 - 1.65 (m, 2 H) 1.80 - 1.88 (m, 1 H) 1.96 - 2.01 (m, 1 H) 3.88 - 3.96 (m, 1 H) 4.03 - 4.09 (m, 1 H) 6 , 91 (d, J = 8.20 Hz, 1 H) 7.41 (d, J = 7.32 Hz, 1 H) 8.18 (s, 1 H). LCMS (ESI) 391 (M + H). Tert-butyl N - [(1 S, 2S) -2 - [[2-Chloro-5- (3,3-dietoxyprop-1-yl) pyrimidin-4-illaminolcyclopentillcarbamate

[00309] N - [(1 S, 2S) -2 - [[2-Chloro-5- (3,3-diethoxyprop-1-in i I) pyrimid-in-4-yl] amino] cyclopentyl] carbamate tert-butyl was synthesized using experimental conditions similar to that used in the synthesis of (2S) -N2- [2-chloro-5- (3,3-dietoxyprop-1-yl) pyrimidin-4-yl] -4-methyl- pentane-1,2-diamine. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.13 (t, 6 H) 1.28 (s, 9 H) 1.42 - 1.52 (m, 2 H) 1.58 - 1.65 (m, 2 H) 1.81 - 1.90 (m, 1 H) 1.99 - 2.08 (m, 1 H) 3.49 - 3.60 (m, 2 H) 3.63 - 3 , 71 (m, 2 H) 3.84 - 3.93 (m, 1 H) 3.96 - 4.04 (m, 1 H) 5.53 (s, 1 H) 6.96 (d, J = 7.90 Hz, 1 H) 7.34 (d, J = 7.03 Hz, 1 H) 8.14 (s, 1 H). LCMS (ESI) 439 (M + H). 7 - [(1 S, 2S) -2- (tert-butoxycarbonylamino) cyclopentyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid

[00310] 7 - [(1 S, 2S) -2- (tert-butoxycarbonylamino) cyclopentyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid was synthesized using synthetic sequence analogous to those described for 7- [1- [(tert-butoxycarbonylamino) methyl] -2-methyl-propyl] -2-chloro-pyrrolo [2,3-d] pyrimidine-6-carboxylic acid. 1H NMR (600 MHz, DMSO-de) δ ppm 1.41 - 1.52 (m, 9 H) 1.55 - 1.68 (m, 1 H) 1.88 - 2.00 (m, 2 H ) 2.05 - 2.15 (m, 1 H) 2.26 - 2.35 (m, 1 H) 2.71 - 2.89 (m, 1 H) 4.01 - 4.16 (m, 1 H) 4.28 - 4.45 (m, 1 H) 7.41 (s, 1 H) 9.11 (s, 1 H). LCMS (ESI) 381 (M + H). Intermediate 1N
[00311] Intermediate 1N was synthesized using a synthetic sequence analogous to those described for intermediate 1A. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.48 - 1.60 (m, 1 H) 1.88 - 1.98 (m, 3 H) 1.99 - 2.08 (m, 1 H ) 2.66 - 2.75 (m, 1 H) 3.63 - 3.74 (m, 1 H) 3.99 - 4.12 (m, 1 H) 7.21 (s, 1 H) 8 , 89 (s, 1 H) 9.04 (s, 1 H). LCMS (ESI) 263 (M + H). Example 3 - Compounds of Example Compound 1

[00312] A (0.050 g) (0.225 mmol) of tricycliclactam chlorine in dioxane (2.0 mL) under nitrogen was added 5- (4-methylpiperazin-1-yl) pyridin-2-amine (0.052 g) (1, 2 eq, 0.270 mmol) followed by the addition of Pd2 (dba) 3 (18.5 mg), BINAP (25 mg) and sodium tert-butoxide (31 mg, 0.324 mmol). The contents of the bottle are degassed for 10 minutes and then heated to 100 degrees for 12 hours. The crude reaction was loaded onto a silica gel column and eluted with DCM / MeOH (0 -15%) to provide the desired product (26 mg). To this compound dissolved in DCM / MeOH (10%) was added 3 N HCI in iso-propanol (2 eq) and stirred overnight. Concentration under vacuum provided the hydrochloride salt. 1HRMN (d6-DMSO) 11.13 (brs, 1H), 9.07 (s, 1H), 8.42 (s, 1H), 8.03 (br m 1H), 7.99 (s, 1H) , 7.67 (brm, 1H), 7.18 (s, 1H), 4.33 (m, 2H), 3.79 (m, 2H), 3.64 (m, 2H), 3.50 ( m, 2H), 3.16 (m, 4H), 2.79 (s, 3H). LCMS (ESI) 379 (M + H) Compound 2

[00313] Chlorine tricycliclactam (0.075 g) (0.338 mmol) in dioxane (3.5 mL) under nitrogen was added 4- (6-amino-3-pyridyl) tert-butyl 4- (6-amino-3-pyridyl) piperazine-0.04 g (1.05 eq) followed by the addition of Pd2 (dba) 3 (27 mg) and BINAP (36 mg) and sodium tert-butoxide (45 mg). The contents were refluxed for 11 h. The crude reaction was loaded onto a silica gel column and eluted with DCM / MeOH (0 - 10%) to provide the desired product (32 mg). 1HRMN (d6-DMSO) 9.48 (s, 1H), 8.84 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 7.99 (s, 1H) , 7.42 (m, 1H), 6.98 (s, 1H), 4.23 (m, 2H), 3.59 (m, 2H), 3.45 (m, 4H), 3.50 ( m, 2H), 3.05 (m, 4H). LCMS (ESI) 465 (M + H) Compound 3

