Substituted pyrimidinilupyrazole as a CDK2 inhibitor

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 of related applications This application claims the interests and priority of U.S. Provisional Patent Application No. 63 / 211,426, filed on 16 June 2021, and U.S. Provisional Patent Application No. 63 / 327,474, filed on 5 April 2022, the respective disclosures of which are incorporated herein by reference in their entirety for all purposes. [Background technology]

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

[0003] Cyclin-dependent kinase 2 (CDK2) is involved in a range of biological activities. CDK2 is a crucial cell cycle regulator, active throughout late G1 and S phases. CDK2 participates in the homologous recombination (HR) pathway-mediated DNA damage response (DDR). CDK2 also regulates 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-CDK2 complex inhibitors), are major regulators of CDK2 activity. In cancer, dysregulation of CDK2 binding by cyclins E1, E2, A1, or A2, or activity of cyclin-dependent kinase inhibitor proteins, may occur. (See S. Tadesse et al., Drug Discovery Today, Volume 25, Number 2 February 2020)

[0004] CDK2 dysregulation can occur through 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 cancer, endometrial cancer, and other cancers are associated with CCNE1 overexpression or amplification (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 CDK2-targeting drugs are currently approved. Therefore, the development of new CDK2 inhibitors is needed. [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 [Overview of the Initiative] [Means for solving the problem]

[0006] The applicant has discovered novel compounds that are effective inhibitors of CDK2 (see Synthesis Examples 1–46). In particular, the compounds of the Disclosure have been demonstrated to effectively inhibit CDK2. The compounds of the Disclosure (also referred to herein as “Disclosed Compounds”) or their pharmaceutically acceptable salts effectively inhibit CDK2 (see Biological Example 1) and can be used in the treatment of various cancers. Importantly, the Disclosed Compounds are selective CDK2 inhibitors, meaning they have little to no activity against CDK1. Advantages associated with such selectivity may include enhanced effective administration and reduced toxicity on targets via CDK1. Some of the Disclosed Compounds also have the advantage of high microsomal stability. The compounds of the Disclosure may also have favorable toxicity profiles related to other non-kinase targets.

[0007] In one embodiment, this disclosure relates to the following structural formula (I), namely [ka] This provides the compound represented by [the given formula], or a pharmaceutically acceptable salt thereof. The definitions of each variable are given below.

[0008] In another embodiment, the pharmaceutical compositions provided in this disclosure comprise a pharmaceutically acceptable carrier or diluent and one or more compounds disclosed herein or pharmaceutically acceptable salts thereof ("Pharmaceutical Compositions of the Disclosure").

[0009] This disclosure provides a method for treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound of the Disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure. In one embodiment, cancer is uterine cancer (including uterine carcinosarcoma, endometrial carcinoma of the uterine body), endometrial cancer, breast cancer (including invasive breast 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 (gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumor), colorectal cancer, These include 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 urothelial carcinoma of the bladder), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., epidermal growth factor receptor variant (EGFRm)+ non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma.

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

[0011] The therapeutic methods disclosed herein further include effective doses of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lymphalza®), niraparib, carboplatin, cisplatin, paclitaxel, gemcitabine, megestrol acetate, medroxyprogesterone acetate, capecitabine (e.g., Xeloda®), regorafenib (e.g., Stivarga®), afatinib (e.g., Giotrif®), osimertinib (e.g., This includes administering to subjects Tagrisso®, gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, pralcetinib, ABT-263 (Navitoclax), MK-1775 (adavocertib), BAY-1895344, belzocertib, ceraracertib, SRA-737, LY2603618 (labcertib), or trastuzumab (e.g., Herceptin®), or a combination thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib (JBJ-04-125-02), alflutinib (AST2818), aumorertinib (formerly amonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, razertinib, and na The antibody may be selected from zartinib (EGF816), abitinib, PCC-0208027, regibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, nesitumumab, HLX07, or JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372))).

[0012] The Disclosure also provides a method for inhibiting CDK2 in subjects in need, the method comprising administering to a subject an effective amount of a compound of the Disclosure (e.g., a compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the Disclosure.

[0013] The disclosure also provides the use of an effective amount of the compound of the disclosure (e.g., the compound of formula (I)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, for the preparation of a drug for the treatment of cancer.

[0014] In another embodiment, compounds of formula (I), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of the present disclosure for use in the treatment of cancer are provided herein.

[0015] In one embodiment, the Disclosure provides a method for treating a subject who has or is at risk of developing a CDK2-related disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically 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 the control expression level of CCNE1. In some embodiments, the CDK2-related disease or disorder is cancer.

[0016] Furthermore, this specification also provides a method for treating patients who have amplified levels of CCNE1 expression and who have or are at risk of developing solid tumors, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0017] The intended solid tumor cancer may be at least one of the following: uterine cancer (including uterine carcinosarcoma and endometrial carcinoma of the uterine body), endometrial cancer, breast cancer (including invasive breast 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 (gastric adenocarcinoma), gastric cancer (including gastrointestinal stromal tumors), 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 urothelial carcinoma of the bladder), lung cancer (squamous cell carcinoma of the lung and non-small cell lung cancer, e.g., epidermal growth factor receptor variant (EGFRm) + non-small cell lung cancer), cholangiocarcinoma, adrenocortical carcinoma, or mesothelioma. [Modes for carrying out the invention]

[0018] Detailed description of the invention definition As used herein, the term "halo" means halogen, and includes chloro, fluoro, bromo, and iodine.

[0019] The term "alkyl," used alone or as part of a larger term such as "alkoxy" or "haloalkyl," refers to a saturated aliphatic linear or branched monovalent hydrocarbon group. Unless otherwise specified, alkyl groups typically have 1 to 4 carbon atoms, i.e., (C1-C4)alkyl. As used herein, a "(C1-C4)alkyl" group refers to a group having 1 to 4 carbon atoms in a linear or branched configuration. Examples include methyl, ethyl, n-propyl, and isopropyl.

[0020] The term "alkoxy" refers to an alkyl group bonded via an oxygen-bonding 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, cycloalkyls have 3 to 6 carbon atoms. For example, C3-C6 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Unless otherwise specified, "cycloalkyl" has 3 to 6 carbon atoms.

[0022] The term "heterocyclyl" or "heterocyclic" refers to a 3- to 6-membered non-aromatic ring system having a ring carbon atom and one or two ring heteroatoms, where each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO), oxygen, and sulfur (including sulfoxides and sulfones) ("4- to 12-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the bond site can be a carbon or nitrogen atom, as long as the valence allows. Exemplary heterocyclyl groups include azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, piperazinyl, morpholinyl, azepanyl, oxepanyl, thiepanyl, and tetrahydropyridinyl.

[0023] Compounds of the Disclosure This specification discloses embodiments of compounds having the general structure of formula (I). The present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for use in the treatment of cancer. These compounds are selective inhibitors of CDK2.

[0024] In the first embodiment, this disclosure relates to the following structural formula (I), i.e. [ka] This provides a compound represented by or a pharmaceutically acceptable salt thereof (wherein each R 1 R is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, where the C1-C4 alkyl and C1-C4 alkoxy may each be substituted with 1 to 3 halos, and each R 2is independently selected from the group consisting of halo, OH, CN, C1-C4 alkyl, and C1-C4 alkoxy, where the C1-C4 alkyl and C1-C4 alkoxy may each be substituted with 1-3 halo, R 3 is C1-C6 alkyl optionally substituted with one or two groups independently selected from the group consisting of halo, OH, C3-C6 cycloalkyl, and 3-6 member heterocyclyl, where the C3-C6 cycloalkyl may be substituted with OH, and where the 3-6 member heterocyclyl has 1-4 ring heteroatoms independently selected from the group consisting of O, S, and NR a and may then be optionally substituted with OH on a ring carbon, or R 3 is C3-C6 cycloalkyl or 3-6 member heterocyclyl, where the C3-C6 cycloalkyl may be substituted with OH or -CH2OH, and where the 3-6 member heterocyclyl has 1-4 ring heteroatoms independently selected from the group consisting of O, S, and NR a and may then be optionally substituted with OH or -CH2OH on a ring carbon, 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 a compound of formula IIA, formula IIB, formula IIC, or formula IID

Chemical formula

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

[0027] In certain embodiments, each R 2R is independently selected from the group consisting of halo, CN, methyl, and ethyl, where methyl and ethyl may each be substituted with 1 to 3 halos. For example, R 2 This is a methyl molecule that may be substituted with 1 to 3 halos, for example, methyl, CF3, CF2. For example, R 2は , CN may also be used. In some embodiments, R 2 This could be a halo, for example, F, Cl, or Br.

[0028] In other embodiments, R 3 This is a C1-C5 alkyl group which may be substituted with one or two groups independently selected from the group consisting of halo, OH, cyclopropyl, and oxetanyl, where the cyclopropyl and oxetanyl groups may each be substituted with OH.

[0029] In some embodiments, R 3 These are C1-C5 alkyl groups substituted with OH groups.

[0030] In a particular embodiment, R 3 is cyclopropyl or oxetanyl, where cyclopropyl and oxetanyl are each (R) OH or CH2OH. 3 If it is oxetanyl, it may be substituted (on the ring carbon).

[0031] In certain embodiments, R3 is tetrahydropyran.

[0032] In other embodiments, each R 1 is methyl, and each R 2 R is independently selected from the group consisting of halo, methyl, and CF3. 3 These are C1-C6 alkyl groups substituted with OH.

[0033] Several embodiments, each R 1 This is a halo, and each R 2 R is independently selected from the group consisting of halo, CN, methyl, ethyl, and CF3. 3is either a C1-C6 alkyl group substituted with OH, or R 3 is oxetanyl or cyclopropyl, where oxetanyl and cyclopropyl are each CH2OH (R 3 If it is oxetanyl, it may be substituted (on the ring carbon).

[0034] In other embodiments, each R 1 is methoxy, and each R 2 R is independently selected from the group consisting of halo, methyl, and CF3. 3 These are C1-C6 alkyl groups 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 one of the compounds disclosed in Examples and Table 1, or a pharmaceutically acceptable salt thereof.

[0037] The term "pharmacopoeiatically acceptable salt" refers to a pharmacopoeiatically acceptable salt that is suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, or allergic reactions, within the bounds of sound medical judgment, and that has a reasonable benefit / risk ratio. Pharmacopoeiatically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmacopoeiatically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0038] This instruction includes pharmaceutically acceptable salts of the compounds disclosed herein. Compounds having a basic group can form pharmaceutically acceptable salts using pharmaceutically acceptable acids. Suitable pharmaceutically 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 this instruction having an acidic group such as a carboxylic acid can form pharmaceutically acceptable salts using pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic 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 containing one or more chiral centers can exist in various stereoisomers; that is, each chiral center can have an R configuration, an S configuration, or a mixture of both. Stereoisomers are compounds that differ only in their spatial configuration. Stereoisomers include all diastereomers and enantiomers of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers containing two or more chiral centers that are neither identical nor mirror images of each other.

[0040] If the stereochemical configuration at a chiral center in a compound having one or more chiral centers is indicated by its chemical name (e.g., if the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., if the configuration is indicated by a "wedge" bond), then the concentration 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). The "concentration of the indicated configuration compared to the opposite configuration" is expressed in mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center(s) by the total number of compounds in the mixture having the same or opposite stereochemical configurations.

