Benzamides of pyrazolyl-amino-pyrimidinyl derivatives and compositions and methods thereof

Abstract

The present invention provides a new class of selectively potent JAK inhibitors that are orally and / or locally available, which are safe and effective therapeutic agents against a variety of different diseases and disorders. The invention also provides pharmaceutical compositions of these compounds and methods of making and using the same.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980076141.2, filed on December 16, 2019, entitled "Benzamide of Pyrazolyl-Amino-Pyrimidinyl Derivatives and Compositions and Methods Thereof".

[0002] Priority claims and related patent applications

[0003] This application claims priority to PCT International Application No. PCT / CN2018 / 121165, filed on December 14, 2018, the entire contents of which are incorporated herein by reference for all purposes. Technical Field

[0004] This invention generally relates to novel compounds and methods for using these compounds for therapeutic purposes. More specifically, this invention relates to a new class of therapeutic agents that are safe and effective JAK inhibitors. This invention also relates to pharmaceutical compositions of these compounds, methods for their preparation, and their use against a variety of diseases and disorders. Background Art

[0005] Janus kinases (JAKs) are a class of intracellular non-receptor tyrosine kinases that transduce cytokine-mediated signals via the Janus kinase-activator of transcription signal transduction (JAK-STAT) pathway. The human JAK enzyme family comprises four members: JAK1, JAK2, JAK3, and TYK2. This family is defined by the presence of two adjacent kinase domains, JH1 and JH2, where JH1 performs phosphorylation involved in pathway activation, while JH2 regulates the function of JH1. (Thomas et al., 2015 British Journal of Cancer 113, 365–371).

[0006] These cytoplasmic tyrosine kinases bind to membrane cytokine receptors such as the common γ-chain receptor and the transmembrane protein glycoprotein 130 (gp130) (Murray et al., 2007 Immunol. 178(5): 2623-2629). Approximately 40 cytokine receptors signal through combinations of these four JAKs with their seven downstream substrates, namely members of the STAT family (Ghoreschi et al., 2009 Immunol Rev. 228(l): 273-287).

[0007] The JAK-STAT signaling pathway communicates with the cell nucleus via extracellular chemical signals, activating genes through transcription and playing a crucial role in many fundamental biological processes such as apoptosis and inflammation. Dysfunction of the JAK-STAT pathway can lead to a wide range of diseases, including cancer and diseases affecting the immune system.

[0008] There is growing interest in JAK inhibitors as drugs that inhibit the activity of one or more members of the JAK family, thereby interfering with the JAK-STAT signaling pathway. Some JAK inhibitors have been shown to have therapeutic benefits in the treatment of cancer or inflammatory diseases such as rheumatoid arthritis. (Kontzias et al., 2012 Current Opinion in Pharmacology 12(4):464–70; Pesu et al., 2008 Immunological Reviews 223:132–42; Norman 2014 Expert Opinion on Investigational Drugs 23(8):1067–77; Forster et al., 2017 Bioorganic & Medicinal Chemistry Letters 27(18):4229–4237).

[0009] The development of JAK inhibitors that are less likely to induce resistance in cancer treatment remains challenging, but is essential for improving the long-term efficacy of such drugs. There is an urgent need across a broad range of therapeutic areas for JAK inhibitors that offer improved efficacy and minimal side effects compared to existing treatments, and that are less likely to induce or overcome resistance. Summary of the Invention

[0010] This invention provides novel selective and potent compounds that are orally and / or topically available, and / or suitable for gastrointestinal (GI) tract localized and / or local administration. These therapeutic agents are safe and effective JAK inhibitors and may exhibit fewer and / or less severe side effects than currently available drugs. This invention provides pharmaceutical compositions of these compounds and methods for their preparation and use.

[0011] This article discloses a series of novel JAK inhibitors specifically designed to suit potential applications for (I) oral administration or (II) GI and / or topical dermal use. For compounds designed for oral administration, they are potent against JAK2 and exhibit superior selectivity compared to other JAK kinases, along with favorable overall pharmacological properties. For compounds potentially suitable for GI-restricted or topical dermal use, they are designed to exhibit strong pan-JAK activity, including JAK1 and / or TYK2. Specifically, these compounds are designed to exhibit minimal oral absorption to limit systemic exposure, but high exposure at the site of action, particularly in the gastrointestinal tract.

[0012] This new class of inhibitors exhibits remarkable efficacy curves, with JAK2 IC50 values ​​in the low nanomolar range at Km ATP concentrations. 50Values. Some of these compounds also show remarkable efficacy against JAK1 and / or TYK2.

[0013] In one respect, the present invention generally relates to a compound having structural formula (I):

[0014]

[0015] in

[0016] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0017] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0018] R 1 It is Cl;

[0019] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is optionally substituted with one or more of halogen, OR', NRR', CN, CONRR', NRCOR' and C1-C6 alkyl, and the one or more of them is further optionally substituted with F, OR' or NRR';

[0020] R 3 It is R', halogen, or CN;

[0021] R 4’ It is an H or C1-C6 alkyl group;

[0022] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0023] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0024] Or its pharmaceutically acceptable form or isotope derivative.

[0025] On the other hand, the present invention generally relates to a compound having structural formula (I):

[0026]

[0027] in

[0028] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0029] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0030] R 1 It is CH3;

[0031] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is replaced by one or more of CN, CONRR' or NRCOR', and the one or more of them are optionally replaced by F, OR' or NRR';

[0032] R 3 It is R', halogen, or CN;

[0033] R 4’ It is an H or C1-C6 alkyl group;

[0034] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0035] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0036] Or its pharmaceutically acceptable form or isotope derivative.

[0037] On the other hand, the present invention generally relates to a compound having structural formula (I):

[0038]

[0039] in

[0040] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0041] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0042] R 1 It is CH3;

[0043] R 2 It is a C3-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is replaced by 0-4 C1-C6 alkyl groups;

[0044] R 3 It is R', halogen, or CN;

[0045] R 4’ It is an H or C1-C6 alkyl group;

[0046] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0047] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0048] Or its pharmaceutically acceptable form or isotope derivative.

[0049] On the other hand, the present invention generally relates to a pharmaceutical composition comprising compounds disclosed herein that are effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and pharmaceutically acceptable excipients, carriers, or diluents.

[0050] On the other hand, the present invention generally relates to a pharmaceutical composition comprising a compound having a structural formula (I) that is effective in treating or alleviating one or more diseases or disorders in mammals, including humans:

[0051]

[0052] in

[0053] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0054] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0055] R 1 It is Cl;

[0056] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is optionally substituted with one or more of halogen, OR', NRR', CN, CONRR', NRCOR' and C1-C6 alkyl, and the one or more of them is further optionally substituted with F, OR' or NRR';

[0057] R 3 It is R', halogen, or CN;

[0058] R 4’ It is an H or C1-C6 alkyl group;

[0059] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0060] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0061] Or its pharmaceutically acceptable form or isotope derivatives, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0062] On the other hand, the present invention generally relates to a pharmaceutical composition comprising a compound having a structural formula (I) that is effective in treating or alleviating one or more diseases or disorders in mammals, including humans:

[0063]

[0064] in

[0065] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0066] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0067] R 1 It is CH3;

[0068] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is replaced by one or more of CN, CONRR' or NRCOR', and the one or more of them are optionally replaced by F, OR' or NRR';

[0069] R 3 It is R', halogen, or CN;

[0070] R 4’ It is an H or C1-C6 alkyl group;

[0071] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0072] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0073] Or its pharmaceutically acceptable form or isotope derivatives, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0074] On the other hand, the present invention generally relates to a pharmaceutical composition comprising a compound having a structural formula (I) that is effective in treating or alleviating one or more diseases or disorders in mammals, including humans:

[0075]

[0076] in

[0077] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0078] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0079] R 1 It is CH3;

[0080] R 2 It is a C3-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is substituted by 0 to 4 C1-C6 alkyl groups;

[0081] R 3 It is R', halogen, or CN;

[0082] R 4’ It is an H or C1-C6 alkyl group;

[0083] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0084] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0085] Or its pharmaceutically acceptable form or isotope derivatives, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0086] On the other hand, the present invention generally relates to a unit dosage form comprising the pharmaceutical compositions disclosed herein.

[0087] On the other hand, the present invention generally relates to a method for treating or alleviating a disease or disorder, the method comprising: administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a compound having a structural formula (I) that is effective in treating, preventing or alleviating one or more inflammatory diseases, immune-mediated diseases, cancer or related diseases or disorders in mammals, including humans:

[0088]

[0089] in

[0090] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0091] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0092] R 1 It is Cl;

[0093] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is optionally substituted with one or more of halogen, OR', NRR', CN, CONRR', NRCOR' and C1-C6 alkyl, and the one or more of them is further optionally substituted with F, OR' or NRR';

[0094] R 3 It is R', halogen, or CN;

[0095] R 4’ It is an H or C1-C6 alkyl group;

[0096] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0097] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0098] Or its pharmaceutically acceptable form or isotope derivatives, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0099] On the other hand, the present invention generally relates to a method for treating or alleviating a disease or disorder, the method comprising: administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a compound having a structural formula (I) that is effective in treating, preventing or alleviating one or more inflammatory diseases, immune-mediated diseases, cancer or related diseases or disorders in mammals, including humans:

[0100]

[0101] in

[0102] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0103] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0104] R 1 It is CH3;

[0105] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is replaced by one or more of CN, CONRR' or NRCOR', and the one or more of them are optionally replaced by F, OR' or NRR';

[0106] R 3 It is R', halogen, or CN;

[0107] R 4’ It is an H or C1-C6 alkyl group;

[0108] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0109] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0110] Or its pharmaceutically acceptable form or isotope derivatives, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0111] On the other hand, the present invention generally relates to a method for treating or alleviating a disease or disorder, the method comprising: administering a pharmaceutical composition to a subject in need, the pharmaceutical composition comprising a compound having a structural formula (I) that is effective in treating, preventing or alleviating one or more inflammatory diseases, immune-mediated diseases, cancer or related diseases or disorders in mammals, including humans:

[0112]

[0113] in

[0114] X is N or CR x , where R x It is R', halogen, CN, or OR';

[0115] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0116] R 1 It is CH3;

[0117] R 2 It is a C3-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic group, wherein the aliphatic group is replaced by 0-4 C1-C6 alkyl groups;

[0118] R 3 is R', halogen, or CN;

[0119] R 4’ It is an H or C1-C6 alkyl group;

[0120] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen, OR', NRR', CN, CONRR', NRCOR', and C1-C6 alkyl groups, and said one or more of said alkyl groups is further optionally substituted with F, OR', or NRR'; and

[0121] Each of R and R' is independently hydrogen or C1-C. 12 Unsubstituted or substituted alkyl groups,

[0122] Or its pharmaceutically acceptable form or isotope derivatives, as well as pharmaceutically acceptable excipients, carriers or diluents.

[0123] On the other hand, the present invention generally relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers or diluents for the preparation of medicaments for the treatment of diseases or disorders.

[0124] definition

[0125] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The general principles of organic chemistry, as well as specific functional components and reactivity, are described in *Organic Chemistry* (Thomas Sorrell, University ScienceBooks, Sausalito: 2006).

[0126] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds falling within its scope, including cis- and trans-isomers, trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and other mixtures thereof. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0127] According to the present invention, mixtures of isomers containing any of a variety of different isomer ratios can be used. For example, in the case of combining only two isomers, the present invention covers mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily recognize that similar ratios have been conceived for more complex mixtures of isomers.

[0128] If, for example, a specific enantiomer of the compound of the present invention is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent. In the latter method, the resulting mixture of diastereomers is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomer salt is formed with a suitable optically active acid or base, and the resulting diastereomer is then resolved by stepwise crystallization or chromatography methods known in the art, followed by recovery of the pure enantiomer.

[0129] Solvates and polycrystalline forms of the compounds of the present invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0130] The definitions of specific functional groups and chemical terms are described in more detail below. When a range of values ​​is listed, it is intended to cover every value and subrange within that range. For example, "C 1-6 The term "alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, and C6 alkyl groups. 1-6 C 1-5 C 1-4 C 1-3 C 1-2 C 2-6 C 2-5 C 2-4 C 2-3 C 3-6 C 3-5 C 3-4 C 4-6 C 4-5 and C 5-6 alkyl.

[0131] Where substituents are described in detail using their conventional chemical formulas written from left to right, they also encompass chemically identical substituents obtained by writing the structure from right to left, for example, -C(=O)-O- is equivalent to -OC(=O)-.

[0132] The structures of the compounds of the present invention are limited by the principles of chemical bonding known to those skilled in the art. Thus, where groups may be substituted by one or more of a variety of substituents, these substitutions are chosen to comply with the principles of chemical bonding and to give compounds that are not inherently unstable and / or that are known to those skilled in the art to be unstable under environmental conditions (e.g., aqueous, neutral, and several known physiological conditions).

[0133] When used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, which is unsaturated and has 1 to 10 carbon atoms (e.g., C10, C20, C30, C40, C50, C60, C70, C80, C9 ... 1-10 Alkyl). Whenever it appears herein, a numerical range, such as "1 to 10," refers to each integer within a given range; for example, "1 to 10 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although this definition also covers the case where the term "alkyl" is not specified within a numerical range. In some embodiments, "alkyl" can be C 1-6Alkyl groups. In some embodiments, the alkyl group has 1 to 10, 1 to 8, 1 to 6, or 1 to 3 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; while saturated branched alkyl groups include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is attached to the parent molecule by a single bond. Unless otherwise stated in this specification, the alkyl group is optionally substituted with one or more substituents, which independently include: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidine, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfone, sulfonate, urea, -Si(R a )3, -OR a -SR a , -OC(O)-R a , -N(R a )2,-C(O)R a -C(O)OR a , -OC(O)N(R a )2,-C(O)N(R a )2,-N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2,-N(R a )C(NR a )N(R a )2,-N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a (R) a ) or -OP(=O)(OR a )2, where each R aIndependently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl, or heteroarylalkyl, and each of these components may optionally be substituted as defined herein. In non-limiting embodiments, the substituted alkyl group may be selected from fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, and phenethyl.

[0134] When used herein, the term "alkoxy" refers to -O-alkyl, including 1 to 10 carbon atoms (C1 to C2) attached to the parent molecule structure via oxygen. 1-10 The straight-chain, branched, saturated cyclic configurations and combinations thereof of alkoxy. Examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, cyclopropoxy, cyclohexyloxy, etc. "Short-chain alkoxy" refers to an alkoxy group containing 1 to 6 carbons. In some embodiments, C 1-3 Alkoxy groups are both straight-chain and branched alkyl groups encompassing 1 to 3 carbon atoms. Unless otherwise stated in this specification, alkoxy groups may optionally be substituted with one or more substituents, which independently include: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryl, amino, amide, amidine, imino, azido, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfone, sulfonate, urea, -Si(R) a )3, -OR a -SR a , -OC(O)-R a , -N(R a )2,-C(O)R a -C(O)OR a , -OC(O)N(R a )2,-C(O)N(R a )2, -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2,-N(R a )C(NR a )N(R a )2,-N(R a )S(O) t N(Ra )2 (where t is 1 or 2), -P(=O)(R a (R) a ) or -OP(=O)(OR a )2, where each R a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl, and each of these components may optionally be substituted as defined herein.

[0135] When used herein, the terms "aromatic" or "aryl" refer to groups having 6 to 14 ring atoms (e.g., C14, C24, C34, C44, C54, C6 ... 6-14 Aromatic compounds or C 6-14 Aryl groups (e.g., phenyl, fluorenyl, and naphthyl) having at least one carbocyclic ring with a conjugated π-electron system. In some embodiments, the aryl group is C... 6-10 Aryl groups. For example, a divalent group formed from a substituted benzene derivative and having a free valence at a ring atom is named a substituted phenylene group. In other embodiments, a divalent group derived from a monovalent polycyclic hydrocarbon group whose name ends in "-yl" by removing a hydrogen atom from a carbon atom having a free valence is named by adding "-yl" to the name of the corresponding monovalent group; for example, a naphthyl group with two attachment points is called a naphthylene group. Whenever it appears herein, numerical ranges such as "6 to 14 aryl" refer to each integer within a given range; for example, "6 to 14 ring atoms" means that the aryl group can consist of 6 ring atoms, 7 ring atoms, etc., up to and including 14 ring atoms. The term includes monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In polycyclic groups, only one ring needs to be aromatic; therefore, groups such as indanyl are covered by the definition of aryl. Non-limiting examples of aryl groups include phenyl, benzo[a]naphthyl, naphthyl, tetrahydronaphthyl, phenanthryl, anthracene, fluorenyl, indole, indanyl, etc. Unless otherwise stated in this specification, the aryl component may optionally be substituted with one or more substituents, which independently include: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidyl, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfone, sulfonate, urea, -Si(R) a )3, -OR a -SR a, -OC(O)-R a , -N(R a )2,-C(O)R a -C(O)OR a , -OC(O)N(R a )2,-C(O)N(R a )2,-N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2,-N(R a )C(NR a )N(R a )2,-N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a (R) a ) or -OP(=O)(OR a )2, where each R a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl, and each of these components may optionally be substituted as defined herein.

[0136] When used herein, the terms "cycloalkyl" and "carbocyclic" each refer to a monocyclic or polycyclic group containing only carbon and hydrogen, and which may be saturated or partially unsaturated. A partially unsaturated cycloalkyl group may be referred to as "cycloalkenyl" if the carbocyclic ring contains at least one double bond, or as "cycloynyl" if the carbocyclic ring contains at least one triple bond. Cycloalkyl groups include groups having 3 to 13 ring atoms (i.e., C16-C16). 3-13 (Cycloalkyl). Whenever it appears herein, numerical ranges, such as "3 to 10," refer to each integer within a given range; for example, "3 to 13 carbon atoms" means that the cycloalkyl group can be composed of 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, etc., up to and including 13 carbon atoms. The term "cycloalkyl" also includes bridging and helical fused cyclic structures without heteroatoms. The term also includes monocyclic or fused polycyclic (i.e., rings sharing adjacent paired ring atoms) groups. Polycyclic aryl groups include bicyclic, tricyclic, tetracyclic, etc. In some embodiments, "cycloalkyl" can be C 3-8 Cycloalkyl group. In some embodiments, "cycloalkyl" may be C10. 3-5 Cycloalkyl groups. Illustrative examples of cycloalkyl groups include, but are not limited to, the following components: C 3-6Carbocyclic groups, including but not limited to cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), etc. 3-7 Examples of carbocyclic groups include noborneol (C7). 3-8 Examples of carbocyclic groups include the C mentioned above. 3-7 Carbocyclic groups, as well as cycloheptyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, etc. 3-13 Examples of carbocyclic groups include the C mentioned above. 3-8 Carbocyclic groups, as well as octahydro-1H indenyl, decahydronaphthyl, spiro[4.5]decyl, etc. Unless otherwise stated in this specification, cycloalkyl groups may optionally be substituted with one or more substituents, which independently include: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidyl, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfone, sulfonate, urea, -Si(R a )3, -OR a -SR a , -OC(O)-R a , -N(R a )2,-C(O)R a -C(O)OR a , -OC(O)N(R a )2,-C(O)N(R a )2,-N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2,-N(R a )C(NR a )N(R a )2,-N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a (R) a ) or -OP(=O)(OR a )2, where each Ra Independently, it is hydrogen, alkyl, haloalkyl, carbocycloyl, carbocycloalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, and each of these components may optionally be substituted as defined herein. The terms “cycloalkenyl” and “cycloynyl” reflect the above description of “cycloalkyl”, wherein the prefix “alkane” is replaced by “ene” or “ynyne” respectively, and the parent terms “alkenyl” or “ynyne” are as described herein. For example, a cycloalkenyl group may have 3 to 13 ring atoms, such as 5 to 8 ring atoms. In some embodiments, a cycloynyl group may have 5 to 13 ring atoms.

[0137] When used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). When used herein, the terms "halide" or "halogenated" mean fluorine, chlorine, bromine, or iodine. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl, and alkoxy structures substituted with one or more halogen groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" respectively include alkyl and alkoxy halogroups wherein the halogen is fluorine, such as, but not limited to, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, etc. Each of the alkyl, alkenyl, alkynyl, and alkoxy groups is as defined herein and may optionally be further substituted as defined herein.

[0138] When used in this document, the term “heteroatoms” refers to oxygen (O), nitrogen (N), sulfur (S), and phosphorus (P).

[0139] When used herein, the term "heteroalkyl" refers to an alkyl group having one or more skeletal chain atoms selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. Numerical ranges can be provided, for example, C. 1-4Heteroalkyl refers to the overall chain length, which in this example is 4 atoms long. For example, the -CH2OCH2CH3 group is called a "C4" heteroalkyl, which includes the heteroatom center in the atomic chain length description. The connection to the parent molecule structure can be via heteroatoms or carbons in the heteroalkyl chain. For example, an N-containing heteroalkyl component refers to a group in which at least one skeletal atom is a nitrogen atom. One or more heteroatoms in the heteroalkyl group may optionally be oxidized. One or more nitrogen atoms, if present, may also optionally be quaternized. For example, heteroalkyl also includes skeletal chains substituted with one or more oxynitride (-O-) substituents. Exemplary heteroalkyl groups include, but are not limited to, ethers such as methoxyethane (-CH2CH2OCH3), ethoxymethane (-CH2OCH2CH3), (methoxymethoxy)ethane (-CH2CH2OCH2OCH3), (methoxymethoxy)methane (-CH2OCH2OCH3), and (methoxyethoxy)methane (-CH2OCH2CH2OCH3), and amines such as (-CH2CH2NHCH3, -CH2CH2N(CH3)2, -CH2NHCH2CH3, -CH2N(CH2CH3)(CH3)), etc.

[0140] When used herein, the term "heteroaryl" or optionally "heteroaromatic" refers to a 5-18 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic, tetracyclic, etc.) aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) having a cyclic carbon atom and 1-6 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-18 membered heteroaryl"). A heteroaryl polycyclic ring system may include one or more heteroatoms in one or two rings. Whenever it appears herein, numerical ranges such as "5 to 18" refer to each integer within a given range; for example, "5 to 18 ring atoms" means that the heteroaryl can consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. In some cases, a heteroaryl can have 5 to 14 ring atoms. In some embodiments, the heteroaryl group has a divalent group derived, for example, from a monovalent heteroaryl group whose name ends with "-aryl" by removing a hydrogen atom from an atom having a free valence, and is named by adding "-pyridyl" to the name of the corresponding monovalent group, for example, a pyridyl group having two attachment points is a pyridylene group.

[0141] For example, an N-containing "heteroaryl" or "heteroaryl" component refers to an aromatic group in which at least one skeletal atom of the ring is a nitrogen atom. One or more heteroatoms in the heteroaryl group may optionally be oxidized. One or more nitrogen atoms, if present, may also optionally be quaternized. Heteroaryls also include ring systems substituted with one or more oxynitride (-O-) substituents, such as pyridyl N-oxide. Heteroaryls are attached to the parent molecular structure via any atom of the ring.

[0142] "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, wherein the attachment point to the parent molecule is on the aryl group or the heteroaryl ring, or ring systems in which a heteroaryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the attachment point to the parent molecule is on the heteroaryl ring. For polycyclic heteroaryl groups (e.g., indole, quinolinyl, carbazolyl, etc.) in which one ring does not contain a heteroatom, the attachment point to the parent molecule can be on either ring, i.e., on a ring with a heteroatom (e.g., 2-indole) or a ring without a heteroatom (e.g., 5-indole). In some embodiments, the heteroaryl is a 5-10 membered aromatic ring system having a cyclic carbon atom and providing 1-4 cyclic heteroatoms in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, phosphorus, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 cyclic heteroatom selected from nitrogen, oxygen, phosphorus, and sulfur.

[0143] Examples of heteroaryl groups include, but are not limited to, aziridinetrienyl, acridine, benzimidazolyl, benzoindolyl, 1,3-benzo[1,4]dioxacyclopentenyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxacycloheptenyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxacyclohexyl, benzonaphthofuranyl, benzooxazolyl, benzo[1,4]dioxacyclopentenyl, benzodioxyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzopyranoneyl, benzofuranyl, benzofuranyl, benzothiazolyl, benzothiophene (benzothiophenyl), benzothiaphene[3,2-d]pyrimidinyl, benzotriazolyl, benzo[1,4]dioxacyclopentenyl, benzo[1,4]oxazinyl, benzo[1,4]dioxacyclohex ... [4,6]Imidazolo[1,2-a]pyridyl, carbazolyl, cyclopentano[d]pyrimidinyl, 6,7-dihydro-5H-cyclopentano[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cynolyl, 6,7-dihydro-5H-benzo[6,7]cycloheptano[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothienoyl, furanyl, furazolidyl, furanone, furano[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclooctano[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocyclo Octano[d]pyridyl, isothiazolyl, imidazolyl, indazole, indolyl, indazole, isoindolyl, indololinyl, isoindololinyl, isoquinolinyl, indene, isoxazolyl, 5,8-bridged methylene-5,6,7,8-tetrahydroquinazolinyl, naphridyl, 1,6-naphridinone, oxadiazolyl, 2-oxazolidinyl heptatrienyl, oxazolyl, oxazolidinyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrroleyl, phenazinyl, phenthiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyranyl, pyrroleyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridyl, pyrido[3,2-d]pyrimidinyl Pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroloyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cycloheptano[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiaranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienoyl).Unless otherwise stated in this specification, the heteroaryl component may optionally be substituted with one or more substituents, which independently include: acyl, alkyl, alkenyl, alkoxy, alkylaryl, cycloalkyl, aralkyl, aryl, aryloxy, amino, amide, amidine, imino, azide, carbonate, carbamate, carbonyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydroxyl, cyano, halogen, haloalkoxy, haloalkyl, ester, ether, mercapto, thio, alkylthio, arylthio, thiocarbonyl, nitro, oxo, phosphate ester, phosphonate, hypophosphonate, silyl, sulfinyl, sulfonyl, sulfonamide, sulfone, sulfonate, urea, -Si(R). a )3, -OR a -SR a , -OC(O)-R a , -N(R a )2,-C(O)R a -C(O)OR a , -OC(O)N(R a )2,-C(O)N(R a )2,-N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)N(R a )2,-N(R a )C(NR a )N(R a )2,-N(R a )S(O) t N(R a )2 (where t is 1 or 2), -P(=O)(R a (R) a ) or -OP(=O)(OR a )2, where each R a Independently, it is hydrogen, alkyl, haloalkyl, carbocyclic, carbocyclic alkyl, aryl, aralkyl, heterocyclic alkyl, heterocyclic alkylalkyl, heteroaryl or heteroarylalkyl, and each of these components may optionally be substituted as defined above.

[0144] When used herein, the term "administration" refers to oral administration, administration as a suppository, local contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal, or subcutaneous administration to a subject, or implantation of a sustained-release device such as a micro-peristaltic pump. The appropriate route of administration for a particular patient depends on the nature and severity of the disease or condition to be treated, or the nature of the therapy used and the nature of the active compound.

[0145] Administration can be administered via any suitable route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intradermal, subcutaneous, intraperitoneal, intravenous, and intracranial administration. Other delivery methods include, but are not limited to, the use of liposomal formulations, intravenous infusion, and transdermal patches.

[0146] "Co-administration" means that the composition described herein is administered at the same time as, just before, or immediately after one or more other therapies.

[0147] The compounds of the present invention can be administered to a patient alone or co-administered. Co-administration means administering the compounds individually or in combination (more than one compound or agent) simultaneously or sequentially. Therefore, the formulations can also be combined with other active substances when needed (e.g., to reduce metabolic degradation).

[0148] The compositions of the present invention can be delivered transdermally, via a local route, or formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jelly, coatings, powders, and aerosols. Oral formulations include tablets, pills, powders, sugar-coated pills, capsules, liquids, lozenges, capsules, gels, syrups, slurries, suspensions, etc., suitable for ingestion by a patient. Solid formulations include powders, tablets, pills, capsules, capsules, suppositories, and dispersible granules. Liquid formulations include solutions, suspensions, emulsions, and gels, such as water or water / propylene glycol solutions.

[0149] The compositions of the present invention may further comprise components that provide sustained release and / or comfort. These components include high molecular weight anionic mucilage-like polymers, gelling polysaccharides, and finely divided drug carrier substances. These components are discussed in more detail in U.S. Patent Nos. 4,911,920, 5,403,841, 5,212,162, and 4,861,760. The entire contents of these patents are incorporated herein by reference for all purposes. The compositions of the present invention may also be delivered as microspheres for slow release in vivo. For example, microspheres can be administered via intradermal injection of drug-containing microspheres that release slowly under the skin (see Rao, 1995 J. Biomater Sci. Polym. Ed. 7:623-645), as a biodegradable and injectable gel formulation (see, for example, Gao 1995 Pharm. Res. 12:857-863), or as microspheres for oral administration (see, for example, Eyles 1997 J. Pharm. Pharmacol. 49:669-674).

[0150] When used herein, the terms “disease,” “symptom,” and “disorder” are used interchangeably and refer to the state of being or health of a patient or subject that can be treated with the compounds, pharmaceutical compositions, or methods provided herein.

[0151] When used herein, the term "effective amount" of an active pharmaceutical agent means an amount sufficient to elicit the desired biological response. As will be appreciated by those skilled in the art, the effective amount of the compounds of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease to be treated, the route of administration, and the patient.

[0152] When used herein, for the purpose of biological target (e.g., JAK) inhibitor interactions, the term "inhibition" means a negative impact (e.g., a reduction) on the activity or function of a protein relative to the absence of said inhibitor. In embodiments, inhibition means a negative impact (e.g., a reduction) on the concentration or level of a protein relative to the absence of said inhibitor. In embodiments, inhibition refers to the reduction of a disease or disease symptoms. In embodiments, inhibition refers to a reduction in the activity of a specific protein target. Inhibition includes at least in part a partial or complete blockage, reduction, inhibition, or delay or inactivation, desensitization, or downregulation of the signal transduction or enzyme activity or amount of a protein. In embodiments, inhibition refers to a reduction in the activity of a target protein caused by a direct interaction (e.g., an inhibitor binding to a target protein). In embodiments, inhibition refers to a reduction in the activity of a target protein caused by an indirect interaction (e.g., an inhibitor binding to a protein that activates the target protein, thereby preventing the target protein from activating).

[0153] When used herein, the terms “isolated” or “purified” refer to material that is substantially or substantially free of the components that are normally associated with it in its original state. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high-performance liquid chromatography.

[0154] When used herein, the term "medicinal form" of the disclosed compounds includes, but is not limited to, pharmaceutically acceptable salts, esters, hydrates, solvates, isomers, prodrugs, and isotopically labeled derivatives thereof. In one embodiment, "medicinal form" includes, but is not limited to, pharmaceutically acceptable salts, esters, prodrugs, and isotopically labeled derivatives thereof. In some embodiments, "medicinal form" includes, but is not limited to, pharmaceutically acceptable isomers and stereoisomers, prodrugs, and isotopically labeled derivatives thereof.

[0155] In some embodiments, the pharmaceutically acceptable form is a pharmaceutically acceptable salt. When used herein, the term "pharmaceutically acceptable salt" means a salt that is suitable for contact with the tissues of a subject to sound medical judgment without excessive toxicity, irritation, anaphylactic response, etc., and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptable salts of the compounds provided herein include salts derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, non-toxic acid addition salts are salts of an amino group formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with an organic acid such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-p-ethylhexanoate, glyceryl phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, p-toluenesulfonate, undecanoate, valerate, etc. In some embodiments, organic acids from which their salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0156] The salts can be prepared in situ during the isolation and purification of the disclosed compounds, or separately, for example, by reacting the free base or free acid of the parent compound with a suitable base or acid, respectively. Pharmaceutically acceptable salts derived from suitable bases include alkali metals, alkaline earth metals, ammonium, and nitrogen. + (C 1-4Alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using balancing ions such as halide ions, hydroxide ions, carboxyl ions, sulfate ions, phosphate ions, nitrate ions, short-chain alkyl sulfonates, and aryl sulfonates. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines include naturally occurring substituted amines, cyclic amines; basic ion exchange resins, etc., such as isopropylamine, trimethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt may be selected from ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0157] In some embodiments, the pharmaceutically acceptable form is a "solvent" (e.g., a hydrate). When used herein, the term "solvent" refers to a compound that also includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. The solvate may be a solvate of the disclosed compound or a pharmaceutically acceptable salt thereof. When the solvent is water, the solvate is a "hydrate". Pharmaceutically acceptable solvates and hydrates are complexes that may, for example, include 1 to about 100, or 1 to about 10, or 1 to about 2, about 3, or about 4 solvent or water molecules. It should be understood that, when used herein, the term "compound" encompasses the compound and its solvates and mixtures thereof.

[0158] In some embodiments, the pharmaceutically acceptable form is a prodrug. When used herein, the term "prodrug" refers to a compound that is converted in vivo to produce the disclosed compound or a pharmaceutically acceptable form of said compound. A prodrug may be inactive upon administration to a subject, but is converted in vivo into an active compound by, for example, hydrolysis (e.g., hydrolysis in the blood). In some cases, a prodrug has improved physical and / or delivery properties compared to the parent compound. A prodrug may improve the bioavailability of the compound upon administration to a subject (e.g., by allowing enhanced absorption into the bloodstream after oral administration) or enhance delivery to biological compartments of interest (e.g., the brain or lymphatic system) relative to the parent compound. Exemplary prodrugs include derivatives of the disclosed compound that have enhanced water solubility relative to the parent compound or active transport via the intestinal membrane.

[0159] The prodrug compounds typically offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see, for example, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam)). Discussions of prodrugs are provided in Higuchi, T. et al., “Prodrugs as Novel Delivery Systems,” ACSSymposium Series, No. 14, and “Bioreversible Carriers in Drug Design,” edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

[0160] Prodrug forms typically offer advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms. (See Bundgard, *Design of Prodrugs*, pp. 7-9, 21-24, Elsevier, Amsterdam 1985; and Silverman, *The Organic Chemistry of Drug Design and Drug Action*, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugs known in the art include well-known acid derivatives, such as esters prepared by reacting a parent acid with a suitable alcohol, amides prepared by reacting a parent acid compound with an amine, and basic derivatives formed by reacting a basic group to form an acylated base. Other prodrug derivatives may incorporate other features disclosed herein to enhance bioavailability. Therefore, those skilled in the art will recognize that certain compounds of this disclosure having free amino, amide, hydroxyl, or carboxyl groups can be converted into prodrugs. Prodrugs include compounds having a carbonate, carbamate, amide, or alkyl ester component covalently bonded to any of the substituents disclosed herein.

[0161] Exemplary advantages of prodrugs include, but are not limited to, their physical properties, such as enhanced water solubility compared to the parent compound, for parenteral administration at physiological pH, or their ability to enhance absorption from the digestive tract, or their ability to improve drug stability for long-term storage.

[0162] When used herein, the terms “medicinal” excipient, carrier, or diluent refer to a pharmaceutically acceptable material, composition, or medium, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material, which participates in carrying or transporting the subject pharmaceutical agent from one organ or body part to another. Each carrier must be “acceptable” in the sense of compatibility with other components of the said formulation and being harmless to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; astragalus gum powder; malt; gelatin; talc; excipients, such as cocoa butter and suppository waxes; oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols, such as propylene glycol; polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters, such as ethyl oleate and ethyl laurate; agar; buffers, such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffer solutions; and other non-toxic compatible substances used in pharmaceutical formulations. Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-propylene oxide copolymers, as well as colorants, release agents, coating agents, sweeteners, flavoring agents and flavor enhancers, preservatives, and antioxidants may also be present in the composition.

[0163] When used herein, the term “object” means any animal (e.g., a mammal) that is a recipient of a particular treatment, including but not limited to humans, non-human primates, rodents, etc. Objects to which the drug is administered are contemplated, including but not limited to humans (e.g., males or females of any age group, such as pediatric objects (e.g., infants, children, adolescents) and adult objects (e.g., young adults, middle-aged adults, or elderly adults)) and / or other non-human animals such as non-human mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys; commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs), rodents (e.g., rats and / or mice)), etc. In some embodiments, the non-human animal is a mammal. The non-human animal can be male or female at any developmental stage. The non-human animal may be a genetically modified animal. Generally, the terms “object” and “patient” are used interchangeably herein to refer to a human object.

