Substituted pyrimidinyl-pyrazoles as CDK2 inhibitors

Abstract

The present disclosure relates to a compound represented by structural formula (I): The present disclosure provides a compound useful for treating cancer, represented by TIFF2024523892000102.tif53164, or a pharma- ceutically acceptable salt thereof. In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or diluent and one or more compounds disclosed herein or a pharma- ceutically acceptable salt thereof ("pharmaceutical composition of the present disclosure"). The present disclosure provides a method for treating a subject with cancer, comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of formula (I)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 211,426, filed June 16, 2021, and U.S. Provisional Patent Application No. 63 / 327,474, filed April 5, 2022, the disclosures of each of which are incorporated by reference in their entirety for all purposes. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are serine / threonine protein kinases that have a central role in cell cycle progression. CDK levels remain relatively constant throughout the cell cycle, and selective activation of specific CDKs allows for the proper ordering of steps in cell cycle progression. Activation of CDKs requires heterodimerization with regulatory subunits known as cyclins. Cell cycle deregulation is a common feature of human cancers.

[0003] Cyclin-dependent kinase 2 (CDK2) is involved in a range of biological activities. CDK2 is a key cell cycle regulator, active throughout late G1 and S phases. CDK2 is involved in the DNA damage response (DDR) via the homologous recombination (HR) pathway. CDK2 also controls aspects of the apoptotic pathway. Cyclin E1 (CCNE1), cyclin E2 (CCNE2), cyclin A1 (CCNA1) and cyclin A2 (CCNA2), as well as p21Cip1 / Waf1, p27Kip1 and p57Kip2 (cyclin-dependent kinase inhibitors of the cyclin-CDK2 complex), are key regulators of CDK2 activity. Dysregulation of CDK2 binding by cyclins E1, E2, A1 or A2, or activity of cyclin-dependent kinase inhibitor proteins can occur in cancer. (See S. Tadesse et al., Drug Discovery Today, Volume 25, Number 2 February 2020)

[0004] Dysregulation of CDK2 can occur by several mechanisms. Amplification or overexpression of CCNE1 has been identified in ovarian and breast cancer (see Scaltriti, M. et al., Proc. Natl Acad. Sci. USA 108, 3761-3766 (2011), and Etemadmoghadam, D. et al. Proc. Natl Acad. Sci. USA 110, 19489-19494 (2013)). Poor outcomes in gastric, endometrial, and other cancers have been associated with overexpression or amplification of CCNE1 (see Ooi et al. Hum Pathol. (2017) 61:58-67, and Noske et al, Oncotarget (2017) 8: 14794-14805). These findings indicate that CDK2 is a potential target for cancers with unregulated CDK2 activity, but no drugs targeting CDK2 are currently approved, necessitating the development of new CDK2 inhibitors. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] S. Tadesse et al.,Drug Discovery Today,Volume 25,Number 2 February 2020 [Non-Patent Document 2] Scaltriti,M. et al.,Proc. Natl Acad. Sci. USA 108,3761-3766(2011) [Non-Patent Document 3] Etemadmoghadam,D. et al. Proc. Natl Acad. Sci. USA 110,19489-19494(2013) [Non-Patent Document 4] Ooi et al. Hum Pathol.(2017) 61:58-67 [Non-Patent Document 5] Noske et al, Oncotarget (2017) 8: 14794-14805 Summary of the Invention [Means for solving the problem]

[0006] Applicants have discovered novel compounds that are effective inhibitors of CDK2 (see Synthesis Examples 1-46). In particular, compounds of the present disclosure have been demonstrated to effectively inhibit CDK2. Compounds of the present disclosure (also referred to herein as "disclosed compounds"), or pharma- ceutically acceptable salts thereof, effectively inhibit CDK2 (see Biological Example 1) and can be used to treat various cancers. Importantly, the disclosed compounds are selective CDK2 inhibitors, i.e., the disclosed compounds have no or low activity against CDK1. Advantages associated with such selectivity may include facilitating effective administration and reducing toxicity on CDK1-mediated targets. Some of the disclosed compounds also have the advantage of having high microsomal stability. Compounds of the present disclosure may also have favorable toxicity profiles associated with other non-kinase targets.

[0007] In one embodiment, the present disclosure provides a compound having the following structural formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein each variable is defined below.

[0008] In another aspect, the present disclosure provides a pharmaceutical composition comprising a pharma- ceutical carrier or diluent and one or more compounds disclosed herein or a pharma- ceutical acceptable salt thereof ("pharmaceutical composition of the present disclosure").

[0009] The present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of formula (I)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is selected from the group consisting of uterine cancer (including uterine carcinosarcoma, uterine endometrial carcinoma), endometrial cancer, breast cancer (including breast invasive carcinoma, triple negative breast cancer (TNBC), estrogen receptor (ER)+ human epidermal growth factor 2 (HER2)- breast cancer, and HER2+ breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, leukemia (including acute myeloid leukemia (AML)), lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., epidermal growth factor receptor mutant (EGFRm)+ non-small cell lung cancer), bile duct carcinoma, adrenocortical carcinoma, or mesothelioma.

[0010] In one embodiment, the cancer to be treated has amplification or overexpression of CCNE1.

[0011] The therapeutic methods disclosed herein further include administering to the patient an effective amount of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib (e.g., sirolimus), or combinations thereof. , Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selarasertib, SRA-737, LY2603618 (ravusertib), or trastuzumab (e.g., Herceptin®), or a combination thereof, are administered to the subject. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinibJBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, and nafatinib. It may be selected from zarutinib (EGF816), avitinib, PCC-0208027, resibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759) or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g. amivantamab ((JNJ-61186372, JNJ-372)).

[0012] The present disclosure also provides a method of inhibiting CDK2 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure.

[0013] The present disclosure also provides the use of an effective amount of a compound of the present disclosure (e.g., a compound of Formula (I)) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure, for the preparation of a medicament for the treatment of cancer.

[0014] In another aspect, provided herein is a compound of formula (I), or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition of the present disclosure for use in the treatment of cancer.

[0015] In one aspect, the disclosure provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has an amplification of the CCNE1 gene and / or has a CCNE1 expression level higher than a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0016] Also provided herein is a method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0017] Contemplated solid tumor cancers may be at least one of uterine cancer (including uterine carcinosarcoma, uterine endometrial carcinoma), endometrial cancer, breast cancer (including breast invasive carcinoma, triple negative breast cancer (TNBC), estrogen receptor (ER)+ human epidermal growth factor 2 (HER2)- breast cancer, and HER2+ breast cancer), ovarian cancer (including ovarian serous cystadenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumors), colorectal cancer, pancreatic cancer, renal cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including lung squamous cell carcinoma and non-small cell lung cancer, e.g., epidermal growth factor receptor mutant (EGFRm)+ non-small cell lung cancer), bile duct carcinoma, adrenocortical carcinoma, or mesothelioma. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Detailed Description of the Invention definition The term "halo" as used herein means halogen and includes chloro, fluoro, bromo and iodo.

[0019] The term "alkyl" used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl" means a saturated aliphatic straight or branched chain monovalent hydrocarbon group. Unless otherwise specified, an alkyl group typically has 1 to 4 carbon atoms, i.e., (C1-C4) alkyl. As used herein, a "(C1-C4) alkyl" group means a group having 1 to 4 carbon atoms in a linear or branched arrangement. Examples include methyl, ethyl, n-propyl, iso-propyl, and the like.

[0020] The term "alkoxy" refers to an alkyl group attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0021] The term "cycloalkyl" refers to a monocyclic saturated hydrocarbon ring system. Unless otherwise specified, cycloalkyl has 3 to 6 carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, "cycloalkyl" has 3 to 6 carbon atoms.

[0022] The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 6-membered non-aromatic ring system having ring carbon atoms and one to two ring heteroatoms, each heteroatom being independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), oxygen, and sulfur (including sulfoxide and sulfone) ("4- to 12-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, where valence permits. Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, tetrahydropyridinyl, and the like.

[0023] Compounds of the Disclosure Disclosed herein are embodiments of compounds having the general structure of formula (I).The present invention provides the compounds of the present invention or pharma- ceutically acceptable salts thereof for use in the treatment of cancer.These compounds are selective inhibitors of CDK2.

[0024] In a first embodiment, the present disclosure provides a compound represented by the following structural formula (I): [ka] or a pharma- ceutically acceptable salt thereof, wherein each R 1 is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, wherein said C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 halo; 2is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, wherein the C1-C4 alkyl and C1-C4 alkoxy are each optionally substituted with 1 to 3 halo; R 3 is a C1-C6 alkyl optionally substituted with 1 or 2 groups each independently selected from the group consisting of halo, OH, C3-C6 cycloalkyl, and 3- to 6-membered heterocyclyl, wherein the C3-C6 cycloalkyl is optionally substituted with OH, and wherein the 3- to 6-membered heterocyclyl is selected from the group consisting of O, S, and NR a and optionally substituted on the ring carbons with OH, or R 3 is a C3-C6 cycloalkyl or a 3-6 membered heterocyclyl, wherein the C3-C6 cycloalkyl is optionally substituted with OH or -CH2OH, and wherein the 3-6 membered heterocyclyl is selected from the group consisting of O, S and NR a and each R a is independently H or C1-C6 alkyl, m is selected from the group consisting of 0, 1, 2, 3, and 4, and n is selected from the group consisting of 0, 1, and 2).

[0025] In some embodiments, the compound is of formula IIA, formula IIB, formula IIC, or formula IID. [ka] or a pharma- ceutically acceptable salt thereof.

[0026] In some embodiments, each R 1 are independently selected from the group consisting of halo, methyl and methoxy. For example, R 1 is halo, e.g., F, Cl, Br.

[0027] In certain embodiments, each R 2is independently selected from the group consisting of halo, CN, methyl and ethyl, wherein said methyl and ethyl are each optionally substituted with 1 to 3 halo. For example, R 2 is methyl optionally substituted with 1 to 3 halo, for example, methyl, CF3, CF2. For example, R 2は , CN. In some embodiments, R 2 may be halo, e.g., F, Cl, Br.

[0028] In other embodiments, R 3 is a C1-C5 alkyl optionally substituted with 1 or 2 groups independently selected from the group consisting of halo, OH, cyclopropyl, and oxetanyl, wherein said cyclopropyl and oxetanyl are each optionally substituted with OH.

[0029] In some embodiments, R 3 is a C1-C5 alkyl substituted with OH.

[0030] In certain embodiments, R 3 is cyclopropyl or oxetanyl, where the cyclopropyl and oxetanyl are OH or CHOH, respectively (R 3 When is oxetanyl, it may be substituted on the ring carbons.

[0031] In certain embodiments, R3 is tetrahydropyran.

[0032] In other embodiments, each R 1 is methyl, and each R 2 is independently selected from the group consisting of halo, methyl, and CF; R 3 is a C1-C6 alkyl substituted with OH.

[0033] In some embodiments, each R 1 is the halo, and each R 2 is independently selected from the group consisting of halo, CN, methyl, ethyl, and CF; R 3is C1-C6 alkyl substituted with OH, or R 3 is oxetanyl or cyclopropyl, where the oxetanyl and cyclopropyl are each CHOH (R 3 When is oxetanyl, it may be substituted on a ring carbon.

[0034] In other embodiments, each R 1 is methoxy, and each R 2 is independently selected from the group consisting of halo, methyl, and CF; R 3 is a C1-C6 alkyl substituted with OH.

[0035] In certain embodiments, m may be 0. In some embodiments, m may be 1. In other embodiments, m may be 2. In certain embodiments, n may be 0. In some embodiments, n may be 1. In other embodiments, n may be 2.

[0036] In one embodiment, the compound of the present disclosure is any one of the compounds disclosed in the Examples and Table 1, or a pharma- ceutically acceptable salt thereof.

[0037] The term "pharmaceutical acceptable salt" refers to a pharmaceutical salt that is suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, and allergic reaction within the scope of sound medical judgment, and is commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, SM Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0038] The present teachings include pharma- ceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharma- ceutically acceptable salts with pharma- ceutically acceptable acid(s). Suitable pharma- ceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, ethanesulfonic acid, methanesulfonic acid, and succinic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharma- ceutically acceptable salts with pharma- ceutically acceptable base(s). Suitable pharma- ceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0039] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are neither identical nor mirror images of each other.

[0040] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., when the configuration is indicated in the chemical name by "R" or "S") or structure (e.g., when the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration compared to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9% (unless the structure or name is accompanied by the designation "rac" or "racemic", as described in the following two paragraphs). "Enrichment of the indicated configuration compared to the opposite configuration" is a mole percentage and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center(s) by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0041] A racemic mixture is intended when the stereochemical configuration at a chiral center in a compound is indicated by the chemical name (e.g., when the configuration is indicated in the name by "R" or "S") or by the structure (e.g., when the configuration is indicated by a "wedge" bond) and the structure is accompanied by the designation "rac" or "racemic" or specified in the chemical name.

[0042] Where two stereoisomers are depicted by their chemical names or structures and the chemical names or structures are connected by "and," a mixture of the two stereoisomers is intended.

[0043] When two stereoisomers are depicted by their chemical names or structures and the names or structures are connected by "or," either one or the other of the two stereoisomers is intended, but not both.

[0044] When a disclosed compound having a chiral center is depicted by a structure without indicating the configuration at that chiral center, the structure is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating the configuration at that chiral center with "S" or "R," the name is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0045] A racemic mixture means a mixture that is 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched racemic and diastereomeric mixtures of the compounds disclosed herein.

[0046] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, examples of which include chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent, etc. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0047] "Peak 1" in the experimental section refers to a target reaction product compound obtained from chromatographic separation / purification that elutes earlier than a second target reaction product compound from the same aforementioned reaction, which is referred to as "Peak 2."

[0048] If a disclosed compound is designated by a name or structure that denotes a single enantiomer, unless otherwise indicated, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as "enantiomerically pure"). Optical purity is the weight of the named or indicated enantiomer in a mixture divided by the total weight of both enantiomers in the mixture.

[0049] When the stereochemistry of a disclosed compound is designated or depicted by structure, and the designated or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included, unless otherwise indicated. It is further to be understood that the stereoisomeric purity of the designated or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0050] In the compounds of the present disclosure, any position specifically designated as "D" or "deuterium" is understood to have deuterium enrichment of 50%, 80%, 90%, 95%, 98% or 99%. "Deuterium enrichment" is a molar percentage and is determined by dividing the number of compounds having deuterium at the indicated position by the total number of all compounds. If a position is designated as "H" or "hydrogen", the position has hydrogen at its natural abundance. If a position is unspecified as to whether hydrogen or deuterium is present, the position has hydrogen at its natural abundance. One specific and alternative embodiment is directed to compounds of the present disclosure having deuterium enrichment of at least 5%, 10%, 25%, 50%, 80%, 90%, 95%, 98% or 99% at one or more positions not specifically designated as "D" or "deuterium".

[0051] As used herein, many moieties (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as "substituted" or "optionally substituted". When a moiety is modified by one of these terms, unless otherwise specified, it means that any part of the moiety known to one of skill in the art to be available for substitution may be substituted, including one or more substituents. When more than one substituent is present, each substituent may be independently selected. Such substitution means are well known in the art and / or taught by this disclosure. An optional substituent may be any suitable substituent for attachment to the moiety.