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

[0042] When two stereoisomers are indicated by their chemical names or structures, and the chemical names or structures are linked by "and", a mixture of the two stereoisomers is intended.

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

[0044] If a disclosed compound having a chiral center is shown by structure without indicating the configuration at the chiral center, this structure means that it encompasses compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. If a disclosed compound having a chiral center is shown by its chemical name without indicating the configuration at the chiral center with "S" or "R", this name means that it encompasses compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0045] A racemic mixture means a mixture in which one enantiomer is 50% and its corresponding enantiomer is 50%. This instruction encompasses all enantiomerically pure, enantiomerically concentrated, diastereomerically pure, diastereomerically concentrated racemic and diastereomeric mixtures of the compounds disclosed herein.

[0046] Enantiomerous and diastereomerous mixtures can be decomposed into their enantiomers or stereoisomers by known methods, including chiral phase gas chromatography, chiral phase high-performance liquid chromatography, crystallization of compounds as chiral salt complexes, or crystallization of compounds in chiral solvents. Enantiomers and diastereomers can also be obtained from diastereomerically or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthesis methods.

[0047] In the experimental section, "Peak 1" refers to the target reaction product obtained from chromatographic separation / purification. This reaction product elutes faster than the second target reaction product from the same aforementioned reaction. The second target product is called "Peak 2".

[0048] If a disclosed compound is specified by a name or structure that represents a single enantiomer, unless otherwise indicated, the compound is optically pure (also called “enantiomerically pure”) to at least 60%, 70%, 80%, 90%, 99%, or 99.9%. Optical purity is calculated by dividing the weight of the specified or indicated enantiomer in the mixture by the total weight of the mixture of both enantiomers.

[0049] If the stereochemistry of a disclosed compound is specified or shown by structure, and this specified or shown structure includes more than one stereoisomer (for example, as in the case of a diastereomer pair), it should be understood that, unless otherwise indicated, it includes one of the included stereoisomers or any mixture of the included stereoisomers. It should further be understood that the stereoisogenic purity of the specified or shown stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisogenic purity is determined by dividing the total weight of the mixture of stereoisomers included by name or structure by the total weight of the mixture of all stereoisomers.

[0050] In the compounds of this disclosure, any position specifically designated as “D” or “deuterium” is understood to have a deuterium concentration of 50%, 80%, 90%, 95%, 98%, or 99%. “Deuterium concentration” is a mole percent 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”, that position has hydrogen in its natural abundance. If a position is not specified as to whether hydrogen or deuterium is present, that position has hydrogen in its natural abundance. One specific and alternative embodiment relates to a compound of this disclosure having a deuterium concentration 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 parts (e.g., alkyl, alkoxy, cycloalkyl, or heterocyclyl) are referred to as “substituted” or “may be substituted.” When a part is modified by one of these terms, unless otherwise specified, it means that any part of the part known to those skilled in the art as being available for substitution may be substituted, and this includes one or more substituents. If more than one substituent is present, each substituent may be selected independently. Such substitution methods are well known in the art and / or taught herein. Any optional substituent may be any substituent suitable for bonding to this part.

[0052] The compounds disclosed herein are CDK2 inhibitors. As used herein, the term “selective CDK2 inhibitor” means a compound that selectively inhibits CDK2 more than other CDKs and quinomes. In other words, selective CDK2 inhibitors have no activity or low activity towards other CDKs and quinomes. The inhibitory activity of selective CDK2 inhibitors towards CDK2 is compared to their inhibitory activity towards other CDKs and many other kinases, with respect to IC2. 50 Value (i.e., IC) 50 It is more effective in terms of values ​​being below nanomolar. Effectiveness can be measured using known biochemical assays.

[0053] In some embodiments, the compounds of the present disclosure are selective to CDK2 compared to CDK1. In some such embodiments, the compounds exhibit at least 10 times greater selectivity to CDK2 compared to CDK1. In other embodiments, the compounds exhibit at least 20 times greater selectivity to CDK2 compared to CDK1. In certain embodiments, the compounds exhibit at least 30 times greater selectivity to CDK2 compared to CDK1. In certain embodiments, the compounds exhibit at least 40 times greater selectivity to CDK2 compared to CDK1. In other embodiments, the compounds exhibit at least 50 times greater selectivity to CDK2 compared to CDK1. For example, the compounds exhibit at least 100 times greater selectivity to CDK2 compared to CDK1. In some embodiments, the compounds of the present invention are selective to CDK2 compared to CDK4 and / or CDK6. In some such embodiments, the compounds exhibit at least 10 times greater selectivity to CDK2 compared to CDK4 and / or CDK6. In other embodiments, the compound exhibits at least 20 times greater selectivity for CDK2 compared to CDK4 and / or CDK6. In specific embodiments, the compound exhibits at least 30 times greater selectivity for CDK2 compared to CDK4 and / or CDK6.

[0054] Some of the compounds in this disclosure have the advantage of good metabolic stability. One indicator of good metabolic stability is high microsomal stability. Hepatic metabolism is the dominant excretion pathway for small molecule drugs. The clearance of compounds 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 consumption of the compound is measured to determine the intrinsic clearance (Clint) in vitro. Clint is scaled to systemic clearance (CL), and the hepatic extraction rate (ER) is determined by dividing CL by the standard human hepatic blood flow. Compounds with a low hepatic extraction rate are considered to have good metabolic stability. In some embodiments, the compounds in this disclosure have calculated ERs of <0.3, <0.4, <0.5, and <0.6.

[0055] Pharmaceutical composition The pharmaceutical compositions of this disclosure (also referred to herein as “Disclosed Pharmaceutical Compositions”) comprise one or more pharmaceutically acceptable carriers or diluents and one or more compounds of this disclosure (e.g., compounds of formula (I)) or pharmaceutically acceptable salts thereof.

[0056] "Pharmacopoeia-acceptable carriers" and "pharmacopoeia-acceptable diluents" refer to substances that can be included in the pharmaceutical compositions of this disclosure to assist in the formulation and / or administration of active agents to subjects and / or absorption by subjects, without causing significant adverse toxicity to subjects. Non-limiting examples of pharmacopoeia-acceptable carriers and / or diluents include water, NaCl, physiological saline, lactated Ringer's solution, usually sucrose, usually glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and colorants. Such preparations can be sterilized and optionally mixed with excipients, examples of which include lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatics, which do not react adversely 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 pharmaceutically acceptable salts thereof.

[0057] The pharmaceutical compositions of this disclosure may contain one or more pharmaceutically acceptable carriers and / or diluents thereof, examples of which include lactose, starch, cellulose, and dextrose. Other excipients such as flavoring additives and sweeteners, and preservatives such as methyl, ethyl, propyl, and butylparabens may also be included. Handbook of Pharmaceutical Excipients (5) thA more complete list of suitable excipients is provided in Ed., Pharmaceutical Press (2005). Those skilled in the art will know how to prepare formulations suitable for various routes of administration. Conventional procedures and components for the selection and preparation of suitable formulations are described, for example, in Remington's Pharmaceutical Sciences (2003 - 20th edition) and in The United States Pharmacopeia: The National Formulary (USP 24 NF19), published in 1999. Carriers, diluents, and / or excipients are “acceptable” in the sense that they are compatible with the other components of the pharmaceutical composition and are not harmful to its recipient.

[0058] Treatment methods The compounds disclosed herein inhibit CDK2 and are therefore useful in treating diseases in which CDK2 is dysregulated, such as cancer. This disclosure provides a method for inhibiting CDK2 in a subject who needs to have CDK2 inhibited, the method comprising administering to the subject an effective amount of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

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

[0060] Subjects who "need to inhibit CDK2" are those with a disease in which inhibiting CDK2 could achieve beneficial therapeutic effects, such as delaying disease progression, alleviating one or more disease-related symptoms, or extending the subject's lifespan considering the disease.

[0061] In some embodiments, the Disclosure provides a method for treating a disease / condition / or cancer related to or modulated by CDK2, wherein inhibition of said CDK2 is therapeutically beneficial, and this benefit includes, but is not limited to, the treatment of cancer in a subject requiring treatment for cancer. The method comprises administering to a subject an effective amount of one of the compounds disclosed herein, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0062] In another embodiment, the Disclosure provides a method for treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically 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] Therefore, in some embodiments of this method, the subject or patient is predetermined to have amplified cyclin E1 (CCNE1) gene and / or a CCNE1 expression level higher than the control expression level of CCNE1 in the biological sample obtained from the subject or patient.

[0064] In another embodiment, the disclosure provides a method for inhibiting the proliferation of tumor (e.g., cancer) cells in vitro. This 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 disclosure provides a method for inhibiting the proliferation of tumor (e.g., cancer) cells, involving amplification and overexpression of CCNE1 in a subject or patient. This 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.

[0065] In another embodiment, the present disclosure provides a method for treating a subject having cancer, the method comprising administering to the subject an effective amount of a compound disclosed herein, a pharmaceutically 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. Cancers include solid tumors, blood, bone marrow, or lymphatic cancers, named after the type of cells that form them. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancers also include primary cancers that occur in a specific site in the body, metastatic cancers that spread from the site of origin to other parts of the body, recurrences of the first primary cancer after remission, and secondary primary cancers (new primary cancers in a person with a history of a previous cancer of a different type than the latter). In some such embodiments, cancers are characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0067] Cancers 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), kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, gastric cancer (i.e., stomach cancer), urothelial carcinoma, brain cancer, mesothelioma, skin cancer (e.g., melanoma), sarcoma, or thyroid cancer, and metastases of all listed cancers (particularly 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, a subject is confirmed to have 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 adenocarcinoma, carcinoma, or cystadenoma.

[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 each of the aforementioned embodiments, 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 embodiments, the cancer is ovarian cancer.

[0072] In some embodiments, the compounds of the Disclosure are administered as first-line therapy. In other embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with endocrine agents and / or CDK4 / CDK6 inhibitors. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with endocrine agents such as aromatase inhibitors, SERMs, or SERDs. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with CDK4 / CDK6 inhibitors. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with one or more chemotherapy regimens including, for example, taxanes or platinum-based drugs. In some embodiments, the compounds of the Disclosure are administered as second (or later)-line therapy following treatment with HER2-targeted agents (e.g., trastuzumab).

[0073] In some embodiments, CDK2-related diseases or disorders include 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 cancers with FBW7 mutations and CCNE1 overexpression (see Takada, et al., Cancer Res, 2017. 77(18): 4881-4893).

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

[0075] Examples of cancers treatable with the compounds of this disclosure include bone cancer, pancreatic cancer, skin cancer, head and neck cancer, malignant melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, testicular cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, Hodgkin's disease, non-Hodgkin lymphoma, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, chronic or acute leukemia including acute myeloid leukemia. This includes, but is not limited to, myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, childhood solid tumors, lymphocytic lymphoma, bladder cancer, cancer of the kidney or urethra, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial 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 said cancers. The compounds of this disclosure are also useful in the treatment of metastatic cancers.