[0164] When used herein, the term “treatment” for a disease or disorder refers to a method of reducing, delaying, or improving such a condition before or after its onset. Treatment may target one or more effects or symptoms of the disease and / or the underlying pathology. Treatment can be any reduction and may be, but is not limited to, the complete elimination of the disease or its symptoms. Thus, treatment refers to any sign of success in the therapy or improvement of an injury, disease, pathology, or symptom, including any objective or subjective parameter such as elimination, relief, reduction of symptoms, or making said injury, pathology, or symptom more tolerable to the patient, slowing the rate of deterioration or decline, reducing the debilitating effects of degenerative endpoints, or improving the patient’s physical or mental health. Treatment or improvement of symptoms may be based on objective or subjective parameters such as the results of a physical examination, neuropsychiatric examination, and / or psychiatric assessment. When measured by any standard technique, the degree of such reduction or improvement compared to an equivalent untreated control may be at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95%, or 100%.

[0165] Treatment methods include administering a therapeutically effective amount of the compound described herein to the subject. The administration step may be a single dose or may include a series of doses. The duration of treatment depends on various factors, such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used in the treatment, or combinations thereof. It should also be recognized that the effective dose of the agent used for treatment may increase or decrease during a particular mode of treatment. Dosage variations may play a role and become apparent through standard diagnostic assays known in the art. In some cases, prolonged administration may be required. For example, the composition may be administered to the subject in an amount and duration sufficient to treat the patient. Invention Details

[0167] This invention is based on the unexpected discovery of novel selective and potent compounds that are orally and / or topically available and / or suitable for gastrointestinal (GI) tract-limited administration. A series of novel JAK inhibitors are disclosed herein, which have been potentially suited for (I) oral administration or (II) GI and / or topical application. For compounds designed for oral administration, they are potent against JAK2 and exhibit superior selectivity over other JAK kinases, as well as favorable overall pharmaceutical properties. For compounds potentially suitable for GI-limited or topical application, they are designed to exhibit strong pan-JAK activity, including JAK1 and / or TYK2. Specifically, these compounds are designed to exhibit minimal oral absorption to limit systemic exposure, but high exposure at the site of action, particularly in the gastrointestinal tract.

[0168] Inhibition of JAK2 inevitably suppresses immune function and may increase the risk of both bacterial and viral infections. By restricting JAK inhibition to the GI tract for GI-limited compounds or to a localized location for compounds designed for topical application to the skin, systemic exposure to these compounds can be significantly reduced or eliminated, thereby preserving immune function. In oncology indications where JAK2 is a driver of cancer and JAK2 inhibition is a suitable therapeutic approach, selective JAK2 inhibitors preserve immune function independent of JAK2 signaling.

[0169] The selected compounds of this invention are suitable for oral administration to combat cancer. These compounds are engineered to exhibit good efficacy against JAK2 and possess good oral absorption and good in vivo stability. Furthermore, the compounds may be selective for other JAK kinases, such as JAK1.

[0170] The selected compounds of this invention are suitable for treating GI diseases and have limited systemic exposure after oral administration. These compounds are highly potent against JAK kinases (e.g., JAK1, TYK2, and JAK2) and exhibit high exposure at the site of action through limited absorption.

[0171] The selected compounds of this invention are suitable for topical dermal administration. These compounds exhibit good efficacy against JAK kinases (e.g., JAK1, TYK2, and JAK2), with limited systemic exposure and high exposure in the dermis / epidermis and therefore at the site of action in the skin.

[0172] This invention also provides pharmaceutical compositions of these compounds and methods for their preparation and use. The JAK inhibitors disclosed herein exhibit excellent efficacy characteristics while enjoying favorable pharmacokinetic characteristics and pharmaceutical properties suitable for the target indications.

[0173] On the one hand, the present invention generally relates to a compound having structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof:

[0174]

[0175] in

[0176] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0177] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0178] R 1It is an unsubstituted or substituted alkyl group or OR' of hydrogen, halogen (e.g., Cl, F), CN, C1-C6 (e.g., C1-C3);

[0179] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are optionally substituted with one or more of halogens (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR' and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of them are further optionally substituted with F (e.g., CH2F, CHF2 or CF3), OR' or NRR';

[0180] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0181] R 4 and R 4’ Each of the C1-C atoms is independently selected from hydrogen and optionally contains one or more heteroatoms selected from N, O, and S. 12 (e.g., C1-C6, C7-C) 12 Aliphatic groups, and R 4 and R 4’ They can together form 3 to 7-membered (e.g., 3 or 4-membered) rings having 0 to 3 heteroatoms selected from O, N, and S, and wherein R 4 and R 4’ Each of the terms in the equation is optionally replaced by CN, CF3, or OR'; provided that if R 4 and R 4’ If one of them is hydrogen, then the other is not hydrogen; and

[0182] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0183] In some implementations,

[0184] X is CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0185] Z1 is CR' and Z2 is N;

[0186] R 1It is a halogen (e.g., Cl, F), CN, C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl group or OR';

[0187] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are optionally substituted with one or more of halogens (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR' and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of them are further optionally substituted with F (e.g., CH2F, CHF2 or CF3), OR' or NRR';

[0188] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0189] R 4 and R 4’ Each of the C1-C atoms is independently selected from hydrogen and optionally contains one or more heteroatoms selected from N, O, and S. 12 (e.g., C1-C6, C7-C) 12 Aliphatic groups, and R 4 and R 4’ They can together form 3 to 7-membered (e.g., 3 or 4-membered) rings having 0 to 3 heteroatoms selected from O, N, and S, and wherein R 4 and R 4’ Each of the terms in the equation is optionally replaced by CN, CF3, or OR'; provided that if R 4 and R 4’ If one of them is hydrogen, then the other is not hydrogen; and

[0190] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0191] On the other hand, the present invention generally relates to a compound having structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof:

[0192]

[0193] in

[0194] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0195] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0196] R 1 It is Cl;

[0197] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are optionally substituted with one or more of halogens (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR' and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of them are further optionally substituted with F (e.g., CH2F, CHF2 or CF3), OR' or NRR';

[0198] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0199] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0200] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0201] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0202] In some implementations, X is CR x .

[0203] In some implementations, X is N.

[0204] In some implementations, R x It’s H.

[0205] In some implementations, R 4’ H is H, X is CR x Z1 is CH and Z2 is N, and the compound has structural formula (II):

[0206]

[0207] In some implementations, R x It is an unsubstituted or substituted alkyl or alkoxy group of hydrogen, halogen (e.g., Cl, F), or C1-C6 (e.g., C1-C3).

[0208] In some implementations, R 3 It’s H.

[0209] In some implementations, R 3 It is F, CH3, or Cl.

[0210] In some implementations, X is CR x , R 4’ The compound is H, Z1 is CH and Z2 is N, and has structural formula (III):

[0211]

[0212] In some implementations, R x "It is H, R" is CH3, R 3 is H and R 5 It's CN.

[0213] In some implementations, R 2 It is a C1-C6 (e.g., C1-C3) aliphatic (e.g., straight-chain or cyclic) group in which 0 to 2 carbon atoms are replaced by one or more heteroatoms selected from N, O and S and optionally by CN or CF3 groups.

[0214] In some implementations, R 2 It is a C7-C structure in which 0 to 3 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S, and optionally by CN or CF3 groups. 16 Aliphatic groups (e.g., straight-chain or cyclic).

[0215] In some implementations, R 2 A C3-C group in which 0 to 8 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S, and optionally by CN or CF3 groups. 16 Cycloalkyl.

[0216] In some implementations, R 2 It contains C3-C6 cycloalkyl groups.

[0217] In some implementations, R 2 It is cyclopropyl.

[0218] In some embodiments, the compound has the structural formula (II):

[0219]

[0220] in

[0221] R 2 It is a C1-C6 (e.g., C1-C3) alkyl group;

[0222] R 3 It is R';

[0223] R 5 Includes CN;

[0224] R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0225] R' is hydrogen or C1-C 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3); and

[0226] R” is H, C1-C6 (e.g., C1-C3) alkyl group,

[0227] Or its pharmaceutically acceptable form or isotope derivative.

[0228] In some embodiments, R” adopts an S-configuration, and the compound has structural formula (III):

[0229]

[0230] In some implementations, R” is a methyl group.

[0231] In some implementations, R x It is H, R 3 is H and R 5 It's CN.

[0232] In some implementations, R 2 It contains C3-C6 cycloalkyl groups.

[0233] In some implementations, R 2 It is cyclopropyl.

[0234] On the other hand, the present invention generally relates to a compound having structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof:

[0235]

[0236] in

[0237] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0238] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0239] R 1 It is CH3;

[0240] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16 Aliphatic groups (e.g., linear or cyclic), wherein the aliphatic groups are replaced by one or more of CN, CONRR' or NRCOR', and the one or more of them are optionally replaced by F (e.g., CH2F, CHF2 or CF3), OR' or NRR'.

[0241] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0242] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0243] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0244] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0245] In some implementations, X is N.

[0246] In some implementations, X is CR x .

[0247] In some implementations, R x It’s H.

[0248] In some implementations, R 2 It is a C1-C6 (e.g., C1-C3) aliphatic group that has been replaced by a CN group.

[0249] In some implementations, R 2 It is a C1-C3 alkyl group substituted with a CN group.

[0250] In some implementations, R 2 It is CH2CN.

[0251] In some implementations, R 4’ It’s H.

[0252] In some implementations, R 4 Yes -CH2R 5 , where R 5 Includes CN or CF3.

[0253] In some implementations, R 5 It's CN.

[0254] In some implementations, R 3 It’s H.

[0255] In some implementations, Z1 is CH and Z2 is N.

[0256] In some implementations, R 2 It is CH2CN, R 3 It is H, R 4’ H is H, X is CR x , where R x Z1 is H, Z2 is CH and Z3 is N.

[0257] In some implementations, R 4 Yes, it is -CH2CN.

[0258] On the other hand, the present invention generally relates to a compound having structural formula (I) or thereof.

[0259] Pharmaceutical forms or isotope derivatives:

[0260]

[0261] in

[0262] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0263] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is selected from N and CR' respectively.

[0264] It is N and the other is CR';

[0265] R 1 It is CH3;

[0266] R 2 It is a C3-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic group is composed of 0-4 C1-C6 atoms (e.g., C1-C6).

[0267] Such as C1-C3) alkyl substitution;

[0268] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0269] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0270] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and

[0271] R 5 It is CN, CF3, OR', or 0 to 4 carbon atoms of which are separated by one or more atoms selected from N, O

[0272] C1-C with heteroatom substitution of S 11 Aliphatic groups, wherein the aliphatic groups are optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, and said one or more are further optionally substituted with F.

[0273] (e.g., CH2F, CHF2, or CF3), OR' or NRR' substitution; and each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0274] In some implementations, R 4’ H is H, X is CR xZ1 is CH and Z2 is N, and the compound has structural formula (II):

[0275]

[0276] In some implementations, X is CR x , where R x It is hydrogen, halogens (e.g., Cl, F),

[0277] C1-C6 (e.g., C1-C3) unsubstituted or substituted alkyl or alkoxy groups.

[0278] In some implementations, R x It’s H.

[0279] In some implementations, X is N.

[0280] In some implementations, R 3 It’s H.

[0281] In some implementations, R 3 It is F, CH3, or Cl.

[0282] In some implementations, Z1 is CH and Z2 is N.

[0283] In some implementations, R ” is H and R 5 It's CN.

[0284] In some implementations, X is CR x , R 3 It is H, R 4’ Z1 is H, Z2 is CH, and Z3 is N, and the compound has structural formula (III):

[0285]

[0286] In some implementations, R ” It is CH3 and R 5 It's CN.

[0287] In some implementations, R 2 It is a C5-C7 aliphatic group (e.g., straight-chain or cyclic) optionally containing one or more heteroatoms selected from N, O and S, wherein the aliphatic group is substituted by two or more C1-C6 (e.g. C1-C3) alkyl groups.

[0288] In some implementations, R 2 It is a 6-membered cyclic aliphatic group containing O, wherein the aliphatic group is replaced by two or more C1-C3 alkyl groups.

[0289] In some implementations, R 2 It is a 6-membered cyclic aliphatic group containing O, wherein the aliphatic group is replaced by two or more methyl groups.

[0290] In some implementations, R 2 It is a 6-membered cyclic aliphatic group containing O, wherein the aliphatic group is replaced by four methyl groups.

[0291] In some implementations, R 2 yes:

[0292]

[0293] in

[0294] Z3 is N, CH, or O, where when Z3 is O, R 6 does not exist;

[0295] Each of m and n is independently 0, 1, 2, 3, or 4; provided that m and n are not both 0 at the same time, and

[0296] R 6 It is a C1-C6 (e.g., C1-C3) alkyl, CN, halogen (e.g., Cl, F) or C(O)R 7 , where R 7 It is a C1-C6 (e.g., C1-C3) alkyl; provided that when Z3 is N, R6 is not CN or a halogen.

[0297] In some embodiments, the compound has structural formula (IV):

[0298]

[0299] where R x It is H, R 3 =H, R” is H or C1-C6 (e.g. C1-C3) alkyl, R 6 It is a C1-C6 (e.g., C1-C3) alkyl or C(O)R 7 , where R 7 It is a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group (e.g., linear or cyclic), wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR' and C1-C6 (e.g., C1-C3) alkyl group, wherein the one or more of the halogen is optionally substituted with F (e.g., CH2F, CHF2 or CF3), OR' or NRR'.

[0300] In some implementations, R 2 It is R 8 -CN, where R 8 It is (CH2) m , where m is 1, 2, 3, 4, 5 or 6.

[0301] In some implementations, m is 1.

[0302] In which R 4 and R 4’ In some embodiments of (I) where 3 to 7-membered (e.g., 3 or 4-membered) rings are formed together, the compound has the structural formula (V):

[0303]

[0304] Where k is 0, 1, 2 or 3.

[0305] In some implementations of (V), k is 0 or 1.

[0306] In some embodiments of (V), R 1 It’s H.

[0307] In some embodiments of (V), R 1 It is F, CH3, or Cl.

[0308] The amide of compound (I) (i.e., -C(=O)NR) 4 R 4’ A list of non-restricted instances of the components is provided in Table 1.

[0309] Table 1

[0310]

[0311] R of compound (I) 2 A list of unrestricted instances is provided in Table 2.

[0312] Table 2

[0313]

[0314] Non-limiting examples of compounds according to the present invention include:

[0315] (S)-4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0316] 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide

[0317] (S)-4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0318] (S)-4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide-2,3,5,6-d4

[0319] (S)-4-(5-chloro-2-((1-isopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0320] (S)-4-(5-chloro-2-((1-ethyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide-4-methylbenzenesulfonate

[0321] (S)-4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0322] (S)-4-(5-chloro-2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanopropyl)benzamide

[0323] (S)-4-(5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0324] 4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide

[0325] (S)-4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0326] 4-(5-chloro-2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide

[0327] (S)-4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanopropyl)benzamide

[0328] (S)-4-(5-chloro-2-((1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0329] (S)-4-(5-chloro-2-((1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanopropyl)benzamide

[0330] 4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide

[0331] (S)-4-(5-chloro-2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0332] (S)-4-(5-chloro-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanopropyl)benzamide

[0333] (S)-4-(2-((1H-pyrazol-4-yl)amino)-5-chloropyrimidin-4-yl)-N-(1-cyanoethyl)benzamide.

[0334] Non-limiting examples of compounds according to the present invention include:

[0335] (S)-N-(1-cyanobutyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0336] (S)-N-(1-Cyanoethyl)-4-(2-((1-Cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0337] N-(cyanomethyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0338] N-(cyanomethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0339] (S)-N-(1-cyanoethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0340] (S)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(1-cyanopropyl)benzamide

[0341] (S)-N-(1-Cyanoethyl)-4-(5-Methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0342] (S)-N-(cyano(cyclopropyl)methyl)-4-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0343] (S)-N-(1-cyanopropyl)-4-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0344] (S)-N-(1-cyanopropyl)-4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0345] N-(cyanomethyl)-4-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0346] N-((S)-1-cyanoethyl)-4-(2-((1-(trans-2,6-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0347] N-((S)-1-cyanoethyl)-4-(2-((1-((2S,4s,6R)-2,6-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0348] N-((S)-1-cyanoethyl)-4-(2-((1-((2S,4r,6R)-2,6-dimethylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0349] (S)-N-(cyano(cyclopropyl)methyl)-4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0350] (S)-N-(1-cyanoethyl)-4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0351] (S)-N-(1-cyanobutyl)-4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0352] (S)-N-(1-cyanopropyl)-4-(2-((1-(2-hydroxyethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0353] N-(cyanomethyl)-4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0354] N-(cyanomethyl)-4-(5-methyl-2-((1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0355] (S)-N-(1-Cyanoethyl)-4-(5-Methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0356] (S)-N-(1-Cyanoethyl)-4-(5-Methyl-2-((1-(2,2,6,6-Tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0357] N-(cyanomethyl)-2-fluoro-4-(5-methyl-2-((1-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0358] (S)-N-(1-Cyanopropyl)-4-(5-Methyl-2-((1-(2,2,6,6-Tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0359] (S)-N-(1-Cyanopropyl)-4-(5-Methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0360] N-((1-cyanocyclopropyl)methyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0361] N-(2-cyano-2-methylpropyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0362] (S)-N-(1-cyanoethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0363] N-(cyanomethyl)-4-(5-methyl-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0364] N-(cyanomethyl)-4-(5-methyl-2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0365] N-(cyanomethyl)-4-(5-methyl-2-((1-(1-(1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0366] (S)-N-(1-Cyanoethyl)-4-(2-((1-(1-(2-hydroxyacetyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide

[0367] 4-(2-((1-(trans-4-cyanocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-((S)-1-cyanoethyl)benzamide

[0368] N-((S)-1-cyanoethyl)-4-(5-methyl-2-((1-((S*)-1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0369] N-((S)-1-cyanoethyl)-4-(5-methyl-2-((1-((R*)-1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0370] (S)-N-(1-Cyanoethyl)-4-(5-Methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0371] (S)-4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(1-cyanoethyl)benzamide

[0372] N-((S)-1-cyanopropyl)-4-(5-methyl-2-((1-((R*)-1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide

[0373] N-((S)-1-cyanopropyl)-4-(5-methyl-2-((1-((S*)-1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide.

[0374] On the other hand, the present invention generally relates to a pharmaceutical composition comprising compounds disclosed herein that are effective in treating or alleviating one or more diseases or disorders in mammals, including humans, as well as pharmaceutically acceptable excipients, carriers, or diluents.

[0375] On the other hand, the present invention generally relates to a pharmaceutical composition comprising a compound having a structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof, effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent:

[0376]

[0377] in

[0378] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0379] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0380] R 1 It is Cl;

[0381] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are optionally substituted with one or more of halogens (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR' and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of them are further optionally substituted with F (e.g., CH2F, CHF2 or CF3), OR' or NRR';

[0382] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0383] R4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0384] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0385] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0386] On the other hand, the present invention generally relates to a pharmaceutical composition comprising a compound having a structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof, effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent:

[0387]

[0388] in

[0389] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0390] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0391] R 1 It is CH3;

[0392] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16Aliphatic groups (e.g., linear or cyclic), wherein the aliphatic groups are replaced by one or more of CN, CONRR' or NRCOR', and the one or more of them are optionally replaced by F (e.g., CH2F, CHF2 or CF3), OR' or NRR'.

[0393] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0394] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0395] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0396] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0397] On the other hand, the present invention generally relates to a pharmaceutical composition comprising a compound having a structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof, effective in treating or alleviating one or more diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier, or diluent:

[0398]

[0399] in

[0400] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0401] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0402] R 1 It is CH3;

[0403] R 2 It is a C3-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are substituted by 0 to 4 C1-C6 (e.g., C1-C3) alkyl groups;

[0404] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0405] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0406] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0407] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0408] In some embodiments, the pharmaceutical compositions of the present invention are suitable for oral administration.

[0409] In some embodiments, the pharmaceutical compositions of the present invention are used for topical administration.

[0410] In some embodiments, the pharmaceutical compositions of the present invention are suitable for GI-limited administration.

[0411] In some embodiments, the pharmaceutical compositions of the present invention can be used to treat or alleviate one or more inflammatory diseases, immune-mediated diseases, and cancer or related diseases or disorders.

[0412] In some implementations, the disease or disorder suitable for treatment is an inflammatory disease.

[0413] In some implementations, the disease or disorder suitable for treatment is an immune-mediated disease.

[0414] In some implementations, the disease or disorder suitable for treatment is cancer.

[0415] In some embodiments, the diseases or disorders suitable for treatment are selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0416] On the other hand, the present invention generally relates to a unit dosage form comprising the pharmaceutical compositions disclosed herein.

[0417] In some embodiments, the unit dosage form is in the form of a tablet.

[0418] In some embodiments, the unit dosage form is in the form of capsules.

[0419] In some embodiments, the unit dosage form is in the form of a topical dosage form.

[0420] On the other hand, the present invention generally relates to a method for treating or alleviating a disease or disorder, the method comprising: administering a pharmaceutical composition to a desired subject, the pharmaceutical composition comprising a compound having a structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof that is effective in treating, preventing or alleviating one or more inflammatory diseases, immune-mediated diseases, cancer or related diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier or diluent:

[0421]

[0422] in

[0423] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0424] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0425] R 1 It is Cl;

[0426] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are optionally substituted with one or more of halogens, OR', NRR', CN, CONRR', NRCOR' and C1-C6 (e.g. C1-C3) alkyl groups, wherein the one or more of them are further optionally substituted with F (e.g. CH2F, CHF2 or CF3), OR' or NRR';

[0427] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0428] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0429] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0430] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0431] On the other hand, the present invention generally relates to a method for treating or alleviating a disease or disorder, the method comprising: administering a pharmaceutical composition to a desired subject, the pharmaceutical composition comprising a compound having a structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof that is effective in treating, preventing or alleviating one or more inflammatory diseases, immune-mediated diseases, cancer or related diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier or diluent:

[0432]

[0433] in

[0434] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0435] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0436] R 1 It is CH3;

[0437] R 2 It is a C1-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 (e.g., C1-C6, C7-C) 16 Aliphatic groups (e.g., linear or cyclic), wherein the aliphatic groups are replaced by one or more of CN, CONRR' or NRCOR', and the one or more of them are optionally replaced by F (e.g., CH2F, CHF2 or CF3), OR' or NRR'.

[0438] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0439] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0440] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0441] Each of R and R' is independently hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0442] On the other hand, the present invention generally relates to a method for treating or alleviating a disease or disorder, the method comprising: administering a pharmaceutical composition to a desired subject, the pharmaceutical composition comprising a compound having a structural formula (I) or a pharmaceutically acceptable form or isotopic derivative thereof that is effective in treating, preventing or alleviating one or more inflammatory diseases, immune-mediated diseases, cancer or related diseases or disorders in mammals, including humans, and a pharmaceutically acceptable excipient, carrier or diluent:

[0443]

[0444] in

[0445] X is N or CR x , where R x It is R', halogen (e.g., Cl, F), CN, or OR';

[0446] Each of Z1 and Z2 is independently selected from N and CR', provided that one of Z1 and Z2 is N and the other is CR';

[0447] R 1 It is CH3;

[0448] R 2 It is a C3-C that optionally contains one or more heteroatoms selected from N, O, and S. 16 Aliphatic groups (e.g., straight-chain or cyclic), wherein the aliphatic groups are substituted by 0-4 C1-C6 (e.g., C1-C3) alkyl groups;

[0449] R 3 It is R', halogen (e.g., Cl, F) or CN;

[0450] R 4’ It is an H or C1-C6 (e.g., C1-C3) alkyl group;

[0451] R 4 It is -CHR"-R 5 Where R” is H or a C1-C6 (e.g., C1-C3) alkyl group, and R 5 It is a C1-C compound consisting of CN, CF3, OR', or where 0 to 4 carbon atoms are replaced by one or more heteroatoms selected from N, O, and S. 11 An aliphatic group, wherein the aliphatic group is optionally substituted with one or more of a halogen (e.g., Cl, F), OR', NRR', CN, CONRR', NRCOR', and C1-C6 (e.g., C1-C3) alkyl groups, wherein the one or more of these groups is further optionally substituted with F (e.g., CH2F, CHF2, or CF3), OR', or NRR'; and

[0452] Each R and R' is independently either hydrogen or C1-C. 12 (e.g., C1-C6, C7-C) 12 Unsubstituted or substituted alkyl groups (e.g., CH2F, CHF2, or CF3).

[0453] In some embodiments, the present invention generally relates to a method of treating or alleviating a disease or disorder, the method comprising administering to a subject in need a pharmaceutical composition comprising compounds disclosed herein, wherein the disease or disorder is one or more inflammatory diseases, immune-mediated diseases, and cancer or related diseases or disorders.

[0454] In some implementations, the disease or disorder is an inflammatory disease.

[0455] In some implementations, the disease or disorder is an immune-mediated disease.

[0456] In some implementations, the disease or obstacle is cancer.

[0457] In some embodiments, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0458] In some implementations, administration is performed orally.

[0459] In some implementations, administration is performed locally.

[0460] In some implementations, administration is performed via GI-limited administration.

[0461] On the other hand, the present invention generally relates to the use of the compounds disclosed herein and pharmaceutically acceptable excipients, carriers or diluents for the preparation of medicaments for the treatment of diseases or disorders.

[0462] In some implementations, the disease or disorder is one or more inflammatory diseases, immune-mediated diseases, and cancer.

[0463] In some implementations, the disease or disorder is an inflammatory disease.

[0464] In some implementations, the disease or disorder is an immune-mediated disease.

[0465] In some implementations, the disease or obstacle is cancer.

[0466] In some embodiments, the drug is administered orally.

[0467] In some embodiments, the drug is used for topical administration.

[0468] In some embodiments, the drug is used for GI-limited administration.

[0469] A list of non-limiting examples of the compounds of the present invention is provided in Table 3. Exemplary data for selected compounds are provided in Table 4.

[0470] As discussed herein, the present invention envisions isotope derivative compounds having one or more (e.g., 1, 2, 4, 5, 6, 7, 8, 9, 10, etc.) hydrogen atoms replaced by deuterium atoms.

[0471] The term "inflammatory disease" refers to a disease or condition characterized by abnormal inflammation, such as an elevated level of inflammation compared to a control group, such as a healthy person without the disease. Examples of inflammatory diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include autoimmune diseases, traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile-onset diabetes, type 1 diabetes, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjögren's syndrome, and vasculitis. Glomerulonephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, ischemic-reperfusion injury, stroke, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, scleroderma, and atopic dermatitis. These conditions are often inevitably intertwined with other diseases, disorders, and symptoms. An unrestricted list of inflammatory-related diseases, disorders, and symptoms, for example, caused by inflammatory cytokines, includes arthritis, kidney failure, lupus, asthma, psoriasis, colitis, pancreatitis, allergies, fibrosis, surgical complications (e.g., inflammatory cytokines preventing healing), anemia, and fibromyalgia. Other diseases and disorders that may be associated with chronic inflammation include Alzheimer's disease, congestive heart failure, stroke, aortic stenosis, arteriosclerosis, osteoporosis, Parkinson's disease, infections, inflammatory bowel disease (IBD), allergic contact dermatitis and other eczemas, systemic sclerosis, transplantation, and multiple sclerosis. Certain of the aforementioned diseases, disorders, and conditions for which the compounds disclosed herein may be particularly effective (due to limitations of current therapies, for example) are described in more detail below.

[0472] The term "autoimmune disease" refers to a disease or condition in which the immune system of a subject exhibits an abnormal immune response to a substance that would not normally elicit an immune response in a healthy subject. Examples of autoimmune diseases that can be treated with the compounds, pharmaceutical compositions, or methods described herein include acne vulgaris, acute diffuse encephalomyelitis, acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, gamma globulinemia, Aicardi-Goutières syndrome (AGS), alopecia areata, alopecia totalis, amyloidosis, ankylosing spondylitis, anti-GBM / anti-TBM nephritis, antiphospholipid syndrome, autoimmune angioedema, autoimmune aplastic anemia, autoimmune autonomic dysfunction, autoimmune hepatitis, autoimmune hyperlipidemia, autoimmune immunodeficiency, autoimmune inner ear disease, autoimmune myocarditis, and autoimmune ovarian disorders. Inflammation, autoimmune pancreatitis, autoimmune retinopathy, autoimmune thrombocytopenic purpura, autoimmune thyroid disease, autoimmune urticaria, axonal or neuronal neuropathy, Baroque disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic atypical neutrophilic dermatitis (CANDLE) with lipid metabolism disorders and fever, chronic active hepatitis, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathy, chronic relapsing multifocal osteomyelitis, Churg-Strauss syndrome, cicatricial pemphigoid / benign mucosal pemphigoid, Crohn's disease, Cogans syndrome, cold agglutination Diseases such as congenital heart block, Coxsackievirus myocarditis, CREST disease, Cushing's syndrome, demyelinating neuropathy, depression, herpetic dermatitis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus, Deslesler syndrome, dry eye syndrome (DES, keratoconjunctivitis sicca), endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, erythema nodosum, primary mixed cryoglobulinemia, experimental allergic encephalomyelitis, Evans syndrome, fibromyalgia, fibrotic alveolitis, giant cell arteritis (temporal arteritis), giant cell myocarditis, glomerulonephritis, pulmonary hemorrhage nephritis syndrome, granulomatous polyangiitis, and graft-versus-host disease. GVDH), Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, hemolytic anemia, Henscher's purpura, herpes gestationis, hidradenitis suppurativa, hypogammaglobulinemia, idiopathic thrombocytopenic purpura, IgA nephropathy, IgG4-related sclerosis, inflammatory bowel disease (IBD), immunomodulatory lipoprotein, inclusion body myositis, interstitial cystitis, juvenile arthritis, juvenile diabetes mellitus (type 1 diabetes), juvenile dermatomyositis (JDM), juvenile myositis, Kawasaki syndrome, Lambert-Eaton syndrome, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, woody conjunctivitis, linear IgA disease, lupus, chronic Lyme disease.Meniere's disease, microscopic polyangiitis, mixed connective tissue disease, keratodermal ulcer, Mucha-Habermann disease, multiple sclerosis (MS), myasthenia gravis, myositis, somnolencephaly, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, striated rheumatoid arthritis, streptococcal-associated childhood autoimmune neuropsychiatric disorders, paraneoplastic cerebellar degeneration, paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome, Parsonnage-Turner syndrome, ciliary body flats (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, polyarteritis nodosa, polycystic ovary syndrome (PCOS), autoimmune polyglandular syndromes type I, I, and III, polymyalgia rheumatica, polymyositis, myocardial infarction syndrome, post-pericardiotomy syndrome, progesterone dermatitis, primary biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, plaque psoriasis, idiopathic pulmonary fibrosis, pyoderma gangrenosa, pure red cell aplasia, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, etc. Rye's leg syndrome, retroperitoneal fibrosis, rheumatic diseases, rheumatoid arthritis, sarcoidosis, Schmidt syndrome, scleritis, scleroderma, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome, infantile onset of STING-associated vascular disease (SAVI), subacute bacterial endocarditis, Susac syndrome, sympathetic ophthalmia, systemic lupus erythematosus (SLE), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura, Tolosa-Hunt syndrome, transplant rejection (allogeneic graft rejection), transverse myelitis, type 1 diabetes mellitus, ulcerative colitis, undifferentiated connective tissue disease, uveitis, vasculitis, bullous dermatitis, vitiligo, or Wegener's granulomatosis.

[0473] The term "immune-mediated disease" refers to chronic inflammatory diseases that persist due to antibody and cellular immunity. Immune-mediated diseases include, but are not limited to, asthma, allergies, arthritis (e.g., rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis), juvenile arthritis, inflammatory bowel diseases (e.g., ulcerative colitis and Crohn's disease), endocrine disorders (e.g., type 1 diabetes and Graves' disease), neurodegenerative diseases (e.g., multiple sclerosis (MS)), autism spectrum disorders, depression, Alzheimer's disease, Guillain-Barré syndrome, obsessive-compulsive disorder, optic neuritis, retinal degeneration, dry eye syndrome (DES), Sjögren's syndrome, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, and other related conditions. Lim-Barré syndrome, myasthenia gravis, chronic idiopathic demyelinating disease (CID), vascular diseases (e.g., autoimmune deafness, systemic vasculitis, and atherosclerosis), skin diseases (e.g., acne vulgaris dermatomyositis, pemphigus, systemic lupus erythematosus (SLE), discoid lupus erythematosus, scleroderma, psoriasis, plaque psoriasis, vasculitis, vitiligo, and alopecia), Hashimoto's thyroiditis, pernicious anemia, Cushing's syndrome, Addison's disease, chronic active hepatitis, polycystic ovary syndrome (PCOS), celiac disease, pemphigus, transplant rejection (allogeneic graft rejection), and graft-versus-host disease (GVDH).

[0474] When used herein, the term "cancer" refers to all types of cancer, tumors, or malignant tumors present in mammals such as humans, including blood cancers such as leukemia and lymphoma, T-ALL, large B-cell lymphoma, and solid tumors such as epithelial carcinoma and sarcoma. Exemplary cancers include blood cancers, brain cancer, glioma, glioblastoma, neuroblastoma, prostate cancer, colorectal cancer, pancreatic cancer, cervical cancer, stomach cancer, ovarian cancer, lung cancer, and cancers of the head. Exemplary cancers include thyroid cancer, endocrine system cancers, brain cancer, breast cancer, cervical cancer, colon cancer, head and neck cancer, liver cancer, kidney cancer, lung cancer, non-small cell lung cancer, melanoma, mesothelioma, ovarian cancer, sarcoma, stomach cancer, uterine cancer, myeloma, colorectal cancer, and pancreatic cancer. Other examples include penile, cutaneous (non-melanoma), anal, hepatobiliary, esophageal, gastric, uterine sarcoma, gastrointestinal stromal tumor, salivary glands, peripheral nervous system, soft tissue sarcoma, bone, kidney, myeloproliferative neoplasms, thyroid cancer, bile duct cancer, pancreatic adenocarcinoma, cutaneous melanoma, colonic adenocarcinoma, rectal adenocarcinoma, gastric adenocarcinoma, esophageal cancer, head and neck squamous cell carcinoma, invasive breast cancer, lung adenocarcinoma, lung squamous cell carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, and primary platelet-secreting tumors. Polycythemia, primary macroglobulinemia, primary brain tumor, cancer, malignant pancreatic islet tumor, malignant carcinoid tumor, bladder cancer, precancerous skin lesions, testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenocortical cancer, endocrine or exocrine pancreatic tumors, medullary thyroid carcinoma, medullary thyroid epithelial carcinoma, melanoma, colorectal cancer, papillary thyroid carcinoma, hepatocellular carcinoma, metastatic leiomyosarcoma, synovial sarcoma, undifferentiated pleomorphic sarcoma, round cell liposarcoma, or prostate cancer.

[0475] In some embodiments of the described use, the disease or disorder is selected from inflammatory bowel disease, psoriasis, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer, and ovarian cancer.

[0476] Isotope-labeled compounds are also within the scope of this disclosure. When used herein, "isotope-labeled compound" refers to the compounds of this disclosure, each as described herein, including their pharmaceutical salts and prodrugs, wherein one or more atoms are replaced by atoms with atomic weights or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds of this disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, respectively, for example... 2 H. 3 H. 13C 14 C 15 N. 18 O. 17 O. 31 P. 32 P. 35 S, 18 F and 36 Cl.

[0477] By isotopically labeling the compounds of this disclosure, the compounds can be used in tissue distribution assays for drugs and / or substances. Tritium ( 3 H) and carbon-14 ( 14 Compounds labeled with C are particularly preferred because they are easy to prepare and detect. Furthermore, compounds labeled with heavier isotopes such as deuterium (C) are also preferred. 2 H) substitution can yield certain therapeutic advantages due to increased metabolic stability, such as improved in vivo half-life or reduced dose requirements, and may therefore be preferred in some cases. The isotopically labeled compounds of this disclosure, including their pharmaceutical salts, esters, and prodrugs, can be prepared by any means known in the art.

