Cdk2 inhibitors and methods of using same

Abstract

The present invention provides novel compounds of formula (I) as CDK2 inhibitors which are useful in the treatment of diseases or conditions mediated by CDK2, in particular cancer and other diseases caused by abnormal cell proliferation. The invention also includes methods of preparation, pharmaceutical compositions, and methods of use of the compounds.

Description

(19) State Intellectual Property Office (12) Invention Patent Application (10) Application Publication Number (43) Application Publication Date (21) Application Number 20248004 2008.6 (22) Application Date 2024.04.23 (30) Priority Data 63 / 501,034 2023.05.09 US 63 / 615,863 2023.12.29 US (66) Domestic Priority Data PCT / CN2023 / 090329 2023.04.24 CN PCT / CN2023 / 127659 2023.10.30 CN (85) PCT International Application Entering National Phase Date 2025.12.23 (86) PCT International Application Application Data PCT / CN2024 / 089320 2024.04.23 (87) Publication data of PCT international application WO2024 / 222678 EN 2024.10.31 (71) Applicant Shenzhen Yuanli Life Science Co., Ltd. Address 518118 Pingshan District, Shenzhen, Guangdong Province Applicant Foshan Yuanli Biotechnology Co., Ltd. Guangdong Institute of Innovative Drug Translational Medicine Co., Ltd. (72) Inventors Yang Hongjian Cao Yexing Bai Chang Qin Jialiang Su Jing (74) Patent Agency Beijing Gaowo Law Firm 11569 Patent Attorney Wang Zixuan (51) Int.Cl. C07D 401 / 14 (2006.01) A61K 31 / 506 (2006.01) A61P 35 / 00 (2006.01) (54) Invention title CDK2 inhibitor and method of use thereof (57) Abstract This invention provides a novel compound of formula (I) as a CDK2 inhibitor, which can be used to treat diseases or conditions mediated by CDK2, especially cancer and other diseases caused by abnormal cell proliferation. The present invention also includes methods for preparing the said compound, pharmaceutical compositions, and methods of use. Claims 10 pages, Description 78 pages CN 121443596 A 2026.01.30 CN 1 21 44 35 96 A 1. A compound of formula (I), wherein X is CH or N; Z is CH or N; ring A is aryl, heteroaryl, cycloalkyl, heterocyclic, or aryl fused heterocyclic, each of which is optionally and independently substituted by one R1 and one to four R2; wherein the carbon atom of said aryl fused heterocyclic group is optionally substituted by one oxygen, and its heteroatom is optionally substituted by one or two oxygens; R1 is -S(O)2-R10, -NH-S(O)2-R10, or -SF5; each R2 is independently H, alkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -NO2, halogen, or haloalkyl.R3 is H, halogen, alkyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, cycloalkyl, or heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R7 groups; R4 and R6 are each independently H, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-N-R9R9, -CN, cycloalkyl, or heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally substituted with one or more R7 groups; R5 is H, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-N-R9R9, -CN, cyanoalkyl, cycloalkyl, or heterocyclic; Alkoxyalkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -alk-N-R9R9, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic, -alk-cycloalkyl, -alk-heterocyclic, -O-cycloalkyl, or -O-heterocyclic; wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic, -alk-cycloalkyl, -alk-heterocyclic, -O-cycloalkyl, or -O-heterocyclic is optionally substituted by one or more R7s; each R7 is independently alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -CN, cyanoalkyl, oxo (=O), R8 -S (O)2-, R8 -O-C(=O)-, R8-C(=O)-O-, R8-C(=O)-, cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more R7 groups; each R8 is independently H, alkyl, or -NR9R9; each R9 is independently H, cycloalkyl, -alk-cycloalkyl, or alkyl; R10 is H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic group, or -NR11R11; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R7 groups; each R11 is independently H, alkyl, cycloalkyl, heterocyclic group, -alk-cycloalkyl, -alk-heterocyclic group, hydroxyalkyl, -alk-O- R12, -alk-C(O)-OR9, or -alk-N-R9R9; wherein the cycloalkyl, -alk-cycloalkyl, -alk-heterocyclic group, or heterocyclic group is optionally substituted by one or more R7 groups; Claims 1 / 10 page 2 CN 121443596 A Each R12 is independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclic; the heteroaryl and heterocyclic groups independently contain one or more cyclic skeleton heteroatoms each time they appear, each heteroatom being independently oxygen, sulfur, or nitrogen;The heterocyclic group is saturated or partially unsaturated each time it appears; and the H in each alkyl group is optionally substituted with deuterium (D); or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. 2. The compound of claim 1, wherein ring A is 3. The compound of claim 1 or 2, wherein the hydroxyalkyl group is linear or branched hydroxyalkyl. 4. The compound of claim 1 or 2, wherein the cyanoalkyl group is linear or branched cyanoalkyl. 5. The compound of claim 1 or 2, wherein the cycloalkyl, cycloalkenyl, or heterocyclic group of ring A is monocyclic or bicyclic. 6. The compound of claim 1, wherein X is N. 7. The compound of claim 1, wherein Z is N. 8. The compound of claim 1, wherein the compound is of formula (II): wherein the definition of ring A is the same as in claim 1. 9. The compound of claim 1, wherein the compound is of formula (IIa), (IIb), (IIc), (IId), or (IIe): Claims 2 / 10 Page 3 CN 121443596 A wherein ring C is a bridged ring or spirocyclic bicyclic heterocyclic alkyl group; ring D is a 4-8 membered cyclic alkyl or heterocyclic group fused with an adjacent aryl group; optionally, ring D is substituted by one or two oxo groups; Y is N, O, or CH; and when Y is O, R1 is absent; M1 and M2 are each independently N or CH; and the definitions of R1, R2, R3, R4, R5, and R6 are the same as in claim 1. 10. The compound of any one of claims 1 to 9, wherein R1 is NHR11-S(O)2-, heterocyclic-S(O)2-, C1-6 alkyl-S(O)2-, (C1-6 alkyl)2-N-S(O)2-, (deuterated C1-6 alkyl)2-N-S(O)2-, (deuterated C1-6 alkyl)-HN-S(O)2-, C1-6 alkyl-S(O)2-NH-, or -SF5. 11. The compound of any one of claims 1 to 10, wherein R2 is H, a halogen, a haloalkyl, a hydroxyl, an alkyl, a cycloalkyl, or a heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R7 groups. 12. The compound of any one of claims 1 to 11, wherein R3 is H, a halogen, an alkyl, a haloalkyl, an alkynyl, -CN, or a cyanoalkyl. 13. The compound of any one of claims 1 to 12, wherein the halogen is F, Cl, or Br. 14. The compound of claim 1, wherein the compound is of formula (III), wherein R1, R2, R3, R4, R5, and R6 are defined as in claim 1. 15. The compound of any one of claims 1 to 14, wherein the compound is selected from the following compounds: Claims 3 / 10 Page 4 CN 121443596 A Claims 4 / 10Page 5 CN 121443596 A Claims 5 / 10 Page 6 CN 121443596 A Claims 6 / 10 Page 7 CN 121443596 A Claims 7 / 10 Page 8 CN 121443596 A Claims 8 / 10 Page 9 CN 121443596 A 16. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in any one of claims 1-15, and a pharmaceutically acceptable carrier or excipient. 17. The pharmaceutical composition of claim 16, further comprising a second therapeutic agent. 18. The pharmaceutical composition of claim 17, wherein the second therapeutic agent is a CDK4 / 6 inhibitor, an estrogen receptor antagonist, a hormone therapy drug, a PARP inhibitor, an S-phase inhibitor, an M-phase inhibitor, or a BCL-2 inhibitor. 19. A method for treating a CDK2-mediated disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-15 or the pharmaceutical composition of any one of claims 16-18. 20. The method of claim 19, wherein the CDK2-mediated disease or condition is cancer. (Claims 9 / 10 pages 10 CN 121443596 A) 21. The method of claim 20, wherein the cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, prostate cancer, glioblastoma, or sarcoma. 22. Use of the compound of any one of claims 1-15 in the preparation of a medicament for treating CDK2-mediated diseases. Claims 10 / 10 pages 11 CN 121443596 A Cross-Reference to Related Applications for CDK2 Inhibitor and Method of Use Thereof

[0001] This application claims priority to International Application No. PCT / CN2023 / 090329, filed April 24, 2023; U.S. Application No. 63 / 501,034, filed May 9, 2023; International Application No. PCT / CN2023 / 127659, filed October 30, 2023; and U.S. Application No. 63 / 615,863, filed December 29, 2023, the entire contents of which are incorporated herein by reference. Background of the Invention

[0002] Cyclin-dependent kinases (CDKs) are a class of serine / threonine kinases whose activity depends on the regulatory subunit—cyclin. In the absence of cyclin, CDK exhibits almost no kinase activity; it only becomes an active kinase when cyclin binds to CDK to form a complex, and the kinase activity can be further enhanced by phosphorylation.Further regulation is carried out on CDKs and other binding proteins. Based on the kinase domain sequence, CDKs belong to the CMGC kinase group, which also includes mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3β (Gsk3β), members of the dual-specific tyrosine-regulated kinase (DYRK) family, and CDK-like kinases (see Genome Biol. 2014; 15(6):122). CDKs play an important role in cell growth, proliferation, and transcriptional regulation in response to intracellular and extracellular signals. Through the study of the evolutionary relationship between CDK subfamilies, it was found that CDK subfamilies can be divided into two categories: one category directly or indirectly participates in cell cycle regulation (including CDK1-6, 11, and 14-18), and the other category mainly regulates transcriptional processes (including CDK7-13, 19, and 20) (see Pharmacol Ther. 2017 May; 173:83-105).