[0076] In some embodiments, cancers treatable with the compounds of the Disclosure include melanoma (e.g., metastatic melanoma, BRAF and HSP90 inhibitor-resistant melanoma), renal cell carcinoma (e.g., clear cell carcinoma), prostate cancer (e.g., hormone-resistant 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). Furthermore, the Disclosure includes refractory or recurrent malignancies whose growth can be inhibited by using the compounds of the Disclosure.

[0077] In some embodiments, cancers treatable with the compounds of the 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, stomach cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), etc.), DLBCL, mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin lymphoma, or multiple myeloma), and combinations of the said cancers.

[0078] In some embodiments, cancers treatable with the compounds of the Disclosure include, but are not limited to, cholangiocarcinoma, cholangiocarcinoma, triple-negative breast cancer, rhabdomyosarcoma, small cell lung cancer, leiomyosarcoma, hepatocellular carcinoma, Ewing's sarcoma, brain cancer, brain tumors, astrocytoma, neuroblastoma, neurofibroma, basal cell carcinoma, chondrosarcoma, epithelioid sarcoma, ocular cancer, fallopian tube cancer, gastrointestinal cancer, gastrointestinal stromal tumor, hairy cell leukemia, intestinal cancer, islet cell carcinoma, oral 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 cord cancer, tongue cancer, tubular adenocarcinoma, urethral cancer, and ureteral cancer.

[0079] In some embodiments, the diseases and indications treatable with the compounds of this disclosure include, but are not limited to, hematological cancers, sarcomas, lung cancers, gastrointestinal cancers, urogenital cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0080] Exemplary blood cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, non-Hodgkin lymphoma (including relapsed or refractory NHL and relapsed follicular lymphoma), Hodgkin 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, 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 carcinoma, anaplastic small cell carcinoma, anaplastic large cell carcinoma, adenocarcinoma, alveolar epithelial (bronchiolar) carcinoma, bronchial adenoma, chondrodic 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), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), and colorectal cancer.

[0083] Exemplary urogenital 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 (seminal carcinoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenoid tumor, lipoma).

[0084] Typical liver cancers include 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 (reticular cell sarcoma), multiple myeloma, malignant giant cell chordoma, osteochondromas (osteochondrectomy), benign chondromas, chondroblastomas, chondromyxofibromas, osteoid osteomas, and giant cell tumors.

[0086] Exemplary neurological cancers include skull cancer (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meningeal cancer (meningioma, meningiosarcoma, gliomatosis), brain cancer (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord cancer (neurofibroma, meningioma, glioma, non-epithelial malignancies), as well as neuroblastoma and Lhermitt-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, unclassifiable carcinoma), granulosa-theca cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma)), and fallopian tube cancer (epithelial malignant tumor).

[0088] Exemplary skin cancers include melanoma, basal cell carcinoma, Merkel cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, dysplastic moles, lipomas, hemangiomas, dermatofibromas, and keloids. In some embodiments, diseases and indications treatable with the compounds of this 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 this disclosure may be administered as a single agent or in combination with other anticancer agents, particularly a standard of care agents appropriate for a particular cancer.

[0090] As used herein, the term “additional anticancer therapeutic agent” means any one or more therapeutic agents other than the compounds of this disclosure that are used or may be used to treat cancer. In some embodiments, such additional anticancer therapeutic agents include compounds belonging to the following classifications: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormones and antagonists, growth factor inhibitors, radiation, signaling inhibitors such as protein tyrosine kinase and / or serine / threonine kinase inhibitors, cell cycle inhibitors, biological reaction modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic agents, and immuno-oncological agents.

[0091] In some embodiments, additional anticancer agents are endocrine drugs such as aromatase inhibitors, SERDs, or SERMs.

[0092] In other embodiments, the compounds of the Disclosure may be administered in combination with standard care agents. In some embodiments, the compounds of the Disclosure may be administered in combination with endocrine therapies, such as drugs such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, the compounds of the 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 Disclosure may be administered in combination with anti-HER2 agents (e.g., trastuzumab or pertuzumab).

[0093] In some embodiments, additional anticancer agents are anti-angiogenic agents, which include, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCb inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (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 anti-angiogenic agents include batalanib (CGP79787), sorafenib (Nexavar®), pegaptanib octasodium (Macugen®), vandetanib (Zactima®), PF-0337210 (Pfizer), SU14843 (Pfizer), AZD2171 (AstraZeneca), ranibizumab (Lucentis®), Neovastat® (AE941), tetrathiomolybdata (Coprexa®), AMG706 (Amgen), VEGF Trap (AVE0005), CEP7055 (Sanofi-Aventis), XL880 (Exelixis), teratinib (BAY57-9352), and CP-868,596 (Pfizer). Other anti-angiogenic agents include enzastaurin (LY317615), midostaurin (CGP41251), perifosin (KRX0401), teprenone (Selbex®), and UCN01 (Kyowa Hakko). Other examples of anti-angiogenic agents include celecoxib (Cerelecbrex®), parecoxib (Dynastat®), dracoxib (SC59046), lumiracoxib (Preige®), valdecoxib (Bextra®), rofecoxib (Vioxx®), iguratimod (Careram®), IP751 (Investdus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia®).Other anti-angiogenic agents include exixrind (Aptosyn®), sarsalat (Amigesic®), diflunisal (Dolobid®), ibuprofen (Motrin®), ketoprofen (Ordis®), nabumetone (Lirafen®), piroxicam (Felden®), naproxen (Aleve®, Naprosyn®), diclofenac (Voltaren®), indomethacin (Indocin®), sulindac (Clinoril®), tolmetin (Tolectin®), etodolac (Lodine®), ketrolac (Toradol®), and oxaprozin (Daypro®). Other anti-angiogenic agents include ABT510 (Abbott), aplatast (TMI005), AZD8955 (AstraZeneca), incyclinide (Metastat®), and PCK3145 (Procyon).

[0094] Other anti-angiogenic agents include acitretin (Neotigason®), pritchidepsin (Apridin®), cilentide (EMD121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofdinone (Tempostatin®), Panzem® (2-methoxyestradiol), PF-03446962 (Pfizer), levimast (BMS 275291), catumaxomab (Removab®), lenalidomide (Revlimid®), squalamine (EVIZON®), thalidomide (Thalomid®), Ukraine® (NSC 631570), Vitaxin® (MEDI522), and zoledronic acid (Zometa®).

[0095] In other embodiments, additional anticancer agents are so-called signaling inhibitors (e.g., those that inhibit the way regulatory molecules governing the fundamental processes of cell proliferation, differentiation, and survival are transmitted within cells). Signaling inhibitors include small molecules, antibodies, and antisense molecules. Signaling inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signaling 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, WNT pathway inhibitors, and so-called multi-target kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in conjunction with the compounds of the present invention and the pharmaceutical compositions described herein include BMS214662 (Bristol-Myers Squibb), ronafarnib (Salazar®), peritrexol (AG2037), matuzumab (EMD7200), nimotuzumab (TheraCIM h-R3®), panitumumab (Vectibix®), vandetanib (Zactima®), pazopanib (SB 786034), ALT110 (Alteris Therapeutics), BIBW2992 (Boehringer Ingelheim), and Celven® (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), gedatricib (Pfizer), canertinib (CI1033), pertuzumab (Omnitarg®), lapatinib (Tycerb®), peritinib (EKB569), miltefosine (miltefosine®), and BMS599626 (Bristol-Myers). This includes Squibb), LapuruCel-T (Neuvenge®), NeuVax® (E75 cancer vaccine), Osidem® (IDM1), Mbritinib (TAK-165), CP-724,714 (Pfizer), Panitumumab (Vectibix®), ARRY142886 (Array Biopharm), Everolimus (Certican®), Zotarolimus (Endeavor®), Temsirolimus (Tricel®), AP23573 (ARIAD), and VX680 (Vertex), XL647 (Exelixis), Sorafenib (Nexavar®), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signaling inhibitors include ABT751 (Abbott), arbosidib (flavopyridol), BMS387032 (Bristol-Myers), EM1421 (Elimos), indishram (E7070), sericiclib (CYC200), BIO112 (Onc Bio), BMS387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG024322 (Pfizer).

[0096] In other embodiments, additional anticancer agents are so-called classic antitumor agents. Classic antitumor agents include, but are not limited to, hormones and other hormonal regulators, antihormones, androgen agonists, androgen antagonists and anti-estrogen therapeutics, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activators, ribonucleases, proteosomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., thalazoparib, olaparib, lucaparib, niraparib, iniparib, veliparib, etc.), microtubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum-coordinate compounds, gene therapies, antisense oligonucleotides, vascular targeted drugs (VTAs), and statins.Examples of classic antitumor agents used in combination therapy with the compounds of the present invention (which may be used in combination with one or more other agents) include glucocorticoids (dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone, etc.), progestins such as medroxyprogesterone, megestrol acetate (Megaace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; tamoxifen, raloxifen, rasofoxifen, afimoxifen, aldoxifen, bazedoxifen, fispemifene, olmeroxifen, ospemifene, tesmillifen, toremifene, trilostane, CHF4227 (Cheisi), etc.), and selective estrogen receptor modulators. Gonadotropin-releasing hormone (GnRH; also commonly known as luteinizing hormone-releasing hormone [LHRH]) agonists (buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), etc.), abalelix (Plenaxis), cyproterone, flutamide (Eurexin), megestrol, nilutamide (nilandrone), and osaterone, dutasteride, epristeride, finasteride, saw palmetto, PHL This includes, but is not limited to, antiandrogens such as 00801, abalerix, goserelin, leuprorelin, triptorelin, bicalutamide; enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof.Other examples of classic antitumor agents used in combination with the compounds of the present invention include suberoranilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethyl butyrate and PXD-101; Onconase (Rampillase), PS-341 (MLN-341), Velcade (Bortezomib), 9-aminocamptothecin, berotecan, BN-80915 (Roche), camptothecin, diflomothecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, and irino Tecan HCl (Camptosal), Lulutotecan, Orasecin (Rubitecan, Supergen), SN-38, Topotecan, Camptothecin, 10-Hydroxycamptothecin, 9-Aminocamptothecin, Irinotecan, SN-38, Edtecarin, Topotecan, Acralubicin, Adriamycin, Amonafide, Amrubicin, Anamycin, Daunorubicin, Doxorubicin, Elsamitrusine, Epirubicin, Etoposide, Idarubicin, Galarubicin, Hydroxycarbamide, Nemorubicin, Novant Lon (mitoxantrone), pirarubicin, pisanthrone, procarbazine, rebeccamycin, sobuzoxane, tafluposide, barrubicin, Zinecard (dexrazoxane), nitrogen mustard N-oxide, cyclophosphamide, AMD-473, altretamine, AP-5280, apadiquan, brostaricin, bendamustinbusulfan, carboquan, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, gluphosphamide, ifosphamide This includes, but is not limited to, KW-2170, lomustine, maphosphamide, mechloretamine, melphalan, mitobronitol, mitractol, mitomycin C, mitoxatron, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinate alkylated compounds (e.g., cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozosin, subtoruplatin) and combinations thereof.