[0478] In addition, the usually abundant hydrogen ( 1 H) Replacing with a heavier isotope, such as deuterium, can yield certain therapeutic advantages due to improved absorption, distribution, metabolism, and / or excretion (ADME) properties, resulting in drugs with improved efficacy, safety, and / or tolerability. From typically abundant... 12 C was 13 The substitution of C may also yield benefits. (See WO 2007 / 005643, WO2007 / 005644, WO 2007 / 016361 and WO 2007 / 016431).

[0479] The stereoisomers (e.g., cis and trans isomers) and all optical isomers (e.g., R and S enantiomers) of the compounds disclosed herein, as well as racemic, diastereomer, and other mixtures of these isomers, are all within the scope of this disclosure.

[0480] The compounds of the present invention are preferably isolated and purified after their preparation to obtain compositions containing an amount equal to or greater than 95% by weight (“substantially pure”), which are then used or formulated as described herein. In some embodiments, the compounds of the present invention have a purity exceeding 99%.

[0481] Solvates and polycrystalline forms of the compounds of the present invention are also contemplated herein. Solvates of the compounds of the present invention include, for example, hydrates.

[0482] Any suitable route of administration can be used, such as parenteral, intravenous, subcutaneous, intramuscular, intraventricular, internal, intraperitoneal, rectal, or oral administration. The most suitable route of administration for a particular patient will depend on the nature and severity of the disease or condition being treated, the nature of the therapy being used, and the nature of the active compound.

[0483] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the compounds described herein or their derivatives are mixed with at least one inert, conventional excipient (or carrier), such as sodium citrate or dicalcium phosphate, or (i) a filler or extender, such as starch, lactose, sucrose, glucose, mannitol, and silica; (ii) a binder, such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic; (iii) a humectant, such as glycerin; (iv) a disintegrant, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain complex silicates, and sodium carbonate; (v) a solution retarder, such as paraffin; (vi) an absorption enhancer, such as a quaternary ammonium compound; (vii) a wetting agent, such as cetyl alcohol and glyceryl monostearate; (viii) an adsorbent, such as kaolin and bentonite; and (ix) a lubricant, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also contain buffers. Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules, using excipients such as lactose or toffee and high molecular weight polyethylene glycol. Solid dosage forms such as tablets, sugar-coated pills, capsules, pills, and granules can be prepared using coatings and shells, such as enteric coatings and other coatings known in the art.

[0484] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitol, or mixtures thereof. Besides these inert diluents, the compositions may also include other agents such as wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, or aroma enhancers.

[0485] The materials, compositions, and components disclosed herein can be used with the disclosed methods and compositions, in their preparation, or as products thereof. It should be understood that when combinations, subsets, interactions, groups, etc., of these materials are disclosed, each is specifically contemplated and described herein, although the specific designation of each of the various individual and collective combinations and arrangements of these compounds may not be explicitly disclosed. For example, if a method is disclosed and discussed, and numerous modifications that can be made to a large number of molecules included in said method are discussed, then each combination and arrangement of said method, and possible modifications, is specifically contemplated unless specifically stated otherwise. Similarly, any subsets or combinations thereof are specifically contemplated and disclosed. This concept applies to all aspects of this disclosure, including but not limited to steps in methods using the compositions of this disclosure. Therefore, if various different additional steps are available, it should be understood that each of these additional steps can be performed in conjunction with any particular method step or combination of steps of the method of this disclosure, and each of these combinations or subsets of combinations is specifically contemplated and should be considered as disclosed.

[0486] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds falling within its scope, including their cis and trans isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, racemic mixtures, and other mixtures. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are intended to be included in the present invention.

[0487] According to the present invention, mixtures of isomers containing any of a variety of different isomer ratios can be utilized. For example, when only two isomers are combined, the present invention envisions mixtures containing isomer ratios of 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. Those skilled in the art will readily recognize that similar ratios are envisioned for more complex mixtures of isomers.

[0488] If, for example, a specific enantiomer of the compound of the present invention is required, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary agent. In the latter case, the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as an amino group or an acidic functional group such as a carboxyl group, a diastereomeric salt is formed with a suitable optically active acid or base, and the resulting diastereomeric salt is then resolved by stepwise crystallization or chromatography methods known in the art, and the pure enantiomer is then recovered. Example

[0489] A series of analogues were designed, synthesized, and tested. Examples of these compounds are provided below.

[0490] Abbreviations

[0491] The following is a list of some abbreviations:

[0492] Methanol: MeOH

[0493] Dichloromethane: DCM

[0494] Petroleum ether: PE

[0495] Ethyl acetate: EtOAc

[0496] Acetonitrile: ACN

[0497] Tetrahydrofuran: THF

[0498] Triethylamine: TEA

[0499] 4-Dimethylaminopyridine: DMAP

[0500] Tetra(triphenylphosphine)palladium: Pd(PPh3)4

[0501] 1,2-Dichloroethane: DCE

[0502] N,N-Diisopropylethylamine: DIPEA

[0503] N,N-Dimethylformamide: DMF

[0504] Dicyclohexyl(2',4',6'-triisopropyl-[1,1'-biphenyl]-2-yl)phosphine: X-Phos

[0505] O-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate: HATU

[0506] Tris(diphenylmethylacetone)palladium: Pd2(dba3)

[0507] [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloro:Pd(dppf)Cl2

[0508] Room temperature: RT

[0509] Hours: hrs

[0510] Representative methods of preparative HPLC: (flow rate and gradient can be changed)

[0511] The following provides an exemplary method for preparative HPLC.

[0512] Method A: NH4HCO3:

[0513] (Column: XBrige Prep C185μm OBD 19*150mm, PN 186002979; Mobile phase: CH3CN aqueous solution (0.1% NH4HCO3) from 20% to 60%, Flow rate: 15mL / min).

[0514] Method B: Formic acid

[0515] (Column: XBridge Prep C185μm OBD 19*150mm, PN 186002979; Mobile phase: CH3CN aqueous solution (0.1% formic acid) from 15% to 40%, Flow rate: 15mL / min)

[0516] Representative methods of analytical HPLC

[0517] Method 1: Analysis was performed on an Agilent 1260 series HPLC-6120MS. UHPLC long gradient was equivalent to 5% to 95% acetonitrile aqueous solution (containing 0.02% NH4OAc), with a run time of 6.5 min and a flow rate of 1.5 mL / min. An XBridge C18 column (5 μm, 4.6 × 50 mm; PN 186003113) was used at 40 °C.

[0518] Method 2: Analysis was performed on an Agilent 1260 series HPLC-6120MS. UHPLC long gradient was equivalent to 5% to 95% acetonitrile aqueous solution (containing 0.1% trifluoroacetic acid), with a run time of 6.5 min and a flow rate of 1.5 mL / min. An XBridge C18 column (5 μm, 4.6 × 50 mm; PN 186003113) was used at 40 °C.

[0519] Method 3: Analysis was performed on an Agilent 1260 series HPLC-6120MS. The UHPLC long gradient was equivalent to 5% to 95% acetonitrile aqueous solution (containing 0.02% NH4OAc), with a run time of 6.5 min and a flow rate of 2 mL / min. A Diamonsil Plus C18 column (5 μm, 4.6*30 mm Cat#99436) was used at 40 °C.

[0520] Example 1

[0521]

[0522] Step 1. Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)benzoate (1b)

[0523] A mixture of 2,4-dichloro-5-methylpyrimidine (12.86 g, 78.9 mmol) in 1,4-dioxane (100 mL) and H₂O (20 mL) was sequentially added with (4-(methoxycarbonyl)phenyl)boronic acid (14.2 g, 78.9 mmol), Na₂CO₃ (6.73 g, 157.8 mmol), and Pd(dppf)Cl₂ (4.04 g, 5.52 mmol). The mixture was stirred at 60 °C for 7 hrs under a N₂ atmosphere. After cooling, the mixture was concentrated to remove volatiles and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL), separated, and then concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 1:1) to give the title product (4.8 g, 23% yield) as a white solid. 1 H NMR (400MHz, CDCl3) δ8.54 (s, 1H), 8.15 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H), 3.95 (s, 3H), 2.38 (s, 3H).

[0524] Step 2. 4-(4-((4-(4-(methoxycarbonyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1c)

[0525] Compound 1b (2.96 g, 11.28 mmol), tert-butyl 4-(4-amino-1H-pyrazol-1-yl)piperidin-1-carboxylate (3.0 g, 11.28 mmol), Cs₂CO₃ (7.3 g, 22.56 mmol), X-Phos (1.08 g, 2.26 mmol), and Pd₂(dba)₃ (1.03 g, 1.13 mmol) were dissolved in 1,4-dioxane (100 mL), and the resulting mixture was stirred at 110 °C for 7 hrs under a N₂ atmosphere. After cooling, the mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 1:1) to give the title product (5.5 g, 99% yield) as a yellow solid. LC-MS (Method 1): t R =1.85min, m / z(M+H)+=492.8.

[0526] Step 3. 4-(2-((1-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (1d)

[0527] NaOH (406 mg, 10.15 mmol) was added in a single addition to a solution of compound 1c (1.0 g, 2.03 mmol), MeOH (10 mL), and H₂O (2 mL). The mixture was stirred at 40 °C for 7 hrs. The pH of the mixture was adjusted to 6–7 with a 10% aqueous HCl solution. The mixture was extracted with a mixture of DCM and MeOH (55 mL, V / V = 10 / 1). The organic layer was separated and concentrated under vacuum to give the title product (980 mg, 100% yield) as a yellow solid. LC-MS (Method 1): t R = 1.25 min, m / z(M+H) + =478.8.

[0528] Step 4. 4-(4-((4-(4-((cyanomethyl)carbamoyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (1e)

[0529] Compound 1d (272 mg, 0.57 mmol), 2-aminoacetonitrile (33 mg, 0.57 mmol), HATU (258 mg, 0.68 mmol), and DIPEA (220 mg, 1.71 mmol) were dissolved in 5 mL of DMF, and the resulting mixture was stirred at RT for 3 hrs. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (Method A) to give the title product (225 mg, 77% yield) as a yellow solid. LC-MS (Method 1): t R = 3.62 min, m / z(M+H) + =517.3; 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),8.09(s,1H),7.92(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.45(s,1H),7.23(s,1H),6.87(s,1H),4.41( d,J=5.6Hz,2H),4.32-4.26(m,1H),4.17-4.13(m,2H),2.98-2.91(m,2H),2.29(s,3H),2.14-2.12(m,2H),1.90-1.86(m,2H),1.47(s,9H).

[0530] Step 5. Hydrochloride (1f)

[0531] A solution of HCl (g) in EtOAc (2N, 2mL) was added dropwise to a mixture of compound 1e (200 mg, 0.39 mmol) and EtOAc (6 mL) at 0 °C. The mixture was stirred at this temperature for 3 hours. The mixture was filtered and the filter cake was dried to give the title product (100 mg, 63% yield) as a yellow solid. LC-MS (Method 1): t R = 1.08 min, m / z(M+H) + =416.8.

[0532] Step 6. N-(cyanomethyl)-4-(2-((1-(1-(cyanomethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (1)

[0533] Compound 1f (100 mg, 0.24 mmol), 2-bromoacetonitrile (29 mg, 0.24 mmol), and K₂CO₃ (133 mg, 0.96 mmol) were dissolved in DMF (3 mL). The resulting mixture was stirred overnight at 30 °C. The mixture was diluted with EtOAc (30 mL) and washed with water (30 mL). The organic layer was separated and concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 20:1) to give the title product (50 mg, 46% yield) as a yellow solid. LC-MS (Method 1): t R = 3.03 min, m / z(M+H) + =456.2; 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),9.32(t,J=5.2Hz,1H),8.37(s,1H),8.00(d,J=8.0Hz,2H),7.89(s,1H),7.80(d,J=7.6Hz,2H),7.54(s ,1H),4.35(d,J=5.6Hz,2H),4.09-4.13(m,1H),3.76(s,2H),2.87(d,J=10.8Hz,2H),2.34(t,J=9.6Hz,2H),2.19(s,3H),2.02-1.90(m,4H).

[0534] Example 2

[0535]

[0536] Step 1. Methyl 4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (2a)

[0537] Using a similar preparation procedure as in the second step of Example 1, compound 2a (2.8 g) was synthesized in 74% yield using compound 1b (3.1 g, 11.8 mmol) and 1-methyl-1H-pyrazole-4-amine (1.14 g, 11.8 mmol) as starting materials. 1 HNMR(400MHz, CDCl3)δ8.31(s,1H),8.15(d,J=7.6Hz,2H),7.82(s,1H),7.68(d,J=7.6Hz,2H),7.45(s,1H),7.03-7.18(br s,1H),3.96(s,3H),3.87(s,3H),2.23(s,3H).

[0538] Step 2. 4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (2b)

[0539] Using a preparation procedure similar to the third step of Example 1, compound 2b (2.67 g) was synthesized in 100% yield using compound 2a (2.8 g, 8.72 mmol) as the starting material. 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.35(s,1H),8.03(d,J=8.0Hz,2H),7.85(s,1H),7.69(d,J=8.0Hz,2H),7.47(s,1H),3.78(s,3H),2.19(s,3H).

[0540] Step 3. N-(2-cyanoethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (2)

[0541] Using a similar preparation procedure to step four of Example 1, compound 2 (36 mg) was synthesized in 43% yield using compound 2b (70 mg, 0.23 mmol) and 3-aminopropionitrile (16.1 mg, 0.23 mmol) as starting materials. LC-MS (Method 1): t R = 2.82 min, m / z(M+H) + =362.0; 1H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.95(t,J=5.6Hz,1H),8.36(s,1H),7.98(d,J=8.0Hz,2H),7.83(s,1H) ,7.77(d,J=8.0Hz,2H),7.47(s,1H),3.78(s,3H),3.53(q,J=6.4Hz,2H),2.80(t,J=6.8Hz,2H),2.19(s,3H).

[0542] Example 3

[0543]

[0544] Step 1. Methyl 4-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate hydrochloride (3a)

[0545] A solution of HCl (g) in MeOH (2N, 15 mL) was added to a solution of compound 1c (1.0 g, 2.0 mmol) and MeOH (10 mL) at RT. The mixture was stirred at RT for 3 hrs and then concentrated to dryness to give the crude title product (1.1 g, 100% yield) as a yellow solid. LC-MS (Method 3): t R = 1.09 min, m / z(M+H) + =393.0.

[0546] Step 2. Methyl 4-(2-((1-(1-(tert-butylcarbamoyl)piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (3b)

[0547] 2-Isocyano-2-methylpropane (91 mg, 0.92 mmol) was added dropwise to a well-stirred mixture of compound 3a (300 mg, 0.77 mmol), DMAP (18.7 mg, 0.15 mmol), TEA (232 mg, 2.28 mmol), and DCM (15 mL). The mixture was stirred at RT for 2 hours, and then DCM (30 mL) and water (30 mL) were added. The organic layer was separated and concentrated to dryness. The residue was purified by reversed-phase column chromatography (gradient eluent: 5% to 95% acetonitrile in water) to give the title product as a yellow solid (239 mg, 64% yield). LC-MS (Method 3): t R = 1.72 min, m / z(M+H) + =491.8.

[0548] Step 3. 4-(2-((1-(1-(tert-butylcarbamoyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (3c)

[0549] Solid LiOH·H₂O (72.6 mg, 1.73 mmol) was added in a single addition to a solution of compound 3b (170 mg, 0.35 mmol), THF (4 mL), and H₂O (0.7 mL). The mixture was stirred at 40 °C for 5 hrs and then adjusted to pH 6–7 with a 10% aqueous HCl solution. The mixture was extracted with a solution of DCM and MeOH (55 mL, V / V = 10 / 1). The organic layer was separated and then concentrated to dryness under vacuum to give the title product (140 mg, 85% yield) as a yellow solid. LC-MS (Method 1): t R = 2.73 min, m / z(M+H) + =478.2.

[0550] Step 4. N-(tert-butyl)-4-(4-((4-(4-(((cyanomethyl)carbamoyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxamide (3)

[0551] Using a similar preparation procedure to step four of Example 1, compound 3 (30 mg) was synthesized in 21% yield using compound 3c (130 mg, 0.27 mmol) and 2-aminoacetonitrile hydrochloride (25 mg, 0.27 mmol) as starting materials. LC-MS (Method 1): t R = 3.42 min, m / z(M+H) + =516.2; 1 H NMR (400MHz, DMSO-d6) δ9.41 (s, 1H), 9.34 (s, 1H), 8.38 (s, 1H), 8.00 (d, J = 7. 6Hz,2H),7.88(s,1H),7.80(d,J=6.8Hz,2H),7.54(s,1H),5.85(s,1H),4.36 (d,J=3.2Hz,2H),4.24-4.22(m,1H),4.02(d,J=13.6Hz,2H),2.75(t,J=12.4 Hz, 2H), 2.19 (s, 3H), 1.91 (d, J = 11.2Hz, 2H), 1.76-1.70 (m, 2H), 1.25 (s, 9H).

[0552] Example 4

[0553]

[0554] Step 1. 4-Nitro-1H-pyrazole-1-carboxylic acid tert-butyl ester (4b)

[0555] DMAP (23.14 g, 106.1 mmol) was added in a single addition to a solution of compound 4a (10.0 g, 88.44 mmol), di-tert-butyl dicarbonate (19.3 g, 88.50 mmol), and DCM (100 mL). The mixture was stirred at 30 °C for 2 hours under a nitrogen atmosphere. The mixture was diluted with water (300 mL) and then extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated to give the title product (18 g, 96% yield) as a white solid. LC-MS (Method 1): t R = 1.60 min, m / z(M+H) + =214.1; 1 H NMR (400MHz, DMSO-d6) δ9.29(s,1H),8.52(s,1H),150(s,9H).

[0556] Step 2. 4-Amino-1H-pyrazole-1-carboxylic acid tert-butyl ester (4c)

[0557] Pd / C (2 g, 10% carbon-supported palladium, wetted with 55% water) was added in a single addition to a well-stirred solution of compound 4b (18.0 g, 84.5 mmol) and EtOH (200 mL). The mixture was hydrogenated at 30 °C for 18 hours under H2 (50 psi). The mixture was then subjected to… Filtration. The filtrate was concentrated to dryness to give the title product (15 g, 97% yield) as a brown solid. LC-MS (Method 1): t R = 1.18 min, m / z(M+H-56) + =128.0; 1 H NMR (400MHz, DMSO-d6) δ7.34(s,1H),7.32(s,1H),4.40(br.s,2H),1.53(s,9H).

[0558] Step 3. Methyl 4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (4d)

[0559] Compounds 4c (3.49 g, 19.08 mmol), 1b (5.0 g, 19.08 mmol), Cs₂CO₃ (12.36 g, 38.16 mmol), X-Phos (1.82 g, 3.82 mmol), and Pd₂(dba)₃ (1.75 g, 1.91 mmol) were dissolved in 1,4-dioxane (100 mL). The resulting mixture was stirred at 110 °C for 3 hrs under a N₂ atmosphere. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 10:1) to give the title product (3.5 g, 59% yield) as a yellow solid. LC-MS (Method 1): t R = 1.45 min, m / z(M+H-100) + =310.0; 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 8.49 (s, 1H), 8.44 (s, 1H), 8.10 (d, J = 8.0Hz ,2H),7.86(d,J=8.0Hz,2H),7.82(s,1H),3.90(s,3H),2.23(s,3H),1.55(s,9H).

[0560] Step 4. 4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (4e)

[0561] Solid NaOH (2.27 g, 56.75 mmol) was added in a single addition to a solution of 4d (3.5 g, 11.33 mmol), MeOH (120 mL), and H₂O (24 mL). The mixture was stirred at 40 °C for 18 hrs and then adjusted to pH 6–7 with a 10% aqueous HCl solution. The reaction was extracted with a mixture of DCM and MeOH (110 mL, V / V = 10:1). The organic layer was separated and then concentrated to dryness to give the title product (3.1 g, 93% yield) as a yellow solid. LC-MS (Method 1): t R =0.92min, m / z(M+H)+=296.0.

[0562] Step 5. 4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(cyanomethyl)benzamide (4f)

[0563] Compound 4e (3.1 g, 10.51 mmol), 2-aminoacetonitrile (972 mg, 10.51 mmol), HATU (4.2 g, 11.04 mmol), and DIPEA (5.4 g, 42.04 mmol) were dissolved in DMF (50 mL). The resulting mixture was stirred at RT for 18 hrs. The mixture was diluted with water (100 mL) and then extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and filtered. The filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 10:1) to give the title product (2.26 g, 65% yield) as a yellow solid. LC-MS (Method 1): t R = 1.13 min, m / z(M+H) + =334.0; 1 H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.37(s,1H),9.32(br.s,1H),8.37(s,1H),8.00(d, J=8.0Hz,2H),7.79(d,J=8.0Hz,2H),7.75(br.s,1H),4.35(d,J=5.2Hz,2H),2.19(s,3H).

[0564] Step 6. N-(cyanomethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (4)

[0565] Cs₂CO₃ (292 mg, 0.9 mmol) was added in a single addition to a solution of compound 4f (100 mg, 0.3 mmol), 2-chloroacetonitrile (46 mg, 0.6 mmol), and DMF (2 mL). The mixture was stirred at 120 °C for 4 hours under microwave irradiation. After cooling to RT, the mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 10:1) to give the title product (9.9 mg, 9% yield) as a yellow solid. LC-MS (Method 1): t R = 3.20 min, m / z(M+H) + =373.1; 1H NMR (400MHz, DMSO-d6) δ9.60 (s, 1H), 9.36 (t, J = 5.6Hz, 1H), 8.41 (s, 1H), 8.04-8.00 (m, 3 H), 7.82 (d, J = 8.0Hz, 2H), 7.64 (s, 1H), 5.45 (s, 2H), 4.36 (d, J = 5.2Hz, 2H), 2.21 (s, 3H).

[0566] Example 5

[0567]

[0568] Step 1. 1-(4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (5a)

[0569] Using a similar preparation procedure to step 5 of Example 4, compound 5a (648 mg) was synthesized in 77% yield using compound 4f (696 mg, 2.36 mmol) and aziridine-3-carboxynitrile (420 mg, 3.54 mmol) as starting materials. LC-MS (Method 1): t R = 1.12 min, m / z(M+H) + =360.0.

[0570] Step 2. 1-(4-(5-methyl-2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (5)

[0571] Using a similar preparation procedure to the last step of Example 4, compound 5 (17.4 mg) was synthesized in 9% yield using compound 5a (150 mg, 0.42 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (194 mg, 0.84 mmol) as starting materials. LC-MS (Method 1): t R = 3.43 min, m / z(M+H) + =442.0; 1 H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.41(s,1H),8.03(s,1H),7.77(s,4H),7.65(s,1H),5.12- 5.05(m,2H),4.63-4.57(m,2H),4.41-4.35(m,1H),4.22(s,1H),3.91-3.84(m,1H),2.21(s,3H).

[0572] Example 6

[0573]

[0574] N-(2-methoxyethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (6)

[0575] Compound 2b (65 mg, 0.21 mmol), 2-methoxyethylamine (19 mg, 0.25 mmol), HATU (160 mg, 0.42 mmol), and DIPEA (109 mg, 0.84 mmol) were dissolved in DMF (1 mL), and the resulting mixture was stirred overnight at 30 °C. The mixture was diluted with water (10 mL) and then extracted with EtOAc (20 mL). The organic layer was separated, dried on Na2SO4, and filtered. The filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title product (22.5 mg, 26% yield) as a yellow solid. LC-MS (Method 1): t R = 4.04 min, m / z(M+H) + =367.0; 1 HNMR(400MHz,DMSO-d6)δ9.38(s,1H),8.64-8.62(m,1H),8.36(s,1H),7.98(d,J=8.0Hz,2H),7.84(s ,1H),7.75(d,J=8.0Hz,2H),7.48(s,1H),3.78(s,3H),3.50-3.44(m,4H),3.28(s,3H),2.19(s,3H).

[0576] Example 7

[0577]

[0578] N-(3-hydroxypropyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (7)

[0579] Using a similar preparation procedure to step four of Example 1, compound 7 (19.9 mg) was synthesized in 29% yield using compound 2b (65 mg, 0.21 mmol) and 3-aminoprop-1-ol (19 mg, 0.25 mmol) as starting materials. LC-MS (Method 1): t R = 2.48 min, m / z(M+H) + =367.0; 1H NMR (400MHz, DMSO-d6) δ9.37(s,1H),8.56-8.53(m,1H),8.36(s,1H),7.96(d,J=8.4Hz,2H),7.83(s,1H),7.74(d,J=8.0Hz ,2H),7.48(s,1H),4.49-4.47(m,1H),3.78(s,3H),3.51-3.46(m,2H),3.37-3.32(m,2H),2.19(s,3H),1.74-1.67(m,2H).

[0580] Example 8

[0581]

[0582] N-(2-hydroxyethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (8)

[0583] Using a similar preparative procedure to step four of Example 1, compound 8 (20 mg) was synthesized in 25% yield using compound 2b (70 mg, 0.23 mmol) and 2-aminoethanol (14 mg, 0.23 mmol) as starting materials. The mixture was purified by preparative HPLC (Method A). LC-MS (Method 1): t R = 2.89 min, m / z(M+H) + =353.0; 1 H NMR (DMSO-d6, 400MHz): δ9.37 (s, 1H), 8.55-8.51 (m, 1H), 8.36 (s, 1H), 7.98 (d, J = 8.4Hz, 2H), 7.8 (s, 1H), 7.75 (d, J=8.4Hz,2H),7.48(s,1H),4.73(t,J=5.6Hz,1H),3.78(s,3H),3.56-3.51(m,2H),3.38-3.34(m,2H),2.19(s,3H).

[0584] Example 9

[0585]

[0586] N-(3-hydroxycyclobutyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (9)

[0587] Using a similar preparation procedure to step four of Example 1, compound 9 (43 mg) was synthesized in 49% yield using compound 2b (70 mg, 0.23 mmol) and 3-aminocyclobutanol (56 mg, 0.28 mmol) as starting materials. LC-MS (Method 1): t R = 2.97 min, m / z(M+H) + =379.0; 1 H NMR (400MHz, DMSO-d6): 9.40 (s, 1H), 8.68 (t, J = 8.0Hz, 1H), 8.36 (s, 1H), 7 .97(d,J=6.8Hz,2H),7.84(s,1H),6.82(s,1H),7.74(d,J=6.8Hz,2H),7.49 (s,1H),4.48-4.31(m,1H),3.96-3.84(m,1H),3.78(s,3H),2.59-2.54(m, 1H),2.33-2.27(m,1H),2.19(s,3H),2.17-2.14(m,1H),1.97-1.90(m,1H).

[0588] Example 10

[0589]

[0590] N-Methyl-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (10)

[0591] Using a similar preparation procedure to step four of Example 1, compound 10 (51.5 mg) was synthesized in 69% yield using compound 2b (70 mg, 0.23 mmol) and methylamine hydrochloride (16 mg, 0.23 mmol) as starting materials. LC-MS (Method 1): t R = 3.08 min, m / z(M+H) + =323.0; 1 H NMR (400MHz, CDCl3)8.30(s,1H),7.87(d,J=8.4Hz,2H),7.82(s,1H),7.68(d,J=8.4Hz,2H),7.48(s,1H),6.82(s,1H),6.19(br s, 1H), 3.87 (s, 3H), 3.06 (d, J = 6.0Hz, 3H), 2.23 (s, 3H).

[0592] Example 11

[0593]

[0594] N-(cyanomethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (11)

[0595] Using a similar preparation procedure to step four of Example 1, compound 11 (40 mg) was synthesized in 50% yield using compound 2b (70 mg, 0.23 mmol) and 2-aminoacetonitrile hydrochloride (21 mg, 0.23 mmol) as starting materials. LC-MS (Method 1): t R = 3.01 min, m / z(M+H) + =348.1; 1 H NMR(400MHz, DMSO-d6)9.39(s,1H),9.32(t,J=5.6Hz,1H),8.38(s,1H),8.00(d,J=8.4Hz,2H),7 .83(s,1H),7.79(d,J=8.0Hz,2H),7.48(s,1H),4.35(d,J=5.6Hz,2H),3.78(s,3H),2.19(s,3H).

[0596] Example 12

[0597]

[0598] N-((1-cyanocyclopropyl)methyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (12)

[0599] Using a similar preparation procedure to step four of Example 1, compound 12 (45 mg) was synthesized in 40% yield using compound 2b (90 mg, 0.29 mmol) and 1-(aminomethyl)cyclopropaneformonitrile (56 mg, 0.58 mmol) as starting materials. LC-MS (Method 1): t R = 2.97 min, m / z(M+H) + =388.2; 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.92(d,J=8.4Hz,2H),7.84(s,1H),7.71(d,J=8.0Hz,2H),7.47(s,1H),6.86(br s,1H),6.73(t,J=6.4Hz,1H),3.88(s,3H),3.61(d,J=6.0Hz,2H),2.24(s,3H),1.35-1.32(m,2H),1.29-1.22(m,2H).

[0600] Example 13

[0601]

[0602] N-(2-cyano-2-methylpropyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (13)

[0603] Using a similar preparation procedure to step four of Example 1, compound 13 (52 mg) was synthesized in 46% yield using compound 2b (90 mg, 0.29 mmol) and 3-amino-2,2-dimethylpropionitrile (57 mg, 0.58 mmol) as starting materials. LC-MS (Method 1): t R = 2.74 min, m / z(M+H) + =390.2; 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.92(d,J=8.0Hz,2H),7.82(s,1H),7.71(d,J=8.4Hz,2H),7.46(s,1H),6.94(br s, 1H), 6.62 (t, J = 6.0Hz, 1H), 3.88 (s, 3H), 3.66 (d, J = 6.8Hz, 2H), 2.23 (s, 3H), 1.45 (s, 6H).

[0604] Example 14

[0605]

[0606] N-(2,3-dihydroxypropyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (14)

[0607] Using a similar preparative procedure to step four of Example 1, compound 14 (30 mg) was synthesized in 27% yield using compound 2b (90 mg, 0.29 mmol) and 3-aminopropane-1,2-diol (535 mg, 5.82 mmol) as starting materials. The mixture was purified by preparative HPLC (Method B). LC-MS (Method 1): t R = 2.49 min, m / z(M+H) + =383.0; 1H NMR(DMSO-d6,400MHz): δ9.39(s,1H),8.50(t,J=5.2Hz,1H),8.36(s,1H),7.98(d,J=8.4Hz,2H),7.83(s,1H),7.75 (d,J=8.0Hz,2H),7.48(s,1H),3.78(s,3H),3.46-3.41(m,2H),3.40-3.36(m,2H),3.26-3.20(m,1H),2.19(s,3H).

[0608] Example 15

[0609]

[0610] 1-(4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (15)

[0611] Using a similar preparation procedure to step four of Example 1, compound 15 (30 mg) was synthesized in 36% yield using compound 2b (70 mg, 0.23 mmol) and aziridine-3-carboxynitrile hydrochloride (27 mg, 0.23 mmol) as starting materials. LC-MS (Method 1): t R = 2.78 min, m / z(M+H) + =374.1; 1 H NMR(DMSO-d6,400MHz): δ9.38(s,1H),8.37(s,1H),7.83(s,1H),7.79-7.74(m,4H),7.48( s,1H),4.65-4.55(m,2H),4.38-4.22(m,2H),3.89-3.86(m,1H),3.78(s,3H),2.20(s,3H).

[0612] Example 16

[0613]

[0614] N-((cis)-3-cyanocyclobutyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (16)

[0615] Using a similar preparation procedure to step four of Example 1, compound 16 (20 mg) was synthesized in 14% yield using compound 2b (117 mg, 0.38 mmol) and (cis)-3-aminocyclobutaneformonitrile hydrochloride (50 mg crude, 0.38 mmol) as starting materials. LC-MS (Method 1): tR = 3.19 min, m / z(M+H) + =388.2; 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),8.88(d,J=7.6Hz,1H),8.36(s,1H),7.97(d,J=8.4Hz,2H),7.83(s,1H),7.76(d,J=8.4 Hz,2H),7.48(s,1H),4.55-4.44(m,1H),3.78(s,3H),3.15-3.06(m,1H),2.72-2.65(m,2H),2.49-2.41(m,2H),2.19(s,3H).

[0616] Example 17

[0617]

[0618] N-(1-Cyanoethyl)-4-(5-Methyl-2-((1-Methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (17)

[0619] Using a similar preparation procedure to step four of Example 1, compound 17 (180 mg) was synthesized in 77% yield using compound 2b (200 mg, 0.65 mmol) and 2-aminopropionitrile hydrochloride (69 mg, 0.65 mmol; CAS: 59981-03-2) as starting materials. LC-MS (Method 1): t R = 2.69 min, m / z(M+H) + =362.0; 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.88(d,J=8.0Hz,2H),7.78(s,1H),7.70(d,J=8.4Hz,2H),7.45(s,1H) ,7.01(s,1H),6.68(d,J=8.4Hz,1H),5.22-5.15(m,1H),3.86(s,3H),2.22(s,3H),1.70(d,J=7.2Hz,3H).

[0620] Example 18

[0621]

[0622] (S)-N-(1-cyanoethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (18)

[0623] Using a similar preparative procedure to step four of Example 1, compound 18 (40 mg) was synthesized in 49% yield using compound 2b (70 mg, 0.23 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (55 mg, 0.23 mmol; CAS: 2119588-41-7) as starting materials. The mixture was purified by preparative HPLC (Method A). LC-MS (Method 1): t R = 2.95 min, m / z(M+H) + =362.2; 1 H NMR (DMSO-d6, 400MHz): δ9.40 (s, 1H), 9.26 (d, J = 7.2Hz, 1H), 8.38 (s, 1H), 8.01 (d, J = 8.4Hz, 2H), 7 .83-7.78(m,3H),7.48(s,1H),5.04-5.01(m,1H),3.78(s,3H),2.19(s,3H),1.57(d,J=7.2Hz,3H).

[0624] Example 19

[0625]

[0626] N-(cyanomethyl)-4-(2-((1-(1-(2,2-difluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (19)

[0627] Compound 1f (50 mg, 0.11 mmol), 2,2-difluoroethyltrifluoromethanesulfonate (117.7 mg, 0.55 mmol), and DIPEA (42 mg, 0.33 mmol) were dissolved in THF (5 mL). The resulting mixture was stirred at 40 °C for 4 hours and then concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title product (12 mg, 23% yield) as a yellow solid. LC-MS (Method 1): t R = 3.29 min, m / z(M+H) + =481.2; 1H NMR (400MHz, CDCl3) δ8.31(s,1H),7.92-7.88(m,3H),7.72(d,J=8.0Hz,2H),7.50(s,1H),6.91(s,1H),6.76(t,J=4.0Hz,1H),6.04-5.76(m,1 H), 4.43 (d, J = 8.0Hz, 2H), 4.12-4.07 (m, 1H), 3.06 (d, J = 8.0Hz, 2H), 2.83-2.75 (m, 2H), 2.41 (t, J = 8.0Hz, 2H), 2.24 (s, 3H), 2.14-2.04 (m, 4H).

[0628] Example 20

[0629]

[0630] 4-(2-((1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(cyanomethyl)benzamide (20)

[0631] Acetic anhydride (29.8 mg, 0.29 mmol) was added to a well-stirred solution of compound 1f (110 mg, 0.24 mmol), TEA (131 mg, 1.30 mmol), and DCM (5 mL) at 0 °C. The mixture was stirred at RT for 2 hours and then concentrated to dryness to give the residue, which was further purified by preparative HPLC (Method A) to give the title product (30 mg, 21% yield) as a yellow solid. LC-MS (Method 1): t R = 2.79 min, m / z(M+H) + =459.0; 1 H NMR (DMSO-d6, 400MHz): δ9.40 (s, 1H), 9.32 (t, J=5.2Hz, 1H), 8.38 (s, 1H), 8.00 (d, J= 8.4Hz,2H),7.90(s,1H),7.80(d,J=8.0Hz,2H),7.55(s,1H),4.45-4.40(m,1H),4.39 -4.33(m,3H),3.89(d,J=13.6Hz,1H),3.18(t,J=12.4Hz,1H),2.70(d,J=12.4Hz,1H) ,2.20(s,3H),2.03(s,3H),1.99-1.96(m,2H),1.86-1.83(m,1H),1.70-1.66(m,1H).