[0052] The compounds of the present disclosure are CDK2 inhibitors. As used herein, the term "selective CDK2 inhibitor" refers to a compound that selectively inhibits CDK2 over other CDKs and kinomes. In other words, selective CDK2 inhibitors have no or low activity against other CDKs and kinomes. The inhibitory activity of selective CDK2 inhibitors against CDK2 is higher than that against other CDKs and many other kinases, and is generally higher than that against other kinases, and is generally higher than that against other kinases, and is generally higher than that against other kinases. 50 value (i.e., IC 50 The potency can be measured using known biochemical assays.

[0053] In some embodiments, the compounds of the present disclosure are selective for CDK2 versus CDK1. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 versus CDK1. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 versus CDK1. In certain embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 versus CDK1. In certain embodiments, the compounds exhibit at least 40-fold selectivity for CDK2 versus CDK1. In other embodiments, the compounds exhibit at least 50-fold selectivity for CDK2 versus CDK1. For example, the compounds exhibit at least 100-fold selectivity for CDK2 versus CDK1. In some embodiments, the compounds of the present disclosure are selective for CDK2 versus CDK4 and / or CDK6. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 versus CDK4 and / or CDK6. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 over CDK4 and / or CDK6. In certain embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 over CDK4 and / or CDK6.

[0054] Some compounds of the present disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the predominant excretion route for small molecule drugs. The clearance of a compound by hepatic metabolism can be evaluated in vitro using human liver microsomes (HLM) or human hepatocytes. The compound is incubated with HLM plus appropriate cofactors or human hepatocytes, and the compound depletion is measured to determine the in vitro intrinsic clearance (Clint). The Clint is scaled to the total body clearance (CL) and the hepatic extraction ratio (ER) is determined by dividing the CL by the standard hepatic blood flow rate in humans. Compounds with low hepatic extraction ratio are considered to have good metabolic stability. In some embodiments, the compounds of the present disclosure have a calculated ER of <0.3, <0.4, <0.5, <0.6.

[0055] Pharmaceutical Compositions A pharmaceutical composition of the present disclosure (also referred to herein as the "disclosed pharmaceutical composition") comprises one or more pharma- ceutically acceptable carrier(s) or diluent(s) and a compound of the present disclosure (e.g., a compound of formula (I)) or a pharma- ceutically acceptable salt thereof.

[0056] "Pharmaceutically acceptable carrier" and "Pharmaceutically acceptable diluent" refer to substances that aid in the formulation and / or administration of an active agent to a subject and / or its absorption by a subject and that can be included in the pharmaceutical compositions of the present disclosure without causing significant adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable carriers and / or diluents include water, NaCl, saline, lactated Ringer's solution, regular sucrose, regular glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohol, oils, gelatin, carbohydrates (such as lactose, amylose or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and coloring agents. Such preparations can be sterilized and, if desired, mixed with auxiliary agents, examples of which include lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents and / or aromatic substances, which do not deleteriously react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds or pharma-ceutically acceptable salts thereof.

[0057] The pharmaceutical compositions of the present disclosure may contain one or more pharma- ceutically acceptable carriers and / or diluents therefor, examples of which include lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butyl parabens, may also be included. thA more complete list of suitable excipients is provided in Remington's Pharmaceutical Sciences (2003 - 20th edition), Pharmaceutical Press (2005). A person skilled in the art would know how to tailor suitable formulations for various types of administration routes. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition), and The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. A carrier, diluent and / or excipient is "acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.

[0058] Treatment methods The compounds disclosed herein inhibit CDK2, and are therefore useful for treating diseases in which CDK2 is dysregulated, such as cancer.The present disclosure provides a method for inhibiting CDK2 in a subject in need thereof, comprising administering to the subject an effective amount of the compounds disclosed herein, their pharma- ceutically acceptable salts, or pharmaceutical compositions disclosed herein.

[0059] In some embodiments, the disclosure provides a method of treating a disease or disorder associated with CDK2 in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or any formula described herein, or a pharma- ceutically acceptable salt thereof. In some embodiments, the disease or disorder associated with CDK2 is associated with amplification of the cyclin E1 (CCNE1) gene and / or overexpression of CCNE1. In some embodiments, the disease or disorder is cancer.

[0060] A subject "in need of inhibiting CDK2" is a subject having a disease in which inhibiting CDK2 can achieve a beneficial therapeutic effect, e.g., slowing the progression of the disease, alleviating one or more symptoms associated with the disease, or extending the subject's lifespan in view of the disease.

[0061] In some embodiments, the present disclosure provides a method for treating a disease / condition / or cancer associated with or regulated by CDK2, where inhibition of said CDK2 is therapeutically beneficial, including but not limited to treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound disclosed herein, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0062] In another embodiment, the present disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In another embodiment, the cancer is characterized by amplification or overexpression of CCNE1 or CCNE2.

[0063] Thus, in some embodiments of the method, the subject or patient has been previously determined to have amplification of the Cyclin E1 (CCNE1) gene and / or a CCNE1 expression level higher than a control expression level of CCNE1 in a biological sample obtained from the subject or patient.

[0064] In another embodiment, the present disclosure provides a method for inhibiting the proliferation of tumor (e.g., cancer) cells in vitro. The method comprises contacting tumor (e.g., cancer) cells in vitro with a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another embodiment, the present disclosure provides a method for inhibiting the proliferation of tumor (e.g., cancer) cells associated with amplification and overexpression of CCNE1 in a subject or patient. The method comprises administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to a subject or patient in need thereof.

[0065] In another embodiment, the disclosure provides a method of treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, in combination with other agents or standard cancer treatments, as described below.

[0066] As used herein, "cancer" refers to any malignant and / or invasive growth or tumor caused by abnormal cell proliferation. Cancer includes solid tumors, named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancers that begin at a specific site in the body, metastatic cancers that have spread from where they began to other parts of the body, recurrence of a first primary cancer after remission, and second primary cancers (new primary cancers in people with a history of a previous cancer of a different type than the latter). In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0067] Cancers that may be treated according to the disclosed methods include breast cancer, ovarian cancer, bladder cancer, uterine cancer (e.g., uterine carcinosarcoma), prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer (e.g., colon cancer), renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer (i.e., cancer of the stomach), urothelial carcinoma, brain cancer, mesothelioma, skin cancer (e.g., melanoma), sarcoma, or thyroid cancer, metastases of all of the listed cancers (especially brain metastases). In some embodiments, the cancer is characterized by overexpression or amplification of CCNE1 and / or CCNE2 as described herein. In some embodiments of the methods provided herein, the subject has been identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0068] In further embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, or gastric cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0069] In some embodiments, the disease or disorder associated with CDK2 is an adenocarcinoma, carcinoma, or cystadenocarcinoma.

[0070] In other embodiments, the cancer is breast cancer, including, for example, ER positive / HR positive, HER2 negative breast cancer, ER positive / HR positive, HER2 positive breast cancer, triple negative breast cancer (TNBC) or inflammatory breast cancer. In some embodiments, the breast cancer is chemotherapy or radiotherapy resistant breast cancer, endocrine resistant breast cancer, trastuzumab resistant breast cancer, or breast cancer exhibiting primary or acquired resistance to CDK4 / CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0071] In some embodiments, the cancer is ovarian cancer. In some such embodiments, the cancer is ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In some such embodiments, the cancer is (a) ovarian cancer, (b) characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2), or (c) both (a) and (b). In some such embodiments, the cancer is ovarian cancer.

[0072] In some embodiments, the compounds of the present disclosure are administered as first-line therapy. In other embodiments, the compounds of the present disclosure are administered as second (or later) line therapy. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with an endocrine therapeutic agent and / or a CDK4 / CDK6 inhibitor. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with an endocrine therapeutic agent, such as an aromatase inhibitor, a SERM or a SERD. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with a CDK4 / CDK6 inhibitor. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with one or more chemotherapy regimens, such as, for example, a taxane or a platinum agent. In some embodiments, the compounds of the present disclosure are administered as second (or later) line therapy following treatment with a HER2-targeted agent (e.g., trastuzumab).

[0073] In some embodiments, the disease or disorder associated with CDK2 is N-myc amplified neuroblastoma cells (see Molenaar, et al., Proc Natl Acad Sci USA 106(31): 12968-12973), K-Ras mutated lung cancer (see Hu, S., et al., Mol Cancer Ther, 2015. 14(11): 2576-85), and cancer with FBW7 mutation and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017. 77(18): 4881-4893).

[0074] In some embodiments, compounds of the present disclosure can be used to treat sickle cell disease and sickle cell anemia.

[0075] Examples of cancers treatable using the compounds of the present disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, stomach cancer, testicular cancer, uterine cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, Hodgkin's disease, non-Hodgkin's lymphoma, esophageal cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia, chronic ... Cancers that can be treated include, but are not limited to, myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, kidney or urethra cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphomas, tumor angiogenesis, spinal axis tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, T-cell lymphoma, environmentally induced cancers, including asbestos-induced cancers, and combinations of the above cancers.The compounds of the present disclosure are also useful for treating metastatic cancers.

[0076] In some embodiments, cancers treatable by the compounds of the present disclosure include melanoma (e.g., metastatic malignant melanoma, BRAF and HSP90 inhibition resistant melanoma), renal cancer (e.g., clear cell carcinoma), prostate cancer (e.g., hormone refractory prostate adenocarcinoma), breast cancer, colon cancer, lung cancer (e.g., non-small cell lung cancer and small cell lung cancer), squamous cell head and neck cancer, urothelial carcinoma (e.g., bladder), and cancers with high microsatellite instability (MSIhigh). Additionally, the present disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the present disclosure.

[0077] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), blood cancers (e.g., lymphoma, leukemia (acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), etc.), DLBCL, mantle cell lymphoma, non-Hodgkin's lymphoma (follicular lymphoma, including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, or multiple myeloma), and combinations of the above cancers.

[0078] In some embodiments, cancers treatable using the compounds of the present disclosure include, but are not limited to, cholangiocarcinoma, bile duct carcinoma, triple negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumor, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, eye cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, cancer of the mouth, oral cavity cancer, throat cancer, laryngeal cancer, lip cancer, mesothelioma, cervical cancer, nasal cavity cancer, eye cancer, ocular melanoma, pelvic cancer, rectal cancer, renal cell carcinoma, salivary gland cancer, paranasal sinus cancer, spinal cancer, tongue cancer, tubular adenocarcinoma, urethral cancer, and ureteral cancer.

[0079] In some embodiments, diseases and indications treatable using compounds of the present disclosure include, but are not limited to, blood cancers, sarcomas, lung cancer, gastrointestinal cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, gynecological cancer, and skin cancer.

[0080] Exemplary hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin's lymphoma (including relapsed or refractory NHL and relapsed follicular), Hodgkin's lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), T-cell acute lymphoblastic lymphoma (T-ALL), and multiple myeloma (MM).

[0081] Exemplary sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyoma, rhabdomyosarcoma, fibroma, lipoma, hamartoma, and teratoma.

[0082] Exemplary lung cancers include non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), bronchial carcinoma, squamous cell, small cell undifferentiated, large cell undifferentiated, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondroitin hamartoma, and mesothelioma. Exemplary gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (tubular adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colon cancer (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), and colorectal cancer.

[0083] Exemplary genitourinary tract cancers include kidney cancer (adenocarcinoma, Wilms' tumor, [nephroblastoma]), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

[0084] Exemplary liver cancers include hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0085] Exemplary bone cancers include, for example, osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostosis), benign chondroma, chondroblastoma, chondromyxoid fibroma, osteoid osteoma, and giant cell tumor.

[0086] Exemplary nervous system cancers include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteitis deformans), meningeal cancer (meningioma, meningeal sarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cancer (neurofibroma, meningioma, glioma, non-epithelial malignant tumors), as well as neuroblastoma and Lhermitte-Dacros disease.

[0087] Exemplary gynecological cancers include uterine cancer (endometrial carcinoma), cervical cancer (cervical carcinoma, preneoplastic cervical dysplasia), ovarian cancer (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, sarcoma botryoides (embryonal rhabdomyosarcoma), and cancer of the fallopian tubes (epithelial carcinoma).

[0088] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lenticular dysplastic nevus, lipoma, hemangioma, dermatofibroma, and keloid. In some embodiments, diseases and indications treatable using the compounds of the present disclosure include, but are not limited to, sickle cell disease (e.g., sickle cell anemia), triple negative breast cancer (TNBC), myelodysplastic syndrome, testicular cancer, cholangiocarcinoma, esophageal cancer, and urothelial carcinoma.

[0089] combination The compounds of the present disclosure may be administered as single agents or in combination with other anti-cancer therapeutics, particularly standard of care agents appropriate for the particular cancer.

[0090] As used herein, the term "additional anti-cancer therapeutic agent" refers to any one or more therapeutic agents other than the compounds of the present disclosure that are or may be used in the treatment of cancer. In some embodiments, such additional anti-cancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, and immuno-oncology agents.

[0091] In some embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD or a SERM.

[0092] In other embodiments, the compounds of the present disclosure may be administered in combination with standard care agents.In some embodiments, the compounds of the present disclosure may be administered in combination with endocrine therapy, such as drugs such as letrozole, fulvestrant, tamoxifen, exemestane or anastrozole.In some embodiments, the compounds of the present disclosure may be administered in combination with chemotherapeutic agents (e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine or vinorelbine).In other embodiments, the compounds of the present invention may be administered in combination with anti-HER2 agents (e.g., trastuzumab or pertuzumab).

[0093] In some embodiments, the additional anti-cancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrin (alpha-v / beta-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU14813 (Pfizer), and AG13958 (Pfizer). Additional antiangiogenic agents include vatalanib (CGP79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE941), tetrathiomolybdate (Coprexa™), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), telatinib (BAY57-9352), and CP-868,596 (Pfizer). Other antiangiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosine (KRX0401), teprenone (Selbex™), and UCN01 (Kyowa Hakko). Other examples of antiangiogenic agents include celecoxib (Cerelecbrex™), parecoxib (Dynastat™), dracoxib (SC59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP751 (Investdus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™).Further antiangiogenic agents include excisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Ordis™), nabumetone (Rilafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoryl™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Further anti-angiogenic agents include ABT510 (Abbott), aplatast (TMI005), AZD8955 (AstraZeneca), inciclinide (Metastat™), and PCK3145 (Procyon).

[0094] Further antiangiogenic agents include acitretin (Neotigasone™), plitidepsin (Aplidine™), cilentide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), revimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukraine™ (NSC 631570), Vitaxin™ (MEDI522), and zoledronic acid (Zometa™).