[0097] In further embodiments, additional anticancer agents include so-called dihydrofolate reductase inhibitors (such as methotrexate and nutrexin (trimethrexate glucuronide)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nerarabine, and larcitrexed), pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda®), cytosine arabinoside, gemzar® (gemcitabine, Eli Lilly), tegafur (UFT Orzel or Uforal), and tegafur, gimethat and otostat) (including TS-1 combination), doxifluridine, carmofur, cytarabine (including ocphosphate, stearate phosphate, sustained-release and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine and ethinylcytidine), and other antimetabolites, such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thimitax), triapine, trimethrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazoline-6-ylmethyl)-N-methylamino)]-2-tenoyl)-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 classic antitumor cytotoxic agents include Abraxane (Abraxis BioScience, Inc.), Batablin (Amgen), EPO906 (Novartis), Vinflunin (Bristol-Myers Squibb Company), Actinomycin D, Bleomycin, Mitomycin C, Neocartinostatin (Zinostatin), Vinblastine, Vincristine, Vindesine, Vinorelbine (Navelbine), Docetaxel (Taxotere), Ortataxel, Paclitaxel (including Taxoplexin, a DHA / Paciltaxel complex), Cisplatin, Carboplatin, Nedaplatin, Oxaliplatin (Eloxatin), Satraplatin, Camptosar, Capecitabine (Xeloda), Oxaliplatin (Eloxatin), Taxotere, Altretinoin, Camphosphamide ( This includes, but is not limited to, Telcyta(trademark), DMXAA(Antisoma), ibandronate, L-asparaginase, Pegaspargus(Oncaspar(trademark)), Efaproxyn(trademark)-radiotherapy, Bexarotene(Targretin(trademark)), Tesmilifen(DPPE-enhancing cytotoxic drug efficacy), Ceratops(trademark)(Biomira), Tretinoin(Vesanoid(trademark)), Tirapazamine(Trizaone(trademark)), Motexafingadolinium(Xcytrin(trademark)), Cotara(trademark)(mAb), and NBI-3001(Protox Therapeutics), polyglutamic acid-paclitaxel(Xyotax(trademark)), and combinations thereof.Further examples of classic antitumor agents include Advexin (ING201), TNFerade (GeneVec, a compound that expresses TNFα in response to radiotherapy), RB94 (Baylor College of Medicine), Genasense (Obrimarcen, 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 (Baylor, Bayer), Rosuvastatin (Crestor, AstraZeneca), Lovostatin, Niacin (Advicor, Kos Pharmaceuticals include, but are not limited to, Caduet, Lipitor, Torcetrapib, and combinations thereof.

[0099] In other embodiments, additional anticancer agents include epigenetic modulators, such as inhibitors or EZH2, Smarca 4, 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, additional anticancer agents include immunomodulators (such as CTLA-4, PD-1, or PD-L1 inhibitors (e.g., pembrolizumab, nivolumab, or avelumab)), LAG-3, TIM-3, Tigit, 4-1BB, OX40, GITR, CD40, or CAR-T cell therapy. In some embodiments, additional anticancer agents include EGFR inhibitors such as afatinib, EGFR antibodies such as osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib or gefitinib or cetuximab, panitumumab or nesitumumab.

[0101] Alternatively, the compounds of the Disclosure herein, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein may be administered in combination with other anticancer agents that are not EGFR inhibitors, for example, in combination with MEK, including, for example, mutant MEK inhibitors (trametinib, cobimtetinib, binimetinib, selumetinib, refametinib); c-MET, mutant c-Met inhibitors (savolitinib, cabozantinib, foretinib), and MET antibodies (emibetuzumab); mitotic methyl These include anase inhibitors (CDK4 / 6 inhibitors such as palbociclib, ribociclib, and abemacisilib); anti-angiogenic agents (e.g., bevacizumab, nintedanib); apoptosis inducers such as Bcl-2 inhibitors (e.g., venetoclax, ovatoclax, navitoclax) and Mcl-1 inhibitors (e.g., AZD-5991, AMG-176, S-64315); and mTOR inhibitors (e.g., rapamycin, temsirolimus, everolimus, lidoforolimus).

[0102] The compounds disclosed herein, their pharmaceutically acceptable salts, or the pharmaceutical compositions disclosed herein include effective amounts of palbociclib (e.g., Ibrance®), ribociclib, abemaciclib, tamoxifen, letrozole, olaparib (e.g., Lymphalza®), 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 drug selected from the group consisting of Tagrisso®, gefitinib (e.g., Iressa®), erlotinib (e.g., Tarceva®), ramucirumab (e.g., Cyramza®), EGFR inhibitors, pralcetinib, ABT-263 (Navitoclax), MK-1775 (adavocertib), BAY-1895344, belzocertib, ceraracertib, SRA-737, LY2603618 (labcertib), and trastuzumab (e.g., Herceptin®), or combinations thereof. EGFR inhibitors include afatinib, osimertinib, lapatinib, erlotinib, dacomitinib, poziotinib, neratinib, gefitinib (JBJ-04-125-02), alflutinib (AST2818), aumorertinib (formerly amonertinib) (HS10296), BBT-176, BI-4020, BPI-361175, BPI-D0316, CH7233163, gilteritinib, icotinib, JND-3229, razertinib, and na The antibody may be selected from zartinib (EGF816), abitinib, PCC-0208027, regibertinib (BPI-7711), TQB3804, zolifertinib (AZ-3759), or DZD9008, or from EGFR antibodies such as cetuximab, panitumumab, nesitumumab, HLX07, or JMT101, or from bispecific EGFR and MET antibodies (e.g., amivantamab ((JNJ-61186372, JNJ-372))).

[0103] Biomarkers and pharmacodynamic markers The Disclosure further provides predictive markers (e.g., biomarkers and pharmacodynamic markers, e.g., gene copy number, gene sequence, expression level, or phosphorylation level) to identify human subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder for which administration of a CDK2 inhibitor is likely to be effective (as used herein, “CDK2 inhibitor” means the compounds of the Disclosure or their pharmaceutically acceptable salts).

[0104] CCNE1 In one embodiment, the biomarker is CCNE1. In particular, amplification of the cyclin E1 (CCNE1) gene and / or the expression level 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 pharmaceutically acceptable salt thereof.

[0105] CCNE1 is an essential cell cycle factor for regulating the cell cycle during G1 / S transition (Ohtsubo et al., 1995, Mol. Cell. Biol. 15:2612-2624). CCNE1 acts as a regulatory subunit of CDK2, interacting 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 number NM_001238). The amino acid sequence of human CCNE1 is described in Genbank accession number NP_001229 / UniProtKB accession number P24864).

[0106] In one embodiment, the Disclosure provides a method for treating a subject who has or is at risk of developing a CDK2-related disease or disorder, the method comprising administering to the subject a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically 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 the control expression level of CCNE1. In some embodiments, the CDK2-related disease or disorder is cancer.

[0107] Furthermore, this specification also provides a method for treating patients who have amplified levels of CCNE1 expression and who have or are at risk of developing solid tumors, the method comprising administering to the patient a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein.

[0108] Amplification of the CCNE1 gene and / or CCNE1 expression levels higher than the control expression level of CCNE1 indicate / predict a response to a CDK2 inhibitor in human subjects who have or are at risk of developing a CDK2-related disease or disorder. In some embodiments, the CCNE1 expression level may be at the level of CCNE1 mRNA. In other embodiments, the CCNE1 expression level may be at the level of CCNE1 protein.

[0109] Other biomarkers In some embodiments, the intended 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, the intended biomarker may be phosphorylation of Rb at serine corresponding to amino acid position 780. Rb is a cell cycle regulator 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] Furthermore, the intended biomarker may 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 A biological sample suitable for the methods described herein includes any sample containing blood or tumor cells obtained from or derived from a human subject in need of treatment. For example, a biological sample may include tumor cells obtained from a biopsy of a patient with a solid tumor. Tumor biopsies can be obtained by various means known in the art. Alternatively, a blood sample can be obtained from a patient with a hematological malignancy.

[0112] Biological samples can be obtained from human subjects who have, are suspected of having, or are at risk of developing a CDK2-related disease or disorder. In some embodiments, the CDK2-related disease or disorder is cancer (e.g., as described above).

[0113] Methods for 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 skilled in the art. For example, a biological sample may be further exposed to 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 changes to the molecules in the sample.

[0114] Method of administration and dosage form The precise amount of compound administered to provide a “effective dose” to a subject will depend on the mode of administration, the type and severity of cancer, and the subject’s characteristics (such as overall health, age, sex, weight, and drug tolerance). A person skilled in the art would be able to determine the appropriate dosage based on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with anticancer drugs, the “effective dose” of any additional therapeutic agent(s) will depend on the type of drug used. Appropriate dosages of approved therapeutic agents are publicly known and reported, for example, in the literature, and can be adjusted by a person skilled in the art, depending on the subject’s condition, the type of condition being treated, and the amount of compound of formula (I) used, by following the dosages recommended in Physician’s Desk Reference (57th Ed., 2003).

[0115] "To treat" or "to treat" means to obtain a desired pharmacological and / or physiological effect. The effect is therapeutic and includes achieving one or more of the following results, in part or substantially: namely, a partial or substantially reduction in the degree of disease, condition, or cancer; improvement or enhancement of clinical symptoms or indicators associated with disease, condition, or cancer; slowing, inhibiting, or reducing the likelihood of progression of disease, condition, or cancer; or reducing the likelihood of recurrence of disease, condition, or cancer.

[0116] The term "effective dose" refers to the amount administered to a subject that, when administered, produces a beneficial or desired outcome (including clinical outcomes), such as inhibiting, suppressing, or reducing the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective dose can be administered in unit dosage form (e.g., 0.1 mg to approximately 50 g per day, alternatively 1 mg to approximately 5 g per day, and even more alternatively 10 mg to 1 g per day).

[0117] As used herein, terms such as “administer,” “give delivery,” and “dosage” refer to methods that may be used to enable the delivery of a composition to a desired site of action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, and rectal methods. Administration techniques that may be employed in conjunction 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] Furthermore, the compounds of the Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the Disclosure may be administered co-administered with other therapeutic agents. As used herein, the terms “co-administered” and “administered in combination,” and their grammatical equivalents, mean 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 Disclosure, their pharmaceutically acceptable salts, or the pharmaceutical compositions of the Disclosure will be administered co-administered with other agents. These terms mean that by administering two or more agents to a subject, both agents and / or their metabolites will be present in that subject simultaneously. These include co-administration in separate compositions, administration in separate compositions at different times, and / or administration in a composition in which both agents are present. Thus, in some embodiments, the compounds and other agents described herein are administered in a single composition. In some embodiments, the compounds and other agents described herein are mixed in a composition.

[0119] Specific dosing regimens and dosages are selected by the attending clinician, taking into account the details of the case (e.g., subject, disease, disease state involved, specific treatment). Treatment may involve daily or multiple daily doses or less than daily doses (weekly, monthly, etc.) over a period of several days to several months, and in some cases several years. However, those skilled in the art will immediately recognize appropriate and / or equivalent doses by looking at the dosages of approved compositions for treating diseases using CDK2 inhibitors disclosed as guidance.

[0120] As those skilled in the art will understand, the compounds of this disclosure or pharmaceutically acceptable salts thereof can be administered to patients in various forms depending on the chosen route of administration. The compounds of this teaching may be administered, for example, orally, parenterally, buccally, sublingually, nasally, rectally, by patch, pump, or transdermally, and by pharmaceutical compositions formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasally, intrapulmonary, subarachnoid, rectal, and topical administration methods. Parenteral administration may be by continuous infusion over a selected period of time.