[0003] Given its core regulatory role in key biological processes such as cell division and gene transcription, CDKs have become a highly attractive pharmacological target. Over the past two decades, the development of CDK inhibitors has received widespread attention. This research direction initially stemmed from the discovery that different CDK subtypes play a key role in cancer cell proliferation by disrupting the cell cycle (a hallmark of cancer). The cell cycle consists of four phases: cell growth (G1 phase), DNA replication (S phase), division preparation (G2 phase), and cell division (M phase). At each checkpoint, multiple proteins participate in a series of precisely coordinated biochemical reactions to ensure that cells divide only when they are fully grown, have completed DNA replication, and are under suitable conditions. CDKs are the main drivers of cell cycle regulation mechanisms, promoting DNA synthesis and mitosis by phosphorylating key substrates. Therefore, abnormal activation of CDKs can lead to cell cycle disorder and uncontrolled cell proliferation, ultimately resulting in malignant tumors. Existing research also shows that CDKs can regulate other biological processes, especially playing an important role at multiple levels of gene transcription (see Pharmacol Ther. 2017 May; 173:83-105; Transcription. 2017; 8(2):81-90). Therefore, CDK inhibitors have the potential to treat various diseases caused by CDK abnormalities, including cancer, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, and infectious diseases.

[0004] Initially, drug research focused on extracting active compounds from natural substances to address the problem of CDK overactivation in human cancers. Based on the analysis of the molecular structures of these compounds, combined with further biochemical and structural biological research, researchers have gained a deeper understanding of the inhibitory potential of these compounds, and thus, based on structural information, have been able to conduct CDK inhibitory research.Rational design of formulations. First-generation CDK inhibitors have relatively low selectivity and are broad-spectrum CDK inhibitors. Due to their limitations such as toxic side effects, the development of second-generation CDK inhibitors with higher selectivity has been promoted. These specific inhibitors improve efficacy while reducing the risk of adverse reactions. Among them, CDK4 / 6 inhibitors became the first category to be approved by the US FDA for clinical treatment. These inhibitors can specifically inhibit CDK4 / 6 activity and have low toxicity to normal cells. Currently, FDA-approved CDK4 / 6 inhibitors include palbociclib (Pfizer), reboxiclib (Novartis), abeciclib (Eli Lilly), and triamcinolone (see J. Med. Chem. 2022, 65, 9, 6356-6389).

[0005] Similar to other CDK family members, CDK2 needs to bind to cyclin chaperones (cyclin E or A) to be activated. Activation of CDK2 triggers phosphorylation of proteins involved in the initiation of DNA synthesis and the cell cycle progression from G1 to S phases (Cell Cycle 9:22, 4533-4541; November 15, 2010). During the G1 / S phase, CDK4 and / or CDK6, bound to cyclin D, initially phosphorylate retinoblastoma (Rb) proteins. Subsequently, E-type cyclins (cyclins E1 and E2, encoded by the CCNE1 and CCNE2 genes, respectively) bind to CDK2 to form a complex, completing the phosphorylation of Rb proteins. This process releases and activates the E2F transcription factor family, propelling the cell into S phase. In addition to Rb protein phosphorylation, the activated CDK2 / cyclin E complex also regulates MCM proteins (mini chromosome maintenance proteins), which are essential for initiating DNA replication. During late S phase, type A cyclins bound to CDK2 or CDK1 regulate the transition of the cell cycle from S phase to G2 phase by phosphorylating their substrates (including MCM proteins, Cdc7, ribonucleotide reductase R2, etc.) (Oncogene. 2016 Mar 3; 35(9):1170-1179).

[0006] The oncogenic activation of the CDK2 / cyclin complex is associated with abnormal cell cycle regulation, which can induce replication stress and DNA damage, thereby promoting the occurrence and development of human tumors. Therefore, targeting and inhibiting the oncogenic activity of the CDK2 / cyclin complex has become a highly promising cancer treatment strategy. Despite the huge investment in related research, no drug targeting CDK2 has yet been approved by the US FDA. In view of this, the present invention provides a novel drug that can be used as a selective CDK2 inhibitor.Compounds, their preparation methods, and their use in treating CDK2-mediated diseases (such as cancer or other proliferative diseases). Summary of the Invention

[0007] This invention relates to compounds of formula (I) and their pharmaceutically acceptable salts, tautomers, or stereoisomers. The compounds are capable of inhibiting the activity of CDKs (especially CDK2). In some embodiments, the compounds selectively inhibit CDK2 activity, thus showing promising clinical application prospects. The invention also provides pharmaceutical compositions comprising the compounds, and methods of using the compounds to treat CDK2-mediated diseases.

[0008] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof, wherein: X is CH or N; Z is CH or N; ring A is aryl, heteroaryl, cycloalkyl, heterocyclic, or aryl fused heterocyclic; each of these groups is optionally and independently substituted by one R1 and one to four R2; wherein the carbon atom of said aryl fused heterocyclic group is optionally substituted by one oxo (=O), and its heteroatom is optionally substituted by one or two oxo; R1 is R10-S(O)2-, R10-S(O)2-NH-, or -SF5; each R2 is independently H, alkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -NO2, halogen, halogenated, or halogenated. The cycloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, cycloalkyl, or heterocyclic group is selected; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R7 groups; R3 is H, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, -CN, or cyanoalkyl; R4 and R6 are each independently H, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-N-R9R9, -CN, cyanoalkyl, cycloalkyl, or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R7 groups; R5 is H, alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy) Alkyl, alkoxyalkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -alk-N-R9R9, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic, -alk-cycloalkyl, -alk-heterocyclic, -O-cycloalkyl, or -O-heterocyclic; wherein the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclic, -alk-cycloalkyl, -alk-heterocyclic, -O-cycloalkyl, or -O-heterocyclic is optionally substituted by one or more R7s; each R7 is independently alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (halogenated)R8 is an alkyl group, an amino group, an alkylamino group, a dialkylamino group, a -CN group, a cyanoalkyl group, an oxoyl group (=O), an R8-S(O)2- group, an R8-O-C(=O)- group, an R8-C(=O)-O- group, an R8-C(=O)- group, a cycloalkyl group, or a heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further substituted by one or more R7 groups; each R8 is independently H, an alkyl group, or a -NR9R9 group; each R9 is independently H, a cycloalkyl group, a -alk-cycloalkyl group, a heterocyclic group, a -alk-heterocyclic group, or an alkyl group; R10 is H, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkoxyalkyl group, a cycloalkyl group, a heterocyclic group, or a -NR11R11 group; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R7 groups; Each R11 is independently H, alkyl, cycloalkyl, heterocyclic, -alk-cycloalkyl, -alk-heterocyclic, hydroxyalkyl, alkoxyalkyl, -alk-O-R12, -alk-C(O)-OR9 or -alk-N-R9R9; wherein the cycloalkyl, -alk-cycloalkyl, -alk-heterocyclic or heterocyclic is optionally substituted by one or more R7; each R12 is independently H, alkyl, cycloalkyl, haloalkyl or heterocyclic; the heteroaryl and heterocyclic groups each time they appear independently contain one or more cyclic skeleton heteroatoms, each heteroatom being independently oxygen, sulfur or nitrogen; the heterocyclic group each time it appears is saturated or partially unsaturated; and the H in each alkyl group is optionally substituted by deuterium (D).

[0009] In some preferred embodiments, the compound of formula (I) adopts formula (II): wherein the definitions of rings A, R1, R2, R3, R4, R5 and R6 are as described above. Specification 3 / 78 pages 14 CN 121443596 A

[0010] In some embodiments, ring A is:

[0011] The hydroxyalkyl group may be linear or branched; the cyanoalkyl group may be linear or branched; and the cycloalkyl, cycloalkenyl or heterocyclic group may be monocyclic or bicyclic.

[0012] In other embodiments, the compound of formula (I) adopts formula (IIa), (IIb), (IIc), (IId) or (IIe): wherein ring C is a bridged ring or spirocyclic bicyclic heterocyclic alkyl group; ring D is a 4-8 membered cycloalkyl or heterocyclic group fused with an adjacent aryl group; wherein the cycloalkyl or heterocyclic alkyl group is optionally substituted by one or two oxo groups; Y is N, O or CH; but when Y is O, R1 is absent; M1 and M2 are each independently N or CH; and the definitions of R1, R2, R3, R4, R5 and R6 are as described above.