[00314] To a solution of Compound 2 (23 mg) in 10% DCM / MeOH was added 10 ml of a 3 M solution of HCI in iso-propanol. The contents were stirred overnight for 16 h. Concentration of the reaction mixture provided the hydrochloride salt. 1HRMN (d6-DMSO) 9.01 (s, 1H), 7.94 (m, 1H), 7.86 (m, 1H), 7.23 (s, 1H), 4.30 (m, 2H) , 3.64 (m, 2H), 3.36 (m, 4H), 3.25 (m, 4H). LCMS (ESI) 465 (M + H) Compound 4

[00315] To the chlorine-N-methyltricyclic amide (0.080 g) (0.338 mmol) in dioxane (3.5 ml) under nitrogen was added 4- (6-amino-3-pyridyl) piperazine-1-carboxylate tert- butyl (0.102 g) (1.1 eq) followed by the addition of Pd2 (dba) 3 (27 mg), BINAP (36 mg) and sodium tert-butoxide (45 mg). The contents were refluxed for 11 h. The crude product was purified using column chromatography with a dichloromethane / methanol eluent (0 - 5%) to provide the desired product (44 mg). 1HRMN (d6-DMSO) 9.49 (s, 1H), 8.85 (s, 1H), 8.32 (m, 1H), 8.02 (s, 1H), 7.44 (m, 1H) , 7.00 (s, 1H), 4.33 (m, 2H), 3.80 (m, 2H), 3.48 (m, 4H), 3.07 (m, 4H), 3.05 ( s, 3H), 1.42 (s, 9H). LCMS (ESI) 479 (M + H) Compound 5

[00316] To 32 mg of Compound 4, 10 ml of 3 N HCI in isopropanol was added and the contents stirred at room temperature overnight for 16 h. Concentration provided the hydrochloride salt. 1HRMN (d6-DMSO) 9.13 (m, 2H), 8.11 (m, 1H), 8.10 (s, 1H), 7.62 (m, 1H), 7.21 (s, 1H) , 4.43 (m, 2H), 3.85 (m, 2H), 3.41 (m, 4H), 3.28 (m, 4H), 3.08 (s, 3H). LCMS (ESI) 379 (M + H) Compound 6

[00317] Compound 6 was synthesized using experimental conditions similar to that described for Compound 2. 1H NMR (600 MHz, DMSO-de) δ ppm 0.79 (d, J = 7.03 Hz, 3 H) 1.01 ( d, J = 6.73 Hz, 3 H) 1.35 - 1.48 (m, 9 H) 2.16 (dd, J = 14.64, 6.73 Hz, 1 H) 3.00 - 3 , 14 (m, 4 H) 3.40 - 3.51 (m, 4 H) 3.51 - 3.60 (m, 1 H) 3.63 - 3.74 (m, 1 H) 4.44 (dd, J = 7.90, 3.81 Hz, 1 H) 6.99 (s, 1 H) 7.46 (dd, J = 8.93, 2.78 Hz, 1 H) 7.94 - 8.09 (m, 2 H) 8.31 (dd, J = 9.08, 1.46 Hz, 1 H) 8.85 (s, 1 H) 9.46 (s, 1 H). LCMS (ESI) 507 (M + H). 7

[00318] Compound 7 was synthesized using experimental conditions similar to that described for Compound 1 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-d6) δ ppm 0.77 - 0.86 (m, 3 H) 0.96 (d, J = 7.03 Hz, 3 H) 2.10 - 2.24 (m , 1 H) 3.07 (s, 3 H) 3.37 - 3.79 (m, 8 H) 4.00 (dd, J = 13.61.4.54 Hz, 2 H) 4.63 - 4.73 (m, 1 H) 7.20 (s, 1 H) 7.58 - 7.71 (m, 1 H) 7.99 (d, J = 2.34 Hz, 1 H) 8.12 (d, J = 9.37 Hz, 1 H) 9.11 (s, 1 H) 9.41 (br. s., 2 H) 11.76 (br. s., 1 H). LCMS (ESI) 421 (M + H). Compound 8

[00319] Compound 8 was synthesized using experimental conditions similar to that described for Compounds 2 and 3 and was recovered as an HCI salt. Characterization data (NMR and LCMS) were consistent with that reported for Compound 9. Compound 9

[00320] Compound 9 was synthesized using experimental conditions similar to that described for Compounds 2 and 3 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.79 (d, J = 6.73 Hz, 3 H) 1.01 (d, J = 6.73 Hz, 3 H) 2.18 (dd, J = 14.49, 7.17 Hz, 1 H) 3.18 - 3.84 (m, 10 H) 4.53 - 4.71 (m, 1 H) 7.24 (s, 1 H) 7 , 65 (d, J = 9.37 Hz, 1 H) 8.01 (d, J = 2.64 Hz, 1 H) 8.14 (d, J = 1.46 Hz, 1 H) 8.35 (d, J = 5.27 Hz, 1 H) 9.14 (s, 1 H) 9.46 (s, 2 H) 11.80 (s, 1 H) LCMS (ESI) 407 (M + H) . Compound 10

[00321] Compound 10 was synthesized using experimental conditions similar to that described for Compounds 2 and 3 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.77 (d, J = 7.03 Hz, 3 H) 0.99 (d, J = 6.73 Hz, 3 H) 2.10 - 2, 24 (m, 1 H) 3.18 - 3.81 (m, 10 H) 4.54 - 4.69 (m, 1 H) 7.22 (s, 1 H) 7.63 (d, J = 9.08 Hz, 1 H) 7.99 (d, J = 2.63 Hz, 1 H) 8.11 (s, 1 H) 8.33 (d, J = 5.27 Hz, 1 H) 9 , 12 (s, 1 H) 9.43 (s, 2 H) 11.77 (s, 1 H). LCMS (ESI) 407 (M + H). Compound 11