[0095] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., inhibiting the way in which regulatory molecules governing the fundamental processes of cell proliferation, differentiation and survival are transmitted within the cell). Signal transduction inhibitors include small molecules, antibodies and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, Panerb, IGF1R inhibitors, Mec, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of the WNT pathway and so-called multi-targeted kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with the compounds of the invention and pharmaceutical compositions described herein include BMS214662 (Bristol- Myers Squibb), lonafarnib (Salazar™), peritrexol (AG2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Cerven™ (TP38).Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatricisib (Pfizer), canertinib (CI1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB569), miltefosine (Miltefosine™), BMS599626 (Bristol-Myers Sci. Squibb), Lapurucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Trisel™), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT751 (Abbott), alvocidib (flavopiridol), BMS387032 (Bristol Myers), EM1421 (Erimos), indiculam (E7070), seliciclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol- Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0096] In other embodiments, the additional anticancer agent is a so-called classical antitumor agent.Classical antitumor agents include, but are not limited to, hormone regulators such as hormones, antihormones, androgen agonists, androgen antagonists and antiestrogenic therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activators, ribonucleases, proteomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, metabolic antagonists, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib, etc.), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum coordination compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTA) and statins.Examples of classical antineoplastic agents used in combination therapy with the compounds of the present invention (optionally in combination with one or more other agents) include glucocorticoids (e.g., dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (Megaace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; e.g., tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, CHF4227 (Cheisi), etc. ... agonists (SERMs; e.g., tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemif Regulators (SERD, fulvestrant, etc.), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly known as luteinizing hormone-releasing hormone [LHRH]) agonists (such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar)), abarelix (Plenaxis), cyproterone, flutamide (Eurexin), megestrol, nilutamide (Nilandrone), and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL Antiandrogens such as, but not limited to, 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof.Other examples of classical antitumor agents that may be used in combination with the compounds of the invention include suberanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethylbutyrate and PXD-101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinoside, iodine, iodine-10-carboxylate ... Tecan HCl (Camptosar), Lurtotecan, Oracecin (Rubitecan, Supergen), SN-38, Topotecan, Camptothecin, 10-Hydroxycamptothecin, 9-Aminocamptothecin, Irinotecan, SN-38, Edotecarin, Topotecan, Aclarubicin, Adriamycin, Amonafide, Amrubicin, Annamycin, Daunorubicin, Doxorubicin, Elsamitrucin, Epirubicin, Etoposide, Idarubicin, Galarubicin, Hydroxycarbamide, Nemorubicin, Novant Lon (mitoxantrone), pirarubicin, pisanthrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide , KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol, mitomycin C, mitoxatrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds (e.g., cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satorplatin), and combinations thereof.

[0097] In yet other embodiments, the additional anticancer drug is a so-called dihydrofolate reductase inhibitor (such as methotrexate and nutrexin (trimethrexate glucuronate)), a purine antagonist (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine, raltitrexed), a pyrimidine antagonist (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), tegafur (UFT Orzel or Uforal, as well as the drugs tegafur, gimestat and otostat). TS-1 combination), doxifluridine, carmofur, cytarabine (including ocphosphate, phosphate stearate, sustained release and liposomal forms), enocitabine, 5-azacytidine (Vidaza), decitabine and ethinylcytidine), and other antimetabolites such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitac), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino)]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals), and GPI 18180 (Guilford Pharm) Inc., and combinations thereof.

[0098] Other examples of classical antitumor cytotoxic agents include Abraxane (Abraxis BioScience, Inc.), butabulin (Amgen), EPO906 (Novartis), vinflunine (Bristol-Myers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarzinostatin (zinostatin), vinblastine, vincristine, vindesine, vinorelbine (navelbine), docetaxel (Taxotere), ortataxel, paclitaxel (including taxoplexin, a DHA / paclitaxel complex), cisplatin, carboplatin, nedaplatin, oxaliplatin (Eloxatin), satraplatin, camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), taxotere alitretinoin, canfosfamide ( These include, but are not limited to, Telcyta™), DMXAA (Antisoma), Ibandronic acid, L-asparaginase, Pegaspargas (Oncaspar™), Efaproxiral (Efaproxyn™ - radiation therapy), Bexarotene (Targretin™), Tesmilifene (DPPE - enhances the effectiveness of cytotoxic drugs), Seratope™ (Biomira), Tretinoin (Vesanoid™), Tirapazamine (Trizaone™), Motexafin Gadolinium (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), Polyglutamic acid-paclitaxel (Xyotax™) and combinations thereof.Further examples of classical antitumor agents include Advexin (ING201), TNFerade (GeneVec, a compound that expresses TNFα in response to radiation therapy), RB94 (Baylor College of Medicine), Genasense (Oblimasen, Genta), combretastatin A4P (CA4P), Oxy-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), provastatin (Pravachol, Bristol- Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycor, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, Torcetrapib and combinations thereof.

[0099] In other embodiments, the additional anticancer agent is an epigenetic modulator, such as an inhibitor or EZH2, Smalca4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2 or BCL6.

[0100] In further embodiments, the additional anti-cancer agent is an immunomodulatory agent (such as an inhibitor of CTLA-4, PD-1 or PD-L1 (e.g., pembrolizumab, nivolumab or avelumab)), LAG-3, TIM-3, Tigit, 4-1BB, OX40, GITR, CD40 or CAR-T cell therapy. In some embodiments, the additional anti-cancer agent is an EGFR inhibitor such as afatinib, an EGFR antibody such as osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib or gefitinib or cetuximab, panitumumab or necitumumab.

[0101] Alternatively, the compounds of the present disclosure, pharma- ceutically acceptable salts thereof, or pharmaceutical compositions disclosed herein can be administered in combination with other anti-cancer agents that are not EGFR inhibitors, for example in combination with MEK, examples of which include mutant MEK inhibitors (trametinib, cobimutetinib, binimetinib, selumetinib, refametinib); c-MET, mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib) and MET antibodies (emibetuzumab); mitotic kinase inhibitors (mRAK, MY ... These include kinase inhibitors (CDK4 / 6 inhibitors such as palbociclib, ribociclib, abemaciclib); antiangiogenic agents (e.g., bevacizumab, nintedanib); apoptosis inducers such as Bcl-2 inhibitors (e.g., venetoclax, obatoclax, navitoclax) and Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, S-64315); and mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, lidforolimus).

[0102] The compound of the present disclosure, a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein may be administered in the form of an effective amount of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lynparza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib ( For example, it may be administered in combination with a second agent selected from the group consisting of Tagrisso®), gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), an EGFR inhibitor, pralsetinib, ABT-263 (navitoclax), MK-1775 (adavosertib), BAY-1895344, beruzosertib, selarasertib, SRA-737, LY2603618 (ravusertib) and trastuzumab (e.g., Herceptin®), or a combination thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinibJBJ-04-125-02, alflutinib (AST2818), aumoretinib (formerly almonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, lazertinib, and nafatinib. It may be selected from zarutinib (EGF816), avitinib, PCC-0208027, resibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759) or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, necitumumab, HLX07, JMT101, or from bispecific EGFR and MET antibodies (e.g. amivantamab ((JNJ-61186372, JNJ-372)).

[0103] Biomarkers and Pharmacodynamic Markers The present disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, such as gene copy number, gene sequence, expression levels, or phosphorylation levels) to identify human subjects having, suspected of having, or at risk of developing a CDK2-related disease or disorder that is likely to be effective against administration of a CDK2 inhibitor (as used herein, "CDK2 inhibitor" refers to a compound of the present disclosure, or a pharmaceutically acceptable salt thereof).

[0104] CCNE1 In one embodiment, the biomarker is CCNE1. In particular, amplification of the cyclin E1 (CCNE1) gene and / or expression levels of CCNE1 in a biological sample would indicate that a patient or subject may benefit from administration of a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0105] CCNE1 is a cell cycle factor essential for cell cycle control at the G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2 and interacts with CDK2 to form a serine / threonine kinase holoenzyme complex. The CCNE1 subunit of this holoenzyme complex provides substrate specificity for the complex (Honda et al., 2005, EMBO 24:452-463). CCNE1 is encoded by the cyclin E1 ("CCNE1") gene (GenBank Accession No. NM_001238). The amino acid sequence of human CCNE1 is available in GenBank Accession No. NP_001229 / UniProtKB Accession No. P24864).

[0106] In one aspect, the disclosure provides a method of treating a subject having or at risk of developing a disease or disorder associated with CDK2, comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, wherein the subject has an amplification of the CCNE1 gene and / or has a CCNE1 expression level higher than a control expression level of CCNE1. In some embodiments, the CDK2-associated disease or disorder is cancer.

[0107] Also provided herein is a method of treating a patient having an amplified expression level of CCNE1 and suffering from or at risk of developing a solid tumor cancer, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0108] Amplification of the CCNE1 gene and / or a CCNE1 expression level higher than a control expression level of CCNE1 indicates / predicts that a human subject having or at risk of developing a disease or disorder associated with CDK2 will respond to a CDK2 inhibitor. In some embodiments, the expression level of CCNE1 may be the level of CCNE1 mRNA. In other embodiments, the expression level of CCNE1 may be the level of CCNE1 protein.

[0109] Other biomarkers In some embodiments, a contemplated biomarker may be p16 (also known as cyclin-dependent kinase inhibitor 2A, cyclin-dependent kinase 4 inhibitor A, multiple tumor suppressor 1, and p16-INK4a), which acts as a negative regulator of normal cell proliferation by interacting with CDK4 and CDK6. In other embodiments, a contemplated biomarker may be phosphorylation of Rb at the serine corresponding to amino acid position 780. Rb is a regulator of the cell cycle and acts as a tumor suppressor. Rb is activated when phosphorylated by cyclin D-CDK4 / 6 at Ser780 and Ser795, and cyclin E / CDK2 at Ser807 and Ser811.

[0110] Contemplated biomarkers may also be selected from the group consisting of RB1, RBL1, RBL2, CDKN2A, CDKN1A, CDKN1B, FBXW7, CCNE1, CCNE2, CCNA1, CCNA2, CCND1, CCND2, CCND3, CDK2, CDK3, CDK4, CDK6, CDKN2A, CDNK1A, CDKN1B, E2F1, E2F2, E2F3, MYC, MYCL, MYCN, EZH2, ER, HER2, HER3, HPV+ and EGFR.

[0111] Biological samples Biological samples suitable for the methods described herein include any sample containing blood or tumor cells obtained or derived from a human subject in need of treatment.For example, biological samples can include tumor cells from a biopsy of a patient suffering from a solid tumor.Tumor biopsies can be obtained by various means known in the art.Alternatively, blood samples can be obtained from patients suffering from blood cancer.

[0112] The biological sample can be obtained from a human subject having, suspected of having, or at risk of developing a disease or disorder associated with CDK2. In some embodiments, the disease or disorder associated with CDK2 is cancer (such as those described above).

[0113] Methods of obtaining and / or storing samples that preserve the activity or integrity of molecules (e.g., nucleic acids or proteins) in the sample are well known to those of skill in the art. For example, a biological sample can be further contacted with one or more additional agents, such as buffers and / or inhibitors (including one or more of nuclease, protease and phosphatase inhibitors), which preserve or minimize alteration of the molecules in the sample.

[0114] Method of administration and dosage form The exact amount of compound administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the cancer, and the characteristics of the subject (such as overall health, age, sex, weight, and tolerance to drugs). Those skilled in the art will be able to determine the appropriate dosage depending on these and other factors. When administered in combination with other therapeutic agents, e.g., in combination with anti-cancer drugs, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are known and can be adjusted by those skilled in the art according to the subject's condition, the type of condition(s) being treated, and the amount of compound of formula (I) used, e.g., by following dosages reported in the literature and recommended in the Physician's Desk Reference (57th Ed., 2003).

[0115] "Treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect, which effect is therapeutic, including partially or substantially achieving one or more of the following results: partially or substantially reducing the extent of the disease, condition, or cancer; ameliorating or improving clinical symptoms or indicators associated with the disease, condition, or cancer; slowing, inhibiting, or reducing the likelihood of progression of the disease, condition, or cancer; or reducing the likelihood of recurrence of the disease, condition, or cancer.

[0116] The term "effective amount" refers to an amount that, when administered to a subject, produces a beneficial or desired result (including a clinical result), e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively 1 mg to about 5 grams per day, and further alternatively 10 mg to 1 gram per day).

[0117] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that may be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that may be employed with the agents and methods described herein are described, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0118] Additionally, the compounds of the present disclosure, their pharma- ceutically acceptable salts, or pharmaceutical compositions of the present disclosure can be co-administered with other therapeutic agents. As used herein, the terms "co-administered" and "administered in combination with" and their grammatical equivalents are meant to encompass the administration of two or more therapeutic agents to a single subject, and are intended to include therapeutic regimens in which the agents are administered by the same or different routes of administration or at the same or different times. In some embodiments, one or more compounds of the present disclosure, their pharma- ceutically acceptable salts, or pharmaceutical compositions of the present disclosure will be co-administered with other agents. These terms encompass the administration of two or more agents to a subject, thereby resulting in the simultaneous presence of both agents and / or their metabolites in the subject. They include co-administration in separate compositions, administration at different times in separate compositions, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds described herein and the other agent(s) are administered in a single composition. In some embodiments, the compounds described herein and the other agent(s) are mixed in the composition.

[0119] The particular mode of administration and dosage regimen will be selected by the attending clinician, taking into consideration the particulars of the case (e.g., subject, disease, disease state involved, particular treatment). Treatment may involve daily or multiple daily or less than daily (weekly, monthly, etc.) administration over a period ranging from several days to several months, and in some cases years. However, those skilled in the art will readily recognize appropriate and / or equivalent dosages, looking at the dosages of approved compositions for treating diseases using CDK2 inhibitors disclosed as a guide.

[0120] As will be understood by those skilled in the art, the compounds of the present disclosure or their pharma- ceutically acceptable salts can be administered to patients in various forms depending on the selected administration route.The compounds of the present teachings can be administered, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, patch, pump or transdermal administration, and by pharmaceutical compositions formulated accordingly.Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, pulmonary, intrathecal, rectal and topical modes of administration.Parenteral administration can be by continuous infusion over a selected period of time.

[0121] The pharmaceutical composition of the present disclosure is formulated to be compatible with its intended route of administration.In some embodiments, the composition is formulated according to conventional procedures as a pharmaceutical composition that is compatible with intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0122] Typically, for oral therapeutic administration, the compounds of the present disclosure, or pharma- ceutically acceptable salts thereof, will be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.

[0123] In general, for parenteral administration, the solution of the compound of the present disclosure or its pharma- ceutically acceptable salt can be prepared in water, generally mixed with a suitable surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, DMSO, and mixtures thereof with or without alcohol, and in oils. These preparations contain a preservative to prevent the growth of microorganisms under normal storage and use conditions.

[0124] Typically, for injectable use, sterile aqueous solutions or dispersions and sterile powders of the compounds of the present disclosure are suitable for the extemporaneous preparation of sterile injectable solutions or dispersions. EXAMPLES

[0125] The following examples are intended to be illustrative and not to limit the scope of the disclosure in any way. Working Example Preparation of Exemplary Compounds definition TsOH 4-Methylbenzenesulfonic acid TEA Triethylamine THF Tetrahydrofuran MsCl Methanesulfonyl chloride DCM Dichloromethane NH4Cl Ammonium chloride MgSO4 Magnesium Sulfate NaN3 Sodium Azide DMF Dimethylformamide EA Ethyl acetate Na2SO4 Sodium Sulfate MeOH Methanol N2 Nitrogen H2 Hydrogen LiAlH4 Lithium Aluminum Hydride NaHCO3 Sodium Bicarbonate CbzCl Benzyl carbonochloridate PE Petroleum Ether DAST N-Ethyl-N-(trifluorosulfanyl)ethanamine HCl Hydrochloride ACN Acetonitrile DIPEA Diisopropylethylamine DMSO Dimethyl sulfoxide DMA Dimethylacetamide h hour(s) HPLC High Performance Liquid Chromatography min Minute(s) C Celsius I C 50 50% inhibitory concentration IPA Isopropyl Alcohol MTBE Methyl tert-butyl ether rt room temperature TFA Trifluoroacetic acid IPA Isopropyl Alcohol

[0126] The method for preparing the compounds of the present invention can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates or products at the temperature at which the reaction is carried out (for example, temperatures ranging from the freezing point of the solvent to the boiling point of the solvent).A given reaction can be carried out in one solvent or a mixture of more than one solvent.Depending on the specific reaction step, those skilled in the art can select a suitable solvent for the specific reaction step.