[0632] Example 21

[0633]

[0634] N-(cyanomethyl)-4-(5-methyl-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (21)

[0635] Neopentanoyl chloride (62.6 mg, 0.52 mmol) was added to a well-stirred solution of compound 1f (180 mg, 0.43 mmol), TEA (131 mg, 1.30 mmol), and DCM (5 mL) at 0 °C. The mixture was stirred at RT for 2 hours and then concentrated to dryness to give the residue, which was purified by preparative HPLC (Method A) to give the title product as a yellow solid (10 mg, 5% yield). LC-MS (Method 1): t R = 3.67 min, m / z(M+H) + =501.0; 1 H NMR (CD3OD, 400MHz): δ8.36 (s, 1H), 8.08 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.83 (d, J = 8.4Hz, 2H), 7.63 (s, 1H), 4.56 (d, J = 13. 6Hz, 2H), 4.46-4.41 (m, 3H), 3.08 (t, J = 12.8Hz, 2H), 2.28 (s, 3H), 2.16 (d, J = 11.2Hz, 2H), 1.97-1.90 (m, 2H), 1.34 (s, 9H).

[0636] Example 22

[0637]

[0638] N-(cyanomethyl)-4-(5-methyl-2-((1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (22)

[0639] Compound 1f (100 mg, 0.24 mmol), 2,2,2-trifluoroethyltrifluoromethanesulfonate (56 mg, 0.24 mmol), and TEA (97 mg, 0.96 mmol) were dissolved in DMF (3 mL), and the resulting mixture was stirred overnight at 30 °C. The mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated to dryness and then purified by preparative TLC (DCM:MeOH = 10:1) to give the title compound as a yellow solid (10.3 mg, 9% yield). LC-MS (ESI): R T = 3.07 min, m / z(M+H) + =499.0. 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),7.91-7.89(m,3H),7.72(d,J=8.4Hz,2H),7.51(s,1H),6.86(s,1H),6.65(t,J=5.6H z,1H),4.42(d,J=5.6Hz,2H),4.10-4.09(m,1H),3.11-3.00(m,4H),2.60-2.53(m,2H),2.23(s,3H),2.11-2.05(m,4H).

[0640] Example 23

[0641]

[0642] Step 1. Methyl 4-(2-((1-(1-(cyanomethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (23a)

[0643] Compound 3a (200 mg, 0.47 mmol), 2-chloroacetonitrile (39 mg, 0.52 mmol), and DIPEA (182 mg, 1.41 mmol) were dissolved in DMF (2 mL). The resulting mixture was stirred overnight at 40 °C and then concentrated to dryness to give a product as a yellow solid (400 mg, crude product). LC-MS (Method 1): tR = 1.61 min, m / z(M+H)+ = 432.1.

[0644] Step 2. 4-(2-((1-(1-(cyanomethyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (23b)

[0645] Compound 23b (387 mg crude) was synthesized using a preparation procedure similar to step three of Example 1. LC-MS (Method 1): tR =1.12min, m / z(M+H)+=418.1.

[0646] Step 3. 1-(4-(2-((1-(1-(cyanomethyl)piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (23)

[0647] Using a similar preparation procedure to step four of Example 1, compound 23 (56 mg) was synthesized in an overall yield of 25% using compound 23b and aziridine-3-carboxynitrile hydrochloride as starting materials. LC-MS (Method 1): t R = 3.01 min, m / z(M+H) + =482.3; 1 HNMR(400MHz,DMSO-d6)δ9.40(s,1H),8.34(s,1H),7.90(s,1H),7.78(s,4H),7.55(s,1H),4.63-4.58(m,2H),4.41-4.36(m,1H),4.23 (s,1H),4.14-4.07(m,1H),3.91-3.84(m,1H),3.77(s,2H),2.88(d,J=8.0Hz,2H),2.37-2.32(m,2H),2.20(s,3H),2.03-1.87(m,4H).

[0648] Example 24

[0649]

[0650] Step 1. Methyl 4-(2-((1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (24a)

[0651] To a mixture of compound 3a (200 mg, 0.684 mmol), DIPEA (265 mg, 2.050 mmol), and DMF (2 mL), cyclopropane carbonyl chloride (86 mg, 0.823 mmol) was added dropwise. The reaction mixture was stirred at RT for 4 hours. The mixture was concentrated to dryness, and the residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated to dryness to give the title crude compound (220 mg, 70% yield) as a brown solid. LC-MS (Method 3): t R = 1.52 min, m / z(M+H) + =461.2.

[0652] Step 2. 4-(2-((1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (24b)

[0653] A solution of NaOH (96 mg, 2.40 mmol) in H₂O (2 mL) was added dropwise to a mixture of compound 24a (220 mg, 0.478 mmol) and MeOH (2 mL). The mixture was stirred at 40 °C for 2 hours. The pH of the mixture was adjusted to 6–7 with a 10% aqueous HCl solution, and extracted with a mixed solution of DCM and MeOH (110 mL; V / V = 10:1). The organic layer was separated and concentrated under vacuum to give the title crude compound (210 mg, 99%) as a brown solid. LC-MS (Method 3): t R = 1.37 min, m / z(M+H) + =447.0.

[0654] Step 3. N-(cyanomethyl)-4-(2-((1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (24)

[0655] Using a similar preparation procedure to step four of Example 1, compound 24 (14.6 mg) was synthesized in 14% yield using compound 24b (100 mg, 0.23 mmol) and 2-aminoacetonitrile hydrochloride (31 mg, 0.33 mmol) as starting materials. LC-MS (Method 1): t R = 3.22 min, m / z(M+H) + =485.2. 1 H NMR (400MHz, DMSO-d6) δ9.41-9.35(m,2H),8.38(s,1H),8.01(d,J=8.0Hz,2H),7.92(s,1H),7.81(d,J=8.0Hz,2H),7.57( s,1H),4.39-4.37(m,5H),3.26-3.24(m,1H),2.76-2.74(m,1H),2.51(s,3H),2.06-1.85(m,3H),1.83-1.71(m,2H),0.75

[0656] -0.71(m,4H).

[0657] Example 25

[0658]

[0659] N-(cyanomethyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (25)

[0660] Compound 4f (100 mg, 0.3 mmol), cyclopropylboronic acid (26 mg, 0.6 mmol), Na₂CO₃ (64 mg, 0.6 mmol), and copper(II) acetate (55 mg, 0.3 mmol) were dissolved in 1,2-dichloroethane (2 mL), followed by the addition of 2,2'-bipyridine (47 mg, 0.3 mmol). The mixture was stirred at 70 °C for 1 hr under a N₂ atmosphere and then diluted with water (10 mL). The mixture was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated to dryness to give the residue, which was purified by chromatography on silica gel (eluent: DCM:MeOH = 10:1) to give the title product as a yellow solid (19.9 mg, 18% yield). LC-MS (Method 1): t R = 2.90 min, m / z(M+H) + =374.0; 1 H NMR (400MHz, DMSO-d6) δ9.42 (s, 1H), 9.35 (t, J = 5.6Hz, 1H), 8.38 (s, 1H), 8.01-7.99 (m, 2H), 7.90 (s, 1H), 7. 81(d,J=8.0Hz,2H),7.47(s,1H),4.36(d,J=5.2Hz,2H),3.67-3.63(m,1H),2.19(s,3H),1.00-0.89(m,4H).

[0661] Example 26

[0662]

[0663] N-(cyanomethyl)-4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (26)

[0664] Using a similar preparative procedure to the last step of Example 4, compound 26 (14.3 mg) was synthesized in 6% yield using compound 4f (200 mg, 0.6 mmol) and tetrahydro-2H-pyran-4-ylmethanesulfonate (217 mg, 1.2 mmol) as starting materials. LC-MS (Method 1): t R = 3.07 min, m / z(M+H) + =418.0; 1H NMR(400MHz,DMSO-d6)δ9.42(s,1H),9.34(br s,1H),8.38(s,1H),8.00(d,J=8.4Hz,2H),7.91(s,1H),7.80(d,J=6.4Hz,2H),7.54(s,1H),4 .37-4.34(m,3H),3.95(d,J=10.8Hz,2H),3.47-3.42(m,2H),2.20(s,3H),1.92-1.88(m,4H).

[0665] Example 27

[0666]

[0667] N-(cyanomethyl)-4-(2-((1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (27)

[0668] Using a similar preparation procedure to the last step of Example 4, compound 27 (6 mg) was synthesized in 14% yield using compound 4f (48 mg, 0.14 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (23 mg, 0.11 mmol) as starting materials. LC-MS (Method 1): t R = 3.27 min, m / z(M+H) + =398.1; 1 H NMR (400MHz, DMSO-d6) δ9.52 (s, 1H), 9.37 (t, J = 5.2Hz, 1H), 8.41 (s, 1H), 8.02-7.99 (m, 3H), 7.82 (d, J=8.0Hz,2H),7.61(s,1H),6.46-6.19(m,1H),4.62-4.54(m,2H),4.37(d,J=5.6Hz,2H),2.22(s,3H).

[0669] Example 28

[0670]

[0671] N-(cyanomethyl)-4-(5-methyl-2-((1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (28)

[0672] Using a similar preparation procedure to the last step of Example 4, compound 28 (14 mg) was synthesized in 12% yield using compound 4f (100 mg, 0.28 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (131 mg, 0.56 mmol) as starting materials. LC-MS (Method 1): t R = 4.20 min, m / z(M+H) + =416.0; 1 H NMR(400MHz,DMSO-d6)δ9.54(s,1H),9.34(t,J=5.6Hz,1H),8.41(s,1H),8.03-7.99(m,3H) ,7.81(d,J=8.0Hz,2H),7.64(s,1H),5.11-5.04(m,2H),4.36(d,J=5.6Hz,2H),2.21(s,3H).

[0673] Example 29

[0674]

[0675] 1-(4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (29)

[0676] A mixture of compound 5a (150 mg, 0.418 mmol) and DCE (3 mL) was sequentially added with cyclopropylboronic acid (71.8 mg, 0.836 mmol), 2,2'-bipyridine (65.3 mg, 0.418 mmol), copper acetate (75.9 mg, 0.418 mmol), and sodium carbonate (88.6 mg, 0.836 mmol). The mixture was stirred at 70 °C for 3 hours and then concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: DCM:MeOH = 60:1) and further purified by preparative HPLC (Method A) to give the title product as a yellow solid (89 mg, 53.6% yield). LC-MS (Method 1): t R = 2.58 min, m / z(M+H) + =400.2; 1H NMR (400MHz, DMSO-d6) δ9.45(s,1H), δ8.42(s,1H), δ7.94(s,1H), δ7.81(s,4H), δ7.52(s,1H),4.65-4.62(m,2H ),4.42-4.41(m,1H),4.28-4.26(m,1H),3.94-3.90(m,1H),3.72-3.66(m,1H),2.24(s,3H),1.01-0.94(m,4H).

[0677] Example 30

[0678]

[0679] 1-(4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (30)

[0680] Using a similar preparation procedure to the last step of Example 4, compound 30 (56 mg) was synthesized in 38% yield using compound 5a (200 mg, 0.56 mmol) and 2-chloroacetonitrile (28 mg, 0.37 mmol) as starting materials. LC-MS (Method 1): t R = 3.06 min, m / z(M+H) + =399.0; 1 H NMR(400MHz,DMSO-d6)δ9.58(s,1H),8.41(s,1H),8.04(s,1H),7.77(s,4H),7.65(s,1H),5.45( s,2H),4.61-4.58(m,2H),4.40-4.36(m,1H),4.24-4.20(m,1H),3.91-3.86(m,1H),2.21(s,3H).

[0681] Example 31

[0682]

[0683] 1-(4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (31)

[0684] Using a similar preparation procedure to the last step of Example 4, compound 31 (40 mg) was synthesized in 16% yield using compound 5a (200 mg, 0.56 mmol) and tetrahydro-2H-pyran-4-yl methanesulfonate (201 mg, 1.12 mmol) as starting materials. LC-MS (Method 1): t R = 2.90 min, m / z(M+H) + =444.0; 1 H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.37(s,1H),7.90(s,1H),7.77(s,4H),7.55(s,1H),4.63-4.58(m,2H), 4.40-4.30(m,2H),4.24-4.19(m,1H),3.95-3.83(m,3H),3.47-3.41(m,2H),2.20(s,3H),1.95-1.86(m,4H).

[0685] Example 32

[0686]

[0687] Step 1. 1-(aminomethyl)cyclopropanol (32b)

[0688] Acetic acid (1 mL) was added to a mixture of compound 32a (300 mg, 1.1 mmol), Pd / C (150 mg, 10% carbon-supported palladium, wetted with 55% water), and MeOH (5 mL). The mixture was hydrogenated at 50 °C for 12 hrs under H2 (50 psi). The mixture was filtered and the filtrate was concentrated to dryness to give the crude title product (97.6 mg, 100% yield) as a colorless oil. 1 H NMR (CDCl3, 400MHz): δ2.84 (s, 2H), 0.77-0.59 (m, 2H), 0.55-0.54 (m, 2H).

[0689] Step 2. N-((1-hydroxycyclopropyl)methyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (32)

[0690] Using a similar preparative procedure to step four of Example 1, compound 32 (15 mg) was synthesized in 18% yield using compound 2b (58 mg, 0.19 mmol) and compound 32b (65 mg, 0.74 mmol) as starting materials. The mixture was purified by preparative HPLC (Method A). LC-MS (Method 1): t R= 2.75 min, m / z(M+H) + =379.0; 1 H NMR (DMSO-d6, 400MHz): δ9.38 (s, 1H), 8.52 (s, 1H), 8.37 (s, 1H), 8.00 (d, J = 7.6Hz, 2H), 7.84 (s, 1H), 7.76 (d,J=7.6Hz,2H),7.49(s,1H),5.45(s,1H),3.79(s,3H),3.47(d,J=5.6Hz,2H),2.20(s,3H),0.58(s,4H).

[0691] Example 33

[0692]

[0693] Step 1. Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate (33b)

[0694] Using a similar preparation procedure to the first step of Example 1, compound 33b (500 mg) was synthesized in 72% yield using compound 33a (388 mg, 2.38 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (500 mg, 2.38 mmol) as starting materials. 1 H NMR (400MHz, CDCl3) δ8.53(s,1H),7.89(d,J=7.6Hz,1H),7.22(d,J=1.2Hz,1H),7.18(dd,J=1.6,7.6Hz,1H),3.97(s,3H),3.92(s,3H),2.37(s,3H).

[0695] Step 2. Methyl 2-methoxy-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (33c)

[0696] Using a similar preparation procedure as in the second step of Example 1, compound 33c (450 mg) was synthesized in 75% yield using compound 33b (500 mg, 1.71 mmol) and 1-methyl-1H-pyrazole-4-amine (166 mg, 1.71 mmol) as starting materials. 1H NMR (400MHz, CDCl3) δ8.31(s,1H),7.89(d,J=8.0Hz,1H),7.84(s,1H),7.48(s,1H),7.25(d,J=8.0Hz ,1H),7.19(dd,J=1.2,8.0Hz,1H),6.93(s,1H),3.96(s,3H),3.91(s,3H),3.88(s,3H),2.23(s,3H).

[0697] Step 3. 2-Methoxy-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (33d)

[0698] Using a similar preparation procedure to step 3 of Example 1, compound 33d (432 mg) was synthesized in 100% yield using compound 33c (450 mg, 1.27 mmol) as the starting material. LC-MS (Method 3): t R =0.96min, m / z(M+H) + =340.0.

[0699] Step 4. N-(cyanomethyl)-2-methoxy-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (33)

[0700] Using a similar preparative procedure to step four of Example 1, compound 33 (30 mg) was synthesized in 35% yield using compound 33d (80 mg, 0.23 mmol) and 2-aminoacetonitrile hydrochloride (21 mg, 0.23 mg) as starting materials. The final compound was purified by preparative HPLC (Method B), yielding the title compound. LC-MS (Method 1): t R = 3.19 min, m / z(M+H) + =378.1; 1 H NMR (400MHz, DMSO-d6) δ9.44(s,1H),8.90(t,J=5.6Hz,1H),8.38(s,1H),7.94(d,J=8.0Hz,1H),7.86(s,1H),7.4 7(s,1H),7.42(s,1H),7.34(d,J=8.0Hz,1H),4.33(d,J=6.0Hz,2H),3.97-3.95(m,3H),3.78(s,3H),2.21(s,3H).

[0701] Example 34

[0702]

[0703] Step 1. Methyl 4-(2,5-dichloropyrimidin-4-yl)benzoate (34b)

[0704] A mixture of compound 34a (2.80 g, 15.3 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (2.76 g, 15.3 mmol), DME (30 mL), and H₂O (10 mL) was sequentially added with Na₂CO₃ (3.26 g, 30.7 mmol) and Pd(PPh₃)₄ (177 mg, 1.53 mmol). The mixture was stirred at 40 °C for 4 hours under a N₂ atmosphere. After cooling to RT, the mixture was concentrated to dryness. EtOAc (100 mL) and water (100 mL) were added. The organic layer was separated, dried on Na₂SO₄, and filtered. The filtrate was concentrated to dryness to give the residue, which was purified by chromatography on silica gel (eluent: PE:EtOAc = 5:1) to give the title compound as a white solid (950 mg, 22% yield). 1H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.18 (d, J = 8.0Hz, 2H), 7.96 (d, J = 8.0Hz, 2H), 3.98 (s, 3H).

[0705] Step 2. Methyl 4-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (34c)

[0706] Compound 34b (950 mg, 3.36 mmol), 1-methyl-1H-pyrazole-4-amine (391 mg, 4.03 mmol), Cs₂CO₃ (2.18 g, 6.72 mmol), X-Phos (320 mg, 0.67 mmol), and Pd₂(dba)₃ (308 mg, 0.33 mmol) were dissolved in 1,4-dioxane (20 mL). The resulting mixture was stirred at 110 °C for 3 hrs under a N₂ atmosphere. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 3:1) to give the title compound as a yellow solid (552 mg, 48% yield). LC-MS (Method 3): t R = 1.58 min, m / z(M+H) + =344.1.

[0707] Step 3. 4-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (34d)

[0708] Using a similar preparation procedure to step 3 of Example 1, compound 34d (140 mg) was synthesized in 97% yield using compound 34c (150 mg, 0.44 mmol) as the starting material. LC-MS (Method 3): t R = 1.09 min, m / z(M+H) + =330.1.

[0709] Step 4. 4-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide (34)

[0710] Using a similar preparation procedure to step four of Example 1, compound 34 (17.4 mg) was synthesized in 11% yield using compound 34d (140 mg, 0.42 mmol) and 2-aminoacetonitrile hydrochloride (59 mg, 0.64 mmol) as starting materials. LC-MS (Method 1): t R = 3.15 min, m / z(M+H) + =367.9; 1 H NMR (400MHz, CD3OD) δ8.46(s,1H),8.00-7.94(s,4H),7.90(s,1H),7.56(s,1H),4.36(s,2H),3.84(s,3H).

[0711] Example 35

[0712]

[0713] Step 1. Methyl 4-(2-chloropyrimidin-4-yl)-3-fluorobenzoate (35b)

[0714] Compound 35a (290 mg, 1.95 mmol), (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (386 mg, 1.95 mmol), Na₂CO₃ (413 mg, 3.90 mmol), and Pd(dppf)Cl₂ (100 mg, 0.1365 mmol) were dissolved in a mixture containing 1,4-dioxane (4 mL) and H₂O (1 mL). The resulting mixture was stirred overnight at 60 °C under a N₂ atmosphere. After cooling to RT, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluent: PE:EtOAc = 5:1), giving the title compound as a white solid (440 mg, 85% yield). LC-MS (Method 3): t R = 1.52 min, m / z(M+H) + =267.1.

[0715] Step 2. Methyl 3-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (35c)

[0716] Compound 35b (440 mg, 1.65 mmol), 1-methyl-1H-pyrazole-4-amine (176 mg, 1.81 mmol), Pd2(dba)3 (151 mg, 0.165 mmol), X-Phos (157 mg, 0.33 mmol), and Cs2CO3 (1.08 g, 3.3 mmol) were dissolved in 1,4-dioxane (6 mL). The resulting mixture was stirred at 100 °C for 8 hrs under N2. After cooling to RT, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography on silica gel (eluent: DCM:MeOH = 50:1), giving the title compound as a brown solid (290 mg, 54% yield). LC-MS (Method 3): t R = 1.49 min, m / z(M+H) + =328.2.

[0717] Step 3. 3-Fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (35d)

[0718] Using a similar preparation procedure to step 3 of Example 1, compound 35d (277 mg) was synthesized in 100% yield using compound 35c (290 mg, 0.89 mmol) as the starting material. LC-MS (Method 3): t R = 1.10 min, m / z(M+H) + =314.2.

[0719] Step 4. N-(cyanomethyl)-3-fluoro-4-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (35)

[0720] Using a preparation procedure similar to step four of Example 1, compound 35 (49.6 mg) was synthesized in 37% yield using compound 35d (120 mg, 0.38 mmol) and 2-aminoacetonitrile hydrochloride (53 mg, 0.56 mmol) as starting materials. 1HNMR(400MHz,DMSO-d6)δ9.64(s,1H),9.43(t,J=5.6Hz,1H),8.54(d,J=5.2Hz,1H),8.17-8.14(m,1 H),7.90-7.81(m,3H),7.53(s,1H),7.14(dd,J=2.4,5.2Hz,1H),4.35(d,J=5.6Hz,2H),3.81(s,3H).

[0721] Example 36

[0722]

[0723] Step 1. Methyl 4-(2-chloro-5-fluoropyrimidin-4-yl)-2-fluorobenzoate (36b)

[0724] Compound 36a (5.0 g, 29.95 mmol) was dissolved in a mixture of 1,4-dioxane (75 mL) and H₂O (15 mL). (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (5.93 g, 29.95 mmol), K₃PO₄ (12.7 g, 59.9 mmol), and Pd(dppf)Cl₂ (2.44 g, 2.99 mmol) were added sequentially to the above solution. The mixture was stirred at 80 °C for 3 hrs under a N₂ atmosphere. After cooling to RT, the mixture was concentrated to dryness. EtOAc (100 mL) and water (100 mL) were added. The organic layer was separated, dried on Na₂SO₄, and filtered. The filtrate was concentrated to dryness to give the residue, which was purified by chromatography on silica gel (eluent: PE:EtOAc = 10:1) to give the title compound as a white solid (7.2 g, 85% yield). LC-MS (Method 3): t R = 1.60 min, m / z(M+H) + =285.0; 1 H NMR (400MHz, CDCl3) δ8.61 (d, J = 2.8Hz, 1H), 8.11-8.07 (m, 1H), 8.03-7.96 (m, 2H), 3.98 (s, 3H).

[0725] Step 2. Methyl 2-fluoro-4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (36c)

[0726] Compound 36b (700 mg, 2.46 mmol), 1-methyl-1H-pyrazole-4-amine (263 mg, 2.71 mmol), Cs₂CO₃ (1.6 g, 4.92 mmol), X-Phos (234 mg, 0.49 mmol), and Pd₂(dba)₃ (225 mg, 0.25 mmol) were dissolved in 1,4-dioxane (10 mL). The mixture was stirred at 110 °C for 16 hrs under a N₂ atmosphere. After cooling to RT, the reaction mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 3:1) to give the title compound as a yellow solid (540 mg, 64% yield). LC-MS (Method 3): t R = 1.38 min, m / z(M+H) + =346.1; 1 H NMR (400MHz, CDCl3) δ8.43 (d, J = 4.4Hz, 1H), 8.14-8.09 (m, 1H), 8.00-7.92 (m, 2H), 7.85 (s, 1H), 7.58 (s, 1H), 6.95 (br s,1H),4.02(s,3H),3.96(s,3H).

[0727] Step 3. 2-Fluoro-4-(5-Fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (36d)

[0728] LiOH (132 mg, 3.14 mmol) was added in a single addition to a solution of compound 36c (540 mg, 1.57 mmol), MeOH (3 mL), THF (3 mL), and H₂O (2 mL). The reaction mixture was stirred at RT for 2 hours. The mixture was adjusted to pH 6–7 with a 10% aqueous HCl solution and then extracted with a mixture of DCM and MeOH (55 mL, V / V = 10:1). The organic layer was separated and concentrated to dryness under vacuum to give the title compound (426 mg, 82% yield) as an orange solid. LC-MS (Method 3): t R = 1.04 min, m / z(M+H) + =332.1.

[0729] Step 4. N-(cyanomethyl)-2-fluoro-4-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (36)

[0730] Using a similar preparation procedure to step four of Example 1, compound 36 (62 mg) was synthesized in 62% yield using compound 36d (90 mg, 0.27 mmol) and 2-aminoacetonitrile hydrochloride (50 mg, 0.54 mmol) as starting materials. LC-MS (Method 1): t R = 2.98 min, m / z(M+H) + =370.1; 1 H NMR (400MHz, DMSO-d6) δ9.70(s,1H),9.19(t,J=4.0Hz,1H),8.64(d,J=3.2Hz,1H),7.96(d,J=8.0Hz,1H),7.92-7.87(m,3H),7.53(br s, 1H), 4.37 (d, J = 5.6Hz, 2H), 3.82 (s, 3H).

[0731] Example 37

[0732]

[0733] Step 1. Ethyl 4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (37a)

[0734] Concentrated sulfuric acid (0.2 mL) was added to a suspension of compound 4e (1.5 g, crude) in ethanol (20 mL). The mixture was heated at 90 °C for 24 hrs. After cooling to RT, the reaction mixture was concentrated to give the desired compound (1.7 g, crude) as a yellow solid, which was used directly in the next step. LC-MS (Method 3): t R = 1.49 min, m / z(M+H) + =324.0; 1 H NMR (400MHz, CD3OD) δ 8.38 (s, 1H), 8.20 (d, J = 8.4Hz, 2H), 8.14 (s, 2H), 7.85 (d, J = 8.4Hz, 2H), 4.42 (q, J = 7.2Hz, 2H), 2.32 (s, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0735] Step 2. 4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (37b)

[0736] Compound 37a (1.7 g, 5.08 mmol), tetrahydro-2H-pyran-4-yl methanesulfonate (2.3 g, 12.7 mmol), and cesium carbonate (8.3 g, 25.4 mmol) were dissolved in DMF (15 mL). The resulting mixture was stirred at 100 °C for 16 hrs. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give the title product 37b (620 mg, 32% yield) as a yellow solid. LC-MS (Method 3): t R = 1.11 min, m / z(M+H) + =380.2.

[0737] Step 3. N-((1-cyanocyclopropyl)methyl)-4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (37)

[0738] Using a similar preparation procedure to step four of Example 1, compound 37 (20 mg) was synthesized in 21% yield using compound 37b (80 mg, 0.21 mmol) and 1-(aminomethyl)cyclopropaneformonitrile (61 mg, 0.63 mmol) as starting materials. LC-MS (Method 1): t R = 3.49 min, m / z(M+H) + =458.0; 1 H NMR(400MHz,MeOH-d4)δ8.32(s,1H),8.02-7.98(m,3H),7.78(d,J=8.4Hz,2H),7.61(s,1H),4.35-4.31(m,1H) ,4.07-4.03(m,2H),3.59-3.52(m,4H),2.24(s,3H),2.06-2.00(m,4H),1.31-1.28(m,2H),1.21-1.18(m,2H).

[0739] Example 38

[0740]

[0741] Step 1. Methyl 4-(5-methyl-2-((1-(1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (38a)

[0742] Compound 3a (380 mg, 0.89 mmol), 1-methylcyclopropanecarboxylic acid (134 mg, 1.34 mmol), HOBT (600 mg, 4.45 mmol), EDCI (877 mg, 4.45 mmol), and DIPEA (574 mg, 4.45 mmol) were dissolved in DMF (1 mL). The mixture was stirred at RT for 3 hours. The mixture was concentrated. The residue was purified by column chromatography on silica gel (eluent: PE:EtOAc = 5:1), giving the title product (380 mg, 90% yield) as a yellow solid. LC-MS (Method 3): t R = 1.55 min, m / z(M+H) + =475.2.

[0743] Step 2. 4-(5-methyl-2-((1-(1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (38b)

[0744] Using a similar preparation procedure to step 3 of Example 1, compound 38b (360 mg) was synthesized in 98% yield using compound 38a (380 mg, 0.8 mmol) as the starting material. LC-MS (Method 3): t R = 1.20 min, m / z(M+H) + =461.2.

[0745] Step 3. N-(cyanomethyl)-4-(5-methyl-2-((1-(1-(1-methylcyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (38)

[0746] Using a similar preparation procedure to step four of Example 1, compound 38 (55.2 mg) was synthesized in 65% yield using compound 38b (80 mg, 0.17 mmol) and 2-aminoacetonitrile hydrochloride (47 mg, 0.51 mmol) as starting materials. LC-MS (Method 1): t R = 3.288 min, m / z(M+H) + =499.3. 1H NMR (400MHz, DMSO-d6) δ9.42(s,1H),9.33(t,J=5.6Hz,1H),8.38(s,1H),8.00(d,J=8.4Hz,2H),7.93(s,1H),7.81(d,J=7.6Hz,2H),7.54(s, 1H),4.40-4.31(m,5H),2.98(s,2H),2.20(s,3H),2.07-2.01(m,2H), 1.76-1.74(m,2H),1.23(s,3H),0.81-0.79(m,2H),0.56-0.53(m,2H).

[0747] Example 39

[0748]

[0749] Step 1. Butyl 4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (39a)

[0750] Using a procedure similar to the second step of Example 1, compound 39a (2.0 g) was synthesized in 44% yield using compound 34b (2.96 g, 11.1 mmol) and 1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (42.40 g, 13.3 mmol) as starting materials. LC-MS (Method 3): t R = 1.85 min, m / z(M+H) + =414.1;

[0751] Step 2. 4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (39b)

[0752] Using a similar preparation procedure to step 3 of Example 1, compound 39b (210 mg) was synthesized in 96% yield using compound 39a (250 mg, 0.55 mmol) as the starting material. LC-MS (Method 3): t R = 1.11 min, m / z(M+H) + =400.1;

[0753] Step 3. (S)-4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (39)

[0754] Using a procedure similar to step four of Example 1, compound 39 (20.2 mg) was synthesized in 22% yield using compound 39b (85 mg, 0.21 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (62.9 mg, 0.26 mmol) as starting materials. LC-MS (Method 1): t R = 3.22 min, m / z(M+H) + =452.2; 1 H NMR(400MHz,MeOH-d4)δ8.49(s,1H),8.03-7.98(m,5H),7.64(s,1H),5.12-5.07(m,1H),4.41 -4.33(m,1H),4.10-4.06(m,2H),3.34-3.32(m,2H),2.08-2.04(m,4H),1.68(d,J=7.2Hz,3H).

[0755] Example 40

[0756]

[0757] Step 1. 2-(4-nitro-1H-pyrazole-1-yl)acetonitrile (40a)

[0758] A mixture of 4-nitro-1H-pyrazole (10.0 g, 88.5 mmol), 2-bromoacetonitrile (21.0 g, 177 mmol), and K₂CO₃ (37.0 g, 266 mmol) in DMF (50 mL) was stirred at 50 °C for 2 hours. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (150 mL). The separated organic layer was concentrated to give 40a (13.5 g, 100% yield) as a brown oil. 1 H NMR (400MHz, CDCl3) δ8.40(s,1H),8.16(s,1H),5.18(s,2H).

[0759] Step 2. 2-(4-amino-1H-pyrazol-1-yl)acetonitrile (40c)

[0760] Fe powder (17.4 g, 310 mmol) was added to a mixture of 40a (13.5 g, 88.5 mmol), NH4Cl (71 g, 1327 mmol), EtOH (50 mL), and H2O (10 mL) at 80 °C. The mixture was stirred at 80 °C for 4 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give 40c (4.0 g, 40% yield) as a brown solid. 1H NMR (400MHz, DMSO-d6) δ7.14(s,1H),7.08(s,1H),5.29(s,2H),4.06(s,2H).

[0761] Step 3. 4-(2-chloro-5-methylpyrimidin-4-yl)benzoic acid (40b)

[0762] 2,4-Dichloro-5-methylpyrimidine (14.7 g, 90.2 mmol), 4-dihydroxyborylbenzoic acid (15 g, 90.2 mmol), Na₂CO₃ (19.2 g, 181.1 mmol), and Pd(PPh₃)₄ (5.3 g, 4.6 mmol) were dissolved in a mixture of ACN and H₂O (200 mL, V / V = 1:1). The resulting solution was stirred overnight at 90 °C under N₂. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL * 3). The aqueous phase was acidified to pH = 2 with 1 N HCl, and the mixture was filtered to give the title product (19.8 g, 88% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.75 (s, 1H), 8.08 (d, J = 8.4Hz, 2H), 7.80 (d, J = 8.4Hz, 2H), 2.35 (s, 3H).

[0763] Step 4. 4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (40d)

[0764] Compounds 40b (3 g, 12.1 mmol), 40c (1.5 g, 12.1 mmol), and TsOH (208 mg, 1.21 mmol) were dissolved in n-BuOH (30 mL). The solution was stirred overnight at 120 °C. The mixture was diluted with water (100 mL) and an aqueous solution of NaOH (0.5 N, 100 mL) and extracted with EtOAc (100 mL x 3). The aqueous phase was acidified to pH 2 with HCl (1 N). The resulting solid was filtered to give the title compound (2.8 g, 70% yield) as a dark green solid. 1 H NMR (400MHz, DMSO-d6) δ9.56(s,1H),8.41(s,1H),8.08(d,J=8.4Hz,2H),8.05(s,1H),7.80(d,J=8.4Hz,2H),7.64(s,1H),5.44(s,2H),2.20(s,3H).

[0765] Step 5. (S)-N-(1-cyanoethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (40)

[0766] Using a similar preparation procedure to step four of Example 1, compound 40 (19 mg) was synthesized in 20% yield using 40d (80 mg, 0.24 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (174 mg, 0.72 mmol) as starting materials. LC-MS (Method 1): t R = 2.97 min, m / z(M+H) + =387.2. 1 H NMR (400MHz, DMSO-d6) δ9.56(s,1H),9.26(d,J=7.2Hz,1H),8.41(s,1H),8.01(s,1H),8.03(d,J=8.4Hz,2H ),7.80(d,J=8.4Hz,2H),7.64(s,1H),5.44(s,2H),5.04-4.99(m,1H),2.20(s,3H),1.56(d,J=7.2Hz,3H).

[0767] Examples 41 and 42

[0768]

[0769] Step 1. Methyl 4-(5-chloro-2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (41a)

[0770] Using a similar preparation procedure to the second step of Example 1, compound 41a (440 mg) was synthesized in 35% yield using 34b (967 mg, 3.42 mmol) and 40c (500 mg, 4.1 mmol) as starting materials. LC-MS (Method 3): t R = 1.58 min, m / z(M+H) + =369.1.

[0771] Step 2. 4-(5-chloro-2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (41b) and 4-(2-((1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)amino)-5-chloropyrimidin-4-yl)benzoic acid (42a)

[0772] Using a similar preparation procedure to step 3 of Example 3, compounds 41b and 42a (282 mg, 1:1 ratio) were synthesized using 41a (440 mg, 1.19 mmol) as the starting material. LC-MS (Method 3): t R1 =0.97min, m / z(M+H) + =373.1. LC-MS (Method 3): t R2 = 1.09 min, m / z(M+H) + =355.1.

[0773] Step 3. 4-(5-chloro-2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide (41) and 4-(2-((1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)amino)-5-chloropyrimidin-4-yl)-N-(cyanomethyl)benzamide (42)

[0774] Using a preparation procedure similar to step four of Example 1, compounds 41 (13.2 mg) and 42 (6.0 mg) were synthesized using 41b and 42a (70 mg) and 2-aminoacetonitrile hydrochloride (37 mg, 0.395 mmol) as starting materials.