[0013] In some embodiments, in formula (IIb), both M1 and M2 are CH.

[0014] In some embodiments, R1 is NHR11-S(O)2-, heterocyclic-S(O)2-, C1-6 alkyl-S(O)2-, (C ...(2-N-S(O)2-, (deuterated C1-6 alkyl)2-N-S(O)2-, C1-6 alkyl-S(O)2-NH-, (deuterated C1-6 alkyl)-HN-S(O)2- or -SF5.

[0015] In some embodiments, the halogen is F, Cl or Br. Specification 4 / 78 pages 15 CN 121443596 A

[0016] In some embodiments, R2 is H, halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl or heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally substituted by one or more R7.

[0017] In some embodiments, R3 is H, halogen, alkyl, haloalkyl, alkynyl, -CN or cyanoalkyl.

[0018] In some embodiments, the compound of formula (I) adopts formula (III): wherein R1, R2, R3, R4, R5 and R6 are defined as described above.

[0019] Without limitation, exemplary compounds of the present invention include: Specification page 5 / 78, 16 CN 121443596 A; Specification page 6 / 78, 17 CN 121443596 A; Specification page 7 / 78, 18 CN 121443596 A; Specification page 8 / 78, 19 CN 121443596 A; Specification page 9 / 78, 20 CN 121443596 A.

[0020] In some embodiments, the compounds of the present invention are selective cyclin-dependent kinase 2 (CDK2) inhibitors.

[0021] Another aspect of the present invention provides pharmaceutical compositions, wherein each pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention, a pharmaceutically acceptable salt thereof, a tautomer or stereoisomer thereof, and a mixture of one or more physiologically or pharmaceutically acceptable carriers or excipients.

[0022] In other embodiments, the pharmaceutical composition may further comprise a second therapeutic agent. Examples of suitable second therapeutic agents include, but are not limited to, CDK4 / 6 inhibitors (such as palbociclib, abeciclib, reboxiclib, or triplaciclib), estrogen receptor antagonists, hormone therapy drugs (such as letrozole and fulvestrant), PARP inhibitors (such as olaparib), S-phase inhibitors (such as carboplatin, gemcitabine, cisplatin, topotecan), M-phase inhibitors (such as paclitaxel), and BCL-2 inhibitors (such as ABT-

[0023] Another aspect of the invention also provides a treatment method for CDK2-mediated diseases or conditions, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition of the invention to a subject in need.

[0024] In some embodiments, the CDK2-mediated disease or condition is cancer or caused by abnormal cell proliferation.Diseases. Examples of said cancers include, but are not limited to: breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, prostate cancer, glioblastoma, or sarcoma.

[0025] Another aspect of the invention also provides the use of the compounds of the invention in the preparation of medicaments for treating diseases or conditions mediated by CDK2. Detailed Description

[0026] Preferred embodiments of the invention will now be described in detail, and examples thereof will be further illustrated. Although the invention will be described in conjunction with preferred embodiments, it should be understood that these preferred embodiments are not intended to limit the invention to these embodiments. Rather, the invention is intended to cover alternatives, modifications, and equivalents that may be included within the spirit and scope of the invention as defined by the claims. Furthermore, in the detailed description, numerous specific details are set forth to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that the invention may be practiced without these specific details. In other instances, well-known methods, procedures, components, and other features have not been described in detail so as not to unnecessarily obscure aspects of the invention.

[0027] Unless the context otherwise requires, all references to formula (I) in this document (including uses, methods and other aspects of the invention) include references to all other formulas, subgroups, preferred embodiments and examples as defined herein.

[0028] Unless otherwise stated, the following terms used in this specification and claims have the meanings described below:

[0029] As used herein, the term “or” is intended to include “and” and “or”. In other words, the term “or” may also be replaced by “and / or”.

[0030] In defining various terms, such as “X” and “Z”, they are used as general symbols to represent specific chemical elements.

[0031] As used herein, the term “unsaturated bond” refers to a double or triple bond.

[0032] As used herein, the term “unsaturated” or “partially unsaturated” refers to a portion containing at least one double or triple bond.

[0033] As used herein, the term “saturated” refers to a portion that does not contain double or triple bonds, i.e., the portion contains only single bonds.

[0034] As used herein, the term “alkyl” itself, or as part of another substituent, refers to a linear (i.e., unbranched or straight-chain) or branched hydrocarbon chain group consisting of carbon and hydrogen atoms, which is free of unsaturation and has a stated number of carbon atoms (e.g., C1-C10 or C1-10 alkyl). Whenever it appears herein, a numerical range (e.g., “1 to 10”) refers to individual integers within a given range; for example, “1 to 10 carbon atoms” means that an alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and 4 carbon atoms, etc., up to a maximum of 10 carbon atoms, although this definition also covers alkyl groups for which no numerical range is specified.The use of the term "alkyl" is included. Representative saturated linear or straight-chain alkyl groups include, but are not limited to: -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; saturated branched alkyl groups include, but are not limited to: -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, etc. The alkyl group is connected to the parent molecule by a single bond. Unless otherwise stated in this specification, the alkyl group may optionally be substituted by one or more substituents. Specification 11 / 78 pages 22 CN 121443596 A

[0035] When any H in "alkyl" is substituted with deuterium (D), the alkyl group is called "deuterated alkyl".

[0036] The term “alkylene” itself, or as part of other molecules, refers to a divalent group derived from an alkane, which may be straight-chain or branched. In this context, prefixes (e.g., C1-4, C1-7, C1-20, C2-7, C3-7, etc.) indicate the number of carbon atoms or a range of carbon atoms. For example, the term “C1-4 alkylene” as used herein refers to an alkylene having 1 to 4 carbon atoms. Examples of linear C1-8 alkylene include, but are not limited to, -(CH2)n-, where n is an integer from 1 to 7, such as -CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-. Examples of branched C1-7 alkylene groups include, but are not limited to, -CH(CH3)-, -CH(CH3)CH2-, -CH(CH3)CH2CH2-, -CH(CH3)CH2CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH(CH3)CH2CH2-, -CH(CH2CH3)-, -CH(CH2CH3)CH2-, and -CH2CH(CH2CH3)CH2-.

[0037] As used herein, the term "alkenyl" itself or as part of other substituents refers to an unsaturated branched or straight chain having at least one carbon-carbon double bond, obtained by removing a hydrogen atom from a single carbon atom of a parent alkene. The group can be in the cis or trans conformation of the double bond. Typical alkenyl groups include, but are not limited to, vinyl, propenyl, etc.

[0038] As used herein, the term "alkynyl" itself or as part of other substituents refers to a carbon chain containing at least one carbon-carbon triple bond, which can be linear or branched or a combination thereof. Examples of alkynyl groups include ethynyl, propynyl, 3-methyl-1-pentynyl, 2-heptyynyl, etc.

[0039] As used herein, the term "cycloalkyl" itself or as part of other substituents refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms. The term cycloalkyl includes monocyclic cycloalkyl, bicyclic cycloalkyl, polycyclic cycloalkyl, bridged cycloalkyl, etc.Alkyl, fused-ring cycloalkyl, and spirocyclic cycloalkyl. In bridged-ring cycloalkyl, the rings share at least two common non-adjacent atoms. In fused-bicyclic cycloalkyl, the two rings share a covalent bond. In spirocyclic cycloalkyl, one atom is shared by two different rings.

[0040] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbonyl ring consisting of at least three carbon atoms and containing at least one carbon-carbon double bond (i.e., C=C). Examples of cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, etc. The term "heterocyclic alkenyl" is a type of cycloalkenyl as defined above, wherein at least one of the carbon atoms of the ring is substituted by a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl and heterocyclic alkenyl can be substituted or unsubstituted.

[0041] The term “heterocyclic alkyl” is a type of cycloalkyl as defined above and is included within the meaning of “cycloalkyl”, wherein at least one of the carbon atoms of the ring is substituted with a heteroatom, such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl and heterocyclic alkyl groups may be substituted or unsubstituted.

[0042] As used herein, the term “heterocyclic” or “heterocyclic group” refers to a group derived from a monocyclic, bridged bicyclic, fused bicyclic, spirocyclic, or polycyclic portion comprising at least one non-aromatic ring containing one or more cyclic skeletal heteroatoms independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents if defined). The heterocyclic group may be saturated or partially unsaturated. In some embodiments, the heterocyclic group may comprise 1 to 4 heteroatoms as ring members. The heterocyclic groups of this disclosure may be linked to a parent molecule portion via carbon atoms or heteroatoms in the group. Therefore, this terminology includes, but is not limited to, “heterocyclic alkyl,” “heteroaryl,” “bicyclic heterocyclic,” and “polycyclic heterocyclic.”