[00322] Compound 11 was synthesized using experimental conditions similar to that described for Compounds 2 and 3 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.84 (d, J = 6.73 Hz, 3 H) 0.98 (d, J = 6.73 Hz, 3 H) 2.12 - 2, 26 (m, 1 H) 3.09 (s, 3 H) 3.22 - 3.81 (m, 8 H) 4.01 (dd, J = 13.61.4.25 Hz, 2 H) 4 , 59 - 4.72 (m, 1 H) 7.19 (s, 1 H) 7.74 (s, 1 H) 7.96 - 8.10 (m, 2 H) 9.08 (s, 1 H) 9.22 (s, 2 H). LCMS (ESI) 421 (M + H). Compound 12

[00323] Compound 12 was synthesized using experimental conditions similar to that described for Compound 1 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.85 (d, J = 4.98 Hz, 3 H) 0.95 (d, J = 4.98 Hz, 3 H) 1.42 - 1, 70 (m, 3 H) 2.77 (d, J = 2.93 Hz, 3 H) 3.07 - 4.14 (m, 10 H) 4.95 (s, 1 H) 7.20 (s , 1 H) 7.66 (d, J = 9.66 Hz, 1 H) 7.94 (s, 1 H) 8.08 - 8.16 (m, 1 H) 8.33 (d, J = 4.68 Hz, 1 H) 9.09 (s, 1 H) 11.38 (s, 1 H) 11.71 (s, 1 H). LCMS (ESI) 435 (M + H). 13

[00324] Compound 13 was synthesized using experimental conditions similar to that described for Compounds 2 and 3 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.87 (d, J = 6.15 Hz, 3 H) 0.94 (d, J = 6.15 Hz, 3 H) 1.57 (d, J = 84.61 Hz, 3 H) 3.05 (s, 3 H) 3.13 - 3.55 (m, 8 H) 3.69 (d, J = 78.17 Hz, 2 H) 4, 90 (s, 1 H) 7.15 (s, 1 H) 7.63 - 7.85 (m, 1 H) 7.93 (s, 1 H) 8.26 (s, 1 H) 9.03 (s, 1 H) 9.20 (s, 2 H). LCMS (ESI) 421 (M + H). Compound 14

[00325] Compound 14 was synthesized using experimental conditions similar to that described for Compound 1 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-ds) δ ppm 0.85 (d, J = 6.44 Hz, 3 H) 0.95 (d, J = 6.44 Hz, 3 H) 1.43 - 1, 70 (m, 3 H) 2.78 (d, J = 2.93 Hz, 3 H) 3.05 (s, 3 H) 3.24 - 3.84 (m, 8 H) 4.01 (d , J = 9.66 Hz, 2 H) 4.89 - 5.01 (m, 1 H) 7.15 (s, 1 H) 7.77 (s, 1 H) 7.91 - 8.05 ( m, 2 H) 9.03 (s, 1 H) 10.96 - 11.55 (m, 2 H). LCMS (ESI) 449 (M + H). Compound 15

[00326] Compound 15 was synthesized using experimental conditions similar to that described for Compounds 2 and 3 and was recovered as an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 0.83 - 0.88 (d, J = 6.15 Hz, 3 H) 0.95 (d, J = 6.15 Hz, 3 H) 1, 40 - 1.71 (m, 3 H) 3.28 - 3.83 (m, 8 H) 4.00 (d, J = 3.22 Hz, 2 H) 4.91 - 5.08 (m, 1 H) 7.17 (s, 1 H) 7.68 (d, J = 9.66 Hz, 1 H) 7.93 (s, 1 H) 8.07 (s, 1 H) 9.06 ( s, 1 H) 9.40 (s, 2 H) 11.59 (s, 1 H). LCMS (ESI) 435 (M + H). 16

[00327] To intermediate 1E (0.060 g) (0.205 mmol) was added 5- (4-methylpiperazin-1-yl) pyridin-2-amine (35.42 mg) (0.9 eq) followed by the addition of 1, 4-dioxane (3 ml). After degassing with nitrogen, Pd2dba3 (12 mg), BINAP (16 mg) and sodium tert-butoxide (24 mg) were added. The contents were then heated to 90 degrees in a CEM Discovery microwave for 3 h. The reaction is then loaded onto a silica gel column and purified eluting with DCM / MeOH (0 - 15%) to provide Compound 16. 1H NMR (600 MHz, DMSO-de) δ ppm 0.75 (t, J = 7.47 Hz, 3 H) 0.91 (d, J = 6.73 Hz, 3 H) 1.04 - 1.20 (m, 2 H) 1.80 - 1.98 (m, 1 H ) 2.77 (d, J = 3.81 Hz, 3 H) 2.94 - 3.90 (m, 10 H) 4.54 - 4.68 (m, 1 H) 7.06 - 7.23 (m, 2 H) 7.56 - 7.75 (m, 1 H) 7.90-8.12 (m, 2 H) 8.29 (s, 1 H) 9.07 (s, 1 H) 10.98 - 11.74 (m, 2 H). LCMS (ESI) 435 (M + H). Compound 17