[0127] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The necessity of protection and deprotection, and the selection of suitable protecting groups, can be easily determined by those skilled in the art. The chemical nature of protecting groups is described, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley&Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0128] The reaction can be monitored according to any suitable method known in the art. For example, the formation of the product can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C) can be monitored by spectroscopic means such as infrared (IR) spectroscopy, spectrophotometric methods (e.g., UV-Vis), mass spectrometry (MS), or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). ) Analytical instruments and methods for compound characterization:

[0129] LC-MS: Liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were acquired using an Agilent model-1260 LC system. The system was equipped with an Agilent Poroshel 120 (EC-C18, particle size 2.7 um, dimensions 3.0 x 50 mm) reversed-phase column at 22.4 degrees Celsius using an Agilent model 6120 mass spectrometer utilizing the ES-API ionization method. The mobile phase consisted of a solvent mixture of 0.1% formic acid in water and 0.1% formic acid in acetonitrile. A constant gradient of the mobile phase from 95% water / 5% organic to 5% water / 95% organic over a period of 4 minutes was utilized. The flow rate was constant at 1 mL / min.

[0130] Alternatively, liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were obtained using a Shimadzu LCMS system. The system was equipped with an Agilent (Poroshel HPH-C18 2.7um particle size, 3.0×50mm dimensions) reversed-phase column at 22.4 degrees Celsius using a Shimadzu LCMS mass spectrometer utilizing ESI ionization. The mobile phase consisted of a solvent mixture of 5mM NH4HCO3 (or 0.05% TFA) in water and acetonitrile. A constant gradient of the mobile phase from 90% water / 10% organic to 5% water / 95% organic over a period of 2 minutes was used. The flow rate was constant at 1.5mL / min.

[0131] Prep LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP® Prep System equipped with an Xtimate 10um 150A 21.2×250mm column at 22.4 degrees Celsius. Under basic conditions, the mobile phase consisted of a mixture of water (0.1% NH4HCO3) and ACN. A constant gradient from 85% water / 15% organic to 5% water / 95% organic over a period of 18 minutes was used. The flow rate was constant at 20 mL / min. Under acidic conditions, the mobile phase consisted of a mixture of water (0.1% FA) and ACN. A constant gradient from 65% water / 35% organic to 55% water / 45% organic over a period of 8 minutes was used.

[0132] Alternatively, preparative HPLC was performed on a Waters preparative system equipped with the following column: XBridge Shield RP18 OBD column, 30×150 mm, 5 um. The mobile phase consisted of a solvent mixture of water (10 mmol / L NH4HCO3+0.05% NH3.H2O) and acetonitrile. A constant gradient of the mobile phase from 95% water / 5% organic to 5% water / 95% organic over a period of 11 minutes was used. The flow rate was constant at 60 mL / min. Reactions performed in the microwave were carried out in a Biotage Initiator microwave instrument.

[0133] Silica gel chromatography: Silica gel chromatography was performed on a Teledyne Isco CombiFlash® Rf instrument, a Biotage® Isolera Four instrument, or a Biotage® Isolera Prime instrument.

[0134] Proton NMR: 1 H NMR spectra were run on a Varian 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.5 seconds with 1 second delay; 16-64 scans), or an Avance 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.99 seconds with 1 second delay; 4-64 scans), or an Avance 300MHz Unity Inova 300MHz NMR instrument (acquisition time = 5.45 seconds with 1 second delay; 4-64 scans). Unless otherwise indicated, all protons in DMSO-d6 solvent are reported as parts per million (ppm) relative to residual DMSO (2.50 ppm).

[0135] Example 1. 3-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0136] Step 1. Synthesis of 1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 1) [ka]

[0137] A mixture of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (1.0 g, 3.75 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.4 g, 11.2 mmol), Na2CO3 (1.18 g, 11.2 mmol) and Pd(dppf)Cl2 (306 mg, 375 μmol) in dioxane (20 mL) and H2O (5 mL) was stirred at 80 °C for 2 h under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 4) to give the title compound (400 mg, 33% yield) as a yellow solid. MS (ES+) C 12 H 12 ClF3N4O theoretical value: 320, observed value: 321 [M+H] + .

[0138] Step 2. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (compound 1) [ka]

[0139] To a mixture of intermediate 1 (40 mg, 124 μmol) and 4-amino-3-fluorobenzenesulfonamide (23.5 mg, 124 μmol) in IPA (2 mL), TsOH (21.3 mg, 124 μmol) was added and then stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (mobile phase: A=water (0.1% NH4HCO3), B=acetonitrile; gradient: B=15% to 95% (18 min); column: Xtimate 10 um 150A 21.2×250 mm) to give the title compound (32.2 mg, 54% yield) as a white solid. MS (ES+) C 18 H 18 F4N6O3S theoretical value: 474, observed value: 475 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 8.77(s,1H),8.25(s,1H),8.02(t,J=8.4Hz,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(br. s.,1H),4.80(s,1H),4.12(s,2H),1.08(s,6H).

[0140] Example 2. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide [ka]

[0141] To a mixture of intermediate 1 (140 mg, 436 μmol) and 4-amino-3-methylbenzenesulfonamide (81.1 mg, 436 μmol) in IPA (10 mL), TsOH (75.0 mg, 436 μmol) was added and then stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (mobile phase: A=water (0.1% NH4HCO3), B=acetonitrile; gradient: B=15% to 95% (18 min); column: Xtimate 10 um 150A 21.2×250 mm) to give the title compound (46.3 mg, 22% yield) as a white solid. MS (ES+) C 19 H 21 F3N6O3S theoretical value: 470, observed value: 471 [M+H] + . 1 H-NMR(400MHz,DMSO-d6) δ ppm 9.68(s,1H),8.70(s,1H),8.22(s,1H),7.91(s,1H),7.75-7.68(m,3H),7.28(s,2H),4.77(s,1H),4.11(s,2H),2.34(s,3H),1.08(s,6H).

[0142] Example 3. 4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide

[0143] Step 1. Synthesis of 1-(4-(2,5-dichloropyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 2) [ka]

[0144] A mixture of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (200 mg, 751 μmol), 2,4,5-trichloropyrimidine (137 mg, 751 μmol), Na2CO3 (279 mg, 2.25 mmol) and Pd(dppf)Cl2 (61.3 mg, 75.1 μmol) in dioxane (10 mL) and H2O (2.5 mL) was stirred at 80 °C for 2 h under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (2 / 1) to give the title compound (200 mg, 93% yield) as a white solid. MS (ES+) C 11 H 12 C l2 Theoretical value for N4O: 286, observed value: 287 [M+H]+.

[0145] Step 2. Synthesis of 4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 3) [ka]

[0146] To a mixture of intermediate 2 (140 mg, 436 μmol) and 4-aminobenzenesulfonamide (100 mg, 584 μmol) in IPA (5 mL) was added TsOH (167 mg, 974 μmol), and the reaction was then stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (25.9 mg, 12% yield) as a white solid. MS (ES+) C 19 H 21 F3N6O3S theoretical value: 422, observed value: 423 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.16(s,1H),8.59(s,1H),8.58(s,1H),8.27(s,1H),7.93(d,J=8.8Hz,2H) ,7.78(d,J=8.8Hz,2H),7.19(s,2H),4.81(s,1H),4.16(s,2H),1.11(s,6H).

[0147] Example 4. 4-((5-(difluoromethyl)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide

[0148] Step 1. Synthesis of 2,4-dichloro-5-(difluoromethyl)pyrimidine (intermediate 3) [ka]

[0149] To a solution of 2,4-dichloropyrimidine-5-carbaldehyde (500 mg, 2.84 mmol) in DCM (10 mL) was added DAST (914 mg, 5.68 mmol) and the reaction was stirred at room temperature for 14 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with PE / EA (20 / 1) to give the title compound (450 mg, 80% yield) as a colorless oil. 1 H-NMR (400MHz, CDCl3) δ ppm 8.82 (s, 1H), 6.90 (t, J=53.6Hz, 1H).

[0150] Step 2. Synthesis of 1-(4-(2-chloro-5-(difluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 4) [ka]

[0151] Following a procedure similar to that described in step 1 of Example 3, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and intermediate 3 was used to obtain the title compound as a pale yellow solid (200 mg, 65% yield). MS (ES+) C 12 H 13 ClF2N4O theoretical value: 302, observed value: 303 [M+H] + .

[0152] Step 3. Synthesis of 4-((5-(difluoromethyl)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 4) [ka]

[0153] To a mixture of intermediate 4 (200 mg, 0.66 mmol) and 4-aminobenzenesulfonamide (114 mg, 0.66 mmol) in IPA (3 mL) was added TsOH (114 mg, 0.66 mmol), and the reaction was then stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (83.6 mg, 28% yield) as a white solid. MS (ES+) C 18 H 20 F2N6O3S theoretical value: 438, observed value: 439 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.38(br. s,1H),8.72(s,1H),8.31(s,1H),8.05(s,1H),7.98(d,J=8.8Hz,2H),7.79(d, J=8.8Hz,2H),7.24(t,J=54.4Hz,1H),4.84(s,1H),4.14(s,2H),1.11(s,6H).

[0154] Example 5. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0155] Following a procedure similar to that described in step 3 of Example 4, intermediate 1 and 4-aminobenzenesulfonamide gave the title compound as a white solid (19.2 mg, 45% yield). MS (ES+) C 18 H 19 F3N6O3S theoretical value: 456, observed value: 457 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.55(br. s,1H),8.82(s,1H),8.32(s,1H),8.03(s,1H),7.96(d,J=8.8Hz,2H),7.80(d,J=8.8Hz,2H),7.21(br. s, 2H), 4.83 (s, 1H), 4.15 (s, 2H), 1.10 (s, 6H).

[0156] Example 6. (S)-3-Fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or (R)-3-Fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide.

[0157] Step 1. Synthesis of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-one (Intermediate 5) [ka]

[0158] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.00 g, 20.6 mmol) and NaH (60%, 880 mg, 22.7 mmol) in anhydrous DMF (200 mL) was stirred from 0° C. to room temperature for 20 min. 3-Bromobutan-2-one (3.76 g, 24.90 mmol) was added at 0° C. and the resulting mixture was stirred at 120° C. for 6 h. The mixture was cooled to room temperature and water and EA were added. The aqueous layer was extracted with EA and the combined EA layers were washed with water and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EA / PE=1 / 3 to give the title product as an oil (4.80 g, 88% yield). MS (ES+) C 13 H 21 BN2O3 theoretical value: 264, observed value: 265 [M+H] + .

[0159] Step 2. Synthesis of 3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-one (Intermediate 6) [ka]

[0160] A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.05 g, 9.45 mmol), intermediate 5 (1.25 g, 4.72 mmol), Pd(dppf)Cl2 (192 mg, 0.24 mmol) and Na2CO3 (751 mg, 7.09 mmol) in dioxane (30 mL) and water (7.5 mL) under N2 was heated at 90°C for 16 h. It was concentrated in vacuum and the aqueous residue was extracted with EA. The combined EA layers were concentrated in vacuum. The residue was purified by flash chromatography on silica gel eluting with EA / PE=1 / 1 to give the title product as an oil (200 mg, 13% yield). MS (ES+) C 12 H 10 ClF3N4O theoretical value: 318, observed value: 319 [M+H] + .

[0161] Step 3. Synthesis of (R)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol and (S)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Intermediate 7 and Intermediate 8) [ka]

[0162] To a mixture of intermediate 6 (800 mg, 2.51 mmol) in THF (5 mL) at 0° C., MeMgBr (3M, 2 mL, 6 mmol) was added and the reaction was stirred at 0° C. to room temperature for 2 h. Saturated aqueous NH4Cl was added at 0° C. and the resulting mixture was extracted with EA. The combined EA layers were concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel eluting with EA / PE=2 / 1 to give 3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol. MS (ES+) C 13 H 14 ClF3N4O theoretical value: 334, observed value: 335 [M+H] + The racemic product was separated by chiral-SFC (column: AD 20×250 mm, 10 um (Daicel), column temperature: 35° C., mobile phase: CO2 / MeOH (0.2% methanolic ammonia)=60 / 40, flow rate: 80 g / min) to give peak 1, intermediate 7, 214 mg, (R)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol or (S)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol.

[0163] Further elution gave peak 2, intermediate 8, 200 mg, (S)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol or (R)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol as a white solid.

[0164] Step 4. Synthesis of (S)-3-fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or (R)-3-fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 6) [ka]

[0165] Following a procedure similar to that described in step 3 of Example 4, intermediate 8 and 4-amino-3-fluorobenzene-1-sulfonamide gave the title compound as a white solid (80.2 mg, 27% yield). MS (ES+) C 19 H 20 F4N6O3S theoretical value: 488, observed value: 489 [M+H] + . 1 H NMR (400MHz,DMSO) δ 10.08(s,1H),8.76(s,1H),8.26(s,1H),8.02(t,J=8.0Hz,1H),7.94(s,1H),7.69(s,1H),7.67(s,1H) ),7.45(s,2H),4.76(s,1H),4.34(q,J=7.0Hz,1H),1.46(d,J=7.0Hz,3H),1.07(s,3H),1.02(s,3H).

[0166] Example 7. (R)-3-fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or (S)-3-fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0167] Following a procedure similar to that described in step 3 of Example 4, intermediate 7 and 4-amino-3-fluorobenzene-1-sulfonamide gave the title compound as a white solid (68.2 mg, 22% yield). MS (ES+) C 19 H 20 F4N6O3S theoretical value: 488, observed value: 489 [M+H] + . 1 H NMR (400MHz,DMSO) δ 10.08(s,1H),8.76(s,1H),8.26(s,1H),8.02(t,J=8.0Hz,1H),7.94(s,1H),7.69(s,1H),7.67(s,1H) ),7.45(s,2H),4.76(s,1H),4.34(q,J=7.0Hz,1H),1.46(d,J=7.0Hz,3H),1.07(s,3H),1.02(s,3H).

[0168] Example 8. 4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide

[0169] Step 1. Synthesis of 4-((4-chloro-5-cyanopyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0170] To a mixture of 2,4-dichloropyrimidine-5-carbonitrile (10.0 g, 57.5 mmol) and 4-aminobenzenesulfonamide (9.90 g, 57.5 mmol) in IPA (100 mL) was added DIPEA (11.1 g, 86.2 mmol) in one portion at 25° C. The mixture was stirred at 50° C. for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The combined crude product was purified by preparative HPLC (acidic condition) to give the title compound (3.0 g) as a yellow solid.

[0171] Step 2. Synthesis of 4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 8) [ka]

[0172] To a mixture of intermediate 9 (74.3 mg, 0.240 mmol) in DMF (3.0 mL) under N2 atmosphere, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (95.7 mg, 0.360 mmol), Cs2CO3 (312 mg, 0.960 mmol), H2O (0.5 mL) and Pd(dppf)Cl2 (12.0 μmol) were added. The reaction mixture was stirred at 100 °C for 16 h. LCMS showed the reaction was complete. The mixture was filtered and the solvent was removed in vacuo. The residue was purified by preparative HPLC (acidic condition) to give the title compound (36.8 mg, 37%). MS (ES+) C 18 H 19 Theoretical value of N7O3S: 413.5, observed value: 414.1[M+H]+. 1H NMR (500MHz,DMSO) δ 10.59(s,1H),8.85(d,J=1.7Hz,1H),8.53(s,1H),8.22(s,1H),7.92-7.84(m,2H) ,7.80-7.71(m,2H),7.18(s,2H),4.77(d,J=1.7Hz,1H),4.11(s,2H),1.05(s,6H).