[0043] As used herein, the term “halogenated” or “halogen” refers to fluorine (fluorinated, -F), chlorine (chlorinated, -Cl), bromine (brominated, -Br), or iodine (iodinated, -I).

[0001] The term “halogenated alkyl” refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been substituted with a halogen independently selected from fluorine, chlorine, bromine, and iodine. “Fluorinated alkyl” refers to an alkyl group as defined above, wherein one or more hydrogen atoms have been substituted with a fluorine atom. Unless otherwise specified in quantity, a haloalkyl group may include the maximum chemically possible number of halogen atoms on the alkyl group as a substituent. For example, a fluoroethyl group may be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0002] As used herein, the term “hydrogen” (or H) includes its isotopes deuterium (D or 2H) and tritium (3H), meaning that any or all hydrogen atoms in the compounds of the present invention may be replaced by deuterium (D or 2H) and tritium (3H).

[0044] As used herein, the term "alkoxy" or "alkoxy group" refers to a saturated straight-chain or branched hydrocarbon bonded to an oxygen atom. Representative saturated straight-chain alkoxy groups include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, etc.; while saturated branched alkoxy groups include isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, isopentoxy, etc. Cyclic alkoxy groups are referred to herein as "cycloalkoxy". "C1-4 alkoxy" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Alkoxy groups can be bonded to a molecule via one or two bonding sites.

[0045] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with one, two, or three alkoxy groups.

[0046] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having 6 to 12 carbon atoms with a fully conjugated π-electron system. Non-limiting examples of aryl groups include phenyl, naphthyl, and anthracene. The “aryl” can be substituted or unsubstituted.

[0047] As used herein, the term “heteroaryl” refers to a monocyclic or fused ring (i.e., a ring sharing adjacent atom pairs) of 5 to 12 ring atoms, containing one, two, three, or four cyclic heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and having a fully conjugated π-electron system. Non-limiting examples of unsubstituted heteroaryl include pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetraazole, triazine, carbazole, benzimidazole, benzoxazole, benzothiazole, indazole, and quinazoline. The heteroaryl can be substituted or unsubstituted.

[0048] As used herein, the term “anelyl” refers to a bidentate group obtained by removing one hydrogen atom from each of two different aromatic ring atoms of an aromatic compound, the group having 3 to 20 ring atoms (unless otherwise stated). Preferably, each ring has 5 to 7 ring atoms.

[0049] As used herein, the term "hydroxyl" or "hydroxy group" refers to the group -OH.

[0050] As used herein, the term "hydroxyalkyl" itself or as part of other substituents refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl substituent. Thus, the term "hydroxyalkyl" is intended to include monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, etc. In "hydroxyalkyl", the alkyl group may be linear (i.e., straight-chain or unbranched) or branched alkyl; accordingly, "hydroxyalkyl" includes linear hydroxyalkyl and branched hydroxyalkyl.

[0051] As used herein, the term "cyano" or "-CN" refers to a -C≡N group; the term "cyanoalkyl" or "-alk-CN" refers to an alkyl group having at least one -CN substituent. Typically, alkylamino groups are linked to the parent compound via their alkylene moiety. In the term "cyanoalkyl", the alkyl group may be linear (i.e., straight-chain or unbranched) or branched alkyl; correspondingly, "cyanoalkyl" includes linear cyanoalkyl and branched cyanoalkyl.

[0052] As used herein, the term "-alk-" (used alone or in combination with other terms) represents an alkylene group, such as -alk-N-R9R9.

[0053] As used herein, the term "oxo" (used alone or in combination with other terms) means =O.

[0054] As used herein, the term "amino" or "amine" means -NH2. The term "alkylamino" means a group of the general formula -NHR, and "dialkylamino" means a group of the general formula -NRR', wherein R and R' are each independently alkyl.

[0055] As used herein, the term "nitro" means -NO2.

[0056] As used herein, the term "SO2" means sulfur dioxide, which has the structural formula

[0057] As used herein, the terms "-C(=O)-" or "-CO-" mean a group of the structural formula

[0058] . Specification 13 / 78 pages 24 CN 121443596 A

[0058] As used herein, the term "carboxyalkyl" means an alkyl group substituted with one, two, or three carboxyl groups.

[0059] The groups defined above may include prefixes and / or suffixes commonly used in the art to produce other recognized substituents. For example, the terms "haloalkoxy" or "(haloalkyl)oxy" mean a haloalkyl group connected to a parent molecule portion by an oxygen atom. The term "(haloalkyl)oxyalkyl" means an alkyl group substituted with one, two, or three (haloalkyl)oxy groups.

[0060] As used herein, the term "absent" means that the defined variable is not present and is replaced by a chemical bond.

[0061] As used herein, the term "bond" means a covalent connection between two atoms, which may be a single bond, a double bond, or a triple bond.

[0062] As used herein, the term "stereoisomer" means isomers having the same molecular formula but different atomic spatial arrangements, rather than different atomic connection sequences. When the stereochemistry of a disclosed compound is not specified in its name or structural description, it should be understood that the name or structure covers all possible stereoisomers, including substantially pure stereoisomers and mixtures thereof. Both enantiomers and diastereomers are stereoisomers. The term "enantiomer" refers to one of a pair of molecular entities that are mirror images of each other and cannot be superimposed. The term "diastereomer" refers to a stereoisomer that is not a mirror image of another. The term "racemic mixture" or "racemic mixture" refers to a mixture of two enantiomers in equimolar amounts, the mixture being optically inactive.

[0063] As used herein, the term "chirality" refers to the property of a molecule that, due to its structural characteristics, cannot be perfectly superimposed on its mirror image.

[0064] As used herein, the term "tautomer" refers to two or more isomers of a compound that coexist, are in equilibrium with each other, and rapidly interconvert through the migration of atoms or groups within the molecule. Therefore, even if the structural formula only describes one of them, this disclosure is intended to cover all possible tautomers.

[0065] The terms “optional” or “optionally” mean that an event or situation described below may but not necessarily occur, and the description includes both the occurrence and non-occurrence of the event or situation. For example, “optionally alkyl-substituted heterocyclic group” means that an alkyl group may but not necessarily be present, and the description includes both cases where the heterocyclic group is alkyl-substituted and cases where the heterocyclic group is not alkyl-substituted.

[0066] The term “pharmaceuticalally acceptable salt” means a salt prepared from a pharmaceutically acceptable non-toxic alkali or acid (including inorganic or organic bases and inorganic or organic acids). Such salts are suitable for contact with patient tissues within reasonable medical judgment without causing excessive toxicity, irritation, allergic reactions or other problems or complications, in proportion to a reasonable benefit / risk ratio, and are effective for their intended use. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganese salts, manganese salts, potassium salts, sodium salts, zinc salts, etc.; particularly preferred are ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic alkaloids include primary, secondary, and tertiary amine salts, substituted amine salts (including naturally occurring substituted amines), cyclic amine salts, and basic ion exchange resin salts, such as arginine salts, betaine salts, caffeine salts, choline salts, N,N'-dibenzylethylenediamine salts, diethylamine salts, 2-diethylaminoethanol salts, 2-dimethylaminoethanol salts, ethanolamine salts, ethylenediamine salts, N-ethylmorpholine salts, N-ethylpiperidine salts, meglumine salts, glucosamine salts, histidine salts, hebamin salts, isopropylamine salts, lysine salts, methylglucamine salts, morpholine salts, piperazine salts, piperidine salts, polyamine resin salts, procaine salts, purine salts, theobromine salts, triethylamine salts, trimethylamine salts, tripropylamine salts, tromethamine salts, etc.

[0067] When the compounds of the present invention are alkaline, their salts can be prepared from pharmaceutically acceptable non-toxic acids (including inorganic and organic acids). Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, mesylic acid, viscous acid, nitric acid, pyric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.; particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid. Specification 14 / 78 pages 25 CN 121443596 A

[0068] It should be understood that references to compounds of formula (I) herein also refer to their pharmaceutically acceptable salts.

[0069] The term "pharmaceutical composition" refers to one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, mixed with other chemical components (e.g., pharmaceutically acceptable excipients). The purpose of a pharmaceutical composition is to facilitate the administration of the compound to a living organism.

[0070] The term "pharmaceuticalally acceptable excipient" refers to an agent added to a pharmaceutical composition to further facilitate the administration of the compound to a living organism.The drug is an inert substance. Examples of excipients include: calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils and polyethylene glycol.

[0071] As used herein, the term “therapeutic effective dose” means a dose of the compound that provides relief to a certain extent from one or more symptoms of the disease being treated. In cancer treatment, a therapeutic effective dose means a dose that produces the following effects: (1) shrinking tumor volume; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and / or (4) relieving one or more symptoms associated with cancer.

[0003] As used herein, the terms “subject” or “patient” are used interchangeably and refer to any animal subject, including but not limited to humans, laboratory animals (such as primates, rats, mice), livestock (such as cattle, sheep, goats, pigs, turkeys and chickens), and domestic pets (such as dogs, cats and rodents).