[0775] 41: LC-MS (Method 1): t1 = 3.43 min, m / z (M+H) + =393.1; 1 H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.38-9.34(m,1H),8.62(s,1H),8.03(d ,J=8.4Hz,3H),7.94(s,2H),7.68(s,1H),5.46(s,2H),4.36(d,J=5.2Hz,2H).

[0776] 42: LC-MS (Method 1): t2 = 3.07 min, m / z (M+H) + =411.1; 1 H NMR (400MHz, DMSO-d6) δ9.88 (s, 1H), 9.36-9.34 (m, 1H), 8.59 (s, 1H), 8.02 (d, J = 8.4Hz, 2H), 7 .95-7.88(m,2H),7.55(s,1H),7.40(s,1H),7.20(s,1H),4.71(s,2H),4.36(d,J=5.6Hz,2H).

[0777] Example 43

[0778]

[0779] Step 1. Methyl 4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (43a)

[0780] Using a similar preparation procedure to the second step of Example 1, compound 43a (50 mg) was synthesized in 11% yield using 34b (300 mg, 1.06 mmol) and 1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-amine (229 mg, 1.27 mmol) as starting materials. LC-MS (Method 3): t R = 1.37 min, m / z(M+H) + =427.0.

[0781] Step 2. Lithium 4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (43b)

[0782] Compound 43a (50 mg, 0.12 mmol) and LiOH·H₂O (25 mg, 0.60 mmol) were dissolved in a mixture of THF and H₂O (1 mL, V / V = 1 / 1). The resulting mixture was stirred at 50 °C for 3 hours. The mixture was concentrated to dryness to give the desired product (48 mg, 100% yield) as a yellow solid. LC-MS (Method 3): t R = 1.26 min, m / z(M+H) + =413.0.

[0783] Step 3. (S)-4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (43)

[0784] Using a similar preparation procedure to step four of Example 1, compound 43 (10.1 mg) was synthesized in 19% yield using 43b (48 mg, 0.12 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (31 mg, 0.13 mmol) as starting materials. LC-MS (Method 1): t R = 2.96 min, m / z(M+H) + =465.2. 1H NMR (400MHz, DMSO-d6) δ9.88(s,1H),9.34(d,J=9.6Hz,1H),8.61(s,1H),8.06(d,J=10.8Hz,2H),7.95-7.87(m,3H),7.59(s,1H),5.0 8-5.03(m,1H),4.10-4.07(m,1H),2.86(d,J=14.0Hz,2H),2.21(s,3H),2.08-2.01(m,2H),1.96-1.89(m,4H),1.60(d,J=9.6Hz,3H).

[0785] Example 44

[0786]

[0787] Step 1. 4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide (44)

[0788] Using a similar preparation procedure to step four of Example 1, compound 44 (5.6 mg) was synthesized in 6% yield using 43b (85 mg, 0.21 mmol) and 2-aminoacetonitrile hydrochloride (23 mg, 0.25 mmol) as starting materials. LC-MS (Method 1): t R = 2.67 min, m / z(M+H) + =451.2. 1 H NMR(400MHz, DMSO-d6)δ9.85(s,1H),9.37(t,J=4.8Hz,1H),8.58(s,1H),8.02(d,J=8.0Hz,2H),7.98-7.88(m,3H),7.56-7.53( m,1H),4.36(d,J=5.6Hz,2H),4.08-4.04(m,1H),2.83(d,J=10.4Hz,2H),2.18(s,3H),2.05(t,J=4.0Hz,2H),2.02-1.84(m,4H).

[0789] Example 45

[0790]

[0791] Step 1. Methyl 4-(2-chloro-5-fluoropyrimidin-4-yl)benzoate (45a)

[0792] Using a similar preparative procedure to the first step of Example 36, compound 45a (1.5 g) was synthesized in 70% yield using compound 36a (1.34 g, 8.04 mmol) and (4-(methoxycarbonyl)phenyl)boronic acid (1.45 g, 8.04 mmol) as starting materials. LC-MS (Method 3): t R = 1.71 min, m / z(M+H) + =267.0.

[0793] Step 2. Methyl 4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-fluoropyrimidin-4-yl)benzoate (45b)

[0794] Using a similar preparation procedure to the second step of Example 1, compound 45b (523 mg) was synthesized in 72% yield using 45a (500 mg, 1.9 mmol) and 40c (274 mg, 2.2 mmol) as starting materials. LC-MS (Method 3): t R = 1.52 min, m / z(M+H) + =353.1.

[0795] Step 2. 4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-fluoropyrimidin-4-yl)benzoic acid (45c)

[0796] Using a similar preparation procedure to step 3 of Example 3, compound 45b (240 mg) was synthesized in 53% yield using 45a (471 mg, 1.3 mmol) as the starting material. LC-MS (Method 3): t R = 1.14 min, m / z(M+H) + =339.1.

[0797] Step 3. N-(cyanomethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-fluoropyrimidin-4-yl)benzamide (45)

[0798] Using a similar preparation procedure to step four of Example 1, compound 45 (27.1 mg) was synthesized in 30% yield using 45b (80 mg, 0.24 mmol) and 2-aminoacetonitrile hydrochloride (44 mg, 0.48 mmol) as starting materials. LC-MS (Method 1): t R = 2.98 min, m / z(M+H) + =377.1; 1H NMR (400MHz, DMSO-d6) δ9.81 (s, 1H), 9.37 (t, J = 5.6Hz, 1H), 8.64 (d, J = 3.6Hz, 1H), 8. 15-8.13(m,2H),8.09-8.05(m,3H),7.68(s,1H),5.48(s,2H),4.36(d,J=5.2Hz,2H).

[0799] Examples 46 and 47

[0800]

[0801] (S)-4-(5-chloro-2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (46) and (S)-4-(2-((1-(2-amino-2-oxoethyl)-1H-pyrazol-4-yl)amino)-5-chloropyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (47)

[0802] Using a preparation procedure similar to step four of Example 1, compounds 46 (21 mg) and 47 (31 mg) were synthesized using 41b and 42a (212 mg) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (291 mg, 1.20 mmol) as starting materials.

[0803] 46: LC-MS (Method 1): t1 = 3.49 min, m / z (M+H) + =407.1; 1 H NMR (400MHz, DMSO-d6) δ10.01(s,1H),9.31(d,J=7.6Hz,1H),8.63(s,1H),8.04(d,J=8.4 Hz, 3H), 7.93 (s, 2H), 7.68 (s, 1H), 5.47 (s, 2H), 5.05-5.01 (m, 1H), 1.57 (d, J = 7.2Hz, 3H).

[0804] 47: LC-MS (Method 1): t2 = 2.57 min, m / z (M+H) + =425.1; 1H NMR (400MHz, DMSO-d6) δ9.91 (s, 1H), 9.31 (d, J = 7.6Hz, 1H), 8.60 (s, 1H), 8.03 (d, J = 8.0Hz, 3H), 7.93-7. 89(m,2H),7.56(s,1H),7.42(s,1H),7.22(s,1H),5.04-5.01(m,1H),4.71(s,2H),1.57(d,J=7.6Hz,3H).

[0805] Example 48

[0806]

[0807] Step 1. Methyl 4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (48b)

[0808] Using a similar preparation procedure to the second step of Example 1, compound 48b (300 mg) was synthesized in 79% yield using 1b (300 mg, 1.15 mmol) and 1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-amine (248 mg, 1.37 mmol) as starting materials. LC-MS (Method 3): t R = 1.54 min, m / z(M+H) + =407.2.

[0809] Step 2. 4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (48c)

[0810] Using a similar preparation procedure to step 3 of Example 3, compound 48c (96 mg) was synthesized in 100% yield using 48b (100 mg, 0.25 mmol) and LiOH·H₂O (52 mg, 1.23 mmol) as starting materials. LC-MS (Method 3): t R =0.33min, m / z(M+H)+=393.2.

[0811] Step 3. (S)-N-(1-cyanoethyl)-4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (48)

[0812] Using a similar preparation procedure to step four of Example 1, compound 48 (33.7 mg) was synthesized in 31% yield using 48c (96 mg, 0.25 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (66 mg, 0.27 mmol) as starting materials. LC-MS (Method 1): t R = 3.34 min, m / z(M+H) + =445.2. 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),9.26(d,J=7.2Hz,1H),8.36(d,J=7.6Hz,1H),8.01(d,J=8.4Hz,2H),7.87(s,1H),7.80(d,J=8.0Hz,2H),7.5 4(s,1H),5.06-5.00(m,1H),4.07-4.02(m,1H),2.85(d,J=11.2Hz,2H),2 .20(s,6H),2.08-1.98(m,2H),1.93-1.87(m,4H),1.58(t,J=7.6Hz,3H).

[0813] Example 49

[0814]

[0815] N-(cyanomethyl)-4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (49)

[0816] Using a similar preparation procedure to step four of Example 1, compound 49 (29.8 mg) was synthesized in 34% yield using 48c (80 mg, 0.2 mmol) and 2-aminoacetonitrile hydrochloride (37 mg, 0.4 mmol) as starting materials. LC-MS (Method 1): t R = 8.84 min, m / z(M+H) + =431.2; 1H NMR (400MHz, DMSO-d6) δ9.39(s,1H),9.33(t,J=4.8Hz,1H),8.37(s,1H),8.00(d,J=8.4Hz,2H),7.88(s,1H),7.80(d,J=7.6Hz,2H),7.5 3(s,1H),4.36(d,J=5.6Hz,2H),4.06-3.99(m,1H),2.82(d,J=10.8Hz,2H),2.19(d,J=4.4Hz,6H),2.04-1.98(m,2H),1.92-1.84(m,4H).

[0817] Example 50

[0818]

[0819] Step 1. Methyl 4-(5-fluoro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (50a)

[0820] Using a similar preparative procedure to the second step of Example 1, compound 50a (2.0 g) was synthesized in 44% yield using compound 45a (2.96 g, 11.1 mmol) and 1-(1-methylpiperidin-4-yl)-1H-pyrazole-4-amine (2.40 g, 13.3 mmol) as starting materials. LC-MS (Method 3): t R = 1.54 min, m / z(M+H) + =411.2;

[0821] Step 2. 4-(5-fluoro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (50b)

[0822] Using a similar preparation procedure to step 3 of Example 3, compound 50b (1.73 g) was synthesized in 90% yield using compound 50a (2.0 g, 4.87 mmol) as the starting material. LC-MS (Method 3): t R = 1.012 min, m / z(M+H) + =397.1;

[0823] Step 3. (S)-N-(1-cyanoethyl)-4-(5-fluoro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (50)

[0824] Using a similar preparation procedure to step four of Example 1, compound 50 (17 mg) was synthesized in 22% yield using 50b (70 mg, 0.177 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (47 mg, 0.193 mmol) as starting materials. LC-MS (Method 1): t R = 2.86 min, m / z(M+H) + =449.2. 1 H NMR (400MHz, DMSO-d6) δ9.66(s,1H),9.33(d,J=7.2Hz,1H),8.60(d,J=3.6Hz,1H),8.13(d,J=8.0Hz,2H),8.06(d,J=8.4Hz,2H),7.93(s,1H),7.5 8(s,1H),5.05-5.01(m,1H),4.10-4.05(m,1H),2.85(d,J=11.6Hz,2H),2 .19(s,3H),2.07-2.00(m,2H),1.95-1.90(m,4H),1.58(d,J=6.8Hz,3H).

[0825] Example 51

[0826]

[0827] Step 1. Methyl 4-(2-((1-(1-(2-hydroxy-2-methylpropionyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (51a)

[0828] Using a similar preparation procedure to step four of Example 1, compound 51a (190 mg) was synthesized in 66% yield using 3a (239 mg, 0.6 mmol) and 2-hydroxy-2-methylpropionic acid (56 mg, 0.6 mmol) as starting materials. LC-MS (Method 3): t R = 1.51 min, m / z(M+H) + =479.3.

[0829] Step 2. 4-(2-((1-(1-(2-hydroxy-2-methylpropionyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (51b)

[0830] Using a similar preparation procedure to step 3 of Example 3, compound 51b (186 mg) was synthesized in 100% yield using 51a (190 mg, 0.4 mmol) as the starting material. LC-MS (Method 3): t R= 1.07 min, m / z(M+H) + =465.2.

[0831] Step 3. N-(cyanomethyl)-4-(2-((1-(1-(2-hydroxy-2-methylpropionyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (51)

[0832] Using a similar preparation procedure to step four of Example 1, compound 51 (30 mg) was synthesized in 32% yield using 51b (90 mg, 0.19 mmol) and 2-aminoacetonitrile hydrochloride (35 mg, 0.38 mmol) as starting materials. LC-MS (Method 1): t R = 3.14 min, m / z(M+H) + =503.2. 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),8.10(s,1H),7.91(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.43(s,1H),7.02(s,1H),4 .56-4.54(m,2H),4.42-4.37(m,3H),4.20(s,1H),3.15-3.03(m,2H),2.28-2.21(m,5H),1.96-1.89(m,2H),1.52(s,6H).

[0833] Example 52

[0834]

[0835] Step 1. (S)-N-(1-cyanoethyl)-4-(2-((1-(1-(2-hydroxy-2-methylpropionyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (52)

[0836] Using a similar preparation procedure to step four of Example 1, compound 52 (43.5 mg) was synthesized in 44% yield using 51b (90 mg, 0.19 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (92 mg, 0.38 mmol) as starting materials. LC-MS (Method 1): t R = 3.34 min, m / z(M+H) + =517.3. 1H NMR(400MHz, CDCl3)δ8.32(s,1H),8.09(s,1H),7.91(d,J=8.0Hz,2H),7.74(d,J=8.0Hz,2H),7.46(s,1H),6.85(s,1H),5.22-5.18(m,1H), 4.53-4.37(m,3H),4.21(s,1H),3.16-3.04(m,2H),2.27-2.21(m,5H),2.00-1.94(m,2H),1.72(d,J=7.2Hz,3H),1.55(s,3H),1.53(s,3H).

[0837] Example 53

[0838]

[0839] (S)-N-(1-cyanoethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-fluoropyrimidin-4-yl)benzamide (53)

[0840] Using a similar preparation procedure to step four of Example 1, compound 53 (24.3 mg) was synthesized in 26% yield using 45c (80 mg, 0.24 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (116 mg, 0.48 mmol) as starting materials. LC-MS (Method 1): t R = 3.28 min, m / z(M+H) + =391.1; 1 H NMR (400MHz, DMSO-d6) δ9.83(s,1H),9.33(d,J=7.6Hz,1H),8.65(d,J=3.2Hz,1H),8.15-8.13( m,2H),8.10-8.04(m,3H),7.68(s,1H),5.49(s,2H),5.07-4.99(m,1H),1.57(d,J=7.2Hz,3H).

[0841] Example 54

[0842]

[0843] Step 1. (R)-(1-Cyanoethyl)carbamate (54b)

[0844] Using a preparation procedure similar to the second step of Example 208, compound 54b (8.8 g) was synthesized in 96% yield using (R)-(1-amino-1-oxopropane-2-yl)carbamate 54a (10 g, 45 mmol) as the starting material. 1 H NMR (400MHz, DMSO-d6) δ8.17(d,J=6.8Hz,1H),7.37-7.31(m,5H),5.08(s,2H),4.63-4.56(m,1H),1.41(d,J=7.2Hz,3H).

[0845] Step 2. (R)-2-aminopropionitrile 4-methylbenzenesulfonate (54c)

[0846] A mixture of 54b (4.0 g, 20 mmol), Pd / C (600 mg, 10% wt, moistened with about 55% water), and Pd(OH)₂ (600 mg, 20% wt, moistened with about 50% water) in EtOAc (30 mL) was stirred at 40 °C for 7 hrs under H₂ (50 psi). The catalyst was filtered off, and TsOH (3.7 g, 20 mmol) was added to the filtrate with stirring. After stirring at RT for 20 min, the solid formed was collected by filtration and dried to give the title product (2.8 g, 59% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ8.69 (s, 3H), 7.48 (d, J = 8.0Hz, 2H), 7.11 (d, J = 8.0Hz, 2H), 4.59-4.54 (m, 1H), 2.29 (s, 3H), 1.51 (t, J = 7.2Hz, 3H).

[0847] Step 3. (R)-N-(1-cyanoethyl)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (54)

[0848] Using a similar preparation procedure to step four of Example 1, compound 54 (6.9 mg) was synthesized in 12% yield using 40d (50 mg, 0.15 mmol) and (R)-2-aminopropionitrile 4-methylbenzenesulfonate 54c (72.6 mg, 0.3 mmol) as starting materials. LC-MS (Method 1): t R =3.37, m / z(M+H) + =387.1; 1H NMR (400MHz, DMSO-d6) δ9.56 (s, 1H), 9.26 (d, J = 6.0Hz, 1H), 8.41 (s, 1H), 8.03-8.01 (m, 3H), 7.80 ( d,J=6.4Hz,2H),7.65(s,1H),5.44(s,2H),5.06-4.98(m,1H),2.20(s,3H),1.57(d,J=6.8Hz,3H).

[0849] Example 55

[0850]

[0851] Step 1. (S)-(1-amino-1-oxobutan-2-yl)carbamate (55b)

[0852] (S)-2-(((benzyloxy)carbonyl)amino)butyric acid 55a (5.0 g, 21.1 mmol) and NMM (6.4 g, 63.2 mmol) were dissolved in THF (40 mL), and then methyl chloroformate (4.0 g, 42.2 mmol) was added dropwise at 0 °C for 1 hour. The solid formed was filtered off. A solution of NH3 (g) in THF (30 mL, 4 M, in THF) was added to the filtrate. The resulting mixture was stirred at 0 °C for 2 hours. The mixture was concentrated to dryness, and the residue was recrystallized from EtOAc (20 mL) to give the title product (4.5 g, 90% yield) as a white solid. LC-MS (Method 3): t R = 1.23 min, m / z(M+H) + =237.1. Step 2. (S)-(1-cyanopropyl)carbamate (55c)

[0853] POCl3 (12.0 mL) was added dropwise to a solution of 55b (4.5 g, 19.0 mmol) in DMF (45 mL) for 1 hour at 0 °C. The mixture was poured into water (100 mL) and extracted with EtOAc (400 mL). The separated organic layer was washed with brine (300 mL x 3). The organic layer was concentrated to give the title product (3.3 g, 80% yield) as a yellow oil. 1 HNMR(400MHz,DMSO-d6)δ8.16(d,J=7.2Hz,1H),7.40-7.31(m,5H),5.09(s,2 H), 4.48 (dd, J = 14.8Hz, 7.2Hz, 1H), 1.79-1.71 (m, 2H), 0.95 (t, J = 7.2Hz, 3H).

[0854] Step 3. (S)-2-aminobutyronitrile (55d)

[0855] A mixture of 55c (3.3 g, 15.1 mmol), Pd / C (330 mg, 10% wt, moistened with about 55% water), and Pd(OH)₂ (330 mg, 20% wt, moistened with about 50% water) in EtOAc (30 mL) was stirred at 40 °C for 6 hours under H₂ (50 psi). The mixture was filtered and the filtrate was concentrated to give a crude product (720 mg, 57% yield) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ3.62 (t, J = 6.8 Hz, 1H), 2.41-2.10 (m, 2H), 1.64-1.57 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H).

[0856] Step 4. (S)-4-(2-((1-(cyanomethyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(1-cyanopropyl)benzamide (55)

[0857] Using a similar preparation procedure to step four of Example 1, compound 55 (13.3 mg) was synthesized in 16% yield using 40 d (70 mg, 0.21 mmol) and (S)-2-aminobutyronitrile (88 mg, 1.05 mmol) as starting materials. LC-MS (Method 1): t R = 8.51 min, m / z(M+H) + =401.2; 1 H NMR (400MHz, DMSO-d6) δ9.58(s,1H),9.26(d,J=7.6Hz,1H),8.41(s,1H),8.01(s,1H),8.02(d,J=8.0Hz,2H),7.80(d ,J=8.0Hz,2H),7.65(s,1H),5.45(s,2H),4.93-4.91(m,1H),2.21(s,3H),1.95-1.90(m,2H),1.03(t,J=7.2Hz,3H).

[0858] Example 56

[0859]

[0860] Step 1. Methyl 4-(5-fluoro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (56a)

[0861] Using a similar preparation procedure as the second step of Example 1, compound 56a (420 mg) was synthesized in 92% yield using 45a (320 mg, 1.2 mmol) and 1-(4-(4-amino-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropane-1-one (300 mg, 1.2 mmol) as starting materials. 1 H NMR (400MHz, CDCl3) δ8.41(d,J=4.4Hz,1H),8.23-8.17(m,4H),7.95(s,1H),7.62(s,1H),6.95(s,1H),4.63-4.58( m,2H),4.42-4.35(m,1H),4.01(s,3H),3.05(t,J=16.0Hz,2H),2.28-2.24(m,2H),2.07-1.99(m,2H),1.36(s,9H).

[0862] Step 2. 4-(5-fluoro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (56b)

[0863] LiOH·H2O (30 mg, 0.711 mmol) was added in a single addition to a solution consisting of 56a (90 mg, 0.237 mmol), THF (2 mL), and H2O (1 mL). The mixture was stirred at RT for 2 hours. The reaction mixture was diluted with 2N HCl aqueous solution and concentrated to dryness, giving a crude product as a yellow solid (87 mg, 100% yield). LC-MS (Method 3): t R = 1.23 min, m / z(M+H) + =467.2.

[0864] Step 3. N-(cyanomethyl)-4-(5-fluoro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (56)

[0865] Using a similar preparation procedure to step four of Example 1, compound 56 (68.5 mg) was synthesized in 73% yield using 56b (87 mg, 0.19 mmol) and 2-aminoacetonitrile hydrochloride (19 mg, 0.21 mmol) as starting materials. LC-MS (Method 1): t R = 6.41 min, m / z(M+H) + =505.2. 1H NMR (400MHz, DMSO-d6) δ9.65(s,1H),9.36(d,J=5.2Hz,1H),8.61(d,J=4.0Hz,1H),8.13(d,J=8.0Hz,2H),8.04(d,J=8.0Hz,2H) ,7.96(s,1H),7.57(s,1H),4.42-4.35(m,5H),2.96(t,J=12.4Hz,2H),2.04(d,J=10.0Hz,2H),1.77-1.74(m,2H),1.22(s,9H).

[0866] Example 57

[0867]

[0868] (S)-N-(1-Cyanoethyl)-4-(5-Fluoro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (57)

[0869] Using a similar preparation procedure to step four of Example 1, compound 57 (49.3 mg) was synthesized in 46% yield using 56b (97 mg, 0.21 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (56 mg, 0.23 mmol) as starting materials. LC-MS (Method 1): t R = 8.33 min, m / z(M+H) + =519.3. 1 H NMR (400MHz, DMSO-d6) δ9.65(s,1H),9.30(d,J=7.2Hz,1H),8.61(d,J=3.2Hz,1H),8.13(d,J=7.6Hz,2H),8.05(d,J=8.8Hz,2H),7.97(s,1H),7.57(s, 1H),5.03(t,J=6.8Hz,1H),4.35-4.27(m,3H),2.96(t,J=12.8Hz,2H),2.0 5(d,J=16.8Hz,2H),1.77-1.73(m,2H),1.57(d,J=7.6Hz,3H),1.22(s,9H).

[0870] Example 58

[0871]

[0872] (R)-4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (58)

[0873] Using a similar preparation procedure to step four of Example 1, compound 58 (5.5 mg) was synthesized in 6% yield using 43b (82.8 mg, 0.20 mmol) and (R)-2-aminopropionitrile 4-methylbenzenesulfonate (48.4 mg, 0.20 mmol) as starting materials. LC-MS (Method 1): t R = 2.97 min, m / z(M+H) + =465.2. 1 H NMR(400MHz, CDCl3)δ8.42(s,1H),7.96-7.90(m,5H),7.50(s,1H),7.26(s,1H),7.07(s,1H),5.22-5.15(m,1H),4. 14-4.07(m,1H),2.99(d,J=10.4Hz,2H),2.34(s,3H),2.18-2.13(m,4H),2.06-1.98(m,2H),1.68(d,J=11.2Hz,3H).

[0874] Example 59

[0875]

[0876] (S)-N-(1-cyanopropyl)-4-(5-fluoro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (59)

[0877] Using a similar preparation procedure to step four of Example 1, compound 59 (2.5 mg) was synthesized in 3% yield using (S)-2-aminobutyronitrile (25 mg, 0.30 mmol) and 50b (60 mg, 0.15 mmol) as starting materials. LC-MS (Method 1): t R = 10.71 min, m / z(M+H) + =463.2; 1H NMR (400MHz, CDCl3) δ8.35(d,J=3.2Hz,1H),8.17(d,J=8.4Hz,2H),7.94(d,J=8.4Hz,3H),7.54(s,1H),7.00(s,1H),6.92( s,1H),5.12-5.06(m,1H),4.16-4.10(m,1H),3.01(d,J=7.6Hz,2H),2.35(s,3H),2.20-1.97(m,8H),1.19(t,J=7.4Hz,3H).

[0878] Example 60

[0879]

[0880] Step 1. Methyl 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (60a)

[0881] Using a similar preparation procedure to the second step of Example 34, compound 60a (2.0 g) was synthesized in 52% yield using 34b (3.0 g, 10.5 mmol) and 1-cyclopropyl-1H-pyrazole-4-amine (1.55 g, 10.5 mmol) as starting materials. 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),8.16(d,J=8.4Hz,2H),7.91(d,J=8.4Hz,2H),7.88(s,1H),7 .49(s,1H),6.97(s,1H),3.97(s,3H),3.60-3.56(m,1H),1.15-1.11(m,2H),1.03-0.96(m,2H).

[0882] Step 2. 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (60b)

[0883] Using a similar preparation procedure to step 3 of Example 3, compound 60b (1.93 g) was synthesized in 100% yield using 60a (2.0 g, 5.42 mmol) and LiOH·H₂O (683 mg, 16.3 mmol) as starting materials. LC-MS (Method 3): t R = 1.166 min, m / z(M+H) + =356.1.

[0884] Step 3. 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-((1-cyanocyclopropyl)methyl)benzamide (60)

[0885] Using a similar preparative procedure to step four of Example 1, compound 60 (14.6 mg) was synthesized in 15% yield using 60b (80 mg, 0.22 mmol) and 1-(aminomethyl)cyclopropaneformonitrile (26 mg, 0.27 mmol) as starting materials. The title compound was purified by preparative HPLC (Method A). LC-MS (Method 1): t R = 3.850 min, m / z(M+H) + =434.0; 1 H NMR(400MHz, DMSO-d6)δ9.83(s,1H),9.04(t,J=5.6Hz,1H),8.58(t,J=5.6Hz,1H),8.02(d,J=8.0Hz,2H),7.78-7.90(m ,3H),7.50(s,1H),3.70-3.66(m,1H),3.47(d,J=6.0Hz,2H),1.26-1.23(m,2H),1.16-1.13(m,2H),0.98-0.92(m,4H).

[0886] Example 61

[0887]

[0888] (S)-4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanopropyl)benzamide (61)

[0889] Using a similar preparation procedure to step four of Example 1, compound 61 (12.5 mg) was synthesized in 21% yield using 60b (50 mg, 0.14 mmol) and (S)-2-aminobutyronitrile (59 mg, 0.70 mmol) as starting materials. LC-MS (Method 1): t R = 3.08 min, m / z(M+H) + =422.1; 1H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.27(d,J=7.6Hz,1H),8.59(s,1H),8.03(d,J=8.4Hz,1H),7.92(t,J=10.0Hz,3 H),7.50(s,1H),4.94–4.88(m,1H),3.69-3.64(m.1H),1.97-1.88(m,2H),1.03(t,J=14.8Hz,3H),0.98-0.89(m,4H).

[0890] Example 62

[0891]

[0892] (R)-N-(1-cyanoethyl)-4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (62)

[0893] Using a similar preparation procedure to step four of Example 1, compound 62 (13.6 mg) was synthesized in 15% yield using 48c (80 mg, 0.20 mmol) and (R)-2-aminopropionitrile 4-methylbenzenesulfonate (99 mg, 0.40 mmol) as starting materials. LC-MS (Method 1): t R = 3.08 min, m / z(M+H) + =445.2; 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),9.26(d,J=7.2Hz,1H),8.37(s,1H),8.01(d,J=8.4Hz,2H),7.87(s,1H),7.80(d,J=8.0Hz,1H),7.54(s, 1H),5.04-4.99(m,1H),4.06-4.00(m,1H),2.83(d,J=11.2Hz,2H),2.1 9(s,6H),2.05-1.99(m,2H),1.95-1.84(m,4H),1.57(d,J=6.8Hz,2H).

[0894] Example 63

[0895]

[0896] (R)-N-(1-cyanoethyl)-4-(5-fluoro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (63)

[0897] HATU (101 mg, 0.27 mmol) and TEA (54 mg, 0.54 mmol) were sequentially added to a mixture consisting of 50b (70 mg, 0.18 mmol), (R)-2-aminopropionitrile 4-methylbenzenesulfonate (51 mg, 0.21 mmol), and DMF (2 mL). The mixture was stirred at RT for 18 hrs. The mixture was concentrated to dryness. The residue was diluted with H2O (30 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were concentrated, and the residue was purified by preparative HPLC (Method A) to give the title product (16.4 mg, 21% yield) as a yellow solid. LC-MS (Method 1): t R = 3.49 min, m / z(M+H) + =449.2. 1 H NMR (400MHz, DMSO-d6) δ9.63(s,1H),9.31(d,J=6.4Hz,1H),8.60(d,J=3.6Hz,1H),8.13(d,J=8.0Hz,2H),8.06(d,J=8.4Hz,2H),7.93(s,1H),7.5 8(s,1H),5.05-5.01(m,1H),4.10-4.05(m,1H),2.84(d,J=11.6Hz,2H),2 .19(s,3H),2.07-1.99(m,2H),1.96-1.90(m,4H),1.58(d,J=7.2Hz,3H).

[0898] Example 64

[0899]

[0900] Step 1. (1R,3s,5S)-3-((methanesulfonyl)oxy)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (64b)

[0901] MsCl (2.5 g, 22.0 mmol) was added to a solution of 64a (2.5 g, 11.0 mmol; CAS No. 194222-05-4) and TEA (3.3 g, 33.0 mmol) in DCM (30 mL) at 0 °C. The mixture was stirred at RT for 2 h. The mixture was diluted with water (100 mL) and extracted with DCM (50 mL x 2). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum to give the desired product 76b (3.4 g, 100% yield) as a yellow solid. 1H NMR(400MHz,DMSO-d6)δ4.99-4.95(m,1H),4.10(s,2H),3.21(s,3H),2.14-2.0 7(m,2H),1.87-1.86(m,2H),1.73-1.72(m,2H),1.62-1.60(m,2H),1.41(s,9H).

[0902] Step 2. (1R,3r,5S)-3-(4-nitro-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate (64c)

[0903] Cs₂CO₃ (5.4 g, 16.7 mmol) was added in a single addition to a well-stirred mixture consisting of 64b (3.4 g, 11.1 mmol), 4-nitro-1H-pyrazole (630 mg, 5.57 mmol), and NMP (40 mL). The mixture was stirred overnight at 120 °C. The mixture was concentrated to dryness to give the desired crude product (1.8 g, 100% yield) as a brown oil. LC-MS (Method 3): t R = 1.66 min, m / z(M+H-56) + =267.1.

[0904] Step 3. (1R,3r,5S)-3-(4-nitro-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane hydrochloride (64d)

[0905] Compound 64d (620 mg) was synthesized in 100% yield using a preparation procedure similar to step 5 of Example 1, with 64c (1.3 g, 4.03 mmol) as the starting material. LC-MS (Method 3): t R =0.50min, m / z(M+H) + =223.1.

[0906] Step 4. Cyclopropyl((1R,3r,5S)-3-(4-nitro-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl) methyl ketone (64e)

[0907] Using a similar preparative procedure to the first step of Example 24, compound 64e (260 mg) was synthesized in 100% yield using 64d (200 mg, 0.90 mmol) and cyclopropane carbonyl chloride (141 mg, 1.35 mmol) as starting materials. LC-MS (Method 3): t R = 1.36 min, m / z(M+H) + =291.1.

[0908] Step 5. ((1R,3r,5S)-3-(4-amino-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl)(cyclopropyl)methyl ketone (64f)

[0909] Using a similar preparation procedure to step 2 of Example 4, compound 64f (230 mg) was synthesized in 100% yield using 64e (260 mg, 0.90 mmol) as the starting material. LC-MS (Method 3): t R =0.98min, m / z(M+H) + =261.1.

[0910] Step 6. 4-(2-((1-((1R,3r,5S)-8-(cyclopropanecarbonyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (64g)

[0911] 64f (250 mg, 0.96 mmol), 40b (238 mg, 0.96 mmol), and 4-methylbenzenesulfonic acid (17 mg, 0.096 mmol) were dissolved in 1,4-dioxane (5 mL). The resulting mixture was stirred in a sealed tube at 120 °C for 3 hrs. After cooling to RT, the mixture was concentrated to dryness. The residue was purified by reversed-phase rapid chromatography to give the title product (320 mg, 71% yield) as a yellow solid. LC-MS (Method 3): t R = 1.14 min, m / z(M+H) + =473.2.

[0912] Step 7. N-(cyanomethyl)-4-(2-((1-((1R,3r,5S)-8-(cyclopropanecarbonyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (64)

[0913] Using a similar preparation procedure to step four of Example 1, compound 64 (30 mg) was synthesized in 39% yield using 64 g (70 mg, 0.15 mmol) and 2-aminoacetonitrile hydrochloride (70 mg, 0.75 mmol) as starting materials. LC-MS (Method 1): t R = 3.38 min, m / z(M+H) + =511.2; 1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),9.35-9.32(m,1H),8.40(s,1H),8.09(s ,1H),8.01(d,J=8.0Hz,2H),7.81(d,J=7.6Hz,2H),7.57(s,1H),4.59(s,1H), 4.45(s,1H),4.37-4.34(m,2H),2.67-2.60(m,2H),2.33-2.24(m,2H),2.21( s,3H),1.97-1.80(m,2H),1.66-1.54(m,2H),1.23(s,1H),0.76-0.64(m,4H).

[0914] Example 65

[0915]

[0916] Step 1. (1R,3r,5S)-3-(4-amino-1H-pyrazole-1-yl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (65b)

[0917] Using a preparation procedure similar to the second step of Example 4, compound 65b (450 mg) was synthesized in 100% yield using 64c (500 mg, 1.55 mmol) as the starting material. 1 H NMR (400MHz, CDCl3) δ7.17 (d, J = 4.8Hz, 2H), 4.23-4.19 (m, 2H), 4.15-4.13 (m, 1H), 2.1 7-2.12(m,2H),1.95-1.94(m,2H),1.85-1.81(m,2H),1.72-1.68(m,2H),1.47(s,9H).

[0918] Step 2. (1R,3r,5S)-3-(4-((4-(4-(methoxycarbonyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-8-azabicyclo[3.2.1] tert-butyl octane-8-carboxylate (65c)

[0919] Using a similar preparation procedure to step six of Example 64, compound 65c (510 mg) was synthesized in 100% yield using 65b (400 mg, 1.37 mmol) and 1b (240 mg, 0.91 mmol) as starting materials. LC-MS (Method 3): t R = 1.83 min, m / z(M+H) + =519.2.

[0920] Step 3. Methyl 4-(2-((1-((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate hydrochloride (65d)

[0921] Using a similar preparation procedure to the second step of Example 1, compound 65d (420 mg) was synthesized in 97% yield using 65c (510 mg, 0.98 mmol) as the starting material. LC-MS (Method 3): t R = 1.46 min, m / z(M+H) + =419.2.

[0922] Step 4. Methyl 4-(5-methyl-2-((1-((1R,3r,5S)-8-(1-methylcyclopropanecarbonyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (65e)

[0923] Using a similar preparative procedure to the first step of Example 38, compound 65e (160 mg) was synthesized in 36% yield using 65d (370 mg, 0.89 mmol) and 1-methylcyclopropanecarboxylic acid (89 mg, 0.89 mmol) as starting materials. LC-MS (Method 3): t R = 1.65 min, m / z(M+H) + =501.2.