[0173] Example 9. 3-Fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or Synthesis of 3-fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0174] Step 1. Synthesis of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol (Intermediate 10) [ka]

[0175] To a solution of intermediate 5 (2 g, 7.57 mmol) in MeOH (20 mL) was added NaBH4 (427 mg, 11.3 mmol) and the reaction was stirred at room temperature for 30 min. LCMS showed the reaction was complete. The reaction was quenched with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with PE / EA (1 / 1) to give the title compound as a colorless oil (1.2 g, 59% yield). MS (ES+) C 13 H 23 Theoretical value of BN2O3: 266, Observed value: 267 [M+H] + .

[0176] Step 2. Synthesis of (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol, (2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol, (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol and (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol (Intermediates 12-P1, 12-P2, 13-P1 and 13-P2) [ka] [ka] [ka]

[0177] A mixture of intermediate 10 (1 g, 3.75 mmol), 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (740 mg, 3.75 mmol), Na2CO3 (1.09 g, 11.2 mmol) and Pd(dppf)Cl2 (275 mg, 375 μmol) in dioxane (15 mL) and H2O (4 mL) under N2 was stirred at 90 °C overnight. LCMS showed the reaction was complete. The residue was purified by flash chromatography on silica gel eluted with EA / PE (1 / 1) followed by preparative HPLC (basic conditions) to give 3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol (800 mg, 71% yield). The product (800 mg) was separated by chiral HPLC to give peak 1, intermediate 12, cis-rac-(2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (280 mg) trans-rac-(2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl ) butan-2-ol, and peak 2, intermediate 13, trans-rac-(2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or cis-rac-(2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol (350 mg).

[0178] Intermediate 12 (280 mg) was separated by chiral-SFC (column: IG 20×250 mm, 10 um (Daicel)); column temperature: 35° C., mobile phase: CO2 / MeOH (0.2% methanolic ammonia)=80 / 20; flow rate: 100 g / min) to give intermediate 12-P1 (110 mg), (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or ( 2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol )pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol and intermediate 12-P2 (100 mg), (2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H- (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol was obtained as a white solid.

[0179] Intermediate 13 (350 mg) was separated by chiral-SFC (column: IG 20 × 250 mm, 10 um (Daicel); column temperature: 35 °C; mobile phase: CO2 / MeOH (0.2% methanolic ammonia) = 80 / 20; flow rate: 100 g / min) to give intermediate 13-P1 (140 mg), (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2 S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol, and intermediate 13-P2 (190 mg), (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H- (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol or (2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)butan-2-ol was obtained as a white solid. MS (ES+) C 12 H 14 F3N5O theoretical value: 301, observed value: 302 [M+H] + .

[0180] Step 3. 3-Fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2R,3R ... Synthesis of fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 9) [ka]

[0181] A mixture of intermediate 12-P2 (100 mg, 331 μmol), 4-bromo-3-fluorobenzene-1-sulfonamide (84.0 mg, 331 μmol), potassium acetate (97.4 mg, 993 μmol) and BrettPhos Pd G4 (50.8 mg, 33.1 μmol) in dioxane (5 mL) under N2 was stirred at 90° C. overnight. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluted with EA / PE (5 / 1) and then by preparative HPLC (basic conditions) to give the title product (29.6 mg, 18% yield) as a white solid. MS (ES+) C 18 H 18 F4N6O3S theoretical value: 474, observed value: 475 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.76(s,1H),8.27(s,1H),8.03(t,J=8.4Hz,1H),7.96(s,1H),7.70-7.67(m,2H),7.43(s,2 H),5.06-5.04(m,1H),4.32-4.28(m,1H),3.88-3.85(m,1H),1.46(d,J=6.8Hz,3H),0.90(d,J=6.0Hz,3H).

[0182] Example 10. 4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide [ka]

[0183] Following the procedure described in Step 3 of Example 4, intermediate 2 and 4-amino-3-fluorobenzenesulfonamide afforded the title compound as a white solid (23.6 mg, 8% yield). MS (ES+) C 17 H 18 ClFN6O3S theoretical value: 440, observed value: 441 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 9.63(br. s,1H),8.55(s,2H),8.19(s,1H),7.98(t,J=8.4Hz,1H),7.69-7.63(m,2H),7.41(br.s,2H),4.82(s,1H),4.14(s,2H),1.10(s,6H).

[0184] Example 11. 4-((5-(difluoromethyl)-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide [ka]

[0185] Following the procedure described in step 3 of example 4, intermediate 4 and 4-amino-3-fluorobenzenesulfonamide gave the title compound as a white solid (156.8 mg, 19% yield). MS (ES+) C18H19F3N6O3S theoretical: 456, observed: 457 [M+H]+. 1H-NMR (400MHz, DMSO-d6) δ ppm 9.84(s,1H), 8.67(s,1H), 8.26(s,1H), 8.10(t,1H,J=8.0Hz), 7.98(s,1H), 7.68-7.65(m,2H), 7.42(s,2H), 7.22(t,1H,J=53.6Hz), 4.79(s,1H), 4.12(s,2H), 1.09(s,6H).

[0186] Example 12. (R)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or (S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0187] Step 1. Synthesis of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol (Intermediate 14) [ka]

[0188] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 2.05 mmol), 2-ethyl-2-methyloxirane (220 mg, 2.05 mmol) and Cs2CO3 (2.02 g, 6.16 mmol) in NMP (10 mL) was heated to 120 °C under microwave irradiation for 30 min, which showed about 75% product by LCMS and the resulting reaction mixture was used directly in the next step. MS (ES+) C14 H 25 Theoretical value of BN2O3: 280, Observed value: 281 [M+H] + .

[0189] Step 2. Synthesis of 1-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (Intermediate 15) [ka]

[0190] To the reaction mixture of step 1 (intermediate 14) was added 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (404 mg, 2.05 mmol), Pd(dppf)Cl2 (38 mg, 0.05 mmol), Cs2CO3, dioxane (3 mL) and H2O (1 mL). The resulting mixture was stirred at 90 °C under N2 for 2 h. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with MeOH / DCM (1 / 20) to give the title compound (250 mg, 39% yield) as a yellow solid. MS (ES+) C 13 H 16 F3N5O theoretical value: 315, observed value: 316 [M+H] + .

[0191] Step 3. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Intermediate 16) [ka]

[0192] A mixture of intermediate 15 (250 mg, 0.79 mmol), 4-bromo-3-fluorobenzene-1-sulfonamide (201 mg, 792 μmol), potassium acetate (232 mg, 2.37 mmol) and BrettPhos Pd G4 in dioxane (5 mL) under N2 was stirred for 2 h at 90° C. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with MeOH / DCM (1 / 10) followed by preparative HPLC (basic conditions) to give the title product (180 mg).

[0193] Step 4. Synthesis of (R)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or (S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 12) [ka]

[0194] Intermediate 16 (180 mg) was separated by chiral-SFC (column: AD-H 20×250 mm, 10 um (Daicel); column temperature: 35° C.; mobile phase: CO2 / IPA (1% methanol ammonia)=80 / 20; flow rate: 80 g / min) to give peak 1, Example 12 (73.2 mg, 19% yield). MS (ES+) C 19 H 20 F4N6O3S theoretical value: 488, observed value: 489 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.11(s,1H),8.77(s,1H),8.25(s,1H),8.04-8.00(m,1H),7.95(s,1H),7.70-7.67(m,2H),7. 45(s,2H),4.67(s,1H),4.12(s,2H),1.34(q,2H,J=7.6Hz),1.00(s,3H),0.87(t,3H,J=7.6Hz).

[0195] Example 13. 3-Fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or or 3-fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0196] Following the procedure described in Step 3 of Example 9, intermediate 13-P1 and 4-bromo-3-fluorobenzene-1-sulfonamide gave the title compound as a white solid (72 mg, 32% yield). MS (ES+) C 18 H 18 F4N6O3S theoretical value: 474, observed value: 475 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.76(s,1H),8.24(s,1H),8.02(t,J=8.4Hz,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(s ,2H),4.95(s,1H),4.32-4.28(m,1H),3.88-3.85(m,1H),1.42(d,J=7.2Hz,3H),0.90(d,J=6.4Hz,3H).

[0197] Example 14. 4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide [ka]

[0198] A mixture of 4-amino-3-methylbenzene-1-sulfonamide (30 mg, 161 μmol) and intermediate 2 (50.8 mg, 177 μmol) in IPA (6 mL) and TsOH (55.4 mg, 322 μmol) was stirred at 120° C. for 2 days. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (2.1 mg, 2% yield) as a white solid. MS (ES+) C 18 H 21 ClN6O3S theoretical value: 436, observed value: 437 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 9.11(s,1H),8.51(s,1H),8.47(s,1H),8.13(s,1H),7.84(d,J=8.4Hz,1H),7.68-7. 64(m,2H),7.23(br.s,2H),4.80(br.s,1H),4.12(s,2H),2.33(s,3H),1.09(s,6H).

[0199] Example 15: 3-Fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or or 3-fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0200] Following the procedure described in Step 3 of Example 9, intermediate 13-P2 and 4-bromo-3-fluorobenzene-1-sulfonamide gave the title compound as a white solid (96.2 mg, 47% yield). MS (ES+) C 18 H 18 F4N6O3S theoretical value: 474, observed value: 475 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.76(s,1H),8.24(s,1H),8.02(t,J=8.0Hz,1H),7.95(s,1H),7.70-7.67(m,2H),7.45(s ,2H),4.93(s,1H),4.33-4.29(m,1H),3.88-3.85(m,1H),1.42(d,J=6.8Hz,3H),1.02(d,J=6.0Hz,3H).

[0201] Example 16: 3-Fluoro-4-((4-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0202] Step 1. Synthesis of methyl 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (Intermediate 17) [ka]

[0203] To a solution of 4-bromo-1H-pyrazole (1 g, 6.80 mmol) in anhydrous DMF was added NaH (326 mg, 13.6 mmol) at 0° C., followed by methyl 2,4-dibromobutanoate (1.94 g, 7.48 mmol). The mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel eluted with EA / PE (1 / 1) to give methyl 1-(4-bromo-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (700 mg, 42% yield) as a white solid.

[0204] A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.08 g, 4.27 mmol), 1-(4-bromo-1H-pyrazol-1-yl)methyl cyclopropane-1-carboxylate (700 mg, 2.85 mmol), Pd(dppf)Cl2 (417 mg, 570 μmol) and KOAc (559 mg, 5.7 mmol) was stirred at 100° C. overnight under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 1) to give the title compound (700 mg, 84% yield) as a white solid. MS (ES+) C 14 H 21 Theoretical value for BN2O4: 292, Observed value: 293 [M+H]+ .

[0205] Step 2. Synthesis of methyl 1-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (Intermediate 18) [ka]

[0206] A mixture of 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (403 mg, 2.04 mmol), intermediate 17 (400 mg, 1.36 mmol), Na2CO3 (288 mg, 2.7 mmol) and Pd(dppf)Cl2 (199 mg, 272 μmol) in dioxane (20 mL) and H2O (5 mL) was stirred at 80 °C overnight under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with MeOH / DCM (5%) to give the title compound (203 mg, 46% yield) as a white solid. MS (ES+) C 13 H 12 Theoretical value for F3N5O2: 327, Observed value: 328 [M+H] + .

[0207] Step 3. Synthesis of methyl 1-(4-(2-((2-fluoro-4-sulfamoylphenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)cyclopropane-1-carboxylate (Intermediate 19) [ka]

[0208] A mixture of intermediate 18 (200 mg, 611 μmol), 4-bromo-3-fluorobenzene-1-sulfonamide (232 mg, 916 μmol), BrettPhos Pd G4 (100 mg) and KOAc (119 mg, 1.22 mmol) in dioxane (5 mL) was stirred at 100° C. overnight under N2. LCMS showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel eluting with MeOH / DCM (5%) to give the title compound (71 mg, 23% yield) as a white solid. MS (ES+) C 19 H 16 F4N6O4S theoretical value: 500, observed value: 501 [M+H] + .

[0209] Step 4. Synthesis of 3-fluoro-4-((4-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 16) [ka]

[0210] To a solution of intermediate 19 (60 mg, 119 μmol) in THF / EtOH (v / v=1:1, 1 mL) was added LiBH4 (25.9 mg, 1.19 mmol) and the mixture was stirred at 0° C. for 1 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (5.6 mg, 10% yield) as a white solid. MS (ES+) C 18 H 16 F4N6O3S theoretical value: 472, observed value: 473 [M+H] + . 1 H-NMR(400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.77(s,1H),8.27(s,1H),8.02(t,J=8.0Hz,1H),7.94(s,1H),7.70-7.6 5(m,2H),7.44(s,2H),5.10(t,J=5.6Hz,1H),3.63(d,J=5.6Hz,2H),1.24-1.05(m,4H).

[0211] Example 17. Synthesis of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)benzenesulfonamide

[0212] Step 1. Synthesis of 1-(4-(2-chloro-5-methylpyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 20) [ka]

[0213] Following the procedure described in step 1 of Example 3, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 2,4,5-trichloropyrimidine gave the title compound as a white solid (170 mg, 85% yield). MS (ES+) C 11 H 12 C l2 Theoretical value for N4O: 266, observed value: 267 [M+H]+.

[0214] Step 2. Synthesis of 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)benzenesulfonamide (Example 17) [ka]

[0215] To a mixture of intermediate 20 (160 mg, 599 μmol) and 4-aminobenzenesulfonamide (123 mg, 718 μmol) in IPA (5 mL) was added TsOH (204 mg, 1.19 mmol). The reaction mixture was stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (76.3 mg, 31% yield) as a white solid. MS (ES+) C18 H 22 N6O3S theoretical value: 402, observed value: 403 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 9.85(s,1H),8.37(s,1H),8.34(s,1H),8.10(s,1H),7.96(d,J=8.8Hz,2H),7.54 (d,J=8.8Hz,2H),7.16(s,2H),4.81(s,1H),4.14(s,2H),2.34(s,3H),11(s,6H).

[0216] Example 18. 4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide

[0217] Step 1. Synthesis of 1-(4-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 21) [ka]

[0218] Following a procedure similar to that described in step 1 of Example 3, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 2,4-dichloro-5-fluoropyrimidine was used to obtain the title compound (200 mg, 62% yield). MS (ES+) C 11 H 12 ClFN4O theoretical value: 270, observed value: 271 [M+H] + .

[0219] Step 2. 4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 18) [ka]

[0220] Following the procedure described in Step 3 of Example 4, intermediate 21 and 4-aminobenzenesulfonamide gave the title compound as a white solid (15.1 mg, 10% yield). MS (ES+) C 17 H 19 FN6O3S theoretical value: 406, observed value: 407 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.59(s,1H,J=2.8Hz),8.39(s,1H),8.13(s,1H),7.94(d,J=8.8Hz ,2H),7.76(d,J=8.8Hz,2H),7.18(s,2H),4.82(s,1H),4.16(s,2H),1.10(s,6H).