[0004] Those skilled in the art will understand that the compounds described herein can be administered to patients via a variety of routes, depending on the chosen route of administration. For example, the drug can be administered orally, parenterally, orally, sublingually, nasally, rectally, via patch, pump, or transdermally, and the pharmaceutical composition can be formulated accordingly. Parenterial administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, pulmonary, intrathecal, rectal, and local administration modes. Parenterial administration can be performed by continuous infusion over a selected time period. Isomeric Forms

[0072] The present invention provides novel compounds of formula (I) as CDK2 inhibitors and pharmaceutically acceptable salts thereof.

[0073] It should be understood that certain compounds of formula I (or their salts, prodrugs, or conjugates) may exist in isomeric forms and be isolated in isomeric forms, including tautomers, geometric isomers (i.e., cis or trans isomers), optical isomers (i.e., enantiomers and diastereomers), racemates, or mixtures of any of the above isomeric forms. It should be clarified that this invention covers compounds of formula (I) existing in any isomer form or mixture thereof, such as active single enantiomers, racemates, or any mixture thereof. This invention aims to include all such isomer forms of compounds of formula (I).

[0074] Furthermore, compounds of formula (I) (or their salts, prodrugs, or conjugates) may exhibit polymorphism or may form solvents with water or organic solvents. This invention also covers any such polymorphs, any solvates, or any mixtures thereof.

[0075] The following examples illustrate some embodiments of the invention and are not intended to limit the scope of the invention. Example 1: 2-(1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)prop-2-ol Specification 15 / 78 Page 26 CN 121443596 A Step 1: 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazol-4-carboxylic acid ethyl ester

[0076] To a solution of 2,4-dichloro-5-fluoropyrimidine (100.0 mg, 0.6 mmol) in DMSO (2 mL), ethyl 1H-pyrazole-4-carboxylate (125.9 mg, 0.9 mmol) and Et3N (0.25 mL, 1.8 mmol) were added. The reaction mixture was stirred at 50 °C for 40 min. The mixture was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give ethyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxylate as a white solid. MS (ES-API positive): 271.1 (M+H)+. Step 2: Ethyl 1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[0077] 1-(methanesulfonyl)piperidin-4-amine (69.2 mg, 0.4 mmol) and Et3N (0.1 mL, 0.8 mmol) were added to a solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)pyrazole-4-carboxylate (70.0 mg, 0.3 mmol) in DMSO (1.5 mL). The reaction mixture was stirred overnight at 50 °C. The mixture was diluted with ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give ethyl 1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate, as a white solid. MS (ES-API positive): 413.3 (M+H)+. Step 3: 2-(1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)prop-2-ol

[0078] At 0°C, methyl magnesium bromide (1M, THF solution, 0.4 mL) was added to a solution of ethyl 1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-carboxylate (54.0 mg, 0.1 mmol) in THF (1.0 mL). The reaction mixture was stirred at 0°C for 30 minutes, and then stirred at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate and water, extracted with ethyl acetate, and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give 2-(1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)prop-2-ol, a yellow liquid. MS (ES-API positive): 399.3 (M+H)+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.35 (d, J = 4.3 Hz, 1H), 7.86(s, 1H), 3.99- 3.93(m, 1H), 3.71(d, J=12.3Hz, 2H), 2.97(td, J=12.0, 2.1Hz, 2H), 2.86(s, 3H), 2.12(dd, J=12.8, 3.0Hz, 2H), 1.65 (ddd, J=12.7, 11.2, 4.0Hz, 2H), 1.57 (s, 6H). Example 2: 4-((4-(4-(2-hydroxy-2-methylpropyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Specification 16 / 78 pages 27 CN 121443596 A Step 1: 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0079] At 0°C, ZnCl2 (2M, THF solution, 8.9mL) was slowly added over 20 minutes to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidin (3.5g, 16.1mmol) in 2-methylprop-2-ol (60mL) and 1,2-dichloroethane (60mL), and stirred at 0°C for 30 minutes. Subsequently, a solution of 4-amino-N-methylbenzenesulfonamide (3.0 g, 16.1 mmol) in 2-methylprop-2-ol (30 mL) and 1,2-dichloroethane (30 mL), and a solution of TEA (2.5 mL, 17.7 mmol) in 2-methylprop-2-ol (30 mL) and 1,2-dichloroethane (30 mL) were added at 0 °C. The reaction mixture was stirred at 0–20 °C for 4 hours. The solvent was removed under vacuum. The residue was suspended in water (20 mL), sonicated for 30 minutes, and then filtered to give 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a yellow solid, which required no further purification. MS (ES-API positive): 367.1 (M+H)+. Step 2: 4-((4-(4-bromo-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0080] At 15°C, 4-bromo-1H-pyrazol (432.8 mg, 2.9 mmol) was added to a mixture of 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (0.9 g, 2.5 mmol) and potassium carbonate (678.3 mg, 4.9 mmol) in DMF (10 mL). The reaction mixture was stirred at 15°C for 16 hours. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (25 mL × 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was extracted with ethyl acetate.The mixture was stirred in petroleum ether (1 / 10, v / v, 20 mL) and then filtered to give 4-[[4-(4-bromopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, an off-white solid. MS (ES-API positive): 476.9, 478.9 (M+H)+. Step 3: Add pyridine-2,6-dimethylammonium sulfonamide

[0081] to a solution of 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino]-N-methylbenzenesulfonamide (100.0 mg, 209.5 μmol) and 1-bromo-2-methylprop-2-ol (64.1 mg, 419.1 μmol) in DMA (1 mL) with pyridine-2,6-dimethylammonium sulfonamide (6.8 mg, 41.9 μmol), nickel diiodide (13.1 mg, 41.9 μmol), zinc (54.8 mg, 838.1 μmol) and TBAI (116.1 mg, 314.3 μmol). The mixture was degassed and purged three times with N2, then stirred at 80°C for 16 hours. The reaction mixture was filtered. The filtrate was poured into water (5 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give 4-[[4-[4-(2-hydroxy-2-methylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a brown solid. MS (ES-API positive): 471.0 (M+H)+. 1HNMR (400MHz, CD3OD) δ8.87 (s, 1H), 8.42 (s, 1H), 7.97 (d, J=8.8Hz, 2H), 7.82 (d, J =8.8Hz, 2H), 7.74(s, 1H), 2.71(s, 2H), 2.54(s, 3H), 1.24(s, 6H). Example 11: 4-((4-(4-cyclopentyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Example 12: 4-((4-(4-(cyclopentyl-1-en-1-yl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Step 1: 4-((4-(4-(cyclopentyl-1-en-1-yl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0082] Pd(dppf)Cl2 (125.6 mg, 171.7 μmol) and Na2CO3 (181.9 mg, 1.7 mmol) were added to a solution of 4-[[4-(4-iodopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (450.0 mg, 858.4 μmol) and cyclopenten-1-ylboronic acid (144.1 mg, 1.3 mmol) in water (2 mL) and dioxane (4 mL). The reaction mixture was stirred at 90 °C for 2 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give compound 4-[[4-[4-(cyclopenten-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, as a brown solid. MS (ES-API positive): 465.2 (M+H)+. 1HNMR (500MHz, CD3OD) δ8.87 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=8.9Hz, 2H), 7.84-7.80 (m, 2H), 6.14 (t, J=2.1Hz, 1H), 2.69-2.65 (m, 2H), 2.55 (d, J=2.6Hz, 1H), 2.54 (s, 3H), 2.53-2.49 (m, 1H), 2.08-2.01 (m, 2H). Step 2: 4-((4-(4-cyclopentyl-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0083] Pd / C (22.9 mg, 21.5 μmol, purity 10%) was added to a solution of 4-[[4-[4-(cyclopentyl-1-en-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (50.0 mg, 107.6 μmol) in THF (5 mL) and ethyl acetate (5 mL). The reactants were stirred at 20 °C for 2 hours under a H2 (20 Psi) atmosphere. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (eluent: 70%-90% acetonitrile / water) to give compound 4-[[4-(4-cyclopentylpyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a white solid. MS (ES-API positive): 467.1 (M+H)+. ¹H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 8.34 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H).=8.8Hz, 2H), 7.74(s, 1H), 3.04(t, J =8.2Hz, 1H), 2.54(s, 3H), 2.18-2.02(m, 2H), 1.92-1.66(m, 4H), 1.66-1.53(m, 2H). Example 16: N-methyl-4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide Specification 18 / 78 Page 29 CN 121443596 A Step 1: 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0084] Same as Example 2. Step 2: N-Methyl-4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0085] Cs₂CO₃ (35.5 g, 109.0 mmol) was added to a solution of 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (20.0 g, 54.5 mmol) and 1H-pyrazole (4.5 g, 65.4 mmol) in DMSO (100 mL). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was poured into water (400 mL) and filtered. The solid was purified by preparative HPLC (eluting with 40%–70% acetonitrile / water) to give N-methyl-4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide as a yellow solid. MS(ES‑API positive): 399.0(M+H)+. 1HNMR (400MHz, CD3OD) δ 8.89 (s, 1H), 8.57 (d, J=2.7Hz, 1H), 7.96 (d, J=8.7Hz, 2H), 7.88-7.76 (m, 3H), 6.61 (dd, J=1.6, 2.6Hz, 1H), 2.54 (s, 3H). Example 32: 2-(ethyldioxo-λ6-thioalkyl)-6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane Step 1: 2-methylpropyl-2-yl 6-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate

[0086] At 0°C, ZnCl2 (5.2 mL, 5.2 mmol) was added to a mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (766.5 mg, 3.5 mmol) in tBuOH and DCE (1:1, 10 mL), and stirred for 0.5 hours. Subsequently, 2-methylpropyl-2-yl-6-amino-2-azaspiro[3.3]heptane-2-carboxylate (500.0 mg, 2.4 mmol) was added at 0 °C to tBuOH and DCE (1:1,The mixture was prepared in 10 mL of water and TEA (0.4 mL, 2.6 mmol). The reactants were stirred at room temperature for 16 hours and concentrated under vacuum. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluent: 23%–30% ethyl acetate / petroleum ether) to give 2-methylpropyl-2-yl-6-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate as a yellow solid. MS (ES-API positive): 393.1 (M+H)+. Step 2: 2-Methylpropyl-2-yl 6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate

[0087] 1H-pyrazole (218.4 mg, 3.2 mmol) and K2CO3 (665.0 mg, 4.8 mmol) were added to a mixture of 2-methylpropyl-2-yl 6-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate (630.0 mg, 1.6 mmol) in DMF (7 mL). The reaction mixture was stirred at 80 °C for 16 hours and concentrated under vacuum. The residue was diluted with water and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluent: 50%–55% ethyl acetate / petroleum ether) to give 2-methylpropyl-2-yl-6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate, as a white solid. MS (ES-API positive): 425.2 (M+H)+. Step 3: 6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane

[0088] TFA (0.5 mL, 6.5 mmol) was added to a mixture of 2-methylpropyl-2-yl 6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate (50.0 mg, 0.1 mmol) in DCM (0.5 mL). The reaction mixture was stirred at 35 °C for 8 hours and concentrated under vacuum. The residue was used directly for the next step without further purification. MS (ES-API positive): 325.2 (M+H)+. Step 4: 2-(ethyldioxo-λ6-thioalkyl)-6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane

[0089] TEA (0.3 mL, 2.1 mmol) was added to a mixture of 6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane (38.2 mg, 0.1 mmol) in DCM (0.5 mL) and stirred for 15 min. Then ethanesulfonyl chloride (15.1 mg, 0.1 mmol) was added, and stirring continued for 2 h. The mixture was diluted with water and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 55%–60% ethyl acetate / petroleum ether) to give 2-(ethyldioxo-λ6-thioalkyl)-6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane as a white solid. MS(ES‑API positive): 417.2(M+H)+. 1HNMR (400MHz, DMSO‑d6) δ8.76‑8.36 (m, 3H), 7.90 (d, J=5.6Hz, 1H), 6.65‑6.57 (m, 1H), 4.37-4.24(m, 1H), 3.95(d, J=10.2Hz, 2H), 3.82(s, 2H), 3.07(t, J=7.3Hz, 2H), 2.60 (s, 2H), 2.23 (dd, J=14.7, 6.4Hz, 2H), 1.20 (t, J=7.4Hz, 3H). Example 36: 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide Specification 20 / 78 Page 31 CN 121443596 A Step 1: N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide

[0090] At 0°C, 4-nitrobenzenesulfonyl chloride (10.4 g, 46.8 mmol) was added to a mixture of 2-((tert-butyldimethylsilyl)oxy)ethyl-1-amine (9.4 g, 53.8 mmol) and Na2CO3 (14.9 g, 140.4 mmol) in water (150 mL) and DCM (150 mL). The reaction mixture was stirred at 30°C for 2 hours. The mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with brine, and concentrated under vacuum to obtain the crude compound N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide, a white solid, which did not require further purification. MS (ES-API positive): 361.1 (M+H)+. Step 2: 4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide

[0091] N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide was reacted with EtOH (150 mL) and water.Iron (20.9 g, 374.4 mmol) and NH4Cl (37.6 g, 701.9 mmol) were added to a solution of 100 mL. The reaction mixture was stirred at 65 °C for 1 hour. The mixture was diluted with ethyl acetate, filtered, and concentrated under vacuum. The residue was diluted with ethyl acetate, washed with saturated NaHCO3, dried, and concentrated. The residue was purified by rapid chromatography (eluent: 3%–16% methanol / dichloromethane) to give compound 4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide, as a white solid. MS (ES-API positive): 331.2 (M+H)+. Step 3: N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0092] At 0°C, ZnCl2 (73.3 mL, 73.3 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (14.5 g, 66.7 mmol) in tBuOH (110 mL) and DCE (110 mL), and stirred at 0°C for 1 hour. Subsequently, 4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide (11.0 g, 33.3 mmol) in a solution of DCE (110 mL) and tBuOH (110 mL) was added dropwise at 0°C, followed by TEA (7.0 mL, 50.0 mmol). The reaction mixture was stirred at 30°C for 24 hours. After removing the solvent, the solution was diluted with ethyl acetate and brine. The organic layer was separated and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 66% ethyl acetate / petroleum ether) to give N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide, a pale yellow solid. MS (ES-API positive): 512.1 (M+H)+. Instructions for Use, Page 21 / 78, 32 CN 121443596 A Step 4: 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide

[0093] 1H-pyrazole (3.6 g, 53.5 mmol) and K2CO3 (11.1 g, 80.2 mmol) were added to a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide (13.7 g, 26.7 mmol) in DMF (50 mL), and the mixture was stirred at 35 °C for 18 hours. The reactants were diluted with ethyl acetate and brine. The organic layer was separated and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 80%-100% ethyl acetate / petroleum ether) to obtain the chemical...The compound 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide is a yellow solid. MS (ES-API positive): 543.2(M+H)+. Step 5: 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide

[0094] TBAF (62.9 mL, 62.9 mmol) was added to a solution of 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide (13.6 g, 25.1 mmol) in THF (100 mL), and the mixture was stirred at room temperature for 2 hours. The solvent was removed under vacuum, and the residue was diluted with ethyl acetate and brine. The organic layer was separated and concentrated under vacuum. The residue was purified by rapid chromatography (eluent: 7% methanol / dichloromethane) to give the crude compound 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide, as a white solid. MS (ES-API positive): 429.1 (M+H)+. 1HNMR (400MHz, DMSO‑d6) δ10.86 (s, 1H), 9.01 (s, 1H), 8.62 (d, J=2.8Hz, 1H), 8.13‑ 7.88 (m, 3H), 7.80 (d, J=8.5Hz, 2H), 7.50 (t, J=6 .0Hz, 1H), 6.71(s, 1H), 4.70(t, J=5.6Hz, 1H), 3.40-3.38(m, 2H), 2.80(q, J=6.2Hz, 2H). Example 42: 1,1-Dioxo-N-[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]-2,3-dihydro-1,2-benzisothiazol-5-amine Step 1: 1,1-Dioxo-2,3-dihydro-1,2-benzisothiazol-5-amine

[0095] Zinc (1.6 g, 25.0 mmol) was added to a mixture of 5-amino-1,1-dioxo-1,2-benzisothiazol-3-one (500.0 mg, 2.5 mmol) in concentrated HCl (5 mL). The mixture was stirred at 25 °C for 2 hours. A saturated NaHCO3 solution was then added to adjust the pH to 7-8. The mixture was filtered and extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄, and concentrated to give the crude compound 1,1-dioxo-2,3-dihydro-1,2-benzisothiazol-5-amine, a yellow solid that required no further purification. MS (ES-API positive): 185.0 (M+H)+.Step 2: 1,1-Dioxo-N-[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]-2,3-dihydro-1,2-benzisothiazol-5-amine Specification 22 / 78 pages 33 CN 121443596 A