[00328] Compound 17 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.75 (t, J = 7.32 Hz, 3 H) 0.90 (d, J = 6.73 Hz, 3 H) 1.07 - 1, 15 (m, 2 H) 1.85 - 1.94 (m, 1 H) 3.17 - 3.75 (m, 10 H) 4.58 - 4.67 (m, 1 H) 7.17 ( s, 1 H) 7.71 (s, 1 H) 7.96 (s, 1 H) 7.98 - 8.05 (m, 1 H) 8.28 (d, J = 4.10 Hz, 1 H) 9.06 (s, 1 H) 9.39 (s, 2 H). LCMS (ESI) 421 (M + H). Compound 18

[00329] Compound 18 was synthesized in a similar manner to that described for compound 16. 1H NMR (600 MHz, DMSO-dθ) δ ppm 0.78 (t, J = 7.32 Hz, 3 H) 0.86 ( d, J = 6.73 Hz, 3 H) 1.13 - 1.21 (m, 2 H) 1.84 - 1.96 (m, 1 H) 2.77 (d, J = 4.39 Hz , 3 H) 3.04 (s, 3 H) 3.11 - 3.84 (m, 8 H) 3.98 (dd, J = 13.61.4.25 Hz, 2 H) 4.66 - 4.74 (m, 1 H) 7.17 (s, 1 H) 7.64 (s, 1 H) 7.96 (d, J = 2.34 Hz, 1 H) 8.03 - 8.13 (m, 1 H) 9.08 (s, 1 H) 11.26 (s, 1 H) 11.66 (s, 1 H). LCMS (ESI) 449 (M + H). 19

[00330] Compound 19 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 0.78 (t, J = 7.32 Hz, 3 H) 0.85 (d, J = 6.73 Hz, 3 H) 1.10 - 1, 27 (m, 2 H) 1.82 - 1.99 (m, 1 H) 3.04 (s, 3 H) 3.28 - 3.77 (m, 8 H) 3.97 (dd, J = 13.91.4.54 Hz, 2 H) 4.62 - 4.75 (m, 1 H) 7.07 - 7.24 (m, 1 H) 7.62 - 7.75 (m, 1 H ) 7.94 (d, J = 2.34 Hz, 1 H) 7.97 - 8.08 (m, 1 H) 9.05 (s, 1 H) 9.29 (s, 2 H). LCMS (ESI) 435 (M + H). Compound 20

[00331] Compound 20 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 0.96 (s, 9 H) 3.15 - 3.87 (m, 10 H) 4.42 - 4.53 (m, 1 H) 6.99 (s, 1 H) 7.24 (s, 1 H) 8.06 (s, 1 H) 8.11 - 8.21 (m, 1 H) 8.79 - 8.98 (m, 2 H) 9.25 (s, 2 H) 9.88 (s, 1 H). LCMS (ESI) 421 (M + H). 21

[00332] Compound 21 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 0.95 (s, 9 H) 2.79 (d, J = 4.10 Hz, 3 H) 3.06 - 3.86 (m, 10 H) 4.56 - 4.67 (m, 1 H) 7.17 (s, 1 H) 7.70 (s, 1 H) 7.96 (d, J = 2.63 Hz, 1 H) 7.99 - 8.08 (m, 1 H) 8.26 (s, 1 H) 9.06 (s, 1 H) 10.80 (s, 1 H). LCMS (ESI) 435 (M + H). 22

[00333] Compound 22 was synthesized in a similar manner to that described for compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 2.75 - 2.81 (m, 3 H) 3.12 - 3.16 (m, 2 H) 3.46 - 3.54 (m, 4 H ) 3.60 - 3.69 (m, 2 H) 3.72 - 3.79 (m, 1 H) 4.07 - 4.18 (m, 2 H) 6.06 - 6.09 (m, 1 H) 6.90 (d, J = 7.61 Hz, 2 H) 7.20 - 7.31 (m, 3 H) 7.33 (s, 1 H) 7.49 - 7.55 (m , 1 H) 7.62 - 7.70 (m, 1 H) 7.92 (d, J = 2.93 Hz, 1 H) 8.22 (s, 1 H) 9.14 (s, 1 H ). LCMS (ESI) 455 (M + H). Compound 23
O
[00334] Compound 23 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dδ) δ ppm 3.21 (s, 4 H) 3.35 - 3.67 (m, 5 H) 4.07 - 4.20 (m, 2 H) 6.13 (s, 1 H) 6.90 (d, J = 7.32 Hz, 2 H) 7.22 - 7.31 (m, 3 H) 7.36 (s, 1 H) 7.48 (d, J = 9.37 Hz, 1 H) 7.93 (d, J = 2.34 Hz, 1 H) 8.04 - 8.11 (m, 1 H) 8.25 (d, J = 4.98 Hz, 1 H) 9.17 (s, 1 H) 11.77 (br, s., 1H). LCMS (ESI) 441 (M + H). Compound 24

[00335] Compound 24 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 0.90 (d, J = 6.15 Hz, 6 H) 1.72 - 1.89 (m, 1 H) 3.15 - 3.92 (m , 9 H) 4.10 - 4.46 (m, 2 H) 7.18 (s, 1 H) 7.59 (d, J = 8.78 Hz, 1 H) 8.00 (s, 1 H ) 8.13 (d, J = 9.37 Hz, 1 H) 8.55 (s, 1 H) 9.09 (s, 1 H) 9.67 (s, 2 H) 11.91 (s, 1 H). LCMS (ESI) 407 (ESI). 25

[00336] Compound 25 was synthesized in a similar manner to compound 24 and was converted to an HCI salt. Characterization data (NMR and LCMS) were similar to that obtained for Compound antipode 24. Compound 26