[0121] The pharmaceutical compositions of this disclosure are formulated to suit their intended route of administration. In some embodiments, the compositions are formulated according to established procedures as pharmaceutical compositions suitable for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to humans. In preferred embodiments, the pharmaceutical compositions are formulated for intravenous administration.

[0122] Typically, for oral therapeutic administration, the compounds of this disclosure, or pharmaceutically acceptable salts thereof, may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, cachets, and the like.

[0123] Typically, for parenteral administration, solutions of the compounds of this disclosure, or pharmaceutically acceptable salts thereof, can be prepared in water, generally in appropriate mixture with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycol, DMSO, and mixtures thereof, with or without alcohol, as well as in oil. These preparations contain preservatives to inhibit microbial growth under normal storage and use conditions.

[0124] Typically, for use by injection, sterile aqueous solutions or dispersions and sterile powders of the compounds disclosed herein are suitable for the immediate preparation of sterile injection solutions or dispersions. [Examples]

[0125] The following examples are illustrative and not intended to limit the scope of this disclosure. Examples 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 Sodium sulfate (Na2SO4) MeOH methanol N2 Nitrogen H2 hydrogen LiAlH4 Lithium Aluminum Hydrogenated (Lithium) NaHCO3 (sodium bicarbonate) CbzCl Benzylcarbonochloride PE (Petroleum Ether) DAST N-ethyl-N-(trifluoro-sulfanyl)ethaneamine HCl hydrochloride ACN Acetonitrile DIPEA Diisopropylethylamine DMSO (Dimethyl Sulfoxide) DMA (dimethylacetamide) h hours (multiple hours possible) HPLC (High-Performance Liquid Chromatography) minutes (multiple minutes allowed) 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] A method for preparing the compounds of the present invention may be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. The suitable solvent can be substantially inactive with the starting materials (reactants), intermediates, or products at the temperature in which the reaction takes place (e.g., within the range from the freezing point to the boiling point of the solvent). A given predetermined reaction may 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 solvent suitable for that particular reaction step.

[0127] The preparation of the compounds of the present invention may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemical properties of protecting groups are 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) It can be monitored by spectroscopic means such as infrared (IR) spectroscopy, spectrophotometric methods (e.g., ultraviolet-visible), and mass spectrometry (MS), or by chromatographic methods such as high-performance liquid chromatography (HPLC) or thin-layer chromatography (TLC). Analytical instruments and methods for characterizing compounds:

[0129] LC-MS: Liquid chromatography-mass spectrometry (LC-MS) data (for samples analyzed for purity and identity) was acquired using an Agilent Model-1260 LC system. This system uses an Agilent Model-6120 mass spectrometer utilizing the ES-API ionization method and is equipped with an Agilent Poroshiel 120 (EC-C18, particle size 2.7 μm, dimensions 3.0 × 50 mm) reversed-phase column at 22.4 degrees Celsius. 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 (for samples analyzed for purity and identity) were acquired using a Shimadzu LC-MS system. This system utilizes a Shimadzu LC-MS mass spectrometer employing ESI ionization and is equipped with an Agilent (Poroshel HPH-C18, 2.7 μm particle size, 3.0 × 50 mm dimensions) reversed-phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of water and 5 mM NH4HCO3 (or 0.05% TFA) solvent in 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 utilized. The flow rate was constant at 1.5 mL / min.

[0131] Prep LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP® preparative system equipped with an Xtimate 10um 150A 21.2×250 mm 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 was used over an 18-minute period. 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 was used over an 8-minute period.

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

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

[0134] Proton NMR: 1 ¹H NMR spectra were performed using a Varian 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.5 seconds with a 1-second delay; 16–64 scans), an Avance 400MHz Unity Inova 400MHz NMR instrument (acquisition time = 3.99 seconds with a 1-second delay; 4–64 scans), or an Avance 300MHz Unity Inova 300MHz NMR instrument (acquisition time = 5.45 seconds with a 1-second delay; 4–64 scans). Unless otherwise indicated, all protons in the DMSO-d6 solvent were 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

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

[0137] Under N2 conditions, a mixture of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-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 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel with EA / PE(1 / 4) elution to obtain the title compound (400 mg, yield 33%) as a yellow solid. MS (ES+) C 12 H 12 Theoretical value of ClF3N4O: 320, Observed value: 321 [M+H] + .

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

[0139] A mixture of intermediate 1 (40 mg, 124 μmol) and 4-amino-3-fluorobenzenesulfonamide (23.5 mg, 124 μmol) in IPA (2 mL) was mixed with TsOH (21.3 mg, 124 μmol), and the mixture was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (mobile phase: A = water (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15%~95% (18 min); column: Xtimate 10 μm 150A 21.2 × 250 mm) to obtain the title compound (32.2 mg, yield 54%) as a white solid. MS (ES+) C 18 H 18 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-3-methylbenzenesulfonamide [ka]

[0141] A mixture of intermediate 1 (140 mg, 436 μmol) and 4-amino-3-methylbenzenesulfonamide (81.1 mg, 436 μmol) in IPA (10 mL) was mixed with TsOH (75.0 mg, 436 μmol), and the mixture was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (mobile phase: A = water (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15%~95% (18 min); column: Xtimate 10 μm 150A 21.2 × 250 mm) to obtain the title compound (46.3 mg, yield 22%) as a white solid. MS (ES+) C 19 H 21 Theoretical value for F3N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide

[0143] Step 1. Synthesis of 1-(4-(2,5-dichloropyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 2) [ka]

[0144] Under N2 conditions, a mixture of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-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 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel with EA / PE(2 / 1) elution to obtain the title compound (200 mg, 93% yield) as a white solid. MS (ES+) C 11 H 12 C l2 Theoretical value of N4O: 286, observed value: 287[M+H]+.

[0145] Step 2. Synthesis of 4-((5-chloro-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-yl)pyrimidine-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), TsOH (167 mg, 974 μmol) was added, and the reaction mixture was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (25.9 mg, yield 12%) as a white solid. MS (ES+) C 19 H 21 Theoretical value of F3N6O3S: 422, Observed value: 423 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 8.59 (s, 1H), 8.58 (s, 1H), 8.27 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz, 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)

Chemical formula

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

Chemical formula

[0151] Following the same procedure as described in Step 1 of Example 3, the title compound was obtained as a pale yellow solid (200 mg, yield 65%) from 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)propan-2-ol and intermediate 3. MS (ES+) C 12 H 13 Theoretical value of ClF2N4O: 302, Observed value: 303 [M+H] + .

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

[0153] A mixture of intermediate 4 (200 mg, 0.66 mmol) and 4-aminobenzenesulfonamide (114 mg, 0.66 mmol) in IPA (3 mL) was mixed with TsOH (114 mg, 0.66 mmol), and the reaction mixture was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (83.6 mg, yield 28%) as a white solid. MS (ES+) C 18 H 20 Theoretical value of F2N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0155] The title compound was obtained as a white solid (19.2 mg, 45% yield) from intermediate 1 and 4-aminobenzenesulfonamide following the same procedure as described in step 3 of Example 4. MS (ES+) C 18 H 19 Theoretical value for F3N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or (R)-3-fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide.

[0157] Step 1. Synthesis of 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-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 minutes. 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 hours. The mixture was cooled to room temperature, and water and EA were added. The aqueous layer was extracted with EA, and the combined EA layer was washed with water and concentrated under vacuum. The residue was purified by flash chromatography on silica gel with EA / PE = 1 / 3 elution to obtain the title product as oil (4.80 g, yield 88%). MS (ES+) C 13 H 21 Theoretical value of BN2O3: 264, Observed value: 265 [M+H] + .

[0159] Step 2. Synthesis of 3-(4-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-one (intermediate 6) [ka]

[0160] Under N2 conditions, 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) was heated at 90°C for 16 hours. This mixture was concentrated under vacuum, and the aqueous residue was extracted with EA. The combined EA layers were concentrated under vacuum. The residue was purified by flash chromatography with silica gel eluting at EA / PE = 1 / 1 to obtain the title product as oil (200 mg, yield 13%). MS (ES+) C 12 H 10 Theoretical value of ClF3N4O: 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)

Chemical formula

[0162] At 0 °C, MeMgBr (3 M, 2 mL, 6 mmol) was added to a mixture of Intermediate 6 (800 mg, 2.51 mmol) in THF (5 mL), and the reaction mixture was stirred at 0 °C to room temperature for 2 hours. 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 residue obtained 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 Theoretical value for ClF3N4O: 334, Observed value: 335 [M + H] + This 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% methanol 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 yielded a peak 2, a white solid intermediate 8, 200 mg, (S)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylbutan-2-ol or (R)-3-(4-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylbutan-2-ol.

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

[0165] Following the same procedure as described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 8 and 4-amino-3-fluorobenzene-1-sulfonamide (80.2 mg, yield 27%). MS (ES+) C 19 H 20 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or (S)-3-fluoro-4-((4-(1-(3-hydroxy-3-methylbutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0167] Following the same procedure as described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 7 and 4-amino-3-fluorobenzene-1-sulfonamide (68.2 mg, yield 22%). MS (ES+) C 19 H 20 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide

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

[0170] A mixture of 2,4-dichloropyrimidine-5-carbonitride (10.0 g, 57.5 mmol) and 4-aminobenzenesulfonamide (9.90 g, 57.5 mmol) in IPA (100 mL) was to be suddenly mixed with DIPEA (11.1 g, 86.2 mmol) at 25 °C. The mixture was stirred at 50 °C for 1 hour. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The combined crude product was purified by preparative HPLC (acidic conditions) to obtain 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide (Example 8) [ka]

[0172] Under an N2 atmosphere, 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-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 to a mixture of intermediate 9 (74.3 mg, 0.240 mmol) in DMF (3.0 mL). The reaction mixture was stirred at 100 °C for 16 hours. LC-MS indicated completion of the reaction. The mixture was filtered, and the solvent was removed under vacuum. The residue was purified by preparative HPLC (acidic conditions) to obtain 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or Synthesis of 3-fluoro-4-((4-((1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

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

[0175] To a solution of intermediate 5 (2 g, 7.57 mmol) in MeOH (20 mL), NaBH4 (427 mg, 11.3 mmol) was added, and the reaction mixture was stirred at room temperature for 30 minutes. LC-MS indicated completion of the reaction. The reaction was quenched with water and extracted by 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 eluted with PE / EA (1 / 1) to obtain the title compound as a colorless oil (1.2 g, yield 59%). 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)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol, (2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol, (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol and (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol (intermediates 12-P1, 12-P2, 13-P1 and 13-P2) [ka] [ka] [ka]

[0177] Under N2 conditions, a mixture of intermediate 10 (1 g, 3.75 mmol), 4-chloro-5-(trifluoromethyl)pyrimidine-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) was stirred overnight at 90°C. LC-MS indicated completion of the reaction. The residue was purified by flash chromatography on silica gel eluted with EA / PE(1 / 1), followed by preparative HPLC (basic conditions) to obtain 3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol (800 mg, 71% yield). This product (800 mg) was separated by chiral HPLC, and peak 1, intermediate 12, cis-rac-(2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or (280 mg)trans-rac-(2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl )butan-2-ol, and peak 2, intermediate 13, trans-rac-(2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or cis-rac-(2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol (350 mg) were obtained.