[0096] TsOH (140.2 mg, 814.3 μmol) was added to a solution of 2-chloro-4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin (202.4 mg, 814.3 μmol) and 1,1-dioxo-2,3-dihydro-1,2-benzisothiazol-5-amine (150.0 mg, 814.3 μmol) in dioxane (2 mL). The mixture was stirred at 100 °C for 2 hours and then filtered. The filtrate was concentrated to obtain the residue. The residue was purified by preparative HPLC (eluent: 35%–55% acetonitrile / water). The crude product was ground with DCM and MeOH (10 mL, v / v = 5 / 1) at 25 °C for 20 min. The suspension was filtered and washed with DCM and MeOH (5 mL × 3, v / v = 5 / 1) to give compound 1,1-dioxo-N-[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]-2,3-dihydro-1,2-benzisisothiazol-5-amine, as a white solid. MS (ES-API positive): 396.9 (M+H)+. 1HNMR (400MHz, DMSO‑d6) δ10.90‑10.74 (m, 1H), 9.02 (s, 1H), 8.60‑8.45 (m, 1H), 8.34-8.16 (m, 1H), 7.98 (s, 1H), 7.94-7.82 (m, 2H), 7.60-7.50 (m, 1H), 6.70 (s, 1H), 4.38 (d, J=5.0Hz, 2H). Example 49: 4-[[4-[4-(1-cyano-1-methylethyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide Step 1: 4-iodo-1-tetrahydropyran-2-yl-pyrazole

[0097] 4-methylbenzenesulfonic acid (490.3 mg, 2.6 mmol) was added to a solution of 4-iodo-1H-pyrazole (5.0 g, 25.8 mmol) and 3,4-dihydro-2H-pyran (4.8 g, 56.7 mmol) in DCM (10 mL), and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was diluted with water (40 mL) and extracted with ethyl acetate (60 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–25% ethyl acetate / petroleum ether) to give compound 4-iodo-1-tetrahydropyran-2-ylpyrazole, a yellow oil. MS (ES-API positive): 278.9 (M+H)+.Step 2: 2-(1-Tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile

[0098] Cs₂CO₃ (3.9 g, 11.9 mmol) was added to a mixture of 4-iodo-1-tetrahydropyran-2-ylpyrazole (1.1 g, 4.0 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)isoxazole (925.7 mg, 4.8 mmol), and cataCXiumA Pd G3 (288.1 mg, 395.6 μmol) in water (10 mL) and dioxane (30 mL). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by rapid chromatography (eluent: 0%-50% ethyl acetate / petroleum ether) to give compound 2-(1-tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile, which was a yellow oil. MS (ES-API positive): 192.4 (M+H)+. Specification 23 / 78 pages 34 CN 121443596 A Step 3: 2-Methyl-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)propionitrile

[0099] At 0°C, NaH (92.0 mg, 2.3 mmol, purity 60%) was added to a solution of 2-(1-tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile (200.0 mg, 1.1 mmol) in THF (3 mL). After the gas was completely released, CH3I (296.9 mg, 2.1 mmol) was added dropwise at 0 °C, followed by stirring at 0–25 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give 2-methyl-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)propionitrile as a yellow oil. MS (ES-API positive): 220.1 (M+H)+. Step 4: 2-Methyl-2-(1H-pyrazol-4-yl)propionitrile

[0100] 2-Methyl-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)propionitrile (120.0 mg, 547.2 μmol) was added to a solution of HCl in dioxane (2 mL). The mixture was stirred at 50 °C for 2 hours. Subsequently, the reaction mixture was concentrated under vacuum to give a yellow oily residue, which did not require further purification. MS (ES-API positive): 136.3 (M+H)+. Step 5: 4-[[4-[4-(1-cyano-1-methylethyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0101] Cs₂CO₃ (241.0 mg, 739.8 μmol) was added to a solution of 2-methyl-2-(1H-pyrazol-4-yl)propionitrile (50.0 mg, 369.9 μmol) and 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (135.7 mg, 369.9 μmol) in DMSO (2 mL). The mixture was stirred at 40 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (eluting with 60%–80% acetonitrile / water) to give compound 4-[[4-[4-(1-cyano-1-methylethyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a white solid. MS (ES-API positive): 466.1 (M+H)+. 1H NMR (400 MHz, methanol-d4) δ 8.92 (s, 1H), 8.63 (s, 1H), 8.04–7.92 (m, 3H), 7.82 (d, J = 8.8 Hz, 2H), 2.54 (s, 3H), 1.77 (s, 6H). Example 51: 4-[[4-[4-(1-cyanocyclopropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide Step 1: 4-[[4-[4-(cyanomethyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0102] To 4-[[4-(4-iodopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (1.0 g, 1.9 mmol), Cs2CO3 (1.9 g, 5.7 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoxazole (446.4 mg, 2 cataCXiumA Pd G3 (138.9 mg, 190.8 μmol) was added to a mixture of water (4 mL) and dioxane (16 mL). The mixture was stirred at 100 °C for 16 hours under N2 atmosphere. The reaction mixture was added to water (30 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4 (see page 24 / 78 of the instruction manual, CN 121443596 A), filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–100% ethyl acetate / petroleum ether) to give compound 4-[[4-[4-(cyanomethyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, as a brown solid.MS (ES-API positive): 437.9 (M+H)+. Step 2: 4-[[4-[4-(1-cyanocyclopropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0103] Diphenyl(vinyl)sulfonamide (150.0 mg, 413.9 μmol) was added to a solution of 4-[[4-[4-(cyanomethyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (150.0 mg, 342.9 μmol) in DMSO (1.8 mL). The mixture was stirred at 20 °C for 2 min, DBU (157.5 mg, 1.0 mmol) was added, and stirring was continued at 20 °C for 18 h. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (eluent: 42%–62% acetonitrile / water) to give compound 4-[[4-[4-(1-cyanocyclopropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, as a yellow solid. MS (ES-API positive): 464.1 (M+H)+. 1HNMR (400MHz, Methanol‑d4) δ8.93 (s, 1H), 8.65‑8.60 (m, 1H), 8.02‑7.97 (m, 2H), 7.87-7.83(m, 2H), 7.82-7.79(m, 1H), 2.62-2.52(m, 3H), 1.80-1.72(m, 2H), 1.58-1.43(m, 2H). Examples 52 and 53: 4-[[4-[4-(2,2-difluorocyclopropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide Step 1: 1-Tetrahydropyran-2-yl-4-vinylpyrazole

[0104] Na2CO3 (3.7 g, 34.5 mmol) and Pd(dppf)Cl2 (1.3 g, 1.7 mmol) were added to a mixture of 4-iodo-1-tetrahydropyran-2-yl-pyrazole (3.2 g, 11.5 mmol) and potassium trifluoro(vinyl)borate (2.3 g, 17.3 mmol) in dioxane (30 mL) and water (3 mL). The mixture was stirred at 100 °C for 2 hours. The reaction mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–35% ethyl acetate / petroleum ether) to give compound 1-tetrahydropyran-2-yl-4-vinylpyrazole, a yellow oil.MS (ES-API positive): 178.2 (M+H)+. Step 2: 4-(2,2-difluorocyclopropyl)-1-tetrahydropyran-2-yl-pyrazole specification 25 / 78 pages 36 CN 121443596 A

[0105] To a solution of 1-tetrahydropyran-2-yl-4-vinylpyrazole (790.0 mg, 4.4 mmol) in toluene (8 mL), add (bromodifluoromethyl)trimethylsilane (1.1 g, 5.3 mmol) and TBAB (142.9 mg, 443.2 μmol). The mixture is stirred at 110 °C for 1 hour. Add (bromodifluoromethyl)trimethylsilane (1.1 g, 5.3 mmol) again. Continue stirring the mixture at 110 °C for 1 hour. Pour the reaction mixture into water (10 mL) and extract with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%-35% ethyl acetate / petroleum ether) to give compound 4-(2,2-difluorocyclopropyl)-1-tetrahydropyran-2-yl-pyrazole as a yellow oil. MS (ES-API positive): 228.2 (M+H)+. Step 3: 4-(2,2-difluorocyclopropyl)-1H-pyrazole

[0106] The mixture of 4-(2,2-difluorocyclopropyl)-1-tetrahydropyran-2-yl-pyrazole (400.0 mg, 1.8 mmol) in HCl (4 M, dioxane solution, 0.4 mL) was stirred for 1 hour at 25 °C. The reaction mixture was concentrated and purified by rapid chromatography (eluent: 0%–25% ethyl acetate / petroleum ether) to give compound 4-(2,2-difluorocyclopropyl)-1H-pyrazole as a white solid. MS (ES-API positive): 144.1 (M+H)+. Step 4: 4-[[4-[4-(2,2-difluorocyclopropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0107] Cs2CO3 (1.7 g, 5.2 mmol) was added to a solution of 4-(2,2-difluorocyclopropyl)-1H-pyrazole (250.0 mg, 1.7 mmol) and 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (954.3 mg, 2.6 mmol) in DMSO (4 mL). The mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was passed through an SFC chromatography column (DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 μm); [CO₂-MeOH (0.1% NH₃·H₂O)]; B%:Separation was performed using 40% acetonitrile (40%) to obtain Example 52 (retention time: 1.373 min) and Example 53 (retention time: 1.716 min). Purification by preparative HPLC (eluent: 55%–75% acetonitrile / water) yielded Examples 52 and 53 as white solids. MS (ES-API positive): 474.4 (M+H)+. Example 52: 1H NMR (400 MHz, Methanol-d4) δ 8.91 (s, 1H), 8.50 (s, 1H), 7.98 (d, J = 8.8 Hz, 2H), 7.90–7.75 (m, 3H), 2.83 (dt, J = 7.7, 12.2 Hz, 1H), 2.56 (s, 3H), 2.04–1.91 (m, 1H), 1.52–1.47 (m, 1H). Example 53: 1H NMR (400MHz, Methanol-d4) δ 8.91 (s, 1H), 8.50 (s, 1H), 7.98 (d, J = 8.8Hz, 2H), 7.90–7.75 (m, 3H), 2.83 (dt, J = 7.7, 12.2Hz, 1H), 2.56 (s, 3H), 2.04–1.91 (m, 1H), 1.52–1.47 (m, 1H). Example 72: 4-[[4-[4-(2-hydroxy-1,1,2-trimethylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide Step 1: 2-chloro-N-[1,1-dimethyl-2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]ethyl]acetamide