[00337] Compound 26 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.78 (s, 6 H) 3.40 - 3.53 (m, 6 H) 3.64 - 3.73 (m, 4 H) 7.27 (s, 1 H) 7.66 (d, J = 9.37 Hz, 1 H) 7.98 (d, J = 2.34 Hz, 1 H) 8.12 (br. s., 1 H) 8.47 (br. S, 1 H) 9.11 (s, 1 H) 9.45 (br. S, 2H) 11.62 (br. S., 1 H). LCMS (ESI) 393 (M + H). 27

[00338] Compound 27 was synthesized in a similar manner to that described for compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.47 (br. S, 6 H) 1.72 (br. S., 2 H) 1.92 (br. S., 2 H) 2, 77 (br., 3 H) 3.18 (br., 2 H) 3.46 (br., 2 H) 3.63 (br., 2 H) 3.66 ( d, J = 6.15 Hz, 2 H) 3.80 (br., 2 H) 7.25 (s, 1 H) 7.63 (br., 2 H) 7.94 (br . s., 1 H) 8.10 (br., 1 H) 8.39 (br., 1 H) 9.08 (br., 1 H) 11.59 (br. s ., 1 H). LCMS (ESI) 447 (M + H). 28

[00339] Compound 28 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.27 - 1.64 (m, 6 H) 1.71 (br. S., 2 H) 1.91 (br. S., 2 H) 2 , 80 (br., 1 H) 3.17 - 3.24 (m, 2 H) 3.41 (br., 4 H) 3.65 (br., 4 H) 7, 26 (br., 1 H) 7.63 (br., 1 H) 7.94 (br., 1 H) 8.13 (br., 1 H) 8.40 ( br., 1 H) 9.09 (br., 1 H) 9.62 (br., 1 H) 11.71 (br., 1 H). LCMS (ESI) 433 (M + H). Compound 29

[00340] Compound 29 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.64 - 1.75 (m, 2 H) 1.83 - 1.92 (m, 2 H) 1.96 - 2.06 (m, 2 H ) 2.49 - 2.58 (m, 2 H) 2.79 (d, J = 3.81 Hz, 3 H) 3.06 - 3.18 (m, 4 H) 3.59 - 3.69 (m, 2 H) 3.73 - 3.83 (m, 2 H) 4.04 - 4.12 (m, 2 H) 7.17 (br., 1 H) 7.60 - 7, 70 (m, 2 H) 7.70 - 7.92 (m, 2 H) 7.96 (br. S, 1 H) 8.41 (br., 1 H) 8.98 (br. s., 1 H) 10.77 (br. s., 1 H). LCMS (ESI) 433 (M + H). 30

[00341] Compound 30 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 1.64 - 1.75 (m, 2 H) 1.84 - 1.92 (m, 2 H) 1.96 - 2.05 (m, 2 H ) 2.48 - 2.56 (m, 2 H) 3.22 (br. S, 4 H) 3.42 - 3.48 (m, 4 H) 3.60 - 3.69 (m, 2 H) 4.05 - 4.13 (m, 1 H) 7.18 (s, 1 H) 7.65 (d, J = 13.47 Hz, 1 H) 7.70 - 7.77 (m, 1 H) 7.94 (d, J = 1.76 Hz, 1 H) 8.42 (br. S „1 H) 9.00 (s, 1 H) 9.15 (br. S„ 2 H) . LCMS (ESI) 419 (M + H). Compound 31

[00342] Compound 31 was synthesized in a similar manner to that described for compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.76 (br., 2 H) 1.89 (br., 2 H) 2.03 (br., 2 H) 2, 47 - 2.58 (m, 2 H) 3.04 (s, 3 H) 3.22 (br. S., 4 H) 3.39 (br. S., 4 H) 3.66 (s, 2 H) 7.21 (s, 1 H) 7.67 (d, J = 9.37 Hz, 1 H) 7.93 (br. S., 1 H) 7.98 - 8.09 (m, 1 H) 9.04 (s, 1 H) 9.34 (br., 2 H) 11.31 (br., 1 H). LCMS (ESI) 433 (M + H). Compound 32

[00343] Compound 32 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dδ) δ ppm 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m, 2 H) 1.96 - 2.08 (m, 2 H ) 2.48 - 2.57 (m, 2 H) 3.36 - 3.52 (m, 4 H) 3.60 - 3.80 (m, 6 H) 7.21 (s, 1 H) 7 , 53 - 7.74 (m, 2 H) 7.86 (s, 1 H) 8.02 (s, 1 H) 8.45 (s, 1 H) 9.03 (s, 1 H) 11, 19 (br. S., 1 H). LCMS (ESI) 420 (M + H). 33

[00344] Compound 33 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 1.65 - 1.79 (m, 2 H) 1.85 - 1.95 (m, 2 H) 1.97 - 2.08 (m, 2 H ) 2.47 - 2.54 (m, 2 H) 3.40 - 3.58 (m, 5 H) 3.65 (dd, J = 21.67, 5.56 Hz, 1 H) 3.69 - 3.78 (m, 4 H) 7.24 (s, 1 H) 7.97 - 8.17 (m, 2 H) 8.48 (s, 1 H) 9.08 (s, 1 H) 11.81 (s, 1 H). LCMS (ESI) 421 (M + H). Compound 34