[0924] Step 5. 4-(5-methyl-2-((1-((1R,3r,5S)-8-(1-methylcyclopropanecarbonyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (65f)

[0925] Using a similar preparation procedure to step 3 of Example 3, compound 65f (155 mg) was synthesized in 100% yield using 65e (160 mg, 0.32 mmol) as the starting material. LC-MS (Method 3): t R = 1.20 min, m / z(M+H) + =487.2.

[0926] Step 6. N-(cyanomethyl)-4-(5-methyl-2-((1-((1R,3r,5S)-8-(1-methylcyclopropanecarbonyl)-8-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (65)

[0927] Using a similar preparative procedure to step four of Example 1, compound 65 (15 mg) was synthesized in 20% yield using 65f (70 mg, 0.14 mmol) and 2-aminoacetonitrile hydrochloride (67 mg, 0.72 mmol) as starting materials. The title compound was purified by preparative HPLC (Method B). LC-MS (Method 1): t R = 10.25 min, m / z(M+H) + =525.3; 1 H NMR(400MHz, CDCl3)δ8.26(s,1H),8.02(s,1H),7.97(d,J=8.4Hz,2H),7.75(d,J=8.4Hz,2H),7.61(s,1H),7.29-7.26(m,1H),4.66(s,2H),4.4 3(d,J=5.6Hz,2H),4.28-4.25(m,1H),2.46-2.40(m,2H),2.28(s,3H), 2.04(s,2H),1.82-1.71(m,4H),1.36(s,3H),0.94(s,2H),0.59(s,2H).

[0928] Example 66

[0929]

[0930] Step 1. 4-(4-nitro-1H-pyrazol-1-yl)piperidin-2-one (66b)

[0931] DIAD (3.4 g, 17.0 mmol) was added to a suspension consisting of 4a (1.9 g, 17.0 mmol), 4-hydroxypiperidin-2-one (1.3 g, 11.3 mmol), PPh3 (4.5 g, 17.0 mmol), and THF (20 mL) at 0 °C. The mixture was stirred at RT for 18 hrs and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EtOAc = 2:1) to give 66b (1.1 g, 48% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.20 (s, 1H), 8.13 (s, 1H), 5.84 (s, 1H), 4.72-4.69 (m, 1H), 3.46-3.40 (m, 2H), 2.94 (d, J = 7.2Hz, 2H), 2.37-2.39 (m, 2H).

[0932] Step 2. 1-Methyl-4-(4-nitro-1H-pyrazol-1-yl)piperidin-2-one (66c)

[0933] NaH (57.2 mg, 1.43 mmol, 60% in mineral oil) was added to a suspension consisting of 66b (200 mg, 0.95 mmol), CH3I (176 mg, 1.24 mmol), and DMF (2 mL) at 0 °C. The mixture was stirred at RT for 40 mins. The mixture was diluted with water (1 mL) and extracted with EtOAc (6 mL). The separated organic layer was washed with brine (2 mL) and concentrated to dryness to give 66c (180 mg, 85% yield) as a yellow solid. LC-MS (Method 3): t R = 1.03 min, m / z(M+H) + =225.1.

[0934] Step 3. 4-(4-amino-1H-pyrazol-1-yl)-1-methylpiperidin-2-one (66d)

[0935] Using a preparation procedure similar to the second step of Example 4, compound 66d (200 mg) was synthesized in 100% yield using 66c (180 mg, 0.80 mmol) as the starting material. 1 H NMR (400MHz, CDCl3) δ8.25(s,1H),8.12(s,1H),4.66(s,1H),3.97(s,3H),3.46-3.36(m,2H),2.97-2.93(m,2H),2.40-2.37(m,2H).

[0936] Step 4. 4-(5-methyl-2-((1-(1-methyl-2-oxopiridin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (66e)

[0937] Using a similar preparation procedure to step six of Example 64, compound 66e (140 mg) was synthesized in 51% yield using 66d (130 mg) and 40b (166 mg) as starting materials. LC-MS (Method 1): t R = 1.07 min, m / z(M+H) + =407.1.

[0938] Step 5. N-(cyanomethyl)-4-(5-methyl-2-((1-(1-methyl-2-oxopiridin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (66)

[0939] Using a similar preparation procedure to step four of Example 1, compound 66 (2.7 mg) was synthesized in 4% yield using 66e (70 mg, 0.17 mmol) and 2-aminoacetonitrile hydrochloride (79 mg, 0.85 mmol) as starting materials. LC-MS (Method 1): t R = 2.63 min, m / z(M+H) + =445.2; 1 H NMR (400MHz, CDCl3) δ8.24(s,1H),7.99(s,1H),7.89(d,J=8.4Hz,2H),7.67(d,J=8.4Hz,2H),7.41(s,1H),6 .83(s,1H),4.59-4.57(m,1H),4.42-4.27(m,2H),3.26-3.17(m,2H),2.88-2.78(m,5H),2.27-2.19(m,5H).

[0940] Example 67

[0941]

[0942] Step 1. 4-Nitro-1-(Tetrahydro-2H-pyran-3-yl)-1H-pyrazole (67b)

[0943] DIAD (2.57 g, 12.7 mmol) was added to a solution consisting of 4a (1 g, 8.8 mmol), tetrahydro-2H-pyran-3-ol (1 g, 9.8 mmol), PPh3 (3.34 g, 12.7 mmol), and THF (20 mL) at 0 °C. The mixture was stirred at 0 °C to RT for 5 hrs. The reaction mixture was concentrated to dryness and purified by rapid chromatography (PE:EtOAc = 4:1) to give a product as a colorless oil (1.5 g, 78% yield). 1 H NMR(400MHz, CDCl3)δ8.38(s,1H),8.09(s,1H),4.37-4.33(m,1H),4.10-4.08(m, 1H),3.89-3.81(m,2H),3.71-3.66(m,1H),2.23-2.15(m,2H),1.81-1.72(m,2H).

[0944] Step 2. 1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-amine (67c)

[0945] Using a similar preparation procedure to the second step of Example 4, compound 67c (1.2 g) was synthesized in 92% yield using 67b (1.5 g, 7.6 mmol) as the starting material. LC-MS (Method 3): t R =0.60min, m / z(M+H) + =168.1.

[0946] Step 3. Methyl 4-(5-methyl-2-((1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (67d)

[0947] Using a similar preparation procedure to the second step of Example 1, compound 67d (90 mg) was synthesized in 20% yield using 67c (230 mg, 1.37 mmol) and 1b (300 mg, 1.15 mmol) as starting materials. LC-MS (Method 3): t R = 1.55 min, m / z(M+H) + =394.2. 1 H NMR (400MHz, CDCl3) δ8.32 (s, 1H), 8.16 (d, J = 8.4Hz, 2H), 7.97 (s, 1H), 7.70 ( d,J=8.4Hz,2H),7.55(s,1H),6.88(s,1H),4.28-4.22(m,1H),4.15-4.10(m, 1H),3.97(s,3H),3.92-3.90(m,1H),3.69(t,J=9.6Hz,1H),3.53(t,J=10.8H z,1H),2.24(s,3H),2.22-2.20(m,1H),2.15-2.10(m,1H),1.85-1.74(m,2H).

[0948] Step 4. 4-(5-methyl-2-((1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (67e)

[0949] Using a similar preparation procedure to step 3 of Example 3, compound 67e (86 mg) was synthesized in 99% yield using 67d (90 mg, 0.23 mmol) as the starting material. LC-MS (Method 3): t R = 1.36 min, m / z(M+H) + =380.0.

[0950] Step 5. N-(cyanomethyl)-4-(5-methyl-2-((1-(tetrahydro-2H-pyran-3-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (67)

[0951] Using a similar preparation procedure to step four of Example 1, compound 67 (33.1 mg) was synthesized in 34% yield using 67e (86 mg, 0.23 mmol) and 2-aminoacetonitrile hydrochloride (64 mg, 0.69 mmol) as starting materials. LC-MS (Method 1): t R = 4.93 min, m / z(M+H) + =418.2. 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 9.32 (t, J = 5.2Hz, 1H), 8.38 (s, 1H), 8.00 (d,J=8.0Hz,2H),7.97(s,1H),7.81(d,J=7.6Hz,2H),7.55(s,1H),4.35(d,J= 5.6Hz,2H),4.25-4.20(m,1H),3.96-3.92(m,1H),3.78(m,1H),3.57(t,J=9.2 Hz,1H),3.44-3.38(m,1H),2.20(s,3H),2.11-1.99(m,2H),1.73-1.61(m,2H).

[0952] Example 68

[0953]

[0954] Step 1. cis-2,6-dimethyltetrahydro-2H-pyran-4-ol (68b)

[0955] Compound 68a (4 g, 32.2 mmol) and Pd / C (4 g, 10% carbon-supported palladium, wetted with 55% water) were dissolved in EtOH (40 mL), and the resulting suspension was stirred at RT for 18 hrs under H2 (50 psi). The mixture was filtered and the filtrate was concentrated to dryness to give the desired product (4 g, crude product) as a yellow oil. 1 H NMR (400MHz, CDCl3) δ 3.90-3.75 (m, 1H), 3.49-3.42 (m, 2H), 1.96-1.90 (m, 3H), 1.23 (d, J = 6.4Hz, 6H), 1.15-1.09 (m, 2H).

[0956] Step 2. cis-2,6-dimethyltetrahydro-2H-pyran-4-ylmethanesulfonate (68c)

[0957] MsCl (1.76 g, 15.37 mmol) was added to a mixture of 68b (1.0 g, 7.69 mmol), Et3N (2.3 g, 23.07 mmol), and DCM (20 mL) at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (eluent: DCM:MeOH = 100:1) to give the desired product (1.35 g, 84% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3), δ: 4.84-4.76 (m, 1H), 3.54-3.46 (m, 2H), 3.02 (s, 3H), 2.12-2.08 (m, 2H), 1.48-1.37 (m, 2H), 1.25 (d, J = 6.0Hz, 6H).

[0958] Step 3. 1-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-4-nitro-1H-pyrazole (68d)

[0959] A solution of 68c (1.35 g, 6.47 mmol), 4-nitro-1H-pyrazole (366 mg, 3.23 mmol), and Cs₂CO₃ (3.2 g, 9.69 mmol) in 20 mL of NMP was stirred at 140 °C for 18 hrs under a N₂ atmosphere. The mixture was cooled to RT, diluted with water (50 mL), and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 3:1) to give the title product (655 mg, 89% yield) as a yellow solid. LC-MS (Method 3): t R = 1.40 min, m / z(M+H) + =226.1.

[0960] Step 4. 1-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (68e)

[0961] A mixture of 68d (655 mg, 2.89 mmol) and Pd / C (100 mg, 10% carbon-supported palladium, moistened with 55% water) in MeOH (20 mL) was stirred at 50 °C for 18 hours under H2 (50 psi). The mixture was filtered and the filtrate was concentrated to give the desired product (523 mg, 92% yield) as a brown oil. LC-MS (Method 3): t R =0.74min, m / z(M+H)+ =196.2.

[0962] Step 5. Butyl 4-(2-((1-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (68f)

[0963] Using a similar preparation procedure to step four of Example 40, compound 68f (468 mg) was synthesized in 64% yield using 40b (392 mg, 1.58 mmol) and 68e (463 mg, 2.37 mmol) as starting materials. LC-MS (Method 3): t R = 1.89 min, m / z(M+H) + =464.3.

[0964] Step 6. 4-(2-((1-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (68g)

[0965] Using a similar preparation procedure to step 3 of Example 3, compound 68g (411mg) was synthesized in 100% yield using 68f (468mg, 1.01mmol) as the starting material. LC-MS (Method 3): t R = 1.11 min, m / z(M+H) + =408.2.

[0966] Step 7. N-(cyanomethyl)-4-(2-(1-cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (68)

[0967] Using a similar preparation procedure to step four of Example 1, compound 68 (14.9 mg) was synthesized in 23% yield using 68 g (60 mg, 0.15 mmol) and aminoacetonitrile hydrochloride (68 mg, 0.74 mmol) as starting materials. LC-MS (Method 1): t R = 3.25 min, m / z(M+H) + =446.2; 1H NMR(400MHz,CD3OD)δ8.34(s,1H),8.14(s,1H),8.02-8.00(m,2H),7.82-7.79(m,2H),7.62(s,1H),4.5 4(s,1H),4.39(s,2H),3.80-3.76(m,2H),2.31-2.26(m,5H),1.76-1.69(m,2H),1.16(d,J=6.0Hz,6H).

[0968] Example 69

[0969]

[0970] Step 1. (1R,5S)-8-oxabicyclo[3.2.1]oct-3-ol (69b)

[0971] A LiAlH4 solution (13 mL, 32 mmol, 2.5 M, in THF) was added to a solution of 69a (2 g, 15.9 mmol) in THF (20 mL) at 0 °C. After stirring at RT for 1 hour, the mixture was diluted with THF (100 mL) and recooled to 0 °C. The reaction mixture was quenched with water (1.2 mL) and 10% NaOH aqueous solution (1.2 mL), and then water (3.6 mL) was added. The resulting mixture was diluted with EtOAc (50 mL) and then stirred at RT for 10 hours. The solids were filtered off and the filtrate was concentrated to give the desired compound (2.03 g) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.48-4.37(m,1H),4.14-3.17(m,1H),3.71-3.68(m,1H),2.30-2.23(m,1H),1.97-1.83(m,3H),1.78-1.45(m,4H).

[0972] Step 2. 1-((1R,5S)-8-oxabicyclo[3.2.1]oct-3-yl)-4-nitro-1H-pyrazole (69c)

[0973] MsCl (2.1 g, 18.7 mmol) was added to 69b (1.61 g, 12.5 mmol), TEA (3.8 g, 37.5 mmol), and DCM (20 mL) at 0 °C. The mixture was stirred at RT for 2 hrs, then diluted with EtOAc (100 mL) and washed with water (50 mL). The separated organic phase was concentrated to dryness, giving a crude intermediate (1R,5S)-8-oxabicyclo[3.2.1]oct-3-ylmethanesulfonate (2.5 g, 96% yield) as a yellow oil. A mixture of (1R,5S)-8-oxabicyclo[3.2.1]oct-3-ylmethanesulfonate (2.5 g, 12.1 mmol), 4-nitro-1H-pyrazole (1.4 g, 12.1 mmol), and K2CO3 (5 g, 36.3 mmol) in 40 mL of LDM was stirred overnight at 60 °C. After cooling to RT, the mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL). The separated organic phase was concentrated and purified by silica gel column chromatography (PE:EtOAc = 2:1) to give 69c (2 g, 76% yield) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.29(s,1H),4.70-4.40(m,1H),4.26-4.22(m ,1H),4.05-4.00(m,1H),2.20-1.90(m,4H),1.90-1.85(m,2H),1.57-1.52(m,2H).

[0974] Step 3. 1-((1R,5S)-8-oxabicyclo[3.2.1]oct-3-yl)-1H-pyrazole-4-amine (69d)

[0975] Compound 69c (2 g, 8.96 mmol) and 10% carbon-supported palladium (400 mg) were suspended in MeOH (40 mL). The resulting mixture was stirred at RT for 2 hours under H2 (50 psi). The mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by reversed-phase chromatography (5-95% CH3CN in water) to give the title product as a yellow solid (400 mg, crude product, 23% yield). LC-MS (Method 3): t R =0.42min, m / z(M+H) + =194.0.

[0976] Step 4. 4-(2-((1-((1R,5S)-8-oxabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (69e)

[0977] A mixture of 69d (100 mg, 0.52 mmol), 40b (194 mg, 0.78 mmol), and TsOH (9 mg, 0.052 mmol) in 1,4-dioxane (4 mL) was stirred overnight at 120 °C. The mixture was concentrated to dryness under reduced pressure and purified by reversed-phase rapid chromatography (5% to 60% ACN in water) to give the desired product as a yellow solid (160 mg, 76% yield). LC-MS (Method 3): t R = 1.09 min, m / z(M+H) + =406.2. 1 H NMR (400MHz, CDCl3) δ9.42(s,1H),8.38(s,1H),8.06(d,J=8.0Hz,2H),7.84(s,1H),7.78(d,J=8.0Hz,2H),7.54(d,J=8.0Hz,1H), 4.60-4.51(m,0.6H),4.41(br.s,2H),4.41-4.30(m,0.4H),2.19(s,3H),2.01-1.95(m,2H),1.86-1.82(m,5H),1.72-1.52(m,1H).

[0978] Step 6. 4-(2-((1-((1R,5S)-8-oxabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(cyanomethyl)benzamide (69)

[0979] Using a similar preparation procedure to step four of Example 1, compound 69 (30.1 mg) was synthesized in 56% yield using 69e (50.0 mg, 0.12 mmol) and 2-aminoacetonitrile hydrochloride (34.0 mg, 0.37 mmol) as starting materials. LC-MS (Method 1): t R = 3.29 min, m / z(M+H) + =444.2. 1H NMR(400MHz,DMSO-d6)δ9.41-9.38(m,1H),9.32(t,J=5.6Hz,1H),8.39-8.37(m,1H) ,8.00(d,J=8.4Hz,2H),7.87(s,1H),7.79(d,J=8.0Hz,2H),7.56-7.54(m,1H),4.58 -4.53(m,0.6H),4.41(br.s,2H),4.35(d,J=5.6Hz,2H),4.33-4.31(m,0.4H),2.38- 2.23(m,1H),2.19(s,3H),2.02-1.95(m,2H),1.86-1.83(m,4H),1.66-1.56(m,1H).

[0980] Example 70

[0981]

[0982] 4-(2-((1-((1R,5S)-8-oxabicyclo[3.2.1]oct-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-((S)-1-cyanoethyl)benzamide (70)

[0983] Using a similar preparation procedure to step four of Example 1, compound 70 (27.6 mg) was synthesized in 50% yield using 69e (50.0 mg, 0.12 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (89.0 mg, 0.37 mmol) as starting materials. LC-MS (Method 1): t R = 3.43 min, m / z(M+H) + =458.2. 1 H NMR (400MHz, DMSO-d6) δ9.39(d,J=8.4Hz,1H),9.25(d,J=7.2Hz,1H),8.38(d,J=6.0Hz,1 H),8.02(d,J=6.4Hz,1H),8.00(s,1H),7.87(s,1H),7.79(d,J=8.0Hz,2H),7.55(d,J=7. 2Hz,1H),5.04-5.00(m,1H),4.61-4.51(m,1H),4.36(s,2H),2.50-2.49(m,1H),2.34(d, J=9.6Hz,3H),2.07-1.96(m,2H),1.91(s,3H),1.82-1.71(m,1H),1.57(d,J=6.8Hz,4H).

[0984] Example 71

[0985]

[0986] Step 1. 3-(4-nitro-1H-pyrazole-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (71b)

[0987] A mixture of 4a (2.0 g, 17.7 mmol), tert-butyl 3-hydroxyazacyclobutane-1-carboxylate (3.1 g, 17.7 mmol), and PPh3 (7.0 g, 26.5 mmol) in THF (50 mL) was stirred at 0 °C for 5 min. Then, DIAD (5.4 g, 26.5 mmol) was added to the reaction mixture. After stirring at RT for 16 hours, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (300 mL). The separated organic layer was concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EtOAc = 10:1) to give a crude product as a white solid (4.7 g, 100% yield). 1 H NMR (400MHz, CDCl3) δ8.32(s,1H),8.16(s,1H),5.09-5.06(m,1H),4.45-4.41(m,2H),4.35-4.31(m,2H),1.47(s,9H).

[0988] Step 2. 3-(4-amino-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (71c)

[0989] A mixture of 71b (4.0 g, 14.9 mmol) and 10% carbon-supported palladium (400 mg) in MeOH (8 mL) was stirred at RT for 12 h under H2 (50 psi). The mixture was filtered and the filtrate was concentrated. The residue was purified by rapid column chromatography (DCM:MeOH = 20:1), giving the title product as a red solid (1.3 g, 35% yield). LC-MS (Method 3): t R = 1.160 min, m / z(M+H-56) + =183.1.

[0990] Step 3. 3-(4-((4-(4-(methoxycarbonyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (71d)

[0991] Compounds 71c (800 mg, 3.36 mmol), 1b (880 mg, 3.36 mmol), Pd2(dba)3 (308 mg, 0.34 mmol), XantPhos (320 mg, 0.67 mmol), and Cs2CO3 (2.16 g, 6.72 mmol) were dissolved in dioxane (20 mL). The mixture was stirred at 110 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to RT, concentrated to dryness, and purified by rapid chromatography (PE:EtOAc = 1:1) to give the title product as a white solid (1.5 g, 75% yield). LC-MS (Method 3): t R = 1.67 min, m / z(M+H) + =465.2.

[0992] Step 4. Methyl 4-(2-((1-(azacyclobut-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (71e)

[0993] Compound 71d (1.1 g, 0.25 mmol) was dissolved in MeOH (20 mL), followed by the addition of a solution of HCl (g) in methanol (2 N, 8 mL). The resulting mixture was stirred at RT for 4 hours. The mixture was concentrated and purified by reverse-phase column chromatography (5 to 50% acetonitrile in water), yielding the title product as a yellow solid (600 mg, 70% yield). LC-MS (Method 3): t R = 1.33 min, m / z(M+H) + =365.1. 1 H NMR(400MHz,DMSO-d6)δ9.58(s,1H),9.12(br s,1H),8.40(s,1H),8.10(d,J=8.4Hz,2H),8.03(s,1H),7.82(d,J=7.6Hz,2 H),7.72(s,1H),5.39-5.37(m,1H),4.30(m,4H),3.90(s,3H),3.20(s,3H).

[0994] Step 5. Methyl 4-(2-((1-(1-(cyclopropanecarbonyl)azacyclobut-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (71f)

[0995] A mixture of 71e (200 mg, 0.55 mmol) and DIPEA (213 mg, 1.65 mmol) in DCM (3 mL) was stirred at 0 °C for 5 min. Cyclopropane carbonyl chloride (86 mg, 0.82 mmol) was then added to the reaction mixture. After stirring at RT for 2 hours, the reaction mixture was concentrated and purified by column chromatography on silica gel (PE:EtOAc = 3:7), giving the product as a yellow solid (160 mg, 67% yield). LC-MS (Method 3): t R =1.45min, m / z(M+H)+=433.2. 1 H NMR (400MHz, DMSO-d6) δ9.52(s,1H),8.40(s,1H),8.10(d,J=8.4Hz,2H),8.04(s,1H),7.83(d,J=8.0Hz,2H),7.66(s,1H),5.25(m ,1H),4.67(t,J=8.4Hz,1H),4.46(m,1H),4.27(t,J=9.6Hz,1H),4.05(m,1H),3.32(s,3H),2.20(s,3H),1.57(m,1H),0.72(m,4H).

[0996] Step 6. 4-(2-((1-(1-(cyclopropanecarbonyl)azacyclobut-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (71g)

[0997] Compound 71f (160 mg, 0.37 mmol) and LiOH·H₂O (62.0 mg, 1.48 mmol) were dissolved in a compound of THF and H₂O (6 mL, V:V = 1:1). The mixture was stirred at RT for 4 hours. The reaction mixture was concentrated to dryness, giving a crude product as an orange solid (150 mg, 97% yield). LC-MS (Method 3): t R = 1.05 min, m / z(M+H) + =419.1.

[0998] Step 7. (S)-N-(1-cyanoethyl)-4-(2-((1-(1-(cyclopropanecarbonyl)azacyclobut-3-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (71)

[0999] Using a similar preparation procedure to step four of Example 1, compound 71 (4 mg) was synthesized in 6% yield using 71e (60 mg, 0.14 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (35 mg, 0.14 mmol) as starting materials. LC-MS (Method 1): t R = 2.81 min, m / z(M+H) + =471.3. 1 H NMR (400MHz, CD3OD) δ8.38(s,1H),8.18(s,1H),8.00(d,J=8.0Hz,2H),7.81(d,J=8.0Hz,2H),7.71(s 1H),5.27-5.21(m,1H),5.12-5.06(m,1H),4.79-4.77(m,1H),4.65-4.62(m,1H),4.4 7-4.43(m,1H),4.32-4.28(m,1H),2.26(s,3H),1.69-1.59(m,4H),0.90-0.83(m,4H).

[1000] Example 72

[1001]

[1002] Step 1. 1-(2-Methyltetrahydro-2H-pyran-4-yl)-4-nitro-1H-pyrazole (72b)

[1003] Using a similar preparative procedure to the first step of Example 71, compound 72b (1.8 g) was synthesized in 97% yield using 4a (1.0 g, 8.8 mmol) and 2-methyltetrahydro-2H-pyran-4-ol (1.0 g, 8.8 mmol) as starting materials. LC-MS (Method 3): t R = 1.37 min, m / z(M+H) + =212.1.

[1004] Step 2. 1-(2-Methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine (72c)

[1005] Using a similar preparation procedure to the second step of Example 71, compound 72c (3.4 g) was synthesized in 100% yield using 72b (3.7 g, 17.6 mmol) as the starting material. LC-MS (Method 3): t R =0.60min, m / z(M+H) + =182.1.

[1006] Step 3. 4-(5-methyl-2-((1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (72d)

[1007] Using a similar preparation procedure to step four of Example 69, compound 72d (110 mg) was synthesized in 47% yield using 72c (217 mg, 1.2 mmol) and 1b (150 mg, 0.6 mmol) as starting materials. LC-MS (Method 3): t R = 1.07 min, m / z(M+H) + =394.2.

[1008] Step 4. N-(cyanomethyl)-4-(5-methyl-2-((1-(2-methyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (72)

[1009] Using a similar preparation procedure to step four of Example 1, compound 72 (32 mg) was synthesized in 27% yield using 72 d (110 mg, 0.28 mmol) and 2-aminoacetonitrile hydrochloride (52 mg, 0.56 mmol) as starting materials. LC-MS (Method 1): t R = 7.79 min, m / z(M+H) + =432.2. 1 H NMR (400MHz, CD3OD) δ8.38(s,1H),8.17(s,1H),8.05(d,J=8.0Hz,2H),7.85(d,J=8.0Hz,2H),7.67(s,1H),4.60-4.56( m,1H),4.42(s,2H),3.91-3.87(m,2H),3.81-3.74(m,1H),2.37-2.10(m,6H),1.92-1.83(m,1H),1.23(d,J=8.4Hz,3H).

[1010] Example 73

[1011]

[1012] N-((S)-1-cyanoethyl)-4-(2-((1-(cis-2,6-dimethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (73)

[1013] Using a similar preparation procedure to step four of Example 1, compound 73 (22 mg) was synthesized in 20% yield using 68 g (100 mg, 0.25 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (65 mg, 0.27 mmol) as starting materials. LC-MS (Method 1): t R = 3.34 min, m / z(M+H) + =460.3; 1 H NMR (400MHz, CD3OD) δ8.34(s,1H),8.15(s,1H),8.03(d,J=8.4Hz,2H),7.82(d,J=8.0Hz,2H),7.62(s,1H),5. 13-5.07(m,1H),4.54(s,1H),3.80-3.76(m,2H),2.31-2.26(m,5H),1.76-1.67(m,5H),1.16(d,J=6.0Hz,6H).

[1014] Example 74

[1015]

[1016] Step 1. Methyl 4-(2-((1-(1-(1-hydroxycyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (74b)

[1017] Compound 3a (800 mg, 2.04 mmol), 1-hydroxycyclopropanecarboxylic acid (208 mg, 2.04 mmol), DIPEA (789 mg, 6.12 mmol), EDCI (482 mg, 2.45 mmol), and HOBT (330.7 mg, 2.45 mmol) were dissolved in DMF (8 mL). The resulting mixture was stirred overnight at RT. H2O (10 mL) was added to the above solution, followed by extraction with EtOAc (10 mL x 3). The combined organic phases were concentrated under vacuum to give the residue, which was purified by preparative HPLC to give the desired product (500 mg, 51% yield) as a yellow solid. LC-MS (Method 3): t R = 1.47 min, m / z(M+H) + =477.2.

[1018] Step 2. 4-(2-((1-(1-(1-hydroxycyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (74c)

[1019] Compound 74b (190 mg, 0.4 mmol) and (CH3)3SiOK (154 mg, 1.2 mmol) were dissolved in THF (anhydrous, 2 mL). The resulting solution was stirred at RT for 1 hour. The reaction mixture was adjusted to pH 2–3 using HCl (aqueous solution, 10%) and concentrated under vacuum to give the desired product as a yellow solid (400 mg, crude, 100% yield). LC-MS (Method 3): t R =0.84min, m / z(M+H) + =463.2.

[1020] Step 3. N-(cyanomethyl)-4-(2-((1-(1-(1-hydroxycyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (74)

[1021] Using a similar preparation procedure to step four of Example 1, compound 74 (50 mg) was synthesized in 25% yield using 74c (400 mg, crude, 0.4 mmol) and 2-aminoacetonitrile hydrochloride (44 mg, 0.48 mmol) as starting materials. LC-MS (Method 1): t R = 3.30 min, m / z(M+H) + =501.3; 1 H NMR (400MHz, DMSO-d6) δ9.40 (s, 1H), 9.34 (d, J = 5.6Hz, 1H), 8.38 (s, 1H), 8.00 ( d,J=8.4Hz,2H),7.90(s,1H),7.79(d,J=8.0Hz,2H),7.55(s,1H),6.33(d,J=4.8 Hz,1H),4.45-4.34(m,5H),3.14-2.83(m,2H),2.19(s,3H),2.01(d,J=10.8Hz,2 H), 1.80 (d, J = 2.4Hz, 2H), 0.92 (dd, J1 = 8.4, 4.0Hz, 2H,), 0.76 (d, J = 2.4Hz, 2H).

[1022] Example 75

[1023]

[1024] Step 1. 4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (75b)

[1025] Compound 75a (1.7 g, 5.08 mmol), tetrahydro-2H-pyran-4-ylmethanesulfonate (2.3 g, 12.7 mmol), and cesium carbonate (8.3 g, 25.4 mmol) were dissolved in N,N-dimethylformamide (15 mL). The resulting mixture was stirred at 100 °C for 16 hrs. After cooling to RT, the mixture was filtered and the filtrate was concentrated. The residue was purified by reversed-phase chromatography (eluent: 5% to 95% acetonitrile in water) to give the desired product 89b (620 mg, 32% yield) as a yellow solid. LC-MS (Method 3): t R = 1.11 min, m / z(M+H) + =380.2.

[1026] Step 2. (S)-4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1,1,1-trifluoropropane-2-yl)benzamide (75)

[1027] Using a similar preparation procedure to step four of Example 1, compound 75 (65 mg) was synthesized in 65% yield using 75b (80 mg, 0.21 mmol) and (S)-1,1,1-trifluoropropane-2-amine hydrochloride (63 mg, 0.42 mmol) as starting materials. LC-MS (Method 1): t R = 3.27 min, m / z(M+H) + =475.2; 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.97(d,J=8.4Hz,1H),8.37(s,1H),8.02(d,J=8.4Hz,2H),7.89(s,1H),7.79(d,J=8.0Hz,2H),7.56(s, 1H),4.92-4.86(m,1H),4.35-4.29(m,1H),3.94(d,J=11.2Hz,2H),3.4 7-3.41(m,2H),2.19(s,3H),1.93-1.84(m,4H),1.39(d,J=7.2Hz,3H).

[1028] Example 76

[1029]

[1030] 4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (76)

[1031] Using a similar preparation procedure to step four of Example 1, compound 76 (74.2 mg) was synthesized in 77% yield using 75b (80 mg, 0.21 mmol) and 2,2,2-trifluoroethylamine (42 mg, 0.42 mmol) as starting materials. LC-MS (Method 1): t R = 3.30 min, m / z(M+H) + =461.2; 1 H NMR (400MHz, DMSO-d6) δ9.38(s,1H),9.21(t,J=6.4Hz,1H),8.37(s,1H),8.02(d,J=8.4Hz,2H),7.90(s,1H),7.79(d,J=8.0Hz,2H ),7.55(s,1H),4.37-4.29(m,1H),4.17-4.08(m,2H),3.94(d,J=11.2Hz,2H),3.48-3.41(m,2H),2.19(s,3H),1.92-1.84(m,4H).

[1032] Example 77

[1033]

[1034] 4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(3,3,3-trifluoropropyl)benzamide (77)

[1035] Using a similar preparation procedure to step four of Example 1, compound 77 (69 mg) was synthesized in 69% yield using 75b (80 mg, 0.21 mmol) and 3,3,3-trifluoropropane-1-amine (63 mg, 0.42 mmol) as starting materials. LC-MS (Method 1): t R = 3.42 min, m / z(M+H) + =475.2; 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.81(t,J=5.6Hz,1H),8.37(s,1H),7.96(d,J=8.4Hz,2H),7.90(s,1H),7.78(d,J=8.0Hz,2H),7.55(s ,1H),4.35-4.30(m,1H),3.94(d,J=11.6Hz,2H),3.55-3.50(m,2H),3.47-3.41(m,2H),2.62-2.53(m,2H),2.19(s,3H),1.92-1.83(m,4H).

[1036] Example 78

[1037]

[1038] 4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-((1-cyanocyclopropyl)methyl)benzamide (78)

[1039] Using a similar preparative procedure to step four of Example 1, compound 78 (73.6 mg) was synthesized in 77% yield using 39b (80 mg, 0.2 mmol) and 1-(aminomethyl)cyclopropaneformonitrile (38 mg, 0.4 mmol) as starting materials. The title compound was purified by preparative HPLC (Method B). LC-MS (Method 1): t R = 3.22 min, m / z(M+H) + =478.2; 1 H NMR (400MHz, DMSO-d6) δ9.83(s,1H),9.04(t,J=6.0Hz,1H),8.58(s,1H),8.02(d,J=8.4Hz,2H),7.91(br s,3H),7.57(s,1H),4.36-4.32(m,1H),3.95-3.92(m,2H),3.47-3.42(m,4H),1.93-1.87(m,4H),1.25-1.22(m,2H),1.19-1.13(m,2H).

[1040] Example 79

[1041]

[1042] (S)-N-(1-cyanoethyl)-4-(2-((1-(1-(1-hydroxycyclopropanecarbonyl)piperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (79)

[1043] Using a similar preparative procedure to step four of Example 1, compound 79 (56 mg) was synthesized in 29% yield using 74c (250 mg, crude, 0.378 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (109.7 mg, 0.454 mmol) as starting materials. The title compound was purified by preparative HPLC (Method B). LC-MS (Method 1): t R = 3.03 min, m / z(M+H) + =515.3;1 H NMR (400MHz, CD3OD) δ8.34(s,1H),8.06(s,1H),8.03(d,J=8.4Hz,2H),7.83( d,J=8.4Hz,2H),7.65(s,1H),5.10(dd,J1=14.4,6.8Hz,1H),4.89-4.55(m,2H ),4.49-4.41(m,1H),3.21-2.86(m,2H),2.29(s,3H),2.16(d,J=10.0Hz,2H), 2.07-1.92(m,2H),1.68(d,J=7.2Hz,3H),1.07(s,2H),0.92(d,J=2.4Hz,2H).

[1044] Example 80

[1045]

[1046] 4-(5-chloro-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(2-cyano-2-methylpropyl)benzamide (80)

[1047] Using a similar preparative procedure to step four of Example 1, compound 80 (47.4 mg) was synthesized in 79% yield using 39b (50 mg, 0.12 mmol) and 3-amino-2,2-dimethylpropionitrile 4-methylbenzenesulfonate (68 mg, 0.25 mmol) as starting materials. The title compound was purified by preparative HPLC (Method B). LC-MS (Method 1): t R = 3.30 min, m / z(M+H) + =480.2; 1 H NMR (400MHz, DMSO-d6) δ9.82(s,1H),8.93(t,J=8.0Hz,1H),8.57(s,1H),8.01(d,J=8.0Hz,2H),7.90(s,3H),7.58(s,1H ),4.37-4.31(m,1H),3.93(d,J=11.2Hz,2H),3.50(d,J=6.4Hz,2H),3.48-3.41(m,2H),1.93-1.92(m,4H),1.36(s,6H).