[0221] Example 19. 4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide

[0222] Step 1. Synthesis of 4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine-5-carbonitrile (Intermediate 22) [ka]

[0223] Following a procedure similar to that described in step 1 of Example 3, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile gave the title compound as a yellow solid (400 mg, 85% yield). MS (ES+) C 13 H 15 N5OS theoretical value: 289, observed value: 290 [M+H] + .

[0224] Step 2. Synthesis of 4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (Intermediate 23) [ka]

[0225] To a mixture of intermediate 22 (400 mg, 1.38 mmol) in DCM (20 mL) was added m-CPBA (477 mg, 2.76 mmol). The reaction mixture was stirred at 25° C. for 16 h. The mixture was filtered and the filtrate was purified by flash chromatography on silica gel eluted with EA / PE (5 / 1) to give the title compound (110 mg, 24% yield) as a yellow solid. MS (ES+) C 13 H 15 N5O3S theoretical value: 321, observed value: 322 [M+H] + .

[0226] Step 3. Synthesis of 4-((5-cyano-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Example 19) [ka]

[0227] Following a procedure similar to that described in step 3 of Example 4, intermediate 23 and 4-amino-3-fluorobenzenesulfonamide gave the title compound as a white solid (23.6 mg, 22% yield). MS (ES+) C 18 H 18 FN7O3S theoretical value: 431, observed value: 432 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 9.96(s,1H),8.87(s,1H),8.53(s,1H),8.16(s,1H),8.02-7.98(m,1H), 7.71-7.67(m,2H),7.47(s,2H),4.84(s,1H),4.15(s,2H),1.09(s,6H).

[0228] Example 20. (R)-3-Fluoro-4-((4-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0229] Step 1. Synthesis of (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Intermediate 24) [ka]

[0230] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol), (2R)-2-methyloxirane (448 mg, 7.72 mmol) and Cs2CO3 (5.01 g, 15.4 mmol) in ACN (15 mL) under N2 was stirred at 80 °C overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with PE / EA (1 / 1) to give the title compound (800 mg, 62% yield) as a yellow solid. MS (ES+) C 12 H 21 Theoretical value of BN2O3: 252, Observed value: 253 [M+H] + .

[0231] Step 2. Synthesis of (2R)-1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol (Intermediate 25) [ka]

[0232] A mixture of intermediate 24 (500 mg, 1.98 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (642 mg, 2.96 mmol), Pd(dppf)Cl2 (72.6 mg, 99.0 μmol) and potassium carbonate (409 mg, 2.96 mmol) in dioxane (6 mL) and H2O (1.5 mL) under N2 was stirred at 90 °C overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with PE / EA (1 / 1) to give the title compound (300 mg, 49% yield) as a yellow solid. MS (ES+) C 11 H 10 ClF3N4O theoretical value: 306, observed value: 307 [M+H] + .

[0233] Step 3. Synthesis of (R)-3-fluoro-4-((4-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 20) [ka]

[0234] To a mixture of intermediate 25 (150 mg, 489 μmol) and 4-amino-3-fluorobenzene-1-sulfonamide (111 mg, 586 μmol) in IPA (8 mL) was added TsOH (84.2 mg, 498 μmol) and the reaction was stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (acidic conditions) to give the title compound (21.8 mg, 9% yield) as a white solid. MS (ES+) C 17 H 16 F4N6O3S theoretical value: 460, observed value: 461 [M+H] + . 1H NMR (400MHz,DMSO) δ 10.08(s,1H),8.77(s,1H),8.25(s,1H),8.02(t,J=8.0Hz,1H),7.96(s,1H),7.70-7.67( m,2H),7.44(s,2H),4.98(s,1H),4.14-4.09(m,2H),4.00(s,1H),1.05(d,J=6.0Hz,3H).

[0235] Example 21. 3-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide

[0236] Step 1. Synthesis of 4-bromo-3-fluoro-2-methylbenzenesulfonamide (Intermediate 26) [ka]

[0237] To a mixture of 4-bromo-3-fluoro-2-methylaniline (204 mg, 1.00 mmol) in ACN (12 mL) was added AcOH (0.6 mL) and concentrated hydrochloric acid (0.7 mL) at 0 °C. Sodium nitrite (82.1 mg, 1.19 mmol) in water (0.5 mL) was added slowly. After stirring at 0 °C for 20 min, SO2 was pumped into the reaction mixture at 0-5 °C for 1.5 h, then CuCl2 (159 mg, 1.19 mmol) was added and SO2 was pumped into the resulting mixture for another 1 h. The reaction was then stirred at 0 °C for 1 h, cold water was added and the mixture was extracted with DCM. The organic layer was washed with brine and concentrated. The residue was dissolved in DCM and then slowly added to cold NH3 / MeOH solution. After stirring for 10 min, the reaction was diluted with DCM, washed with water and concentrated. Then, EA / PE=1:5 was added and the resulting solid was collected by filtration to give the title product (120 mg, 45% yield) as a yellow solid. MS (ES+) C7H7BrFNO2S theoretical: 267, observed: 268 [M+H] + .

[0238] Step 2. Synthesis of 1-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 27) [ka]

[0239] Following the procedure described in step 1 of Example 3, 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol gave the title compound as a yellow solid (1.7 g, 74% yield). MS (ES+) C 12 H 14 F3N5O theoretical value: 301, observed value: 302 [M+H] + .

[0240] Step 2. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide (Example 21) [ka]

[0241] Following the procedure described in step 3 of Example 12, 4-bromo-3-fluoro-2-methylbenzene-1-sulfonamide and 1-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol afforded the title compound as a yellow solid (54.8 mg, 25% yield). MS (ES+) C 19 H 20 F4N6O3S theoretical value: 488, observed value: 489 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 9.97(s,1H),8.77(s,1H),8.25(s,1H),7.95(s,1H),7.90-7.84(m,1H),7.74- 7.71(m,1H),7.49(s,2H),5.60(s,1H),4.12(s,2H),2.54(s,3H),1.08(s,6H).

[0242] Example 22. 3-Fluoro-4-((4-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0243] Step 1. Synthesis of 2-methyl-2-(4-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-1-ol (Intermediate 28) [ka]

[0244] Following the procedure described in step 1 of Example 3, 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol and 4-chloro-2-(methylthio)-5-(trifluoromethyl)pyrimidine gave the title compound as a yellow solid (150 mg, 48% yield). MS (ES+) C 13 H 15 F3N4OS theoretical value: 332, observed value: 333 [M+H] + .

[0245] Step 2. Synthesis of 2-methyl-2-(4-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-1-ol (Intermediate 29) [ka]

[0246] To a mixture of intermediate 28 (150 mg, 451 μmol) in DCM (20.0 mL) was added m-CPBA (155 mg, 902 μmol). The reaction mixture was stirred at 25° C. for 16 h. The mixture was filtered and the filtrate was purified by flash chromatography on silica gel eluted with EA / PE (5 / 1) to give the title compound (135 mg, 79% yield) as a yellow solid. MS (ES+) C 13 H 15 F3N4O3S theoretical value: 364, observed value: 365 [M+H] + .

[0247] Step 3. Synthesis of 3-fluoro-4-((4-(1-(1-hydroxy-2-methylpropan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 22) [ka]

[0248] To a mixture of intermediate 29 (90 mg, 247 μmol) and 4-amino-3-fluorobenzenesulfonamide (51 mg, 271 μmol) in IPA (10.0 mL) was added TsOH (4 mg, 24 μmol) and the reaction was stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (4.9 mg, 4% yield) as a white solid. MS (ES+) C 18 H 18 F4N6O3S theoretical value: 474, observed value: 475 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.76(s,1H),8.27(s,1H),8.02(t,J=8.0Hz,1H),7.96(s,1H),7.7 0-7.67(m,2H),7.67(s,1H),7.45(s,2H),5.15(s,1H),3.61(m,2H),1.50(s,6H).

[0249] Example 23. 3-Chloro-4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0250] To a mixture of 4-amino-3-chlorobenzene-1-sulfonamide (70 mg, 338 μmol) and intermediate 2 (97.0 mg, 338 μmol) in IPA (6 mL) was added TsOH (116 mg, 676 μmol), and then the mixture was stirred at 120° C. overnight. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (18.4 mg, 12% yield) as a white solid. MS (ES+) C 17 H 18 Cl2N6O3S theoretical value: 456, observed value: 457 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 9.16(s,1H),8.56(s,1H),8.54(s,1H),8.18(s,1H),8.16(d,J=8.8Hz,1H),7.90(d,J=2.4H z,1H),7.80(dd,J=8.8Hz,2.4Hz,1H),7.43(s,2H),4.79(s,1H),4.13(s,2H),1.09(s,6H).

[0251] Example 24. 4-((5-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide

[0252] Step 1. Synthesis of 1-(4-(2-chloro-5-ethylpyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 30) [ka]

[0253] Following the procedure described in step 1 of Example 3, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol and 2,4-dichloro-5-ethylpyrimidine gave the title compound as a white solid (163 mg, 84% yield). MS (ES+) C 13 H 17 Calculated value for ClNO: 280, observed value: 281 [M+H]+.

[0254] Step 2. 4-((5-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 24) [ka]

[0255] To a mixture of intermediate 30 (140 mg, 498 μmol) and 4-aminobenzenesulfonamide (102 mg, 597 μmol) in IPA (5 mL) was added TsOH (171 mg, 996 μmol) and the reaction was stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (74.6 mg, 36% yield) as a white solid. MS (ES+) C 19 H 24 N6O3S theoretical value: 416, observed value: 417 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 9.87(s,1H),8.39(s,1H),8.31(s,1H),8.06(s,1H),7.96(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H), 7.12(s,2H),4.81(s,1H),4.14(s,2H),2.74(d,J=7.6Hz,2H),1.22(d,J=7.6Hz,3H),1.11(s,6H).

[0256] Example 25. 3-Fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or or 3-fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0257] Following the procedure described in Step 3 of Example 9, intermediate 12-P1 and 4-bromo-3-fluorobenzene-1-sulfonamide gave the title compound as a white solid (43.5 mg, 25% yield). MS (ES+) C 18 H 18 F4N6O3S theoretical value: 474, observed value: 475 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.09(s,1H),8.76(s,1H),8.27(s,1H),8.04(t,J=8.0Hz,1H),7.96(s,1H),7.70-7.67(m,2H),7.43(s,2 H),5.06-5.04(m,1H),4.32-4.28(m,1H),3.88-3.85(m,1H),1.46(d,J=6.8Hz,3H),0.90(d,J=6.0Hz,3H).

[0258] Example 26: (S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or (R)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0259] Intermediate 16 (180 mg) was separated by chiral-SFC (column: AD-H 20×250 mm, 10 um (Daicel); column temperature: 35° C.; mobile phase: CO2 / IPA (1% methanol ammonia)=80 / 20; flow rate: 80 g / min) to give peak 1, Example 12 (73.2 mg, 19% yield) and peak 2, Example 26 (70.8 mg, 18% yield). MS (ES+) C 19 H 20 F4N6O3S theoretical value: 488, observed value: 489 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.11(s,1H),8.77(s,1H),8.25(s,1H),8.04-8.00(m,1H),7.95(s,1H),7.70-7.67(m,2H),7. 45(s,2H),4.67(s,1H),4.12(s,2H),1.34(q,2H,J=7.6Hz),1.00(s,3H),0.87(t,3H,J=7.6Hz).

[0260] Example 27. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxybenzenesulfonamide [ka]

[0261] Following the procedure described in Step 3 of Example 4, intermediate 1 and 4-amino-3-methoxybenzenesulfonamide gave the title compound as a white solid (52.3 mg, 34% yield). MS (ES+) C 19 H 21 F3N6O4S theoretical value: 486, observed value: 487 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 9.00(s,1H),8.77(s,1H),8.30(s,1H),8.22(d,J=8.4Hz,1H),8.00(s,1H),7.51 -7.47(m,2H),7.30(s,2H),4.80(s,1H),4.14(s,2H),3.93(s,3H),1.10(s,6H).

[0262] Example 28. 4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzenesulfonamide [ka]

[0263] A mixture of 4-amino-3-methoxybenzene-1-sulfonamide (100 mg, 494 μmol), intermediate 2 (184 mg, 642 μmol) and TsOH (170 mg, 988 μmol) in dioxane (6 mL) was stirred at 120° C. for 4 days. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (16.7 mg, 7% yield) as a white solid. MS (ES+) C 18 H 21 ClN6O4S theoretical value: 452, observed value: 453 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 8.59(s,1H),8.57(s,1H),8.43(s,1H),8.38(d,J=7.6Hz,1H),8.26(s,1H),7.51 -7.47(m,2H),7.26(s,2H),4.82(s,1H),4.15(s,2H),3.94(s,3H),1.11(s,6H).

[0264] Example 29. Synthesis of 2,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0265] Step 1. Synthesis of 4-bromo-2,3-difluorobenzenesulfonamide (intermediate 31) [ka]

[0266] To a solution of NH3 in dioxane (0.5 M, 5 mL) was added 4-bromo-2,3-difluorobenzene-1-sulfonyl chloride (300 mg, 1.02 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. The reaction mixture was diluted with EA and washed with water and brine. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 2) to give the title compound (270 mg, 97% yield) as a yellow solid.

[0267] Step 2. Synthesis of 2,3-difluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0268] A mixture of intermediate 31 (270 mg, 992 μmol), intermediate 27 (298 mg, 992 μmol), BrettPhos Pd G4 (91.3 mg, 99.2 μmol) and KOAc (291 mg, 2.97 mmol) in dioxane (10 mL) under N2 was stirred at 90° C. for 14 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (100 mg, 20% yield) as a white solid. MS (ES+) C 18 H 17 F5N6O3S theoretical value: 492, observed value: 493 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 8.80(s,1H),8.26(s,1H),7.96(s,1H),7.82(t,J=7.2Hz,1H),7.62(t,J=7.2Hz,1H),4.80(s,1H),4.12(s,2H),1.08(s,6H).

[0269] Example 30. 3-Fluoro-4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0270] Following the procedure described in Step 3 of Example 4, intermediate 21 and 4-amino-3-fluorobenzenesulfonamide gave the title compound as a white solid (6 mg, 5% yield). MS (ES+) C 17 H 18 F2N6O3S theoretical value: 424, observed value: 425 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 9.46(s,1H),8.56(d,J=2.8Hz,1H),8.35(s,1H),8.24(t,J=8.0Hz,1H),8.07( s, 1H), 7.69-7.60 (m, 2H), 7.38 (s, 2H), 4.80 (s, 1H), 4.15 (s, 2H), 1.10 (s, 6H).

[0271] Example 31 4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methylbenzenesulfonamide [ka]

[0272] A mixture of intermediate 21 (80 mg, 296 μmol), 4-amino-3-methylbenzenesulfonamide (55 mg, 296 μmol), KOAc (87 mg, 888 μmol), tBuXPhos (12.5 mg, 29.6 μmol) and Pd2(dba)3 (27.1 mg, 29.6 μmol) in dioxane (2 mL) was stirred at 90° C. for 16 h under N2. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (45.4 mg, 36% yield) as a white solid. MS (ES+) C 18 H 21 FN6O3S theoretical value: 420, observed value: 421 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 8.93(s,1H),8.49(d,J=3.2Hz,1H),8.31(s,1H),8.02(s,1H),7.90(d,J=8.4Hz,1H), 7.66-7.63(m,2H),7.20(s,2H),4.79(s,1H),4.14(s,2H),2.34(s,2H),1.10(s,6H).