[0178] Intermediate 12 (280 mg) was separated by chiral-SFC (column: IG 20 × 250 mm, 10 μm (Daicel)); column temperature: 35 °C, mobile phase: CO2 / MeOH (0.2% methanol ammonia) = 80 / 20; flow rate: 100 g / min) to obtain intermediate 12-P1 (110 mg), (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or ( 2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl (Pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol and intermediate 12-P2 (100 mg), (2S,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or (2R,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H- Pyrazole-1-yl)butan-2-ol or (2R,3S)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)butan-2-ol or (2S,3R)-3-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-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% methanol ammonia) = 80 / 20; flow rate: 100 g / min) to obtain Intermediate 13-P1 (140 mg), (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 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, 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-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 as white solids. MS (ES+) C 12 H 14 Theoretical value of F3N5O: 301, Observed value: 302 [M+H] + .

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

[0181] Under N2 conditions, 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) was stirred overnight at 90°C. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with EA / PE (5 / 1), followed by preparative HPLC (basic conditions) to obtain the title product (29.6 mg, yield 18%) as a white solid. MS (ES+) C 18 H 18 Theoretical value of F4N6O3S: 474, Observed value: 475 [M+H] + . 11H-NMR (400 MHz, DMSO-d6) δ ppm 10.08 (s, 1H), 8.76 (s, 1H), 8.27 (s, 1H), 8.03 (t, J = 8.4 Hz, 1H), 7.96 (s, 1H), 7.70 - 7.67 (m, 2H), 7.43 (s, 2H), 5.06 - 5.04 (m, 1H), 4.32 - 4.28 (m, 1H), 3.88 - 3.85 (m, 1H), 1.46 (d, J = 6.8 Hz, 3H), 0.90 (d, J = 6.0 Hz, 3H).

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

Chemical formula

[0183] According to the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid (23.6 mg, yield 8%) from Intermediate 2 and 4 - amino - 3 - fluorobenzenesulfonamide. MS (ES+) C 17 H 18 Theoretical value for ClFN6O3S: 440, Observed value: 441 [M + H] + . 1 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.63 (br. s, 1H), 8.55 (s, 2H), 8.19 (s, 1H), 7.98 (t, J = 8.4 Hz, 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

Chemical formula

[0185] Following the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 4 and 4-amino-3-fluorobenzenesulfonamide (156.8 mg, yield 19%). MS (ES+) C18H19F3N6O3S theoretical value: 456, observed value: 457[M+H]+. ¹H-NMR (400 MHz, 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or (S)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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-pyrazole-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 for 30 minutes under microwave irradiation. Approximately 75% of the product was shown by LC-MS, 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)pyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylbutan-2-ol (intermediate 15) [ka]

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

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

[0192] Under N2 conditions, 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 didioxane (5 mL) was stirred at 90°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with MeOH / DCM (1 / 10), followed by preparative HPLC (basic conditions) to obtain the title product (180 mg).

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

[0194] Intermediate 16 (180 mg) was separated by chiral-SFC (column: AD-H 20 × 250 mm, 10 μm (Daicel); column temperature: 35 °C; mobile phase: CO2 / IPA (1% methanol ammonia) = 80 / 20; flow rate: 80 g / min) to obtain peak 1, Example 12 (73.2 mg, yield 19%). MS (ES+) C 19 H 20 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0196] Following the procedure described in Step 3 of Example 9, the title compound was obtained as a white solid from the intermediate 13-P1 and 4-bromo-3-fluorobenzene-1-sulfonamide (72 mg, yield 32%). MS (ES+) C 18 H 18 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)pyrimidine-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 state) to obtain the title compound (2.1 mg, yield 2%) as a white solid. MS (ES+) C 18 H 21 Theoretical value of ClN6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2R,3R)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0200] Following the procedure described in Step 3 of Example 9, the title compound was obtained as a white solid from the intermediate 13-P2 and 4-bromo-3-fluorobenzene-1-sulfonamide (96.2 mg, yield 47%). MS (ES+) C 18 H 18 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

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

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

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

[0205] Step 2. Synthesis of 1-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)cyclopropane-1-carboxylate methyl (intermediate 18) [ka]

[0206] Under N2 conditions, a mixture of 4-chloro-5-(trifluoromethyl)pyrimidine-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 overnight at 80°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel with elution in MeOH / DCM (5%) to obtain the title compound (203 mg, yield 46%) as a white solid. MS (ES+) C 13 H 12 Theoretical value of F3N5O2: 327, Observed value: 328 [M+H] + .

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

[0208] Under N2 conditions, 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 overnight at 100°C. LC-MS indicated completion of the reaction. The reaction mixture was purified by flash chromatography on silica gel eluted with MeOH / DCM (5%) to obtain the title compound (71 mg, yield 23%) as a white solid. MS (ES+) C 19 H 16 Theoretical value of F4N6O4S: 500, Observed value: 501 [M+H] + .

[0209] Step 4. Synthesis of 3-fluoro-4-((4-(1-(1-(hydroxymethyl)cyclopropyl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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), LiBH4 (25.9 mg, 1.19 mmol) was added, and the mixture was stirred at 0°C for 1 hour. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (5.6 mg, yield 10%) as a white solid. MS (ES+) C 18 H 16 Theoretical value for F4N6O3S: 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-pyrazole-4-yl)-5-methylpyrimidine-2-yl)amino)benzenesulfonamide

[0212] Step 1. Synthesis of 1-(4-(2-chloro-5-methylpyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 20) [ka]

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

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

[0215] TsOH (204 mg, 1.19 mmol) was added to a mixture of intermediate 20 (160 mg, 599 μmol) and 4-aminobenzenesulfonamide (123 mg, 718 μmol) in IPA (5 mL). The reaction mixture was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (76.3 mg, yield 31%) as a white solid. MS (ES+) C18 H 22 Theoretical value of N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide

[0217] Step 1. Synthesis of 1-(4-(2-chloro-5-fluoropyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 21) [ka]

[0218] Following the same procedure as described in Step 1 of Example 3, the title compound was obtained from 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)propan-2-ol and 2,4-dichloro-5-fluoropyrimidine (200 mg, yield 62%). MS (ES+) C 11 H 12 Theoretical value of ClFN4O: 270, Observed value: 271 [M+H] + .

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

[0220] Following the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 21 and 4-aminobenzenesulfonamide (15.1 mg, yield 10%). MS (ES+) C 17 H 19 Theoretical value of FN6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)-3-fluorobenzenesulfonamide

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

[0223] Following the same procedure as described in Step 1 of Example 3, the title compound was obtained as a yellow solid from 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)propan-2-ol and 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile (400 mg, yield 85%). MS (ES+) C 13 H 15 Theoretical value of N5OS: 289, Observed value: 290 [M+H] + .

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

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

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

[0227] Following a procedure similar to that described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 23 and 4-amino-3-fluorobenzenesulfonamide (23.6 mg, yield 22%). MS (ES+) C 18 H 18 Theoretical value for FN7O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

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

[0230] Under N2 conditions, 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) was stirred overnight at 80°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with PE / EA (1 / 1) to obtain 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)pyrimidine-4-yl)-1H-pyrazole-1-yl)propan-2-ol (intermediate 25) [ka]

[0232] Under N2 conditions, a mixture of intermediate 24 (500 mg, 1.98 mmol) in dioxane (6 mL) and H2O (1.5 mL), along with 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), was stirred overnight at 90°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with PE / EA(1 / 1) to obtain the title compound (300 mg, 49% yield) as a yellow solid. MS (ES+) C 11 H 10 Theoretical value of ClF3N4O: 306, Observed value: 307 [M+H] + .

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

[0234] 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 mixed with TsOH (84.2 mg, 498 μmol), and the reaction was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (acidic conditions) to obtain the title compound (21.8 mg, yield 9%) as a white solid. MS (ES+) C 17 H 16 Theoretical value for F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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), AcOH (0.6 mL) and concentrated hydrochloric acid (0.7 mL) were added at 0°C. Sodium nitrite (82.1 mg, 1.19 mmol) in water (0.5 mL) was slowly added. After stirring at 0°C for 20 minutes, SO2 was pumped into the reaction mixture at 0-5°C for 1.5 hours, then CuCl2 (159 mg, 1.19 mmol) was added, and SO2 was further pumped into the resulting mixture for 1 hour. The reaction mixture was then stirred at 0°C for 1 hour, 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 a cold NH3 / MeOH solution. After stirring for 10 minutes, the reaction mixture was diluted with DCM, washed with water, and concentrated. Next, EA / PE=1:5 was added, and the resulting solid was collected by filtration to obtain the title product (120 mg, yield 45%) as a yellow solid. MS (ES+) C7H7BrFNO2S theoretical value: 267, observed value: 268 [M+H] + .

[0238] Step 2. Synthesis of 1-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 27) [ka]

[0239] Following the procedure described in Step 1 of Example 3, the title compound was obtained as a yellow solid from 4-chloro-5-(trifluoromethyl)pyrimidine-2-amine and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)propan-2-ol (1.7 g, yield 74%). MS (ES+) C 12 H 14 Theoretical value of F3N5O: 301, Observed value: 302 [M+H] + .

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

[0241] Following the procedure described in Step 3 of Example 12, the title compound was obtained as a yellow solid from 4-bromo-3-fluoro-2-methylbenzene-1-sulfonamide and 1-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (54.8 mg, yield 25%). MS (ES+) C 19 H 20 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

[0243] Step 1. Synthesis of 2-methyl-2-(4-(2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)propan-1-ol (intermediate 28) [ka]

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

[0245] Step 2. Synthesis of 2-methyl-2-(4-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)propan-1-ol (intermediate 29) [ka]

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

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

[0248] A mixture of intermediate 29 (90 mg, 247 μmol) and 4-amino-3-fluorobenzenesulfonamide (51 mg, 271 μmol) in IPA (10.0 mL) was mixed with TsOH (4 mg, 24 μmol), and the reaction was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (4.9 mg, yield 4%) as a white solid. MS (ES+) C 18 H 18 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)pyrimidine-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), TsOH (116 mg, 676 μmol) was added, and the mixture was stirred overnight at 120 °C. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (18.4 mg, yield 12%) as a white solid. MS (ES+) C 17 H 18 Theoretical value of Cl2N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide

[0252] Step 1. Synthesis of 1-(4-(2-chloro-5-ethylpyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 30) [ka]

[0253] Following the procedure described in Step 1 of Example 3, the title compound was obtained as a white solid from 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)propan-2-ol and 2,4-dichloro-5-ethylpyrimidine (163 mg, yield 84%). MS (ES+) C 13 H 17 Theoretical value of ClN4O: 280, observed value: 281[M+H]+.