[00345] Compound 34 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.55 - 1.74 (m, 2 H) 1.80 - 1.98 (m, 4 H) 2.48 - 2.60 (m, 2 H ) 3.40 - 3.50 (m, 4 H) 3.57 - 3.72 (m, 2 H) 3.90 - 4.20 (m, 4 H) 7.08 (s, 1 H) 7 , 37 - 7.57 (m, 2 H) 7.70 (m, 2 H) 8.32 (s, 1 H) 8.88 (s, 1 H) 9.98 (s, 1 H). LCMS (ESI) 419 (M + H). 35

[00346] Compound 35 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.30 (d, J = 5.27 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.83 - 1.95 (m , 2 H) 1.97 - 2.10 (m, 2 H) 2.45 - 2.55 (m, 2H) 3.25 - 3.36 (m, 1 H) 3.39 - 3.48 ( m, 4 H) 3.60 - 3.70 (m, 4 H) 3.75 - 4.15 (m, 2 H) 7.24 (s, 1 H) 7.54 - 7.75 (m, 2 H) 7.95 (s, 1 H) 8.10 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H) 11.25 (s, 1 H) 11, 48 (s, 1 H). LCMS (ESI) 461 (M + H). 36

[00347] Compound 36 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-dθ) δ ppm 0.99 (d, J = 6.15 Hz, 6 H) 1.65 - 1.78 (m, 2 H) 1.90 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.08 - 2.17 (m, 1 H) 2.45 - 2.55 (m, 2H) 2.88 - 3.02 (m, 2 H ) 3.33 - 3.48 (m, 4 H) 3.50 - 3.90 (m, 6 H) 7.24 (s, 1 H) 7.67 (s, 2 H) 7.94 (s , 1 H) 8.12 (s, 1 H) 8.49 (s, 1 H) 9.07 (s, 1 H) 10.77 (s, 1 H) 11.51 (s, 1 H). LCMS (ESI) 475 (M + H). Compound 37

[00348] Compound 37 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.13 (d, J = 5.86 Hz, 6 H) 1.66 - 1.77 (m, 2 H) 1.84 - 1.94 (m , 2 H) 1.97 - 2.09 (m, 2 H) 2.40 - 2.53 (m, 2 H) 3.37 - 3.49 (m, 2 H) 3.50 - 3.59 (m, 2 H) 3.59 - 3.73 (m, 4 H) 7.23 (s, 1 H) 7.64 (m, 3 H) 7.85 (s, 1 H) 8.11 ( s, 1 H) 8.47 (s, 1 H) 9.05 (s, 1 H). 11.35 (br s., 1H). LCMS (ESI) 448 (M + H). 38

[00349] Compound 38 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.50 - 1.57 (m, 2 H) 1.62 - 1.68 (m, 3 H) 1.68 - 1.75 (m, 2 H ) 1.84 - 1.92 (m, 2 H) 1.97 - 2.08 (m, 2 H) 2.48 - 2.53 (m, 2 H) 3.14 - 3.23 (m, 4 H) 3.43 - 3.47 (m, 2 H) 3.58 - 3.70 (m, 2 H) 7.22 (s, 1 H) 7.58 - 7.70 (m, 2 H ) 7.85 - 8.00 (m, 1 H) 8.16 (d, 1 H) 8.46 (s, 1 H) 9.04 (s, 1 H) 11.37 (br s „1H) . LCMS (ESI) 418 (M + H). 39

[00350] Compound 39 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.72 (s, 2 H) 1.90 (s, 4 H) 2.03 (s, 2 H) 2.21 (s, 2 H) 2, 48 - 2.54 (m, 2 H) 2.73 (s, 2 H) 3.03 (s, 2 H) 3.25 - 3.35 (m, 1 H) 3.38 - 3.48 ( m, 4 H) 3.65 - 3.99 (m, 5 H) 7.23 (s, 1 H) 7.63 (d, J = 9.66 Hz, 1 H) 7.90 (s, 1 H) 8.13 (s, 1 H) 8.47 (s, 1 H) 9.06 (s, 1 H) 10.50 (brs., 1H). LCMS (ESI) 503 (M + H). Compound 40

[00351] Compound 40 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.63 - 1.85 (m, 6 H) 1.87 - 1.92 (m, 2 H) 1.99 - 2.06 (m, 2 H ) 2.15 - 2.23 (m, 2 H) 2.47 - 2.53 (m, 1 H) 2.69 - 2.79 (m, 2 H) 2.81 - 2.91 (m, 2 H) 2.98 - 3.08 (m, 2 H) 3.32 - 3.48 (m, 4 H) 3.57 - 3.72 (m, 4 H) 3.77 - 3.85 ( m, 2 H) 7.22 (s, 1 H) 7.60 - 7.68 (m, 2 H) 7.90 (s, 1 H) 8.07 (s, 1 H) 8.46 (s , 1 H) 9.04 (s, 1 H). 11.41 (br s „1H). LCMS (ESI) 501 (M + H). Compound 41

[00352] Compound 41 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.64 - 1.76 (m, 2 H) 1.87 - 1.93 (m, 2 H) 2.00 - 2.07 (m, 2 H ) 2.48 - 2.53 (m, 2 H) 2.67 - 2.72 (m, 4 H) 3.44 - 3.47 (m, 2 H) 3.50 - 3.55 (m, 4 H) 7.24 (s, 1 H) 7.61 (d, J = 9.37 Hz, 2 H) 7.86 (d, J = 2.63 Hz, 1 H) 8.09 (d, J = 12.88 Hz, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 11.41 (br s „1H). LCMS (ESI) 436 (M + H). Compound 42