[0273] Example 32. 4-((4-(1-(2-cyclopropyl-2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide

[0274] Step 1. Synthesis of 1-cyclopropyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-one (Intermediate 32) [ka]

[0275] To a solution of 2-bromo-1-cyclopropylethan-1-one (402 mg, 2.47 mmol) in MeCN (6 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 2.06 mmol) and K2CO3 (840 mg, 6.18 mmol). The mixture was stirred at 60° C. overnight. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 4) to give the title compound (362 mg, 64% yield) as a yellow solid. MS (ES+) C 14 H 21 Theoretical value of BN2O3: 276, Observed value: 277 [M+H] + .

[0276] Step 2. Synthesis of 1-cyclopropyl-2-(4-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-one (Intermediate 33) [ka]

[0277] A mixture of intermediate 32 (240 mg, 864 μmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (187.2 mg, 864 μmol), Na2CO3 (183 mg, 1.7 mmol) and Pd(tBu3P)2 (88.2 mg, 173 μmol) in dioxane (4 mL) and H2O (1 mL) was stirred at 90 °C overnight under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 2) to give the title compound (200 mg, 70% yield) as a yellow solid. MS (ES+) C 14 H 13 F3N4OS theoretical value: 342, observed value: 343[[M+H]] + .

[0278] Step 3. Synthesis of 1-cyclopropyl-2-(4-(2-(methylthio)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol (Intermediate 34) [ka]

[0279] To a solution of intermediate 33 (200 mg, 584 μmol) in MeOH (10 mL) was added NaBH4 (43.8 mg, 1.16 mmol). The reaction mixture was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel eluting with MeOH / DCM (5%) to give the title compound (113 mg, 56% yield) as a yellow solid. MS (ES+) C 14 H 15 F3N4OS theoretical value: 344, observed value: 345.

[0280] Step 4. Synthesis of 1-cyclopropyl-2-(4-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol (Intermediate 35) [ka]

[0281] To a solution of intermediate 34 (90 mg, 261 μmol) in DCM (2 mL) was added m-CPBA (90 mg, 522 μmol) and the reaction was stirred at room temperature overnight. LCMS showed the reaction was complete. The reaction mixture was purified by flash chromatography on silica gel eluted with EA / PE (1 / 1) to give the title compound (73 mg, 74% yield) as a yellow solid. MS (ES+) C 14 H 15 Theoretical value of F3N4O3S: 376, observed value: 377.

[0282] Step 5. Synthesis of 4-((4-(1-(2-cyclopropyl-2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Example 32) [ka]

[0283] To a mixture of 4-amino-3-fluorobenzene-1-sulfonamide (20.1 mg, 106 μmol) and intermediate 35 (40 mg, 106 μmol) in dioxane (2 mL) was added TsOH (9.12 mg, 53 μmol). The mixture was stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic conditions) to give the title compound (2.2 mg, 4% yield) as a yellow solid. MS (ES+) C 19 H 18 F4N6O3S theoretical value: 486, observed value: 487 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 8.75(s,1H),8.25(s,1H),8.00(t,J=8Hz,1H),7.85(s,1H),7.68(s,1H),7.66(s,1H),5.02(s,1H),4.29-4 .17(m,2H),3.30-3.20(m,1H),0.85-0.76(m,1H),0.41-0.31(m,2H),0.31-0.26(m,1H),0.12-0.06(m,1H).

[0284] Example 33. 3-Fluoro-4-((4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzenesulfonamide

[0285] Step 1. Synthesis of 2-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (Intermediate 36) or 2-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol [ka]

[0286] A mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (328 mg, 1.38 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (300 mg, 1.38 mmol), Na2CO3 (380 mg, 3.58 mmol) and Pd(dppf)Cl2 (32 mg, 35 μmol) in dioxane (6 mL) and HO (2 mL) was stirred at 90 °C overnight under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with PE / EA (1 / 1) to give peak 1 (15 mg), intermediate 36, 2-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol or 2-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol, and peak 2 (35 mg), 2-(4-(4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)-1H-pyrazol-1-yl)ethan-1-ol or 2-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol as a yellow solid. MS (ES+) C 10 Theoretical value for H8ClF3N4O: 292, observed value: 293 [M+H]+.

[0287] Step 2. Synthesis of 3-fluoro-4-((2-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-4-yl)amino)benzenesulfonamide (Example 33) [ka]

[0288] A solution of intermediate 36 (35 mg, 120 μmol), 4-amino-3-fluorobenzene-1-sulfonamide (22.7 mg, 120 μmol) and TsOH (22.7 mg, 120 μmol) in IPA (2 mL) was stirred at 90° C. for 15 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (24.7 mg, 46% yield) as a white solid. MS (ES+) C 16 H 14 Theoretical value for F4N6O3S: 446, observed value: 447[M+H]+. 1 H NMR (400MHz,DMSO) δ 9.13(s,1H),8.66(s,1H),8.15(s,1H),7.77-7.70(m,4H),7.51(s,2H),4.92-4.90(m,1H),4.19-4.06(m,2H),3.74-3.72(m,2H).

[0289] Example 34. 4-((5-cyano-4-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0290] To a mixture of intermediate 9 (70 mg, 226 μmol) and 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (64.5 mg, 271 μmol) in dioxane (5 mL) and water (0.5 mL), Pd(t-Bu3P)2 (46.1 mg, 90.4 μmol) and Na2CO3 (71.8 mg, 678 μmol) were added and the reaction was stirred at 100 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (9.7 mg, 11% yield) as a white solid. MS (ES+) C 16 H 15 N7O3S theoretical value: 385, observed value: 386 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.67(s,1H),8.91(s,1H),8.59(s,1H),8.30(s,1H),7.96(d,J=9.0Hz,2H),7.82(d,J=9. 0Hz,2H),7.25(s,2H),5.00(t,J=5.2Hz,1H),4.31(t,J=5.2Hz,2H),3.78(q,J=5.2Hz,2H).

[0291] Example 35. ((S)-3-Fluoro-4-((4-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0292] Step 1. Synthesis of (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Intermediate 37) [ka]

[0293] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.0 g, 5.15 mmol), (S)-2-methyloxirane (1.49 g, 25.77 mmol) and Cs2CO3 (5.02 g, 15.45 mmol) in ACN (25 mL) under N2 was stirred at 80 °C for 48 h. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with DCM / MeOH (20 / 1) to give the title compound (700 mg, 54% yield) as a colorless oil. MS (ES+) C 12 H 21 Theoretical value of BN2O3: 252, Observed value: 253 [M+H] + .

[0294] Step 2. Synthesis of (S)-1-(4-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)propan-2-ol (Intermediate 38) [ka]

[0295] A mixture of intermediate 37 (250 mg, 0.99 mmol), 2,4-dichloro-5-(trifluoromethyl)pyrimidine (214 mg, 0.99 mmol), NaHCO3 (249 mg, 2.97 mmol) and Pd(dppf)Cl2 (145 mg, 0.19 mmol) in THF (10 mL) and H2O (3 mL) was stirred at 60 °C for 2 h under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 1) to give the title compound (140 mg, 46% yield) as a yellow solid. MS (ES+) C 11 H 10 ClF3N4O theoretical value: 306, observed value: 307 [M+H] + .

[0296] Step 3. Synthesis of (S)-3-fluoro-4-((4-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 35) [ka]

[0297] Following the procedure described in Step 3 of Example 4, intermediate 38 and 4-amino-3-fluorobenzenesulfonamide gave the title compound as a white solid (39.2 mg, 18% yield). MS (ES+) C 17 H 16 F4N6O3S theoretical value: 460, observed value: 461 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.08(s,1H),8.77(s,1H),8.24(s,1H),8.02(t,J=8.0Hz,1H),7.96(s,1H),7.69(s,1H),7.67(s,1 H),7.44(s,2H),4.97(d,J=4.8Hz,1H),4.17-4.06(m,2H),4.02-3.96(m,1H),1.06(d,J=6.4Hz,3H).

[0298] Example 36. 3-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-methylpyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0299] Following the procedure described in Step 3 of Example 4, intermediate 20 and 4-amino-3-fluorobenzene-1-sulfonamide gave the title compound as a white solid (83.8 mg, 35% yield). MS (ES+) C 18 H 21 FN6O3S theoretical value: 420, observed value: 421 [M+H] + . 1 H NMR (400MHz,DMSO) δ 9.13(s,1H),8.35-8.32(m,3H),8.06(s,1H),7.66-7.60(m,2H),7.35(s,2H),4.78(s,1H),4.12(s,2H),2.34(s,3H),1.10(s,6H).

[0300] Example 37. 4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2,6-dimethylbenzenesulfonamide [ka]

[0301] A mixture of 4-bromo-2,6-dimethylbenzenesulfonamide (130 mg, 0.492 mmol), Intermediate 27 (148 mg, 0.492 mmol), BrettPhos Pd G4 (78 mg, 0.05 mmol) and potassium acetate (74 mg, 0.76 mmol) in dioxane (5 mL) was stirred at 100° C. overnight under N2. LCMS showed the reaction was completely converted. The reaction mixture was purified by preparative HPLC (basic conditions) to give the title product (58.2 mg, 36% yield) as a white solid. MS (ES+) C 20 H 23 F3N6O3S theoretical value: 484, observed value: 485 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.27(s,1H),8.80(s,1H),8.26(s,1H),8.04-7.99(m,1H),7.96(s,1H),7 .85(d,J=8.8Hz,1H),7.72(s,2H),4.78(s,1H),4.12(s,2H),1.08(s,6H).

[0302] Example 38. 2-Chloro-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0303] Step 1. Synthesis of 4-bromo-2-chloro-3-fluorobenzenesulfonyl chloride (Intermediate 39) [ka]

[0304] To a mixture of 4-bromo-2-chloro-3-fluoroaniline (400 mg, 1.78 mmol) in ACN (12 mL) was added AcOH (0.6 mL) and concentrated hydrochloric acid (0.7 mL) at 0 °C. Sodium nitrite (142 mg, 2.14 mmol) in water (0.5 mL) was added slowly. After stirring at 0 °C for 20 min, SO2 was pumped into the reaction mixture at 0-5 °C for 1.5 h, then CuCl2 (287 mg, 2.14 mmol) was added and SO2 was pumped into the resulting mixture for another 1 h. The reaction was stirred at 0 °C for 1 h, cold water was added and the mixture was extracted with DCM. The organic layer was washed with brine and concentrated to give the crude product (200 mg) as a yellow oil, which was used directly in the next step without further purification.

[0305] Step 2. Synthesis of 4-bromo-2-chloro-3-fluorobenzenesulfonamide (Intermediate 40) [ka]

[0306] The crude material from step 1 (Intermediate 39, 200 mg, 0.66 mmol) in DCM (3 mL) was added to cold NH3 / MeOH (10 mL) and the reaction was stirred for 10 min. The reaction was diluted with DCM and washed with water, the organic layer was concentrated, EA was added and the resulting solid was collected by filtration to give the title product (120 mg, 64% yield) as a white solid. MS (ES+) C6H4BrClFNO2S calculated: 287, observed: 288 [M+H] + .

[0307] Step 3. Synthesis of 2-chloro-3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 38) [ka]

[0308] Following the procedure described in Step 3 of Example 9, Intermediate 27 and Intermediate 40 gave the title compound as a yellow solid (60 mg, 28% yield). MS (ES+) C 18 H 17 ClF4N6O3S theoretical value: 508, observed value: 509 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.33(s,1H),8.81(s,1H),8.30(s,1H),8.00(s,1H),7.64(s,2H),7.17(s,2H),4.80(br. s, 1H), 4.13 (s, 2H), 2.59 (s, 6H), 1.10 (s, 6H).

[0309] Example 39. 4-((5-cyano-4-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0310] To a solution of intermediate 9 (100 mg, 322 μmol) and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (96.5 mg, 386 μmol) in dioxane (10 mL) and H2O (1 mL) was added Pd(t-Bu3P)2 (65.4 mg, 128 μmol) and Na2CO3 (102 mg, 965 μmol). The reaction was stirred at 100 °C for 2 h. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (17.2 mg, 13.5% yield) as a white solid. MS (ES+) C 17 H 15 N7O3S theoretical value: 397, observed value: 398 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.70(s,1H),8.93(s,1H),8.69(s,1H),8.43(s,1H),7.96(d,J=8.8Hz,2H) ,7.83(d,J=8.8Hz,2H),7.26(s,2H),5.86-5.82(m,1H),4.98-4.92(m,4H).

[0311] Example 40. 3-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methoxybenzenesulfonamide

[0312] Step 1. Synthesis of 4-bromo-3-fluoro-2-methoxybenzenesulfonyl chloride (Intermediate 41) [ka]

[0313] The title compound (200 mg, crude) was obtained from 4-bromo-3-fluoro-2-methoxyaniline following the procedure described in Step 1 of Example 38.

[0314] Step 2. Synthesis of 4-bromo-3-fluoro-2-methoxybenzenesulfonamide (Intermediate 42) [ka]

[0315] Following a procedure similar to that described in step 2 of example 28, intermediate 41 afforded the title compound as a yellow solid (150 mg, 80% yield). MS (ES+) C7H7BrFNO3S theoretical: 283, observed: 284 [M+H] + .

[0316] Step 3. Synthesis of 3-fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methoxybenzenesulfonamide (Example 40) [ka]

[0317] Following the procedure described in Step 3 of Example 9, Intermediate 27 and Intermediate 42 gave the title compound as a yellow solid (60 mg, 28% yield). MS (ES+) C 19 H 20 F4N6O4S theoretical value: 504, observed value: 505 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.09(s,1H),8.77(s,1H),8.24(s,1H),7.95(s,1H),7.67(dd,J=8.8Hz,6.4Hz,1H),7 .58(d,J=8.8Hz,1H),7.33(s,2H),4.78(s,1H),4.11(s,2H),3.98(s,3H),1.07(s,6H).

[0318] Example 41. 3-Fluoro-4-((4-(1-((3-hydroxyoxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0319] Step 1. Synthesis of 3-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)oxetan-3-ol (Intermediate 43) [ka]

[0320] To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (931 mg, 4.80 mmol), 3-(hydroxymethyl)oxetan-3-ol (500 mg, 4.80 mmol) and triphenylphosphine (1.51 g, 5.76 mmol) in toluene (20 mL) was added dropwise DIAD (1.16 g, 5.76 mmol) at 80° C. The reaction mixture was stirred overnight. LCMS showed the reaction was complete. The reaction was quenched with water and extracted with EA. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with PE / EA (4 / 1) to give the title compound (700 mg, 52% yield) as a yellow solid. MS (ES+) C 13 H 21 Theoretical value of BN2O4: 280, Observed value: 281 [M+H] + .

[0321] Step 2. Synthesis of 3-((4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)methyl)oxetan-3-ol (Intermediate 44) [ka]

[0322] A mixture of intermediate 43 (250 mg, 892 μmol), 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (176 mg, 892 μmol), Na2CO3 (283 mg, 2.67 mmol) and Pd(dppf)Cl2 (65.2 mg, 89.2 μmol) in dioxane (10 mL) and H2O (2.5 mL) was stirred at 80 °C for 4 h under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with DCM / MeOH (5 / 1) to give the title compound (170 mg, 60% yield) as a white solid. MS (ES+) C 12 H 12 Theoretical value for F3N5O2: 315, observed value: 316 [M+H]+.