[1048] Example 81

[1049]

[1050] Step 1. Methyl 4-(2-((1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (81a)

[1051] Compound 1b (5.0 g, 19.10 mmol), tert-butyl 4-amino-1H-pyrazole-1-carboxylate (5.20 g, 28.6 mmol), and TsOH (328 mg, 1.91 mmol) were dissolved in 1,4-dioxane (5 mL). The resulting solution was stirred overnight at 120 °C. The reaction mixture was cooled, diluted with water (500 mL), and extracted with EtOAc (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, and filtered. The filtrate was concentrated to give the residue, which was purified by column chromatography on silica gel (eluent: DCM:MeOH = 20:1) to give the desired product as a green solid (1.6 g, 27% yield). LC-MS (Method 3): t R = 1.40 min, m / z(M+H) + =310.1.

[1052] Step 2. Methyl 4-(2-((1-(2-cyano-2-methylpropyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (81b)

[1053] Compound 81a (300 mg, 0.97 mmol), 2-cyano-2-methylpropyl methanesulfonate (344 mg, 1.94 mmol), and Cs₂CO₃ (629 mg, 1.94 mmol) were dissolved in DMF (1.5 mL). The mixture was stirred overnight at 120 °C and cooled to RT. Water (30 mL) and EtOAc (60 mL) were added to the above solution. The organic layer was separated and concentrated under vacuum to give the residue, which was purified by column chromatography on silica gel (eluent: DCM:MeOH = 10:1) to give the title product as a yellow oil (255 mg, 67% yield). LC-MS (Method 3): t R = 1.55 min, m / z(M+H) + =391.2.

[1054] Step 3. 4-(2-((1-(2-cyano-2-methylpropyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (81c)

[1055] Using a similar preparation procedure to step 3 of Example 3, compound 81c (200 mg) was synthesized in 83% yield using 81b (250 mg, 0.64 mmol) as the starting material. LC-MS (Method 3): tR = 1.10 min, m / z(M+H) + =377.1.

[1056] Step 4. 4-(2-((1-(2-cyano-2-methylpropyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (81)

[1057] Using a similar preparation procedure to step four of Example 1, compound 81 (80 mg) was synthesized in 33% yield using 81c (200 mg, 0.53 mmol) and 2,2,2-trifluoroethylamine (63 mg, 0.64 mmol) as starting materials. LC-MS (Method 1): t R = 3.09 min, m / z(M+H) + =458.2. 1 H NMR (400MHz, DMSO-d6) δ9.51 (s, 1H), 9.22 (t, J = 6.0Hz, 1H), 8.40 (s, 1H), 8.02-8.00 (m, 3H), 7 .81(d,J=7.2Hz,2H),7.59(s,1H),4.28(s,2H),4.17-4.09(m,2H),2.21(s,3H),1.31(s,6H).

[1058] Example 82

[1059]

[1060] Step 1. 4-(4-((4-(4-(((cyanomethyl)carbamoyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazole-1-yl)piperidine-1-carboxylic acid tert-butyl ester (82a)

[1061] Using a similar preparation procedure to step four of Example 1, compound 82a (22.5 mg) was synthesized in 77% yield using 1d (272 mg, 0.57 mmol) and 2-aminoacetonitrile hydrochloride (32.8 mg, 0.57 mmol) as starting materials. LC-MS (Method 1): t R = 3.63 min, m / z(M+H) + =517.3; 1H NMR (400MHz, CDCl3) δ8.31(s,1H),8.09(s,1H),7.92(d,J=8.4Hz,2H),7.77(d,J=8.4Hz,2H),7.45(s,1H),6.87(s,1H),4.41(d,J=5 .6Hz,2H),4.32-4.26(m,1H),4.17-4.13(m,2H),2.98-2.91(m,2H),2.29(s,3H),2.14-2.12(m,2H),1.90-1.86(m,2H),1.47(s,9H).

[1062] Step 2. N-(2-amino-2-oxoethyl)-4-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide hydrochloride (82)

[1063] Compound 82a (50 mg, 0.1 mmol) was dissolved in HCl / EtOAc (2 N, 2 mL), and the resulting solution was stirred at RT for 3 hours. The reaction mixture was concentrated to dryness. The residue was purified by preparative HPLC (Method A) to give title compound 82 (10 mg, 24% yield) as a yellow solid. LC-MS (Method 1): t R = 2.38 min, m / z(M+H) + =435.0; 1 H NMR(400MHz,DMSO-d6)δ9.37(s,1H),8.79(s,1H),8.37(s,1H),8.02(d,J= 7.2Hz,2H),7.88(s,1H),7.77(d,J=7.2Hz,2H),7.53(s,1H),7.41(s,1H), 7.05(s,1H),4.10-4.14(m,1H),3.85(d,J=5.2Hz,2H),3.02(d,J=11.6Hz, 2H),2.61-2.54(m,2H),2.20(s,3H),1.92-1.90(m,2H),1.74-1.71(m,2H).

[1064] Example 83

[1065]

[1066] Step 1. Methyl 5-(2-chloro-5-methylpyrimidin-4-yl)pyridinecarboxylate (83a)

[1067] Compound 1a (632 mg, 3.88 mmol) was dissolved in a mixture of 1,4-dioxane and H₂O (4.5 mL, V / V = 8:1), followed by the sequential addition of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyridinecarboxylate (510 mg, 1.94 mmol), Na₂CO₃ (411 mg, 3.88 mmol), and Pd(dppf)Cl₂ (142 mg, 0.19 mmol). The mixture was stirred at 85 °C for 16 hrs under a N₂ atmosphere. After cooling to room temperature, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 1:1) to give the title product as a white solid (290 mg, 57% yield). LC-MS (Method 3): t R = 1.297 min, m / z(M+H) + =264.0; 1 H NMR (400MHz, CDCl3) δ8.99(dd,J=0.8,2.0Hz,1H),8.59(s,1H),8.29(dd,J=0.8,8.4Hz,1H),8.16(d,J=2.0,8.0Hz,1H),4.06(s,3H),2.43(s,3H).

[1068] Step 2. Methyl 5-(2-((1-cyclopropyl-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)pyridinecarboxylate (83b)

[1069] Using a similar preparation procedure to the second step of Example 1, compound 83b (210 mg) was synthesized in 78% yield using 83a (200 mg, 0.76 mmol) and 1-cyclopropyl-1H-pyrazole-4-amine (112 mg, 0.91 mmol) as starting materials. LC-MS (Method 3): t R = 1.373 min, m / z(M+H) + =351.1.

[1070] Step 3. 5-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)pyridinecarboxylic acid (83c)

[1071] Using a similar preparation procedure to step 3 of Example 1, compound 83c (80 mg) was synthesized in 40% yield using 83b (210 mg, 0.6 mmol) as the starting material. LC-MS (Method 3): t R = 0.994min, m / z(M+H) + =337.1.

[1072] Step 3. N-(cyanomethyl)-5-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)pyridinecarboxamide (83)

[1073] Using a similar preparative procedure to step four of Example 1, compound 83 (7 mg) was synthesized in 16% yield using 83c (40 mg, 0.12 mmol) and 2-aminoacetonitrile hydrochloride (13.3 mg) as starting materials. The title compound was purified by preparative HPLC (Method B). LC-MS (Method 1): t R = 3.070 min, m / z(M+H) + =375.2; 1 HNMR(400MHz, CDCl3)δ8.88(s,1H),8.40(d,J=8.0,1H),8.36(d,J=8.0,1H),8.25(s,1H),8.18(dd,J=2.0,8.0Hz,1H), 7.80(s,1H),7.66(s,1H),4.46(d,J=6.4Hz,2H),3.60-3.55(m,1H),2.32(s,3H),1.14-1.10(m,2H),1.03-0.98(m,2H).

[1074] Example 84

[1075]

[1076] Step 1. 8,8-Difluoro-1,4-dioxaspiro[4.5]decane (84b)

[1077] DAST (1.3 g, 8.2 mmol) was added to a solution of 1,4-dioxanospiro[4.5]dec-8-one (1 g, 6.4 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at 35 °C for 4 hrs. The mixture was diluted with a saturated aqueous solution of NaHCO3 (20 mL) and extracted with DCM (20 mL x 2). A solution of KMnO4 (1.3 g, 8.2 mmol, in 20 mL H2O) was added to the combined organic layers. The resulting mixture was stirred overnight at RT. The organic layers were separated, dried on Na2SO4, and concentrated under vacuum to give the desired product (1 g, 91% yield) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ3.96 (s, 4H), 2.11-2.00 (m, 4H), 1.82-1.78 (m, 4H). 19 F NMR (376MHz, CDCl3) δ-105.03.

[1078] Step 2.4,4-Difluorocyclohexanone (84c)

[1079] Compound 84b (1 g, 5.6 mmol) was dissolved in an aqueous HCl solution (aq. HCl, 2 mL, 2 N). The resulting mixture was stirred at 100 °C for 12 hrs. After cooling to RT, the mixture was diluted with DCM (10 mL) and adjusted to pH 7–8 with a saturated NaHCO3 aqueous solution. The separated organic layer was washed with a saturated NaHCO3 aqueous solution, dried on Na2SO4, and filtered. The filtrate was concentrated to dryness to give the desired product (700 mg, 93% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ2.56-2.53(m,4H),2.36-2.27(m,4H). 19 FNMR (376MHz, CDCl3) δ-100.27.

[1080] Step 3,4,4-Difluorocyclohexanol (84d)

[1081] NaBH4 (395 mg, 10.4 mmol) was added to a solution of 84c (700 mg, 5.2 mmol) in MeOH (15 mL) at 0 °C. The mixture was stirred at 25 °C for 2 hours. The mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL x 2). The combined organic layers were concentrated to dryness to give the desired product (700 mg, 99% yield) as a colorless oil. 1 HNMR (400MHz, CDCl3) δ3.94-3.90(m,1H),2.17-2.01(m,2H),1.90-1.73(m,6H). 19 F NMR (376MHz, CDCl3) δ-99.68,-102.94.

[1082] Step 4. 1-(4,4-difluorocyclohexyl)-4-nitro-1H-pyrazole (84e)

[1083] 4-Nitro-1H-pyrazole (576 mg, 5.1 mmol), 84d (700 mg, 5.1 mmol), PPh3 (2 g, 7.7 mmol), and DIAD (1.56 g, 7.7 mmol) were dissolved in THF (10 mL), and the resulting mixture was stirred overnight at RT. The mixture was concentrated to dryness. The crude product was purified by silica gel chromatography (eluent: PE:EtOAc = 2:1) to give the desired product (220 mg, 19% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ8.18(s,1H),8.08(s,1H),4.32-4.26(m,1H),2.33-2.24(m,4H),2.19-2.11(m,2H),2.04-1.90(m,2H). 19 F NMR (376MHz, CDCl3) δ-95.32,-95.96,-100.89,-101.53.

[1084] Step 5. 1-(4,4-difluorocyclohexyl)-1H-pyrazole-4-amine (84f)

[1085] Compound 84e (220 mg, 0.95 mmol), Fe powder (160 mg, 2.86 mmol), and NH4Cl (252 mg, 4.75 mmol) were suspended in a mixture of EtOH and H2O (4.5 mL, V:V = 8:1) and stirred at 85 °C for 3 hrs. After cooling to RT, the mixture was filtered and the filtrate was concentrated to give the desired product (190 mg, 99% yield) as a black solid. 1 H NMR (400MHz, CDCl3) δ7.20(s,1H),7.11(s,1H),4.17-4.10(m,1H),2.23-2.05(m,6H),1.97-1.82(m,2H). 19 F NMR (376MHz, CDCl3) δ-94.80, -95.43, -100.63, -101.26.

[1086] Step 6. 4-(2-((1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (84g)

[1087] A catalytic H₂SO₄ (cat. H₂SO₄, 0.25 mL, 1 drop, in 1 mL n-BuOH) was added to a mixture of 40b (233 mg, 0.94 mmol) and 84f (190 mg, 0.94 mmol) in n-BuOH (4 mL). The mixture was stirred overnight at 120 °C. After cooling to RT, the mixture was concentrated to dryness and purified by preparative HPLC (Method A) to give the desired product (100 mg, 26% yield) as a black solid. LC-MS (Method 3): t R = 1.13 min, m / z(M+H) + =414.1.

[1088] Step 7. N-(cyanomethyl)-4-(2-((1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (84)

[1089] Using a similar preparation procedure to step four of Example 1, compound 84 (14 mg) was synthesized in 21% yield using 84 g (50 mg, 0.12 mmol) and 2-aminoacetonitrile hydrochloride (55 mg, 0.6 mmol) as starting materials. LC-MS (Method 1): t R = 3.42 min, m / z(M+H) + =452.2. 1 H NMR (400MHz, CD3OD) δ8.34 (s, 1H), 8.03-8.01 (m, 3H), 7.83 (d, J = 8.4Hz, 2H), 7.65(s,1H),4.39(s,2H),4.34-4.30(m,1H),2.28(s,3H),2.21-1.99(m,8H). 19 F NMR (376MHz, CD3OD) δ-95.69,-96.32,-102.62,-103.25.

[1090] Example 85

[1091]

[1092] (S)-N-(1-cyanoethyl)-4-(2-((1-(4,4-difluorocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (85)

[1093] Using a similar preparation procedure to step four of Example 1, compound 85 (32 mg) was synthesized in 36% yield using 84 g (80 mg, 0.19 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (94 mg, 0.38 mmol) as starting materials. LC-MS (Method 1): t R = 3.61 min, m / z(M+H) + =466.2. 1 H NMR (400MHz, CD3OD) δ8.32-8.31(m,1H),8.00-7.99(m,3H),7.78-7.76(m,2H),7.61-7.59(m, 1H),5.09-5.05(m,1H),4.28-4.27(m,1H),2.23(s,3H),2.23-1.96(m,8H),1.67-1.63(m,3H). 19F NMR (376MHz, CD3OD) δ -91.65, -92.28, -98.76, -99.34 (m, CF2).

[1094] Examples 86 and 87

[1095]

[1096] Step 1. Methyl 4-(2-((1-(4-cyanocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (86b)

[1097] Using a similar preparation procedure to the second step of Example 81, compound 86b (55 mg) was synthesized in 16% yield using 86a (250 mg, 0.81 mmol) and 4-cyanocyclohexyl methanesulfonate (328 mg, 1.6 mmol) as starting materials. LC-MS (Method 3): t R = 1.57 min, m / z(M+H) + =417.1.

[1098] Step 2. 4-(2-((1-(4-cyanocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (86c)

[1099] Using a similar preparation procedure to step 3 of Example 3, compound 86c (53 mg) was synthesized in 100% yield using 86b (55 mg, 0.13 mmol) as the starting material. LC-MS (Method 3): t R = 1.11 min, m / z(M+H) + =403.2.

[1100] Step 3. 4-(2-((1-(cis-4-cyanocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (86) and 4-(2-((1-(trans-4-cyanocyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(2,2,2-trifluoroethyl)benzamide (87)

[1101] Using a similar preparative procedure to step four of Example 1, compounds 86 (3.5 mg) and 87 (3.6 mg) were synthesized in 12% yields using 86c (50 mg, 0.12 mmol) and 2,2,2-trifluoroethylamine (15 mg, 0.15 mmol) as starting materials. The residues were purified by preparative TLC (DCM / MeOH = 10 / 1) to give the title compound.

[1102] 86: LC-MS (Method 1): t R = 3.77 min, m / z(M+H) + =484.2. 1 H NMR(400MHz,CD3OD)δ8.24(s,1H),7.97(s,1H),7.91-7.89(m,2H),7.72(s,2H),7.49(s, 1H),4.04-4.02(m,3H),3.04(s,1H),2.24(s,3H),2.17-2.01(m,6H),1.82-1.75(m,2H).

[1103] 87: LC-MS (Method 1): t R = 3.78 min, m / z(M+H) + =484.2. 1 H NMR(400MHz,CD3OD)δ8.22(s,1H),7.90-7.77(m,3H),7.69-7.67(m,2H),7.50(s,1H),4.07 -4.03(m,3H),2.60(s,1H),2.14(s,3H),2.07-1.94(m,2H),1.78-1.63(m,4H),1.20(m,2H).

[1104] Example 88

[1105]

[1106] (S)-4-(5-chloro-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanopropyl)benzamide (88)

[1107] Using a similar preparation procedure to step four of Example 1, compound 88 (200.2 mg) was synthesized in 43% yield using 43b (400 mg, 0.96 mmol) and (S)-2-aminobutyronitrile (122 mg, 1.45 mmol) as starting materials. LC-MS (Method 1): t R = 3.09 min, m / z(M+H) + =479.2. 1H NMR (400MHz, DMSO-d6) δ9.82(s,1H),9.27(d,J=7.6Hz,1H),8.58(s,1H),8.03(d,J=8.4Hz,2H),7.92-7.88(m,3H),7.56(s,1H),4.91( q,J=7.6Hz,1H),4.10-4.01(m,1H),2.83(d,J=11.2Hz,2H),2.19(s,3H),2.07-2.02(m,2H),2.00-1.85(m,6H),1.03(t,J=7.2Hz,3H).

[1108] Example 89

[1109]

[1110] Step 1. 1-Cyclohexyl-4-nitro-1H-pyrazole (89b)

[1111] 4-Nitro-1H-pyrazole (3.39 g, 30 mmol), compound 89a (3 g, 30 mmol), PPh3 (11.8 g, 45 mmol), and DIAD (9.1 g, 45 mmol) were dissolved in THF (40 mL). The resulting mixture was stirred overnight at RT. The mixture was concentrated to dryness. The crude product was purified by silica gel chromatography (eluent: PE:EtOAc = 5:1) to give the desired product (2 g, 34% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.89(s,1H),8.24(s,1H),4.27-4.19(m,1H),2.04-1.98(m,2H),1.83-1.63(m,5H),1.44-1.32(m,2H),1.25-1.20(m,1H).

[1112] Step 2. 1-Cyclohexyl-1H-pyrazole-4-amine (89c)

[1113] Compound 89b (2 g, 10 mmol), Fe (1.68 g, 30 mmol), and NH4Cl (2.65 g, 50 mmol) were suspended in a mixture of EtOH and H2O (45 mL, V:V = 8:1). The resulting mixture was stirred at 85 °C for 3 hrs. After cooling to RT, the mixture was filtered and the filtrate was concentrated to dryness to give a crude product (1.7 g, 100% yield) as a black solid. 1HNMR(400MHz,DMSO-d6)δ7.18(s,1H),6.98(s,1H),3.96-3.90(m,1H),1.94-1.90( m,2H),1.79-1.74(m,2H),1.65-1.58(m,3H),1.39-1.29(m,2H),1.21-1.15(m,1H).

[1114] Step 3. Methyl 4-(2-((1-cyclohexyl-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (89d)

[1115] Compounds 1b (300 mg, 1.14 mmol), 89c (376 mg, 2.28 mmol), and concentrated H₂SO₄ (one drop) were dissolved in n-BuOH (10 mL). The mixture was stirred overnight at 120 °C. After cooling to RT, the reaction mixture was concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 2:1) to give a product as a yellow solid (250 mg, 56% yield). 1 H NMR (400MHz, DMSO-d6) δ9.39(s,1H),8.38(s,1H),8.09(d,J=8.0Hz,2H),7.86(s,1H),7.82(d,J=8.0Hz,2H),7.52(s,1H),4.08-4.02(m,1H ),3.90(s,3H),2.19(s,3H),1.97(d,J=10.8Hz,2H),1.78(d,J=12.8Hz,2H),1.64(d,J=12.0Hz,2H),1.46-1.31(m,3H),0.98-0.94(m,1H).

[1116] Step 4. 4-(2-((1-cyclohexyl-1H-pyrazole-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (89e)

[1117] NaOH (128 mg, 3.20 mmol) was added in a single addition to a solution of 89d (250 mg, 0.64 mmol) in MeOH and H₂O (6 mL, V:V = 1:1). The mixture was stirred at 50 °C for 0.5 h. The reaction mixture was diluted with H₂O (5 mL) and extracted with EtOAc (10 mL * 2). The aqueous phase was adjusted to pH = 3 with an aqueous HCl solution (1 N). The formed solid was filtered and dried to give a crude product (200 mg, 83% yield) as a yellow solid. LC-MS (Method 3): t R = 1.18 min, m / z(M+H) + =378.1.

[1118] Step 5. (S)-N-(1-cyanoethyl)-4-(2-((1-cyclohexyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (89)

[1119] Using a similar preparation procedure to step four of Example 1, compound 89 (51 mg) was synthesized in 56% yield using 89e (80 mg, 0.21 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (57 mg, 0.24 mmol) as starting materials. LC-MS (Method 1): t R = 3.73 min, m / z(M+H) + =430.2. 1 H NMR (400MHz, DMSO-d6) δ9.36 (s, 1H), 9.25 (d, J = 6.8Hz, 1H), 8.37 (s, 1H), 8.01 (d, J=8.4Hz,2H),7.85(s,1H),7.79(d,J=8.4Hz,2H),7.52(s,1H),5.02(t,J=7.6Hz, 1H),4.01-4.07(m,1H),2.19(s,3H),1.98(d,J=10.8Hz,2H),1.79(d,J=13.2Hz,2 H),1.60-1.70(m,3H),1.57(d,J=7.2Hz,3),1.33-1.43(m,2H),1.17-1.24(m,1H).

[1120] Examples 90 and 91

[1121]

[1122] Step 1. 1-(4-methoxycyclohexyl)-4-nitro-1H-pyrazole (90a)

[1123] MsCl (664 mg, 5.77 mmol) was added to a mixture of 4-methoxycyclohexanol (500 mg, 3.85 mmol) and Et3N (1.2 g, 11.5 mmol) in DCM (5 mL) at 0 °C. The mixture was stirred at RT for 2 hrs. The reaction mixture was then diluted with water (5 mL) and extracted with DCM (5 mL x 3). The separated organic layer was washed with brine (5 mL), dried on Na2SO4, and filtered. The filtrate was concentrated to give 4-methoxycyclohexyl methanesulfonate (600 mg crude, 75% yield).

[1124] 4-Methoxycyclohexyl methanesulfonate (167 mg, 1.48 mmol), 4-nitro-1H-pyrazole (400 mg, 1.92 mmol), and K₂CO₃ (612 mg, 4.44 mmol) were dissolved in DMF (1 mL). The mixture was stirred at 100 °C for 1 hour. After cooling to RT, the mixture was diluted with water (1 mL) and extracted with EtOAc (5 mL x 3). The separated organic layer was washed with brine (5 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated to dryness. The residue was purified by FCC (petroleum ether:EtOAc = 5:1) to give the desired compound as a yellow solid (220 mg, 62% yield). LC-MS (Method 3): t R = 1.44 min, m / z(M+H) + =226.1.

[1125] Step 2. 1-(4-methoxycyclohexyl)-1H-pyrazole-4-amine (90b)

[1126] Compound 90a (220 mg, 0.97 mmol) and Pd / C (50 mg, palladium 10% on carbon, wetted with 55% water) were suspended in MeOH (20 mL). The resulting mixture was stirred at 40 °C for 12 hours under a H2 atmosphere (50 psi). The reaction mixture was filtered and the filtrate was concentrated to dryness, giving a crude product as a red solid (220 mg, 100% yield). LC-MS (Method 3): t R =1.00min, m / z(M+H) + =196.1.

[1127] Step 3. Methyl 4-(2-((1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (90c)

[1128] Compounds 90b (120 mg, 0.61 mmol), 1b (108 mg, 0.41 mmol), and TsOH (7 mg, 0.04 mmol) were dissolved in n-butanol (3 mL). The reaction mixture was stirred overnight at 120 °C. The reaction mixture was concentrated to dryness and purified by silica gel column chromatography (PE:EtOAc = 4:1) to give a crude product as a yellow solid (90 mg, 52% yield). LC-MS (Method 3): t R = 1.67 min, m / z(M+H) + =422.2.

[1129] Step 4. 4-(2-((1-(4-methoxycyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (90d)

[1130] Compound 90c (90 mg, 0.21 mmol) and LiOH·H₂O (45 mg, 1.06 mmol) were dissolved in a mixture of THF and H₂O (6 mL, V:V = 1:1). The resulting mixture was stirred overnight at RT. The reaction mixture was extracted with EtOAc (10 mL). The separated aqueous layer was acidified to pH 4.0 with an aqueous solution of HCl (1 N). The mixture was then extracted with EtOAc (10 mL * 3). The organic layer was washed with water (10 mL). The separated organic phase was concentrated to dryness, giving a crude product (65 mg, 76% yield) as a yellow solid. LC-MS (Method 3): t R = 1.24 min, m / z(M+H) + =408.2.

[1131] Step 5. N-((S)-1-cyanoethyl)-4-(2-((1-(cis-4-methoxycyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (90) and N-((S)-1-cyanoethyl)-4-(2-((1-(trans-4-methoxycyclohexyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (91)

[1132] Using a similar preparative procedure to step four of Example 1, compounds 90 (4 mg) and 91 (5.2 mg) were synthesized in yields of 5% and 7% using 90d (65 mg, 0.16 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (78 mg, 0.32 mmol) as starting materials. They were purified by preparative HPLC (Method A).

[1133] 90: LC-MS (Method 1): t R = 3.61 min, m / z(M+H) + =460.3. 1 H NMR (400MHz, CD3OD) δ8.21(s,1H),7.90-7.88(m,3H),7.68(d,J=6.8Hz,2H),7.46(s,1H),4.97(q,J=7.2Hz,1H),4.04-3.98(m,1H),3.39(br s,1H),3.23(s,3H),2.13(s,3H),1.96-1.90(m,4H),1.76-1.74(m,2H),1.56(d,J=7.2Hz,3H),1.50-1.47(m,2H).

[1134] 91: LC-MS (Method 1): tR = 3.52 min, m / z(M+H) + =460.2. 1 H NMR (400MHz, CD3OD) δ8.33(s,1H),8.02-7.97(m,3H),7.79(d,J=8.0Hz,2H),7.61(s,1H),5.09(q,J=7.2Hz,1H),4.15-4.09(m,1 H),3.39(s,3H),3.27-3.24(m,1H),2.25(s,3H),2.23-2.13(m,4H),1.89-1.80(m,2H),1.68(d,J=7.2Hz,3H),1.44-1.35(m,2H).

[1135] Example 92

[1136]

[1137] Step 1. Methyl 4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (92a)

[1138] Iodimethane (165.2 mg, 1.214 mmol) and K₂CO₃ (646 mg, 4.68 mmol) were sequentially added to a mixture of 3a (500 mg, 0.934 mmol) in DMF (5 mL). The mixture was stirred at 60 °C for 16 hrs. After cooling, the mixture was cooled and diluted with EtOAc. The mixture was washed with water and separated. The organic layer was concentrated. The residue was purified by preparative TLC (eluent: DCM:MeOH = 10:1) to give the desired product (82 mg, 22% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.31(s,1H),8.16(d,J=8.4Hz,2H),7.92(s,1H),7.68(d,J=8.4Hz,2H),7.52(s,1H),6.78(s, 1H),4.13(s,1H),3.97(s,3H),3.52-3.49(m,2H),3.04-3.01(m,2H),2.34(s,3H),2.27(s,3H),2.24-2.06(m,4H).

[1139] Step 2. 4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (92b)

[1140] To a solution of 92a (60 mg, 0.148 mmol) in MeOH and H₂O (4 mL, V:V = 3:1), NaOH (8.9 mg, 0.221 mmol) was added. The mixture was stirred at RT for 3 hours. The mixture was adjusted to pH 6-7 with 10% aqueous HCl and filtered to give the title product as a yellow solid (116 mg, 100% yield). LC-MS (Method 3): t R = 1.049 min, m / z(M+H) + =393.2.

[1141] Step 3. 1-(4-(5-methyl-2-((1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (92)

[1142] Compound 92b (116 mg, 0.296 mmol), aziridine-3-carboxynitrile hydrochloride (35 mg, 0.296 mmol), HATU (169 mg, 0.444 mmol), and DIEA (153 mg, 1.184 mmol) were dissolved in DMF (4 mL). The mixture was stirred at 30 °C for 2 hours. The mixture was concentrated, and the residue was purified by preparative HPLC (Method A) to give the title product (8.5 mg, 6% yield) as a yellow solid. LC-MS (Method 3): t R = 2.782 min, m / z(M+H) + =457.0; 1 H NMR(400MHz,CD3OD)δ8.31(s,1H),8.00(s,1H),7.78(s,4H),7.59(s,1H),4.77(s,2H),4.65(s,1H),4.52(s, 1H), 4.11 (s, 1H), 3.81 (t, J = 7.6Hz, 1H), 2.98 (d, J = 11.2Hz, 2H), 2.32 (s, 3H), 2.23 (s, 5H), 2.08-2.01 (m, 4H).

[1143] Example 93

[1144]

[1145] Step 1. Methyl 4-[2-(1-cyclopropyl-1H-pyrazole-4-ylamino)-5-methylpyrimidin-4-yl]-benzoate (93a)

[1146] Using a similar preparation procedure to the second step of Example 1, compound 93a (784 mg) was synthesized in 30% yield using 1b (2.0 g, 7.6 mmol) and 1-cyclopropyl-1H-pyrazole-4-amine (935 mg, 7.6 mmol) as starting materials. LC-MS (Method 3): t R = 1.562 min, m / z(M+H) + =350.1.

[1147] Step 2. 4-[2-(1-cyclopropyl-1H-pyrazol-4-ylamino)-5-methyl-pyrimidin-4-yl]-benzoic acid (93b)

[1148] Using a preparation procedure similar to the third step of Example 1, compound 93b (747 mg) was synthesized in 100% yield using 93a (780 mg, 2.23 mmol) as the starting material. 1 H NMR (400MHz, DMSO-d6) δ9.67 (s, 1H), 8.44 (s, 1H), 8.11 (d, J = 10.8Hz, 2H), 7.96 (s, 1H), 7.84(d,J=10.4Hz,2H),7.53(s,1H),3.73-3.68(m,1H),2.23(s,3H),1.05-0.91(m,4H).

[1149] Step 3. N-((1-cyanocyclopropyl)methyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (93)

[1150] Using a similar preparation procedure to step four of Example 1, compound 93 (38.9 mg) was synthesized in 45% yield using 93b (70 mg, 0.21 mmol) and 1-aminomethyl-cyclopropaneformonitrile (68 mg, 0.83 mmol) as starting materials. LC-MS (Method 1): t R = 3.327 min, m / z(M+H) + =414.0; 1H NMR (400MHz, CDCl3) δ8.31(s,1H),7.92(d,J=8.4Hz,2H),7.88(s,1H),7.71(d,J=8.4Hz,2H),7.46(s,1H),7.04(s,1H),6.87(s,1H) ,3.62(d,J=6.4Hz,2H),3.57-3.55(m,1H),2.24(s,3H),1.35-1.32(m,2H),1.24-1.23(m,2H),1.12-1.11(m,2H),1.00-0.98(m,2H).

[1151] Example 94

[1152]

[1153] (S)-N-(1-Cyanoethyl)-4-(2-((1-Cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (94)

[1154] Using a similar preparative procedure to step four of Example 1, compound 94 (24.3 mg) was synthesized in 26% yield using 93b (60 mg, 0.18 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (87 mg, 0.36 mmol) as starting materials. The title compound was purified by preparative HPLC (Method A). LC-MS (Method 1): t R = 3.28 min, m / z(M+H) + =388.2; 1 H NMR (400MHz, DMSO-d6) δ9.42(s,1H),9.27(d,J=7.2Hz,1H),8.38(s,1H),8.01(d,J=8.0Hz,2H),7.90(s,1H),7.80(d,J =7.2Hz,2H),7.47(s,1H),5.04-4.99(m,1H),3.67-3.63(m,1H),2.19(s,3H),1.57(d,J=7.2Hz,3H),0.97-0.90(m,4H).

[1155] Example 95

[1156]

[1157] 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide (95)

[1158] Using a similar preparation procedure to step four of Example 1, compound 95 (23.3 mg) was synthesized in 42% yield using 60b (50 mg, 0.14 mmol) and 2-aminoacetonitrile hydrochloride (26 mg, 0.28 mmol) as starting materials. LC-MS (Method 1): t R = 8.86 min, m / z(M+H) + =394.1; 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.35(t,J=5.2Hz,1H),8.59(s,1H),8.02(d,J=8.0Hz,2H) ,7.98-7.90(m,3H),7.49(s,1H),4.36(d,J=5.2Hz,2H),3.67-3.66(m,1H),0.98-0.91(m,4H).

[1159] Example 96

[1160]

[1161] Step 1. (R)-N-(1-cyanoethyl)-4-(5-methyl-2-((1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (96)

[1162] Using a similar preparation procedure to step four of Example 1, compound 96 (12.5 mg) was synthesized in 15% yield using 75b (75 mg, 0.20 mmol) and (R)-2-aminopropionitrile 4-methylbenzenesulfonate (53 mg, 0.218 mmol) as starting materials. LC-MS (Method 1): t R = 3.38 min, m / z(M+H) + =432.2. 1 H NMR (400MHz, DMSO-d6) δ9.41(s,1H),9.27(d,J=7.2Hz,1H),8.38(s,1H),8.01(d,J=8.0Hz,2H),7.90(s,1H),7.80(d,J=8.0Hz,2H),7.55(s,1H ),5.02(t,J=7.6Hz,1H),4.37-4.29(m,1H),3.93(d,J=11.2Hz,2H),3.47-3.41(m,2H),2.19(s,3H),1.92-1.87(m,4H),1.57(d,J=7.2Hz,3H).

[1163] Example 97

[1164]

[1165] (R)-4-(5-chloro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (97)

[1166] Using a similar preparation procedure to step four of Example 1, compound 97 (45 mg) was synthesized in 56% yield using 2b (70 mg, 0.21 mmol) and (R)-2-aminopropionitrile 4-methylbenzenesulfonate (103 mg, 0.42 mmol) as starting materials. LC-MS (Method 1): t R = 3.26 min, m / z(M+H) + =382.1. 1 H NMR(400MHz,DMSO-d6)δ9.84(s,1H),9.29(d,J=6.8Hz,1H),8.58(s,1H),8.03(d,J=8.0Hz, 2H),7.99-7.83(m,3H),7.51(s,1H),5.04-5.01(m,1H),3.80(s,3H),1.57(d,J=6.8Hz,3H).

[1167] Example 98

[1168]

[1169] Step 1.2, 2-Dimethyl-1-(4-(4-nitro-1H-pyrazol-1-yl)piperidin-1-yl)propane-1-one (98b)

[1170] Neopentanoyl chloride (2.33 g, 19.35 mmol) was added to a solution of 98a (3.0 g, 12.9 mmol) and TEA (3.9 g, 38.7 mmol) in DCM (30 mL) at 0 °C. The mixture was stirred overnight at RT. The mixture was diluted with DCM (100 mL) and H2O (30 mL). The separated organic phase was dried on Na2SO4 and filtered. The filtrate was concentrated under vacuum to give the title compound (4.0 g, 100% yield) as a white solid. LC-MS (Method 1): t R = 1.48 min, m / z(M+H) + =281.2.

[1171] Step 2. 1-(4-(4-amino-1H-pyrazol-1-yl)piperidin-1-yl)-2,2-dimethylpropane-1-one (98c)

[1172] Compound 98b (4.0 g, 12.9 mmol) and Pd / C (600 mg, 10% carbon-supported palladium, wetted with 55% water) were suspended in MeOH (40 mL). The resulting mixture was stirred overnight at RT under H2 (50 psi). The mixture was filtered and the filtrate was concentrated under vacuum. The residue was purified by reversed-phase chromatography (5 to 95% ACN in water) to give the title compound as a red oil (1.4 g, 44% yield). LC-MS (Method 1): t R = 1.15 min, m / z(M+H) + =251.2.

[1173] Step 3. Methyl 4-(5-chloro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (98d)

[1174] Using a similar preparation procedure to the second step of Example 1, compound 98d (200 mg) was synthesized in 11% yield using 98c (300 mg, 1.06 mmol) and 34b (338 mg, 1.06 mmol) as starting materials. LC-MS (Method 1): t R = 1.72 min, m / z(M+H) + =497.0.

[1175] Step 4. 4-(5-chloro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (98e)

[1176] Using a similar preparation procedure to step three of Example 3, compound 98e (171 mg) was synthesized in 100% yield using 98d (180 mg, 0.36 mmol) as the starting material. LC-MS (Method 1): t R = 1.15 min, m / z(M+H) + =483.0.