[00353] Compound 42 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.29 (d, J = 6.73 Hz, 6 H) 1.66 - 1.79 (m, 2 H) 1.84 - 1.95 (m , 2 H) 1.98 - 2.09 (m, 2 H) 2.46 - 2.55 (m, 2 H) 3.29 - 3.39 (m, 2H) 3.58 - 3.70 ( m, 4H) 3.77 - 3.86 (m, 4H) 7.24 (s, 1 H) 7.66 (d, J = 9.37 Hz, 1 H) 7.96 (d, J = 2 , 93 Hz, 1 H) 8.08 (s, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 9.28 (s, 1 H) 9.67 (s, 1 H) 11.36 (s, 1H). LCMS (ESI) 447 (M + H). Compound 43

[00354] Compound 43 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.73 (s, 2 H) 1.76 - 1.85 (m, 2 H) 1.85 - 1.94 (m, 2 H) 1.98 - 2.07 (m, 2 H) 2.19 - 2.26 (m, 2 H) 2.48 - 2.52 (m, 1 H) 2.70 - 2.81 (m, 4 H) 3 , 13 - 3.20 (m, 1 H) 3.30 - 3.48 (m, 3 H) 3.58 - 3.71 (m, 4 H) 3.78 - 3.84 (m, 4 H ) 7.24 (s, 1 H) 7.62 (d, J = 9.37 Hz, 2 H) 7.89 (d, J = 1.17 Hz, 1 H) 8.09 - 8.18 ( m, 1 H) 8.48 (s, 1 H) 9.06 (s, 1 H) 11.46 (brs., 1H). LCMS (ESI) 519 (M + H). 44

[00355] Compound 44 was synthesized using conditions similar to that described for Compound 16 followed by the deblocking step described for Compound 3 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.65 - 1.75 (m, 2 H) 1.85 - 1.93 (m, 2 H) 1.93 - 1.99 (m, 1 H ) 2.00 - 2.06 (m, 2 H) 2.08 -2.14 (m, 1 H) 2.47 - 2.55 (m, 2 H) 3.07 - 3.25 (m, 2 H) 3.25 - 3.69 (m, 5 H) 4.46 (s, 1 H) 4.67 (s, 1 H) 7.22 (s, 1 H) 7.58 - 7.69 (m, 2 H) 8.46 (s, 1 H) 9.02 (s, 1 H) 9.34 (s, 1 H) 9.65 (s, 1 H). LCMS (ESI) 431 (M + H). 45

[00356] Compound 45 was synthesized using conditions similar to that described for Compound 16 and was converted to an HCI salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.65 - 1.82 (m, 3 H) 1.89 (br. S., 2 H) 1.98 - 2.08 (m, 2 H) 2.13 (br., 2 H) 2.47 - 2.55 (m, 2 H) 2.68 (d, J = 4.98 Hz, 6 H) 2.71 - 2.80 (m , 2 H) 3.29 - 3.71 (m, 10 H) 7.16 - 7.26 (m, 1 H) 7.67 (d, J = 9.66 Hz, 2 H) 7.91 ( d, J = 2.05 Hz, 1 H) 8.14 (br. s, 1 H) 8.48 (br. s, 1 H) 9.05 (s, 1 H) 11.14 (br . s., 1 H) 11.43 (br. s., 1 H). LCMS (ESI) 461 (M + H). Compound 46

[00357] Compound 46 was synthesized in a similar manner to that described for Compounds 2 and 3 and was recovered as an HCI salt. The analytical data were consistent with that described for Compound antipode 13. Compound 47

[00358] Compound 47 was synthesized in a similar manner to that described for Compounds 2 and 3 and was recovered as an HCI salt. The analytical data were consistent with that described for Compound antipode 15. Compound 48

[00359] Compound 48 was synthesized in a similar manner to that described for compound 16 and then converted to its hydrochloride salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.50 - 1.65 (m, 1 H) 1.92 - 2.02 (m, 3 H) 2.06 - 2.15 (m, 1 H ) 2.78 (d, J = 3.81 Hz, 4 H) 3.10 - 3.20 (m, 4 H) 3.47 - 3.51 (m, 2 H) 3.64 - 3.71 (m, 1 H) 3.76 - 3.83 (m, 2 H) 3.98 - 4.14 (m, 1 H) 7.20 (s, 2 H) 7.77 (s, 1 H) 7.97 (s, 2 H) 8.81 (s, 1 H) 9.03 (s, 1 H) 10.97 (brs., 1H). LCMS (ESI) 419 (M + H). 49

[00360] Compound 49 was synthesized in a similar manner to that described for compound 16 and then converted to its hydrochloride salt. 1H NMR (600 MHz, DMSO-de) δ ppm 1.54 - 1.59 (m, 1 H) 1.92-2.01 (m, 3 H) 2.06-2.15 (m, 1 H ) 2.76 - 2.84 (m, 1 H) 3.17-3.24 (m, 6 H) 3.64 - 3.71 (m, 2 H) 4.02 - 4.11 (m, 2 H) 7.22 (s, 2 H) 7.64 (s, 1 H) 7.97 (s, 2 H) 8.75 (s, 1 H) 8.97 (s, 1 H) 9, 21 (s, 1 H). LCMS (ESI) 405 (M + H). 50
Biological activity
[00361] Kinase enzyme reactions were performed in 384-well microplates using a 12-channel Caliper LabChip instrument as a detection device. The enzymatic phosphorylation of a peptide results in a change in net charge, allowing electrophoretic separation of product from substrate. When the substrate and the product are separated, two fluorescence peaks are observed. Change in the relative fluorescence intensity of the substrate and product peaks is the measured parameter, reflecting the enzyme activity. In the presence of an inhibitor, the relationship between product and substrate is changed. The product signal decreases, while the substrate signal increases.
[00362] For the measurement of CDK2 / cyclin E activity, the enzyme (0.22 nM) was incubated with 100 mM ATP and the phosphoaceptor substrate peptide (1 mM) for one hour. For the measurement of CDK4 / Cyclin D activity, the enzyme (0.85 nM) was incubated with 200 mM ATP and the phosphoaceptor substrate peptide (1 mM) for three hours. Potential inhibitory compounds (such as HCI salts) were tested using 12 point single-point dose-response curves in Km for ATP. The IC50 of each compound was determined using GraphPad Prism. The results of the IC50 values demonstrate 200 and 100 fold selectivity for Compound 1 and Compound 3 for Cdk4 / CycD1 over Cdk2 / CycE respectively. The results are provided in Table 1. Table 1.