[0323] Step 3. Synthesis of 3-fluoro-4-((4-(1-((3-hydroxyoxetan-3-yl)methyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 41) [ka]

[0324] To a mixture of intermediate 44 (140 mg, 444 μmol) and 4-bromo-3-fluorobenzenesulfonamide (112 mg, 444 μmol) in dioxane (5 mL) under N2, Pd2(dba)3 (40.6 mg, 44.4 μmol), t-BuXPhos (18.8 mg, 44.4 μmol) and KOAc (130 mg, 1.33 mmol) were added and then stirred at 100 °C for 4 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (30.1 mg, 13% yield) as a white solid. MS (ES+) C 18 H 16 F4N6O4S theoretical value: 488, observed value: 489 [M+H] + . 1 H NMR (400MHz,DMSO) δ 10.10(s,1H),8.78(s,1H),8.26(s,1H),8.02(t,J=8.0Hz,1H),7.98(s,1H),7.71(s,1H), 7.68(s,1H),7.45(s,2H),6.22(s,1H),4.60-4.57(m,2H),4.53(s,2H),4.45-4.44(m,2H).

[0325] Example 42. 4-((5-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide

[0326] Step 1. Synthesis of 1-(4-(2-chloro-5-ethylpyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 45) [ka]

[0327] A mixture of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (270 mg, 1.01 mmol), 2,4-dichloro-5-ethylpyrimidine (357 mg, 2.02 mmol), Na2CO3 (136 mg, 1.29 mmol) and Pd(dppf)Cl2 (37.0 mg, 50.5 μmol) in dioxane (12 mL) and H2O (3 mL) was stirred at 90 °C overnight under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with PE / EA (1 / 1) to give the title compound (150 mg, 53% yield) as a yellow solid. MS (ES+) C 13 H 17 ClNO theoretical value: 280, observed value: 281 [M+H] + .

[0328] Step 2. Synthesis of 4-((5-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-fluorobenzenesulfonamide (Example 42) [ka]

[0329] A mixture of intermediate 45 (120 mg, 427 μmol), 4-amino-3-fluorobenzene-1-sulfonamide (97.3 mg, 512 μmol), TsOH (73.5 mg, 427 μmol) in IPA (10 mL) was stirred at 90° C. for 3 days. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (acidic condition) to give the title compound (24.3 mg, 13% yield) as a white solid. MS (ES+) C 19 H 23 FN6O3S theoretical value: 434, observed value: 435 [M+H] + . 1 H NMR (400MHz,DMSO) δ 9.16(s,1H),8.37-8.28(m,3H),8.02(s,1H),7.65-7.60(m,2H),7.35(s,2H),4 .78(s,1H),4.12(s,2H),2.75(q,J=7.2Hz,2H),1.23-1.16(m,4H),1.10(s,6H).

[0330] Example 43. 3-Fluoro-4-((4-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0331] Step 1. Synthesis of 4-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 46) [ka]

[0332] Following a procedure similar to that described in step 1 of Example 3, 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole gave the title compound as a yellow solid (200 mg, 69% yield). MS (ES+) C 11 H 10 F3N5O theoretical value: 285, observed value: 286 [M+H]+ .

[0333] Step 2. Synthesis of 3-fluoro-4-((4-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 43) [ka]

[0334] A solution of intermediate 46 (150 mg, 525 μmol), 4-bromo-3-fluorobenzene-1-sulfonamide (199 mg, 787 μmol), potassium acetate (154 mg, 1.57 mmol), and BrettPhos Pd G4 (80.6 mg, 52.5 μmol) in dioxane (3 mL) was stirred at 90° C. overnight under N2. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (110.4 mg, 45% yield) as a white solid. MS (ES+) C 17 H 14 F4N6O3S theoretical value: 458, observed value: 459 [M+H] + . 1 H NMR (400MHz,DMSO) δ 10.11(s,1H),8.79(s,1H),8.36(s,1H),8.11(s,1H),8.02(t,J=8.0Hz,1 H),7.71-7.67(m,2H),7.45(s,2H),5.80-5.75(m,1H),4.96-4.89(m,4H).

[0335] Example 44. 3-Chloro-4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)benzenesulfonamide [ka]

[0336] A mixture of intermediate 21 (80 mg, 296 μmol), 4-amino-3-chlorobenzenesulfonamide (61 mg, 296 μmol), KOAc (87 mg, 888 μmol), tBuXPhos (12.5 mg, 29.6 μmol) and Pd2(dba)3 (27.1 mg, 29.6 μmol) in dioxane (2 mL) was stirred at 90° C. for 16 h under N2. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (11.8 mg, 9% yield) as a white solid. MS (ES+) C 17 H 18 ClFN6O3S theoretical value: 440, observed value: 441 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 8.90(s,1H),8.57(d,J=2.8Hz,1H),8.36(s,1H),8.28(d,J=8.8Hz,1H),8.08(s,1H),7.90( s, 1H), 7.80 (dd, J=8.8Hz, 2.4Hz, 1H), 7.39 (s, 2H), 4.80 (s, 1H), 4.15 (s, 2H), 1.10 (s, 6H).

[0337] Example 45. 5-Fluoro-4-((4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-2-methylbenzenesulfonamide [ka]

[0338] A mixture of 4-bromo-5-fluoro-2-methylbenzenesulfonamide (225 mg, 839 μmol), 1-(4-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Intermediate 27, 252 mg, 839 μmol), BrettPhos Pd G4 (100 mg, 1.01 mmol) and potassium acetate (245 mg, 2.51 mmol) in dioxane (5 mL) was stirred at 100 °C overnight under N2. The reaction mixture was cooled to room temperature and concentrated to give a residue which was purified by flash column chromatography on silica gel eluted with PE / EA (1 / 4) and then by preparative HPLC (basic conditions) to give the title product (102 mg, 25% yield) as a white solid. MS (ES+) C 19 H 20 F4N6O3S theoretical value: 488, observed value: 489 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 10.04(s,1H),8.77(s,1H),8.25(s,1H),7.94(s,1H),7.84(d,J=7.6Hz,1H),7.67( d,J=11.2Hz,1H),7.49(s,2H),4.79(s,1H),4.12(s,2H),2.58(s,3H),1.09(s,6H).

[0339] Example 46. 4-((5-fluoro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazol-4-yl)pyrimidin-2-yl)amino)-3-methoxybenzenesulfonamide [ka]

[0340] To a mixture of intermediate 21 (100 mg, 369 μmol) and 4-amino-3-methoxybenzenesulfonamide (74.6 mg, 369 μmol) in dioxane (5 mL) under N2, Pd2(dba)3 (33.7 mg, 36.8 μmol), t-BuXPhos (15.6 mg, 36.7 μmol) and KOAc (107 mg, 1.10 mmol) were added and then stirred at 100 °C for 4 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (2.0 mg, 1% yield) as a white solid. MS (ES+) C 18 H 21 FN6O4S theoretical value: 436, observed value: 437 [M+H] + . 1 H-NMR (400MHz,DMSO-d6) δ ppm 8.59(d,J=2.8Hz,1H),8.48(d,J=8.4Hz,1H),8.41(s,1H),8.25(s,1H),8.14(s,1H),7.50(dd,J= 8.4Hz, 2.8Hz, 1H), 7.46 (s, 1H), 7.23 (s, 2H), 4.80 (s, 1H), 4.16 (s, 2H), 3.96 (s, 3H), 1.10 (s, 6H).

[0341] Example 47. 3-Fluoro-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0342] Step 1. Synthesis of 4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-amine (Intermediate 47) [ka]

[0343] A mixture of 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 1.43 mmol), 4-chloro-5-(trifluoromethyl)pyrimidin-2-amine (422 mg, 2.14 mmol), Na2CO3 (454 mg, 4.29 mmol) and Pd(dppf)Cl2 (104 mg, 143 μmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 80 °C for 2 h under N2. LCMS showed the reaction was complete. The reaction mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with EA / PE (1 / 4) to give the title compound (324 mg, 72% yield) as a yellow solid. MS(ES+)C13H14F3N5O: Calculated value: 313, Observed value: 314 [M+H] + .

[0344] Step 2. Synthesis of 3-fluoro-4-((4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (Example 47) [ka]

[0345] To a mixture of intermediate 47 (324 mg, 1.03 mmol) and 4-bromo-3-fluorobenzenesulfonamide (312 mg, 1.23 mmol) in dioxane (10 mL) under N2, KOAc (202 mg, 2.06 mmol) and BrettPhos Pd G4 (25 mg) were added and then stirred at 90° C. for 16 h. LCMS showed the reaction was complete. The reaction mixture was purified by preparative HPLC (basic condition) to give the title compound (197.6 mg, 39% yield) as a white solid. MS (ES+) C 19 H 18 F4N6O3 theoretical value: 486, observed value: 487 [M+H] + . 1H-NMR (400MHz,DMSO-d6) δ ppm 10.07(br. s.,1H),8.77(s,1H),8.29(s,1H),8.05-7.98(m,2H),7.70-7.66(m,2H),7.45(br. s.,2H),4.59-4.55(m,1H),3.99-3.96(m,2H),3.50-3.43(m,2H),2.01-1.95(m,4H).

[0346] Biological Example 1. Biochemical CDK Inhibition Assay The inhibitory effect of the compounds of the present disclosure is measured by a biochemical assay, which measures the enzymatic phosphorylation activity of CDK enzymes in complex with cyclin proteins to phosphorylate 7.5 micromolar fluorescently labeled peptide substrate 5-FAM-QSPKKG-CONH2 (FL-peptide 18, PerkinElmer, 760362) in the presence of adenosine-5'-triphosphate (ATP) and various concentrations of test compounds in 100 mM 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid (HEPES), pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 1 mM dithiothreitol (DTT), 1.0% dimethylsulfoxide (DMSO). The assay is performed at the Km of ATP of CDK enzymes in complex with cyclin proteins, or at 1.0 mM ATP. The reaction was allowed to proceed at room temperature (25 °C) until 10%-20% of the total peptide was phosphorylated and was terminated with 35 mM 2,2',2",2''-(ethane-1,2-diylnitrilo)tetraacetic acid (EDTA). The products were detected using a caliper mobility shift detection method, in which the phosphorylated peptides (products) and substrates were separated by electrophoresis and measured. Percent activity was plotted against the log concentration of the compound and the points to obtain a visually clearly understood IC 50 These assays used the following CDK enzymes in complexes with different cyclin proteins: CDK1 / cyclin B1, GST-tag (BPS, 40454), 1.5 nM used in the assay CDK2 / cyclin E (Eurofins, 14-475), 1.25 nM was used in the assay Biological assay data for the test compounds are shown below in Table 1. For inhibitory activity against CDK2 / cyclin E mutants, the following designations are used: ≦10 nM=A; >10-20 nM=B; >20-30 nM=C; >30-100 nM=D; >100=E. For inhibition of CDK1 / cyclin B1, GST-tag, ≧500 nM=A; <100-500 nM=B; <100 nM=C. [Table 1-1] [Table 1-2]

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein 【Chemical 101】 m is selected from the group consisting of 0, 1, 2, 3, and 4, Each R １ is independently selected from the group consisting of halo, OH, CN, C １ ~C ４ alkyl and C １ ~C ４ alkoxy, wherein said C １ ~C ４ alkyl and C １ ~C ４ alkoxy may each be substituted with 1 to 3 halos, Each R ２ is independently selected from the group consisting of halo, OH, CN, C １ -C ４ alkyl and C １ -C ４ alkoxy, wherein said C １ -C ４ alkyl and C １ -C ４ alkoxy may each be substituted with 1 to 3 halos, R ３ is C optionally substituted with one or two groups each independently selected from the group consisting of halo, OH, C ３ -C ６ -cycloalkyl and 3- to 6-membered heterocyclyl, wherein said C １ -C ６ -alkyl, wherein said C ３ -C ６ -cycloalkyl may be substituted with OH, wherein said 3- to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N and NR ａ and may be optionally substituted with OH on the ring carbon, or R ３ is C ３ to C ６ cycloalkyl or 3- to 6-membered heterocyclyl, where the C ３ to C ６ cycloalkyl may be substituted with OH or -CH ２ OH, where the 3- to 6-membered heterocyclyl has 1 to 4 ring heteroatoms each independently selected from the group consisting of O, S, N, and NR ａ and may then be substituted with OH or -CH ２ OH on the ring carbon, Each R ａ is independently H or C １ -C ６ alkyl, n is selected from the group consisting of 0, 1, and 2).

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula IIA, formula IIB, formula IIC, or formula IID.

3. 【Chemical Formula 102】

4.

5. Each R １ is independently selected from the group consisting of halo, methyl and methoxy, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. Each R ２ is independently selected from the group consisting of halo, CN, methyl and ethyl, where the methyl and ethyl may each be substituted with 1 to 3 halos, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. R ３ is C optionally substituted with one or two groups independently selected from the group consisting of halo, OH, cyclopropyl and oxetanyl １ -C ５ -alkyl, wherein said cyclopropyl and oxetanyl may each be substituted with OH, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ３ is C substituted with OH １ -C ５ -alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. A compound represented by the following structural formula: Each R １ is methyl, and each R ２ is independently selected from the group consisting of halo, methyl, and CF ３ , and R ３ is C １ to C ６ alkyl substituted with OH, the compound according to claim 1, or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof. Each R １ is a halo, and each R ２ is independently selected from the group consisting of halo, CN, methyl, ethyl, and CF ３ , and R ３ is C １ to C ６ alkyl substituted with OH, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. A compound represented by the following structural formula: 【Chemical 103】 or a pharmaceutically acceptable salt thereof.

11. A compound represented by the following structural formula: 【Chemical 104】 or a pharmaceutically acceptable salt thereof.

12. A compound represented by the following structural formula: 【Chemical 105】 or a pharmaceutically acceptable salt thereof.

13. A compound represented by the following structural formula: 【Chemical 106】 or a pharmaceutically acceptable salt thereof.

14. A compound represented by the following structural formula: 【Chemical 107】 or a pharmaceutically acceptable salt thereof.

15. 【Chemical 108】 A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. A composition for treating a subject suffering from solid tumor cancer, comprising a compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

17. The solid tumor cancer includes at least one of uterine cancer (including uterine carcinosarcoma and endometrial carcinoma of the uterine corpus), endometrial cancer, breast cancer (including breast invasive carcinoma, triple-negative breast cancer (TNBC), estrogen receptor (ER)+human epidermal growth factor 2 (HER2)-breast cancer, and HER2+breast cancer), ovarian cancer (e.g., ovarian serous cystadenocarcinoma), gastric cancer (including gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, pancreatic cancer, kidney cancer, head and neck cancer, liver cancer, prostate cancer, skin cancer, lymphoma (including B-cell lymphoma), sarcoma, esophageal cancer (including esophageal carcinoma), bladder cancer (including bladder urothelial carcinoma), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., epidermal growth factor receptor mutant (EGFRm)+non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma. The composition according to claim 16.

18. The composition according to claim 16, wherein the solid tumor cancer is breast cancer. ​ ​ The composition according to claim 16, wherein the solid tumor cancer is a hormone receptor-positive human epidermal growth factor 2-negative (HR+ / HER2−) breast cancer. The composition according to claim 16, wherein the solid tumor cancer is endometrial cancer. The composition according to claim 16, wherein the solid tumor cancer is ovarian cancer. The composition according to claim 16, wherein the solid tumor cancer has amplification and / or overexpression of CCNE1 or CCNE2.

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