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

[0255] A mixture of intermediate 30 (140 mg, 498 μmol) and 4-aminobenzenesulfonamide (102 mg, 597 μmol) in IPA (5 mL) was mixed with TsOH (171 mg, 996 μmol), and the reaction was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (74.6 mg, yield 36%) as a white solid. MS (ES+) C 19 H 24 Theoretical value of N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((4-(1-((2S,3S)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2R,3S)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-fluoro-4-((4-(1-((2S,3R)-3-hydroxybutan-2-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0257] Following the procedure described in Step 3 of Example 9, the title compound was obtained as a white solid from intermediate 12-P1 and 4-bromo-3-fluorobenzene-1-sulfonamide (43.5 mg, yield 25%). MS (ES+) C 18 H 18 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or (R)-3-fluoro-4-((4-(1-(2-hydroxy-2-methylbutyl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0259] Intermediate 16 (180 mg) was separated by chiral-SFC (column: AD-H 20 × 250 mm, 10 μm (Daicel); column temperature: 35 °C; mobile phase: CO2 / IPA (1% methanol ammonia) = 80 / 20; flow rate: 80 g / min) to obtain peak 1, Example 12 (73.2 mg, yield 19%) and peak 2, Example 26 (70.8 mg, yield 18%). MS (ES+) C 19 H 20 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-3-methoxybenzenesulfonamide [ka]

[0261] Following the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 1 and 4-amino-3-methoxybenzenesulfonamide (52.3 mg, yield 34%). MS (ES+) C 19 H 21 Theoretical value for F3N6O4S: 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-pyrazole-4-yl)pyrimidine-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 state) to obtain the title compound (16.7 mg, yield 7%) as a white solid. MS (ES+) C 18 H 21 Theoretical value of ClN6O4S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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), 4-bromo-2,3-difluorobenzene-1-sulfonyl chloride (300 mg, 1.02 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 1 hour. 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 eluted with EA / PE(1 / 2) to obtain 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0268] Under N2 conditions, 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) was stirred at 90°C for 14 hours. LC-MS indicated that the reaction was complete. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (100 mg, 20% yield) as a white solid. MS (ES+) C 18 H 17 Theoretical value of F5N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0270] Following the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 21 and 4-amino-3-fluorobenzenesulfonamide (6 mg, yield 5%). MS (ES+) C 17 H 18 Theoretical value of F2N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)-3-methylbenzenesulfonamide [ka]

[0272] Under N2 conditions, 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 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (45.4 mg, yield 36%) as a white solid. MS (ES+) C 18 H 21 Theoretical value of FN6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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-pyrazole-1-yl)ethane-1-one (intermediate 32) [ka]

[0275] To a solution of 2-bromo-1-cyclopropylethane-1-one (402 mg, 2.47 mmol) in MeCN (6 mL), 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) were added. The mixture was stirred overnight at 60°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with EA / PE(1 / 4) to obtain the title compound (362 mg, yield 64%) 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)pyrimidine-4-yl)-1H-pyrazole-1-yl)ethane-1-one (intermediate 33) [ka]

[0277] Under N2 conditions, 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 overnight at 90°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel with EA / PE(1 / 2) elution to obtain the title compound (200 mg, 70% yield) as a yellow solid. MS (ES+) C 14 H 13 Theoretical value for F3N4OS: 342, Observed value: 343[[M+H]] + .

[0278] Step 3. Synthesis of 1-cyclopropyl-2-(4-(2-(methylthio)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)ethane-1-ol (intermediate 34) [ka]

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

[0280] Step 4. Synthesis of 1-cyclopropyl-2-(4-(2-(methylsulfonyl)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)ethane-1-ol (intermediate 35) [ka]

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

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

[0283] TsOH (9.12 mg, 53 μmol) was added 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). The mixture was stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic conditions) to obtain the title compound (2.2 mg, yield 4%) as a yellow solid. MS (ES+) C 19 H 18 Theoretical value for F4N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide or 3-Fluoro-4-((2-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-4-yl)amino)benzenesulfonamide

[0285] Step 1. Synthesis of 2-(4-(4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)-1H-pyrazole-1-yl)ethane-1-ol (intermediate 36) or 2-(4-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)ethane-1-ol [ka]

[0286] Under N2 conditions, a mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl)ethane-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 H2O (2 mL) was stirred overnight at 90°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with PE / EA(1 / 1) to obtain a yellow solid, which was Peak 1 (15 mg), Intermediate 36, 2-(4-(2-chloro-5-(trifluoromethyl)pyrimidine-2-yl)-1H-pyrazole-1-yl)ethane-1-ol or 2-(4-(4-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)ethane-1-ol, and Peak 2 (35 mg), 2-(4-(4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)-1H-pyrazole-1-yl)ethane-1-ol or 2-(4-(2-chloro-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)ethane-1-ol. MS (ES+) C 10 Theoretical value of H8ClF3N4O: 292, observed value: 293[M+H]+.

[0287] Step 2. Synthesis of 3-fluoro-4-((2-(1-(2-hydroxyethyl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (24.7 mg, yield 46%) as a white solid. MS (ES+) C 16 H 14 Theoretical value of 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-pyrazole-4-yl)pyrimidine-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-pyrazole-1-yl)ethane-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 mixture was stirred at 100 °C for 2 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (9.7 mg, yield 11%) as a white solid. MS (ES+) C 16 H 15 Theoretical value of N7O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

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

[0293] Under N2 conditions, 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) was stirred at 80°C for 48 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with DCM / MeOH (20 / 1) to obtain the title compound (700 mg, yield 54%) 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)pyrimidine-4-yl)-1H-pyrazole-1-yl)propan-2-ol (intermediate 38) [ka]

[0295] Under N2 conditions, 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 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with EA / PE(1 / 1) to obtain the title compound (140 mg, yield 46%) as a yellow solid. MS (ES+) C 11 H 10 Theoretical value of ClF3N4O: 306, Observed value: 307 [M+H] + .

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

[0297] Following the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 38 and 4-amino-3-fluorobenzenesulfonamide (39.2 mg, yield 18%). MS (ES+) C 17 H 16 Theoretical value for F4N6O3S: 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-pyrazole-4-yl)-5-methylpyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0299] Following the procedure described in Step 3 of Example 4, the title compound was obtained as a white solid from intermediate 20 and 4-amino-3-fluorobenzene-1-sulfonamide (83.8 mg, yield 35%). MS (ES+) C 18 H 21 Theoretical value for FN6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-2,6-dimethylbenzenesulfonamide [ka]

[0301] Under N2 conditions, 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 overnight at 100°C. LC-MS indicated complete inversion of the reaction. The reaction mixture was purified by preparative HPLC (basic conditions) to obtain the title product (58.2 mg, yield 36%) as a white solid. MS (ES+) C 20 H 23 Theoretical value of F3N6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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), AcOH (0.6 mL) and concentrated hydrochloric acid (0.7 mL) were added at 0°C. Sodium nitrite (142 mg, 2.14 mmol) in water (0.5 mL) was slowly added. After stirring at 0°C for 20 minutes, SO2 was pumped into the reaction mixture at 0-5°C for 1.5 hours, then CuCl2 (287 mg, 2.14 mmol) was added, and SO2 was further pumped into the resulting mixture for 1 hour. The reaction mixture was stirred at 0°C for 1 hour, cold water was added, and the mixture was extracted with DCM. The organic layer was washed with brine and concentrated to obtain 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 product from Step 1 (intermediate 39 mg, 200 mg, 0.66 mmol) in DCM (3 mL) was added to cold NH3 / MeOH (10 mL), and the reaction mixture was stirred for 10 minutes. The reaction mixture 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 obtain the title product (120 mg, yield 64%) as a white solid. Theoretical value of MS (ES+) C6H4BrClFNO2S: 287, Observed value: 288 [M+H] + .

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

[0308] Following the procedure described in step 3 of Example 9, the title compound was obtained from intermediates 27 and 40 as a yellow solid (60 mg, yield 28%). MS (ES+) C 18 H 17 Theoretical value of ClF4N6O3S: 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-pyrazole-4-yl)pyrimidine-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), Pd(t-Bu3P)2 (65.4 mg, 128 μmol) and Na2CO3 (102 mg, 965 μmol) were added. The reaction mixture was stirred at 100°C for 2 hours. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (17.2 mg, yield 13.5%) as a white solid. MS (ES+) C 17 H 15 Theoretical value of N7O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-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 product) was obtained from 4-bromo-3-fluoro-2-methoxyaniline according to 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 the same procedure as described in Step 2 of Example 28, the title compound was obtained from intermediate 41 as a yellow solid (150 mg, 80% yield). MS (ES+) C7H7BrFNO3S theoretical value: 283, observed value: 284 [M+H] + .

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

[0317] Following the procedure described in Step 3 of Example 9, the title compound was obtained from intermediates 27 and 42 as a yellow solid (60 mg, yield 28%). MS (ES+) C 19 H 20 Theoretical value for F4N6O4S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

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

[0320] DIAD (1.16 g, 5.76 mmol) was added dropwise at 80°C 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). The reaction mixture was stirred overnight. LC-MS indicated completion of the reaction. 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 eluted with PE / EA(4 / 1) to obtain the title compound (700 mg, yield 52%) 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)pyrimidine-4-yl)-1H-pyrazole-1-yl)methyl)oxetan-3-ol (intermediate 44) [ka]

[0322] Under N2 conditions, a mixture of intermediate 43 (250 mg, 892 μmol), 4-chloro-5-(trifluoromethyl)pyrimidine-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 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with DCM / MeOH(5 / 1) to obtain the title compound (170 mg, 60% yield) as a white solid. MS (ES+) C 12 H 12 Theoretical value of F3N5O2: 315, observed value: 316[M+H]+.

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

[0324] Under N2 conditions, a mixture of intermediate 44 (140 mg, 444 μmol) and 4-bromo-3-fluorobenzenesulfonamide (112 mg, 444 μmol) in dioxane (5 mL) was mixed with Pd2(dba)3 (40.6 mg, 44.4 μmol), t-BuXPhos (18.8 mg, 44.4 μmol), and KOAc (130 mg, 1.33 mmol). The mixture was then stirred at 100 °C for 4 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (30.1 mg, yield 13%) as a white solid. MS (ES+) C 18 H 16 Theoretical value for F4N6O4S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)-3-fluorobenzenesulfonamide

[0326] Step 1. Synthesis of 1-(4-(2-chloro-5-ethylpyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 45) [ka]

[0327] Under N2 conditions, a mixture of 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-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 overnight at 90°C. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with PE / EA(1 / 1) to obtain the title compound (150 mg, yield 53%) as a yellow solid. MS (ES+) C 13 H 17 Theoretical value of ClN4O: 280, Observed value: 281 [M+H] + .

[0328] Step 2. Synthesis of 4-((5-ethyl-4-(1-(2-hydroxy-2-methylpropyl)-1H-pyrazole-4-yl)pyrimidine-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), and TsOH (73.5 mg, 427 μmol) in IPA (10 mL) was stirred at 90°C for 3 days. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (acidic conditions) to obtain the title compound (24.3 mg, yield 13%) as a white solid. MS (ES+) C 19 H 23 Theoretical value of FN6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

[0331] Step 1. Synthesis of 4-(1-(oxetan-3-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-amine (intermediate 46) [ka]

[0332] Following the same procedure as described in Step 1 of Example 3, the title compound was obtained as a yellow solid from 4-chloro-5-(trifluoromethyl)pyrimidine-2-amine and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, yield 69%). MS (ES+) C 11 H 10 Theoretical value of F3N5O: 285, Observed value: 286 [M+H]+ .