[00363] Additional CDK2 / cyclin data are provided in Table 2. IC 50 data are as follows: A - 0.001-0.010 pM; B - 0.010-0.100 pM; C - 0.1-00-1 pM; D - 1 to 100 pM; and E -> 100 pM. Data are also shown for the known CDK4 / 6 inhibitor, PD0332991. Table 2.

Pharmaceutical compositions
[00364] In one embodiment a pharmaceutical composition comprising compounds of the invention is provided. In a first aspect, the pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and / or prophylactic ingredients. Such excipients are known to those skilled in the art. The compounds of the present invention include, without limitation, basic compounds such as free bases. A complete description of excipients and pharmaceutically acceptable salts is available from Remington's Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
[00365] Depending on the intended mode of administration, the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments , lotions or the like, preferably in unit dosage form suitable for single administration of an accurate dosage. The compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
[00366] The invention includes a pharmaceutical composition comprising a compound of the present invention including isomers, racemic and non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more pharmaceutically acceptable carriers and optionally other therapeutic ingredients and / or prophylactic ingredients.
[00367] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate and the like.
[00368] For oral administration, the composition will generally take the form of a tablet, capsule, a non-aqueous solution of a soft gel capsule, suspension or syrup. Tablets and capsules are preferred forms of oral administration. Tablets and capsules for oral use will usually include one or more commonly used vehicles, such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. When liquid suspensions are used, the active agent can be combined with emulsifying and suspending agents. If desired, flavoring, coloring and / or sweetening agents can be added as well. Other optional components for incorporation into an oral formulation here include, but are not limited to, preservatives, suspending agents, thickening agents and the like.
[00369] The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-1000 mg of active ingredient (s) for an individual of about 50 to 70 kg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg, or about 1 to 50 mg of active ingredients. The therapeutically effective dosage of a compound, pharmaceutical composition, or combinations thereof, is dependent on the individual's species, body weight, age and individual condition, the disorder or disease or the severity of the same being treated. A doctor, clinic or veterinarian with ordinary experience can easily determine the effective amount of each of the active ingredients needed to prevent, treat or inhibit the progress of the disorder or disease.
[00370] All publications and patent applications cited in this specification are hereby incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
[00371] Although the previous invention has been described in some detail by way of illustration and example for the purposes of clarity of understanding, it will be easily apparent to someone skilled in the art considering the teachings of this invention that certain changes and modifications can be made to it , without departing from the spirit or scope of the invention as defined in the appended claims.

权利要求:
Claims (16)
[0001]
1. Compound, characterized by the fact that it presents the formula Ii:
[0002]
2. Compound according to claim 1, characterized by the fact that it presents the formula:
[0003]
3. Compound according to claim 1 or 2, characterized by the fact that both X are N.
[0004]
A compound according to any one of claims 1 to 3, characterized in that R is hydrogen or C1-C3 alkyl.
[0005]
Compound according to any one of claims 1 to 3, characterized by the fact that R is hydrogen.
[0006]
A compound according to any one of claims 1 to 5, characterized by the fact that R2 is:
[0007]
7. Compound according to claim 1, characterized by the fact that it presents the formula:
[0008]
8. Compound according to claim 1, characterized by the fact that it presents the formula:
[0009]
9. Compound according to claim 5, characterized by the fact that it presents the formula:
[0010]
10. Compound according to claim 5, characterized by the fact that it presents the formula:
[0011]
11. Composed according to claim 1, characterized by the fact that it is selected from among the structures:
[0012]
12. Composed according to claim 1, characterized by the fact that it is selected among the structures:
[0013]
Pharmaceutical composition, characterized in that it comprises an effective amount of a compound as defined in any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
[0014]
Pharmaceutical composition according to claim 13, characterized in that the composition is in solid form.
[0015]
15. Pharmaceutical composition according to claim 13, characterized by the fact that the composition is in semi-solid form.
[0016]
16. Pharmaceutical composition according to claim 13, characterized by the fact that the composition is in liquid dosage form.

类似技术:

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公开号 | 公开日 | 专利标题

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AU2020203035B2|2021-09-16|CDK Inhibitors

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法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

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2018-04-03| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2019-05-21| B07E| Notice of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

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2019-07-09| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-12-17| B06A| Notification to applicant to reply to the report for non-patentability or inadequacy of the application [chapter 6.1 patent gazette]|

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2020-05-26| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2020-11-10| B16A| Patent or certificate of addition of invention granted|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 25/10/2011, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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US40649810P| true| 2010-10-25|2010-10-25|

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US61/406,498|2010-10-25|

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PCT/US2011/057749|WO2012061156A1|2010-10-25|2011-10-25|Cdk inhibitors|

---