[1177] Step 5. 4-(5-chloro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(cyanomethyl)benzamide (98)

[1178] Using a similar preparation procedure to step four of Example 1, compound 98 (16.1 mg) was synthesized in 16% yield using 98e (95 mg, 0.20 mmol) and 2-aminoacetonitrile hydrochloride (22 mg, 0.24 mmol) as starting materials. LC-MS (Method 1): t R = 4.93 min, m / z(M+H)+ =521.2. 1 H NMR (400MHz, DMSO-d6) δ9.85 (s, 1H), 9.36 (s, 1H), 8.58 (s, 1H), 8.02 (d, J = 8.0Hz, 2H), 7.93 (s, 3H), 7.56 ( s, 1H), 4.37 (s, 5H), 2.95 (t, J = 12.4Hz, 2H), 2.02 (d, J = 11.2Hz, 2H), 1.73 (d, J = 10.4Hz, 2H), 1.21 (s, 9H).

[1179] Example 99

[1180]

[1181] (S)-4-(5-chloro-2-((1-(1-neovalerylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (99)

[1182] Using a similar preparation procedure to step four of Example 1, compound 99 (21.3 mg) was synthesized in 19% yield using 98e (95 mg, 0.20 mmol) and (S)-2-aminopropionitrile 4-methylbenzenesulfonate (57 mg, 0.24 mmol) as starting materials. LC-MS (Method 1): t R = 4.42 min, m / z(M+H) + =535.2. 1 H NMR (400MHz, DMSO-d6) δ9.85(s,1H),9.29(d,J=7.2Hz,1H),8.58(s,1H),8.02(d,J=8.4Hz,2H),7.92(s,3H),7.56(s,1H),5.02(t,J=7.2Hz 1H), 4.43-4.34 (m, 3H), 2.95 (t, J = 12.0Hz, 2H), 2.02 (d, J = 11.2Hz, 2H), 1.73 (d, J = 11.2Hz, 2H), 1.57 (d, J = 7.2Hz, 3H), 1.21 (s, 9H).

[1183] Example 100

[1184]

[1185] Step 1. Methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-fluorobenzoate (100b)

[1186] Compound 100b was synthesized in 85% yield using a similar preparative procedure to the first step of Example 1, with 1a and (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid as starting materials. LC-MS (Method 1): t R = 1.55 min, m / z(M+H) + =281.1.

[1187] Step 2. Methyl 2-fluoro-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (100c)

[1188] Using a similar preparation procedure to the second step of Example 1, compound 100c was synthesized in 60% yield using 100b and 1-methyl-1H-pyrazole-4-amine as starting materials. LC-MS (Method 3): t R = 1.46 min, m / z(M+H) + =342.2.

[1189] Step 3. 2-F-fluoro-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (100d)

[1190] Using a preparation procedure similar to step three of Example 1, compound 100d was synthesized in 100% yield using 100c and NaOH as starting materials. LC-MS (Method 1): t R = 1.03 min, m / z(M+H) + =328.1.

[1191] Step 4. N-(cyanomethyl)-2-fluoro-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (100)

[1192] Using a similar preparation procedure to step four of Example 1, compound 100 was synthesized in 38% yield using 100d and 2-aminoacetonitrile hydrochloride as starting materials. LC-MS (Method 1): t R = 2.97 min, m / z(M+H) + =365.9. 1 HNMR(400MHz,DMSO-d6)δ9.42(s,1H),9.12-9.10(m,1H),8.39(s,1H),7.84-7.81(m, 2H),7.64-7.60(m,2H),7.48(s,1H),4.35(d,J=5.2Hz,2H),3.78(s,3H),2.20(s,3H); 19F NMR(376MHz,DMSO-d6)δ-113.31.

[1193] Example 101

[1194]

[1195] Step 1. (R)-(1-Cyanoethyl)carbamate tert-butyl ester (101b)

[1196] POCl3 (50 mL) was added to a mixture of 101a (5.0 g, 26.56 mmol) in DMF (50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 2 hours and then quenched with H2O (1500 mL). The solution was extracted with DCM (1000 mL * 2). The combined organic layers were concentrated under vacuum, and the residue was purified by column chromatography on silica gel (eluent: PE:EtOAc = 5:1) to give the desired product as a white solid (1.97 g, 44% yield). 1 H NMR (400MHz, DMSO-d6) δ7.72 (d, J = 5.6 Hz, 1H), 4.48-4.51 (m, 1H), 1.41 (s, 9H), 1.37 (d, J = 7.2 Hz, 3H).

[1197] Step 2. (R)-2-aminopropionitrile (101c)

[1198] TFA (0.5 mL, 6.732 mmol) was added to a mixture of 101c (66 mg, 0.388 mmol) in DCM (2 mL). The mixture was stirred at RT for 2 hours and then concentrated to dryness to give a crude product (65 mg, 100%) as a brown oil, which was used directly in the next step without purification.

[1199] Step 3. (R)-N-(1-cyanoethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (101)

[1200] Using a similar preparation procedure to step four of Example 1, compound 101 (27.1 mg) was synthesized in 29% yield using 2b (80 mg, 0.26 mmol) and 101c (44 mg, 0.26 mmol) as starting materials. LC-MS (Method 1): t R = 3.038 min, m / z(M+H) + =362.1; 1H NMR (400MHz, DMSO-d6) δ9.42(s,1H),9.29(d,J=7.2Hz,1H),8.38(s,1H),8.01(d,J=7.6Hz,2H),7. 79-7384(m,3H),7.49(s,1H),5.01-5.05(m,1H),3.79(s,3H),2.20(s,3H),1.57(d,J=7.2Hz,3H).

[1201] Example 102

[1202]

[1203] Step 1. 4-(4-((4-(4-(3-cyanozylidene-1-carbonyl)phenyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylic acid tert-butyl ester (102a)

[1204] Compound 102a was synthesized in 57% yield using a preparation procedure similar to step four of Example 1, with 1d and aziridine-3-carboxynitrile hydrochloride as starting materials. LC-MS (Method 1): t R = 3.706 min, m / z(M+H) + =543.1; 1 H NMR(400MHz,DMSO-d6)δ9.41(s,1H),8.37(s,1H),7.89(s,1H),7.77(s,4H),7.54(s,1H),4.63-4.58(m,2H),4.38-4.22(m,3H) ,4.02-3.96(m,2H),3.91-3.83(m,1H),2.96-2.82(m,2H),2.20(s,3H),1.96(d,J=10.8Hz,2H),1.76-1.67(m,2H),1.41(s,9H).

[1205] Step 2. 1-(4-(5-methyl-2-((1-(piperidin-4-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonite hydrochloride (102b)

[1206] A mixture of 102a (100 mg, 0.18 mmol) in EtOAc (5 mL) was added to a solution of HCl (g) in EtOAc (4 N, 3 mL) at 0 °C. The mixture was stirred at this temperature for 2 hours. The mixture was then concentrated under vacuum at 0–5 °C to give the desired product (150 mg, crude product) as a yellow solid. LC-MS (Method 1): t R= 1.299 min, m / z(M+H) + =443.1.

[1207] Step 3. 1-(4-(2-((1-(1-acetylpiperidin-4-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (102)

[1208] Compound 102b (150 mg, crude, 0.18 mmol), acetic anhydride (18 mg, 0.18 mmol), and TEA (91 mg, 0.9 mmol) were dissolved in DMF (1 mL). The mixture was stirred at RT for 3 hours. The mixture was concentrated under vacuum. The residue was purified by preparative HPLC (Method A) to give the title product (17 mg, 20% yield) as a yellow solid. LC-MS (Method 1): t R = 3.450 min, m / z(M+H) + =485.0; 1 H NMR(400MHz, CDCl3)δ8.32(s,1H),7.89(s,1H),7.74-7.68(m,4H),7.53(s,1H) ),6.80(s,1H),4.71(d,J=12.8Hz,1H),4.60-4.47(m,4H),4.34-4.26(m,1H), 3.94(d,J=14.0Hz,1H),3.64-3.59(m,1H),3.23(t,J=12.0Hz,1H),2.77(t,J= 11.2Hz,1H),2.24(s,3H),2.20-2.13(m,2H),2.10(s,3H),2.01-1.91(m,2H).

[1209] Example 103

[1210]

[1211] 1-(2-fluoro-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoyl)azacyclobutane-3-carboxylonitrile (103)

[1212] Using a similar preparation procedure to step four of Example 1, compound 103 was synthesized in 35% yield using 100 d and aziridine-3-carboxynitrile hydrochloride as starting materials. LC-MS (Method 1): t R = 8.81 min, m / z(M+H) + =392.0. 1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.38(s,1H),7.82(s,1H),7.68(t,J=8.0Hz,1H),7.62 -7.58(m,2H),7.48(s,1H),4.37-4.24(m,4H),3.90-3.86(m,1H),3.78(s,3H),2.21(s,3H); 19 F NMR (376MHz, DMSO-d6) δ-114.27.

[1213] Example 104

[1214]

[1215] Step 1. 2-(benzoxy)-5,8-dioxaspiro[3,4]octane (104b)

[1216] A mixture of 104a (3.9 g, 22.1 mmol), ethylene glycol (1.65 g, 26.52 mol), p-toluenesulfonic acid (42 mg, 0.22 mmol), and toluene (50 mL, anhydrous) was placed in a 250 mL round-bottom flask equipped with a Dean-Stark apparatus. The reaction mixture was heated to 140 °C for 40 hours and azeotropically removed water. After water collection ceased, the mixture was cooled to RT, concentrated, and the residue was purified by silica gel chromatography (5% ethyl acetate in petroleum ether) to give the product (1.29 g, 26%) as a light brown oil. 1 H NMR (400MHz, CDCl3) δ7.39-7.27(m,5H),4.43(s,2H),4.02-2.94(m,1H),3.87(s,4H),2.60-2.52(m,2H),2.42-2.34(m,2H).

[1217] Step 2.5, 8-Dioxaspiro[3.4]oct-2-ol (104c)

[1218] A mixture of 104b (1.29 g, 5.86 mmol), carbon-supported palladium (250 mg, 10% wt.), and carbon-supported palladium hydroxide (250 mg, 20% wt.) in methanol (20 mL) was stirred at 50 °C for 48 hours under a hydrogen atmosphere at 50 psi. The mixture was filtered and the filtrate was concentrated to give the desired product (760 mg, 100% yield) as a colorless oil. 1 H NMR (400MHz, CDCl3) δ4.30-2.20(m,1H),3.88(s,4H),2.70-2.61(m,2H),234-2.27(m,2H).

[1219] Step 3. 4-Nitro-1-(5,8-dioxaspiro[3.4]oct-2-yl)-1H-pyrazole (104d)

[1220] Under a nitrogen atmosphere, DIAD (1.33 g, 6.57 mmol) was slowly added to a solution of 104c (570 mg, 4.38 mmol), 4-nitro-1H-pyrazole (496 mg, 4.38 mmol), and PPh3 (1.73 g, 6.57 mmol) in dichloromethane (15 mL) at 0 °C. The mixture was slowly heated to room temperature and stirred for 16 hours. The mixture was concentrated to dryness and purified by silica gel column chromatography (10% ethyl acetate in petroleum ether) to give the desired product as a white solid (600 mg, 61% yield). LC-MS (Method 3): t R = 1.380 min, m / z(M+H) + =226.1.

[1221] Step 4. 1-(5,8-dioxaspiro[3.4]oct-2-yl)-1H-pyrazole-4-amine (104e)

[1222] A mixture of 104 d (600 mg, 2.67 mmol) and carbon-supported palladium (250 mg, 10% wt.) in ethanol (16 mL) was stirred at room temperature for 1 hour under a hydrogen atmosphere (50 psi). The mixture was filtered and the filtrate was concentrated to dryness to give the desired product (520 mg, 100% yield) as a black solid. LC-MS (Method 3): t R = 0.561 min, m / z(M+H) + =196.1.

[1223] Step 5. Methyl 4-(2-((1-(5,8-dioxaspiro[3.4]oct-2-yl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (104f)

[1224] Compounds 104e (490 mg, 2.51 mmol), 1b (550 mg, 2.10 mmol), tris(diphenylmethylacetone)palladium (192 mg, 0.21 mmol), xphos (200 mg, 0.42 mmol), and cesium carbonate (1.37 g, 4.2 mmol) were dissolved in dioxane (20 mL). The mixture was stirred at 110 °C for 4 hours under a nitrogen atmosphere. The mixture was concentrated and purified by silica gel column chromatography (2% methanol in dichloromethane) to give the desired product as a yellow-brown solid (590 mg, 66% yield). LC-MS (Method 3): t R= 1.444 min, m / z(M+H) + =422.2. 1H NMR (400MHz, CDCl3) δ8.31 (s, 1H), 8.15 (d, J = 8.4Hz, 2H), 7.97 (s, 1H), 7.69 (d, J = 8.0Hz, 2H), 7.54 (s, 1H), 6.88 (br s,1H),4.67-4.58(m,1H),4.00-3.91(m,7H),2.99-2.80(m,4H),2.23(s,3H).

[1225] Step 6. Methyl 4-(5-methyl-2-((1-(3-oxocyclobutyl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (104g)

[1226] Hydrochloric acid (2N, 6 mL) was added dropwise to a solution of 10⁴e (545 mg, 1.29 mmol) in acetonitrile (6 mL) at room temperature. The mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with a saturated aqueous solution of Na₂CO₃ (30 mL). The mixture was extracted with dichloromethane (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The residue was purified by silica gel column chromatography (2% methanol in dichloromethane) to give the desired product as a yellow solid (321 mg, 66% yield). LC-MS (Method 3): t R = 1.392 min, m / z(M+H) + =378.1.

[1227] Step 7. Methyl 4-(2-((1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoate (104h)

[1228] DAST (197 mg, 1.22 mmol) was slowly added to a solution of 104 g (230 mg, 0.61 mmol) in dichloromethane (5 mL) at 0 °C. The mixture was stirred at room temperature for 6 hours. The reaction mixture was quenched with a saturated aqueous solution of Na₂CO₃ (30 mL). The mixture was extracted with dichloromethane (30 mL x 3), washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (1% methanol in dichloromethane) to give the desired product as a yellow solid (120 mg, 49% yield). LC-MS (Method 3): t R = 1.682 min, m / z(M+H+H2O) + =418.1.

[1229] Step 8. 4-(2-((1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzoic acid (104j)

[1230] LiOH·H₂O (25 mg, 0.30 mmol) was added to a solution of 120 mg, 0.30 mmol in methanol (2 mL) and H₂O (0.5 mL) for 104 h. The mixture was stirred at room temperature for 6 h. The mixture was concentrated at room temperature, and then H₂O (3 mL) was added. The pH of the mixture was adjusted to 4 with an aqueous HCl solution (0.5 N). The solid was filtered and dried to give the desired product (92 mg, 80% yield) as a yellow-brown solid. LC-MS (Method 3): t R = 1.230 min, m / z(M+H+H2O) + =404.1.

[1231] Step 9. N-(cyanomethyl)-4-(2-((1-(3,3-difluorocyclobutyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)benzamide (104)

[1232] Compound 104j (30 mg, 0.078 mmol), 2-aminoacetonitrile hydrochloride (14 mg, 0.156 mmol), HATU (59 mg, 0.156 mmol), and N,N-diisopropylethylamine (40 mg, 0.312 mmol) were dissolved in DCM (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC (Method A) to give the title product (4.6 mg, 14% yield) as a pale yellow solid. LC-MS (Method 1): t R = 7.035 min, m / z(M+H+H2O) + =442.1. 1 HNMR (400MHz, DMSO-d6) δ9.30(t,J=5.6Hz,1H),8.86(s,1H),8.33(s,1H),7.97(d,J=8.4Hz,2H),7.74(d,J= 8.4Hz,2H),7.65(d,J=2.8Hz,1H),4.91-4.81(m,1H),4.34(d,J=5.2Hz,2H),3.23-3.06(m,4H),2.17(s,3H). 19 F NMR (376MHz, DMSO-d6) δ -82.48 (d, J = 198Hz, 1F), -97.10 (d, J = 195Hz, 1F).

[1233] Example 105

[1234]

[1235] N-(2-(dimethylamino)ethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzamide (105)

[1236] Using a similar preparation procedure to the last step of Example 2, compound 105 was synthesized in 46% yield using 2b and N,N-dimethylethane-1,2-diamine as starting materials. LC-MS (Method 1): t R = 2.94 min, m / z(M+H) + =380.2; 1 H NMR (400MHz, CDCl3) δ8.29(s,1H),7.91(d,J=8.4Hz,2H),7.83(s,1H),7.67(d,J=8.0Hz,2H),7.47(s,1H), 6.96(s,1H),6.86(s,1H),3.87(s,3H),3.58-3.54(m,2H),3.55(t,J=5.6Hz,2H),2.29(s,6H),2.23(s,3H).

[1237] Example 106

[1238]

[1239] Step 1. 3-Cyanocyclobutyl methanesulfonate (106b)

[1240] NaBH4 (600 mg, 15.78 mmol) was added to a solution of 106a (1 g, 10.52 mmol) in tetrahydrofuran (50 mL) at 0 °C. The mixture was stirred at room temperature for 1 hour. The mixture was filtered. Triethylamine (2.12 g, 21.04 mmol) and MsCl (1.45 g, 12.62 mmol) were added to the filtrate. The mixture was stirred at room temperature for 4 hours. The reaction mixture was then quenched with 50 mL of saturated ammonium chloride aqueous solution. The resulting mixture was extracted with dichloromethane (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (PE:EtOAc = 20:1 to 10:1) to give the desired product (440 mg, 24% yield) as a pale yellow oil. 1H NMR (400MHz, CDCl3) δ5.00-4.91(m,0.9H),4.80-4.72(m,0.1H),3.04(s,3H),2.95-2.88(m,2H),2.84-2.76(m,3H).

[1241] Step 2. 4-(2-((1-(3-cyanocyclobutyl)-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-(cyanomethyl)benzamide (106)

[1242] Compound 4f (68 mg, 0.20 mmol), 106b (105 mg, 0.60 mmol), and cesium carbonate (192 mg, 0.60 mmol) were dissolved in DMF (1 mL). The resulting mixture was microwaved at 120 °C for 2 hours. The mixture was filtered. The filtrate was purified by preparative HPLC (Method A) to give the product as a yellow solid (5.2 mg, 6% yield). LC-MS (Method 1): t R =3.488min&3.688min,m / z(M+H) + =413.2; 1 H NMR (400MHz, CDCl3) δ8.44-8.30(m,1.4H),8.00-7.80(m,3.4H),7.74-7.67(m,1.2H) ,7.58-7.49(m,0.8H),7.47-7.33(m,0.8H),7.12(s,0.4H),7.08(s,0.5H),6.96(t,J= 5.6Hz,0.5H),5.05-4.95(m,0.6H),4.89-4.79(m,0.4H),4.43(d,J=5.6Hz,1H),4.34( d,J=0.6Hz,1H),3.32-3.22(m,0.6H),3.10-2.78(m,4.6H),2.33(s,1H),2.24(s,2H).

[1243] Example 107

[1244]

[1245] Step 1. Methyl 4-(5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzoate (107a)

[1246] Using a similar preparation procedure to the second step of Example 1, compound 107a was synthesized in 64% yield using 1b and 1-methyl-1H-pyrazole-3-amine as starting materials. LC-MS (Method 1): tR = 3.41 min, m / z(M+H) + =324.0. 1 HNMR (400MHz, CDCl3) δ8.34(s,1H),8.15(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),7.61(s, 1H), 7.25 (d, J = 6.4Hz, 1H), 6.74 (d, J = 2.0Hz, 1H), 3.96 (s, 3H), 3.81 (s, 3H), 2.25 (s, 3H).

[1247] Step 2. 4-(5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzoic acid (107b)

[1248] Using a preparation procedure similar to step three of Example 1, compound 107b was synthesized in 100% yield using 107a and NaOH as starting materials. LC-MS (Method 1): t R = 2.28 min, m / z (MH) - =308.0.

[1249] Step 3. N-(cyanomethyl)-4-(5-methyl-2-((1-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)benzamide (107)

[1250] Using a similar preparation procedure to step four of Example 1, compound 107 was synthesized in 27% yield using 107b and 2-aminoacetonitrile hydrochloride as starting materials. LC-MS (Method 1): t R = 2.90 min, m / z(M+H) + =348.1. 1 HNMR(400MHz,DMSO-d6)δ9.61(s,1H),9.31(t,J=5.6Hz,1H),8.38(s,1H),7.99(d,J=8.4Hz,2H), 7.78(d,J=8.4Hz,2H),7.50(s,1H),6.57(s,1H),4.35(d,J=5.2Hz,2H),3.72(s,3H),2.19(s,3H).

[1251] Example 108

[1252]

[1253] N-(cyanomethyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-methylpyrimidin-4-yl)-N-methylbenzamide (108)

[1254] Using a similar preparation procedure to step four of Example 1, compound 108 (5 mg) was synthesized in 6% yield using 93b (70 mg, 0.2 mmol) and 2-(methylamino)acetonitrile (82 mg, 1.1 mmol) as starting materials. LC-MS (Method 1): t R = 6.34m / z(M+H) + =388.0. 1 H NMR (400MHz, CD3OD) δ8.35 (s, 1H), 7.99 (s, 1H), 7.83 (d, J = 8Hz, 2H), 7.67 (d, J = 8.4Hz, 2H), 7.59(s,1H),4.58(s,2H),3.62-3.58(m,1H),3.21(s,3H),2.28(s,3H),1.07-1.02(m,4H).

[1255] Example 109

[1256]

[1257] Step 1. (4-Chloro-2-(methylthio)pyrimidin-5-yl)methanol (109b)

[1258] DIBAL-H (172 mL, 257.8 mmol, 1.5 M, in toluene) was added to a solution of 109a (20 g, 85.95 mmol) in THF (300 mL) at -78 °C. The mixture was gradually heated to RT under a N2 atmosphere and stirred for 18 hrs. The reaction mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL x 2). The combined organic layers were washed with brine (500 mL), dried on Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: PE:EtOAc = 5:1) to give the desired product (11.6 g, 71% yield) as a yellow solid. LC-MS (Method 3): t R = 1.177 min, m / z(M+H) + =191.0.

[1259] Step 2. 4-Chloro-2-(methylthio)pyrimidine-5-carboxaldehyde (109c)

[1260] MnO2 (53 g, 608.4 mmol) was gradually added to a mixture of 109b (11.6 g, 60.84 mmol) in chloroform (200 mL) at 0 °C. After stirring at RT for 18 hs under N2 atmosphere, the mixture was filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: PE:EtOAc = 5:1) to give the desired title product (8.5 g, 74% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.93(s,1H),2.61(s,3H).

[1261] Step 3. Methyl 2-fluoro-4-(5-formyl-2-(methylthio)pyrimidin-4-yl)benzoate (109d)

[1262] Compound 109c (4.0 g, 21.2 mmol) was dissolved in a mixture of DME and H₂O (120 mL, V:V = 5:1), followed by the sequential addition of (3-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (4.2 g, 21.2 mmol), Na₂CO₃ (4.5 g, 42.4 mmol), and Pd(Pph₃)₄ (244 mg, 0.21 mmol). The mixture was stirred at 90 °C for 18 hs under a N₂ atmosphere. After cooling to RT, the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 5:1) to give the desired product (2.3 g, 35% yield) as a yellow solid. LC-MS (Method 3): t R = 1.638 min, m / z(M+H) + =307.0.

[1263] Step 4. Methyl 4-(5-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)-2-fluorobenzoate (109e)

[1264] DAST (2.4 g, 15.02 mmol) was added to a solution of 109 d (2.3 g, 7.5 mmol) in DCM (50 mL) at 0 °C. The mixture was stirred at 30 °C for 18 hrs. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried on Na2SO4, and filtered. The filtrate was concentrated to dryness to give the desired product (2.3 g, crude) as a yellow solid. LC-MS (Method 3): t R = 1.751 min, m / z(M+H) + =329.0.

[1265] Step 5. Methyl 4-(5-(difluoromethyl)-2-(methanesulfonyl)pyrimidin-4-yl)-2-fluorobenzoate (109f)

[1266] m-CPBA (4.87 g, 28.0 mmol) was added to a solution of 109e (2.3 g, 7.0 mmol) in DCM (30 mL) at 0 °C. After stirring at 0 °C for 2 hrs, the mixture was concentrated under vacuum. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 5:1) to give the desired product as a yellow solid (1.86 g, 74% yield). LC-MS (Method 3): t R = 1.486 min, m / z(M+H) + =361.0.

[1267] Step 6. Methyl 4-(2-((1-cyclopropyl-1H-pyrazole-4-yl)amino)-5-(difluoromethyl)pyrimidin-4-yl)-2-fluorobenzoate (109g)

[1268] TsOH (89 mg, 0.51 mmol) was added to a solution of 109 f (1.86 g, 5.1 mmol) and 1-cyclopropyl-1H-pyrazole-4-amine (1.27 g, 10.3 mmol) in 30 mL of THF. The mixture was stirred at 85 °C for 18 hrs. The mixture was concentrated under vacuum. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 3:1) to give the desired product (1.5 g, 72% yield) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ10.15(s,1H),8.76(s,1H),8.05-7.85(m,2H),7.64-7. 44(m,3H),6.99(d,J=14.0Hz,1H),3.90(s,3H),3.69(s,1H),1.00-0.85(m,4H).

[1269] Step 7. 4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-(difluoromethyl)pyrimidin-4-yl)-2-fluorobenzoic acid (109h)

[1270] Add potassium trimethylsilanolate (191 mg, 1.5 mmol) to a solution of 109 g (200 mg, 0.5 mmol) in THF (20 mL). Stir the mixture at 30 °C for 1 hour. Adjust the pH of the mixture to 5–6 with a 10% aqueous HCl solution. Concentrate the organic layer under vacuum to give the desired product (193 mg, crude product) as a yellow solid. LC-MS (Method 3): t R= 1.19 min, m / z(M+H) + =390.3.

[1271] Step 8. N-(cyanomethyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-(difluoromethyl)pyrimidin-4-yl)-2-fluorobenzamide (109)

[1272] Compound 109h (40 mg, 0.10 mmol), 2-aminoacetonitrile hydrochloride (46 mg, 0.5 mmol), HATU (380 mg, 1.0 mmol), and DIEA (129 mg, 1 mmol) were dissolved in DMF (3 mL). The mixture was stirred at RT for 18 hrs. The mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and filtered. The filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (Method A) to give the title product (7.5 mg, 17% yield) as a yellow solid. LC-MS (Method 1): t R = 2.471 min, m / z(M+H) + =428.0; 1 H NMR (400MHz, CD3OD.) δ8.76 (s, 1H), 7.99 (s, 2H), 7.63-7.60 (m, 3H), 6.79 (t, J = 14.4Hz, 1H), 4.41 (s, 2H), 3.63 (s, 1H), 1.06 (s, 4H).

[1273] Example 110

[1274]

[1275] Step 1. Methyl 4-(5-formyl-2-(methylthio)pyrimidin-4-yl)benzoate (110b)

[1276] Using a similar preparation procedure to the third step of Example 109, compound 110b (1.6 g) was synthesized in 30% yield using 109c (3.5 g, 18.6 mmol) and 110a (3.33 g, 18.6 mmol) as starting materials. 1 H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 9.06 (s, 1H), 8.13 (d, J = 8.4Hz, 2H), 7.89 (d, J = 8.4Hz, 2H), 3.91 (s, 3H), 2.65 (s, 3H).

[1277] Step 2. Methyl 4-(5-(difluoromethyl)-2-(methylthio)pyrimidin-4-yl)benzoate (110c)

[1278] Using a similar preparation procedure to step four of Example 109, compound 110c (1.5 g) was synthesized in 93% yield using 110b (1.5 g, 5.2 mmol) as the starting material. LC-MS (Method 3): t R = 1.75 min, m / z(M+H) + =311.1.

[1279] Step 3. Methyl 4-(5-(difluoromethyl)-2-(methanesulfonyl)pyrimidin-4-yl)benzoate (110d)

[1280] Using a similar preparation procedure to step 5 of Example 109, compound 110d (1.5 g) was synthesized in 94% yield using 110c (1.5 g, 4.8 mmol) as the starting material. LC-MS (Method 3): t R = 1.44 min, m / z(M+H) + =343.0.

[1281] Step 4. Methyl 4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-(difluoromethyl)pyrimidin-4-yl)benzoate (110e)

[1282] Using a similar preparation procedure to step six of Example 109, compound 110e (1.4 g) was synthesized in 83% yield using 110d (1.5 g, 4.4 mmol) as the starting material. 1 H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.76(s,1H),8.12(s,2H),7.99-7.88(m,1H),7.80-7.7 4(m,2H),7.54(s,1H),7.07-6.80(m,1H),3.90(s,3H),3.69-3.67(m,1H),1.00-0.93(m,4H).

[1283] Step 5. 4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-(difluoromethyl)pyrimidin-4-yl)benzoic acid (110f)

[1284] Using a similar preparation procedure to step seven of Example 109, compound 110f (96 mg) was synthesized in 100% yield using 110e (100 mg, 0.26 mmol) as the starting material. LC-MS (Method 3): t R= 1.18 min, m / z(M+H) + =372.1.

[1285] Step 6. N-(cyanomethyl)-4-(2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)-5-(difluoromethyl)pyrimidin-4-yl)benzamide (110)

[1286] Using a similar preparation procedure to step four of Example 109, compound 110 (9.4 mg) was synthesized in 8.9% yield using 110f (96 mg, 0.26 mmol) and 2-aminoacetonitrile hydrochloride (48 mg, 0.52 mmol) as starting materials. LC-MS (Method 1): t R = 3.10 min, m / z(M+H) + =410.2. 1 H NMR (400MHz, DMSO-d6) δ10.12(s,1H),9.40(s,1H),8.76(d,J=8.8Hz,1H),8.03-7.91(m,3H),7.79-7.72( m,2H),7.55-7.52(m,1H),6.95(t,J=14.4Hz,1H),4.36(d,J=5.2Hz,2H),3.68(s,1H),1.00-0.94(m,4H).

[1287] Example 111

[1288]

[1289] Step 1. Methyl 4-(2,5-dichloropyrimidin-4-yl)benzoate (34b)

[1290] A mixture of compound 34a (50.0 g, 0.27 mol), (4-(methoxycarbonyl)phenyl)boronic acid (44.3 g, 0.25 mol), DME (500 mL), and H₂O (50 mL) was sequentially added with Na₂CO₃ (57.8 g, 0.55 mol) and Pd(PPh₃)₄ (3.16 g, 2.73 mmol). The mixture was stirred at 90 °C for 9 hs under a N₂ atmosphere. After cooling to RT, the mixture was filtered and the filtrate was concentrated. The residue was diluted with water (1500 mL) and extracted with EtOAc (1500 mL &*2). The combined organic layers were concentrated to dryness. The residue was purified by chromatography on silica gel (eluent: PE:EtOAc = 10:1) to give the title compound (37 g, 52% yield) as a white solid. 1H NMR (400MHz, CDCl3) δ8.69 (s, 1H), 8.18 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 3.98 (s, 3H).

[1291] Step 2. Methyl 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoate (60a)

[1292] Compound 34b (3.0 g, 10.5 mmol), 1-cyclopropyl-1H-pyrazole-4-amine (1.55 g, 11.6 mmol), Cs₂CO₃ (6.9 g, 21.1 mmol), X-Phos (1.0 g, 21.1 mmol), and Pd₂(dba)₃ (961 mg, 1.05 mmol) were dissolved in 1,4-dioxane (50 mL). The resulting mixture was stirred at 70 °C for 2 hrs under a nitrogen atmosphere. After cooling, the mixture was filtered and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (eluent: PE:EtOAc = 1:1) to give the title product (2.0 g, 52% yield) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ8.44(s,1H),8.16(d,J=8.4Hz,2H),7.91(d,J=8.4Hz,2H),7.88(s,1H),7 .49(s,1H),6.97(s,1H),3.97(s,3H),3.60-3.56(m,1H),1.15-1.11(m,2H),1.03-0.96(m,2H).

[1293] Step 3. 4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)benzoic acid (60b)

[1294] A solution of 60a (2.0 g, 5.42 mmol) in a mixture of THF (10 mL) and H₂O (3 mL) was added in a single addition of LiOH·H₂O (683 mg, 16.26 mmol). The mixture was stirred at 40 °C for 2 hours. After cooling to RT, the mixture was adjusted to pH 6–7 with a 10% aqueous HCl solution. The mixture was extracted with DCM (30 mL x 2). The separated organic layers were concentrated under vacuum to give the title product (1.93 g, 100% yield) as a yellow solid. LC-MS (Method 3): t R = 1.166 min, m / z(M+H) +=356.1. Step 4. (S)-4-(5-chloro-2-((1-cyclopropyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-N-(1-cyanoethyl)benzamide (111)

[1295] Compound 60b (80 mg, 0.23 mmol), (S)-2-aminopropionitrile 4-methylbenzenesulfonate (75 mg, 0.31 mmol), HATU (131 mg, 0.34 mmol), and DIEA (148 mg, 1.15 mmol) were mixed in DMF (2 mL). The reaction was stirred at RT for 2 hours. The mixture was diluted with DCM (50 mL) and washed with water (20 mL x 3). The separated organic layers were concentrated to dryness, and the residue was purified by preparative HPLC (Method A) to give the title product (14 mg, 15% yield) as a yellow solid. LC-MS (Method 1): t R = 3.678 min, m / z(M+H) + =408.2; 1 H NMR(400MHz,MeOH-d4)δ8.48(s,1H),8.03-7.97(m,5H),7.59(s,1H),5.10(q ,J=7.2Hz,1H),3.63-3.59(m,1H),1.68(d,J=7.2Hz,3H),1.07-1.02(m,4H).

[1296] Example 112

[1297]

[1298] Step 1. Methyl 4-(5-methyl-2-((1-(1,1,1-trifluoropropane-2-yl)-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)be...

Claims

1. A compound or a pharmaceutically acceptable form or isotopic derivative thereof, wherein the compound is selected from the group consisting of: 。 2. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient, carrier or diluent effective for treating or alleviating one or more diseases or disorders selected from inflammatory diseases, immune-mediated diseases and cancer.

3. The pharmaceutical composition of claim 2, wherein the disease or disorder is an inflammatory disease.

4. The pharmaceutical composition of claim 2, wherein the disease or disorder is an immune-mediated disease.

5. The pharmaceutical composition of claim 2, wherein the disease or disorder is cancer.

6. The pharmaceutical composition according to any one of claims 2 to 5, which is suitable for oral administration.

7. The pharmaceutical composition of any one of claims 2 to 5, which is suitable for topical administration.

8. The pharmaceutical composition according to any one of claims 2 to 5, which is suitable for GI limited administration.

9. The pharmaceutical composition of any one of claims 2-5, wherein the disease or disorder is selected from inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer and ovarian cancer.

10. A unit dosage form comprising the pharmaceutical composition according to any one of claims 2 to 5.

11. The unit dosage form of claim 10, which is a capsule.

12. The unit dosage form of claim 10, which is a dosage form for external use.

13. Use of a compound according to claim 1 in the preparation of a medicament for treating a disease or disorder selected from inflammatory diseases, immune-mediated diseases and cancer.

14. The use of claim 13, wherein the disease or disorder is an inflammatory disease.

15. The use of claim 13, wherein the disease or disorder is an immune-mediated disease.

16. The use of claim 13, wherein the disease or disorder is cancer.

17. The use of claim 13, wherein the disease or disorder is selected from inflammatory bowel disease, psoriasis, psoriatic arthritis, alopecia areata, eczema, vitiligo, atopic dermatitis, systemic lupus erythematosus, asthma, diabetic nephropathy, chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), myelofibrosis (MF), breast cancer and ovarian cancer.

18. The use of claim 13, wherein the medicament is suitable for oral administration.

19. The use of claim 13, wherein the medicament is suitable for topical administration.

20. The use of claim 13, wherein the medicament is suitable for GI limited administration.

21. The use according to claim 13, wherein the drug is a granule.

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