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

[0334] Under N2 conditions, 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 overnight at 90°C. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (110.4 mg, yield 45%) as a white solid. MS (ES+) C 17 H 14 Theoretical value of F4N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)benzenesulfonamide [ka]

[0336] Under N2 conditions, 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 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (11.8 mg, yield 9%) as a white solid. MS (ES+) C 17 H 18 Theoretical value of ClFN6O3S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-2-methylbenzenesulfonamide [ka]

[0338] Under N2 conditions, a mixture of 4-bromo-5-fluoro-2-methylbenzenesulfonamide (225 mg, 839 μmol), 1-(4-(2-amino-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-1-yl)-2-methylpropan-2-ol (intermediate 27 mg, 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 overnight at 100°C. The reaction mixture was cooled to room temperature and concentrated to obtain the residue, which was purified by flash column chromatography with silica gel eluted with PE / EA (1 / 4), and then purified by preparative HPLC (basic conditions) to obtain the title product (102 mg, yield 25%) as a white solid. MS (ES+) C 19 H 20 Theoretical value for F4N6O3S: 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-pyrazole-4-yl)pyrimidine-2-yl)amino)-3-methoxybenzenesulfonamide [ka]

[0340] Under N2 conditions, a mixture of intermediate 21 (100 mg, 369 μmol) and 4-amino-3-methoxybenzenesulfonamide (74.6 mg, 369 μmol) in dioxane (5 mL) was mixed with Pd2(dba)3 (33.7 mg, 36.8 μmol), t-BuXPhos (15.6 mg, 36.7 μmol), and KOAc (107 mg, 1.10 mmol), and the mixture was then stirred at 100 °C for 4 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (2.0 mg, yield 1%) as a white solid. MS (ES+) C 18 H 21 Theoretical value for FN6O4S: 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-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

[0342] Step 1. Synthesis of 4-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole-4-yl)-5-(trifluoromethyl)pyrimidine-2-amine (intermediate 47) [ka]

[0343] Under N2 conditions, 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)pyrimidine-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 hours. LC-MS indicated completion of the reaction. The reaction mixture was concentrated, and the residue was purified by flash chromatography on silica gel eluted with EA / PE(1 / 4) to obtain the title compound (324 mg, yield 72%) as a yellow solid. Theoretical value of MS(ES+)C13H14F3N5O: 313, Observed value: 314[M+H] + .

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

[0345] Under N2 conditions, a mixture of intermediate 47 (324 mg, 1.03 mmol) and 4-bromo-3-fluorobenzenesulfonamide (312 mg, 1.23 mmol) in dioxane (10 mL) was mixed with KOAc (202 mg, 2.06 mmol) and BrettPhos Pd G4 (25 mg), and the mixture was then stirred at 90°C for 16 hours. LC-MS indicated completion of the reaction. The reaction mixture was purified by preparative HPLC (basic state) to obtain the title compound (197.6 mg, yield 39%) as a white solid. MS (ES+) C 19 H 18 Theoretical value of F4N6O3: 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 effects of the compounds disclosed herein are measured by biochemical assays. These biochemical assays measure the enzymatic phosphorylation activity of the CDK enzyme in a complex of a cyclin protein phosphorylating 7.5 micromoles of the fluorescently labeled peptide substrate 5-FAM-QSPKKG-CONH2 (FL-peptide 18, PerkinElmer, 760362) in the presence of various concentrations of the test compound in adenosine-5'-triphosphate (ATP) and 100 mM 2-[4-(2-hydroxyethyl)piperazine-1-yl]ethanesulfonic acid (HEPES), pH 7.5, 10 mM MgCl2, 0.015% Brij-35, 1 mM dithiothreitol (DTT), and 1.0% dimethyl sulfoxide (DMSO). The assays were performed with the CDK enzyme in complex with ATP in Km or 1.0 mM ATP. The reaction was allowed to proceed at room temperature (25°C) until 10% to 20% of the total peptide was phosphorylated, and terminated with 35 mM 2,2',2",2'''-(ethane-1,2-diylnitrilo)tetraacetic acid (EDTA). The product was detected using a caliper mobility shift detection method. In this method, the phosphorylated peptide (product) and substrate were separated and measured by electrophoresis. The activity of the compound was plotted as a percentage against the logarithmic concentration and point for visually clear IC25. 50 These assays generated the following CDK enzymes in complexes with different cyclin proteins. CDK1 / cyclin B1, GST-tag (BPS, 40454), 1.5 nM was used in the assay. CDK2 / cyclin E (Eurofins, 14-475), 1.25 nM was used in the assay. The biological assay data for the test compounds are shown in Table 1 below. The following symbols are used to indicate inhibitory activity against CDK2 / cyclin E mutants: ≤10nM=A; >10~20nM=B; >20~30nM=C; >30~100nM=D; >100=E. For inhibition of CDK1 / cyclin B1 and GST-tag, ≥500nM=A; <100~500nM=B; <100nM=C. [Table 1-1] [Table 1-2] In a particular embodiment, for example, the following items are provided: (Item 1) Equation (I) [ka] A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, Each R 1 HALO, OH, CN, C 1 ~C 4 Alkyl and C 1 ~C 4 Independently selected from the group consisting of alkoxys, where C 1 ~C 4 Alkyl and C 1 ~C 4 Each alkoxy may be substituted with 1 to 3 halos. Each R 2 HALO, OH, CN, C 1 ~C 4 Alkyl and C 1 ~C 4 Independently selected from the group consisting of alkoxys, where C 1 ~C 4 Alkyl and C 1 ~C 4 Each alkoxy may be substituted with 1 to 3 halos. R 3 Halo, OH, C 3 ~C 6 C may be substituted with one or two groups independently selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclines. 1 ~C 6 It is alkyl, where the C 3 ~C 6 The cycloalkyl group may be substituted with OH, where the 3-6 member heterocyclyl group is O, S and NR.a Each of the following groups independently selects 1 to 4 ring heteroatoms, which may then be substituted with OH on the ring carbon, or R 3 is C 3 ~C 6 It is a cycloalkyl or a 3-6 membered heterocycline, where the C 3 ~C 6 Cycloalkyl groups are OH or -CH 2 It may be substituted with OH, where the 3-6 member heterocyclyl is O, S and NR a Each of the following groups independently selects 1 to 4 ring heteroatoms, and then has an OH or -CH group on the ring carbon. 2 It may also be substituted with OH. Each R a H or C 1 ~C 6 It is alkyl, m is selected from the group consisting of 0, 1, 2, 3, and 4. n is selected from the group consisting of 0, 1, and 2. (Item 2) The aforementioned compounds are those of formula IIA, formula IIB, formula IIC, or formula IID.

change

Claims

1. Equation (I) 【Chemistry 101】 A compound of the same, or a pharmaceutically acceptable salt thereof (in the formula, Each R １ is independently selected from the group consisting of halo, OH, CN, C １ to C ４ alkyl and C １ to C ４ alkoxy, wherein the C １ to C ４ alkyl and C １ to C ４ alkoxy may each be substituted with 1 to 3 halos, Each R ２ is Halo, OH, CN, C １ ~C ４ Alkyl and C １ ~C ４ Independently selected from the group consisting of alkoxys, where C １ ~C ４ Alkyl and C １ ~C ４ Each alkoxy may be substituted with 1 to 3 halos. R ３ is Halo, OH, C ３ ~C ６ C may be substituted with one or two groups independently selected from the group consisting of cycloalkyl and 3- to 6-membered heterocyclines. １ ~C ６ It is alkyl, and here, C ３ ~C ６ The cycloalkyl group may be substituted with OH, where the 3-6 member heterocyclyl group is O, S, N and NR ａ Each of the following groups independently selects 1 to 4 ring heteroatoms, which may then be substituted with OH on the ring carbon, or R ３ is C ３ ~C ６ It is a cycloalkyl or a 3-6 membered heterocycline, where the C ３ ~C ６ Cycloalkyl groups are OH or -CH ２ It may be substituted with OH, where the 3-6 member heterocyclyl is O, S, N and NR ａ Each ring has 1 to 4 ring heteroatoms independently selected from the group consisting of the following, and then an OH or -CH group is placed on the ring carbon. ２ It may be substituted with OH groups. Each R ａ H or C １ ~C ６ It is alkyl, m is selected from the group consisting of 0, 1, 2, 3, and 4. n is selected from the group consisting of 0, 1, and 2.

2. The aforementioned compound is formula IIA, formula IIB, formula IIC, or formula IID 【Chemical Engineering 102】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

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

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

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

6. R ３ is a C substituted with OH. １ ~C ５ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

7. Each R １ is methyl, and each R ２ is halo, methyl and CF ３ Independently selected from the group consisting of, R ３ is a C substituted with OH. １ ~C ６ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

8. Each R １ This is a halo, and each R ２ These are halo, CN, methyl, ethyl and CF ３ Independently selected from the group consisting of, R ３ is a C substituted with OH. １ ~C ６ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

9. The following structural formula: 【Chemistry 103】 A compound represented by, or a pharmaceutically acceptable salt thereof.

10. The following structural formula: 【Chemical 104】 A compound represented by, or a pharmaceutically acceptable salt thereof.

11. The following structural formula: 【Chemistry 105】 A compound represented by, or a pharmaceutically acceptable salt thereof.

12. The following structural formula: 【Chemistry 106】 A compound represented by, or a pharmaceutically acceptable salt thereof.

13. The following structural formula: 【Chemistry 107】 A compound represented by, or a pharmaceutically acceptable salt thereof.

14. The following structural formula: 【Chemistry 108】 A compound represented by, or a pharmaceutically acceptable salt thereof.

15. 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 composition according to claim 16, wherein the solid tumor cancer is at least one of the following: uterine cancer (including uterine carcinosarcoma and endometrial carcinoma of the uterine body), endometrial cancer, breast cancer (including invasive breast carcinoma, triple-negative breast cancer (TNBC), estrogen receptor (ER) + human epidermal growth factor 2 (HER2)-breast cancer, and HER2+ breast cancer), ovarian cancer, gastric cancer (including gastric adenocarcinoma), 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 urothelial carcinoma of the bladder), lung cancer (including squamous cell carcinoma of the lung and non-small cell lung cancer), bile duct carcinoma, adrenocortical carcinoma, or mesothelioma.

18. The composition according to claim 17, wherein the ovarian cancer is ovarian serous cystadenocarcinoma.

19. The composition according to claim 17, wherein the non-small cell lung cancer is an epidermal growth factor receptor mutant (EGFRm) + non-small cell lung cancer.

20. The composition according to claim 16, wherein the solid tumor cancer is breast cancer.

21. The composition according to claim 16, wherein the solid tumor is hormone receptor-positive human epidermal growth factor 2-negative (HR+ / HER2-) breast cancer.

22. The composition according to claim 16, wherein the solid tumor cancer is endometrial cancer.

23. The composition according to claim 16, wherein the solid tumor cancer is ovarian cancer.

24. The composition according to claim 16, wherein the solid tumor carcinoma has amplification and / or overexpression of CCNE1 or CCNE2.

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