[0108] At 0°C, 4-[[4-[4-(2-hydroxy-2-methylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]acetamide was added to 4-[[4-[4-(2-hydroxy-2-methylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]acetamide was added to 5-[trifluoromethyl]acetamide. [1,1-Dimethyl-2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]ethyl]acetamide, a white solid, was added dropwise to a solution of 2-chloroacetonitrile (0.9 mL). The mixture was stirred at 20 °C for 1 hour. The reactants were treated with ice water (8 mL) and an aqueous solution of NaHCO3 to adjust the pH to approximately 8. The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude compound 2-chloro-N-[1,1-dimethyl-2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]ethyl]acetamide, which required no further purification. MS (ES-API positive): 546.2 (M+H)+.Step 2: 4-[[4-[4-(2-amino-2-methylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0109] Thiourea (25.1 mg, 329.7 μmol) was added to a solution of 2-chloro-N-[1,1-dimethyl-2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]ethyl]acetamide (90.0 mg, 164.8 μmol) in EtOH (6 mL) and AcOH (1.0 mL). The mixture was stirred at 85 °C for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (eluent: 23%–43% acetonitrile / water) to give compound 4-[[4-[4-(2-amino-2-methylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a white solid. MS (ES-API positive): 470.1 (M+H)+. ¹H NMR (400 MHz, methanol-d4) δ 8.91 (s, 1H), 8.51 (s, 1H), 8.00–7.89 (m, 2H), 7.87–7.76 (m, 3H), 2.91 (s, 2H), 2.54 (s, 3H), 1.40 (s, 6H). Examples 74 and 75: 4-[[4-[4-[(1S,2R)-2-hydroxycyclopentyl]pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide and 4-[[4-[4-[(1R,2S)-2-hydroxycyclopentyl]pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide Step 1: 4-[[4-[4-[trans-2-hydroxycyclopentyl]pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0110] To a mixture of pyridine-2,6-dimethylamidine (34.2 mg, 209.5 μmol), 4-[[4-(4-bromopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (500.0 mg, 1.1 mmol) and 6-oxabicyclo[3.1.0]hexane (176.3 mg, 2.1 mmol) in DMA (10 mL), zinc (274.0 mg, 4.2 mmol), TBAI (580.5 mg, 1.6 mmol), nickel diiodide (65.5 mg, 209.5 μmol), and N,N-diethylethylamine hydrochloride (144.2 mg, 1.1 mmol) were added. The mixture was stirred at 80 °C for 4 hours under a nitrogen atmosphere. The mixture was then poured into water (50 mL) and diluted with ethyl acetate (50 mL × 3).Extraction. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–70% ethyl acetate / petroleum ether) to give 4-[[4-[4-[trans-2-hydroxycyclopentyl]pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a white solid. MS (ES-API positive): 483.1 (M+H)+. Step 2: The residues of 4-[[4-[4-[(1S,2R)-2-hydroxycyclopentyl]pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide and 4-[[4-[4-[(1R,2S)-2-hydroxycyclopentyl]pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0111] were passed through SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3H2O)]; B%: 40%) to give Example 74 (retention time: 2.294 min) and Example 75 (retention time: 3.013 min), as white solids. MS (ES-API positive): 483.1 (M+H)+. Example 74: 1H NMR (400MHz, CD3OD) δ 8.87 (s, 1H), 8.43 (s, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.89–7.76 (m, 3H), 4.07 (q, J = 6.8Hz, 1H), 2.92 (q, J = 7.8Hz, 1H), 2.55 (s, 3H), 2.30–2.17 (m, 1H), 2.13–2.00 (m, 1H), 1.95–1.63 (m, 4H). Example 75: 1H NMR (400MHz, CD3OD) δ 8.86 (s, 1H), 8.42 (s, 1H), 7.96 (d, J = 8.9Hz, 2H), 7.87–7.74 (m, 3H), 4.07 (q, J = 6.8Hz, 1H), 2.92 (q, J = 7.8Hz, 1H), 2.26–2.14 (m, 1H), 2.13–2.01 (m, 1H), 1.93–1.62 (m, 4H). Examples 76 and 77: 4-((4-((1S,2S)-2-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1R,2R)-2-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamideStep 1: 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide is the same as step 1 in Examples 74 and 75. Step 2: [2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]cyclopentyl]4-nitrobenzoate

[0112] PPh3 (326.2 mg, 1.2 mmol) and DIAD (251.5 mg, 1.2 mmol) were added to a solution of 4-nitrobenzoic acid (69.3 mg, 414.5 μmol) and 4-[[4-[4-(2-hydroxycyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (200.0 mg, 414.5 μmol) in THF (3 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was poured into water (2 mL) and extracted with ethyl acetate (2 mL × 3). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give compound [2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]cyclopentyl]4-nitrobenzene ester, a white solid. MS (ES-API positive): 632.2(M+H)+. Step 3: 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0113] to [2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl] Cyclopentyl]4-nitrobenzene ester (180.0 mg, 285.0 μmol) was added to a solution of THF (2 mL) and water (0.4 mL) with LiOH·H2O (59.8 mg, 1.4 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (eluent: 38%–58% acetonitrile / water). MS (ES-API positive): 483.2 (M+H)+. Step 4: The product was passed through an SFC column (DAICEL CHIRALPAK AD (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3H2O); B%: 60%), yielding Example 76 (retention time: 1.055 min) and Example 77 (retention time: 2.025 min), both white solids. MS (ES-API positive): 483.2 (M+H)+. Example 76: ¹H NMR (400 MHz, Methanol-d⁴) δ 8.76 (s, 1H), 8.35 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.75–7.70 (m, 2H), 7.69 (s, 1H), 4.19–4.12 (m, 1H), 2.95–2.83 (m, 1H), 2.02–1.79 (m, 4H), 1.76–1.59 (m, 2H) Example 77: ¹H NMR (400 MHz, Methanol-d⁴) δ 8.88 (s, 1H), 8.47 (s, 1H), 7.99 (d, J = 8.8 Hz, 2H) 8.7Hz, 2H), 7.87-7.83(m, 2H), 7.81(s, 1H), 4.27(s, 1H), 3.07-2.98(m, 1H), 2.13-1.92(m, 4H), 1.87-1.73(m, 2H). Examples 78 and 79: 4-((4-(4-((1S,3S)-3-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1S,3S)-3-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Step 1: [1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]boric acid

[0114] At 20°C, 4-(4,4,5,5-tetramethyl-1,3-yl)pyrazol-4-yl]pyrazol-4-yl]boric acid 1.2 g (6.0 mmol) of 2-dioxaborane-2-yl)-1H-pyrazole (3.6 g, 10.9 mmol) and 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (2.0 g, 5.5 mmol) were added to a solution of 2-dioxaborane-2-yl)-1H-pyrazole (30 mL) in DMF. The mixture was stirred at 20 °C for 60 hours. The reaction mixture was poured into water (150 mL). The pH was adjusted to 7.0 with 2N HCl aqueous solution. The crude product was filtered to give [1-[2-dioxaborane-2-yl]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazole-4-yl]boronic acid, a pale yellow solid, which can be used directly for the next step without further purification. MS(ES‑API positive): 443.0(M+H)+.Step 2: N-Methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0115] To a mixture of [1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]boronic acid (2.5 g, 4.0 mmol) and K2CO3 (2 M, 7.1 mL) in THF (21.2 mL), (3-oxocyclopenten-1-yl)4-nitrobenzenesulfonate (1.0 g, 3.5 mmol) and Pd(dppf)Cl2 (103.3 mg, 141.2 μmol) were added. The mixture was stirred at 30 °C for 16 hours under a N2 atmosphere. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–65% ethyl acetate / petroleum ether) to give N-methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, as a pale yellow solid. MS (ES-API positive): 479.0 (M+H)+. Step 3: N-methyl-4-[[4-[4-(3-oxocyclopentenyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0116] Pd / C (253.6 mg, 238.3 μmol, purity 10%) was added to a solution of N-methyl-4-[[4-[4-(3-oxocyclopentenyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide (600.0 mg, 1.2 mmol) in MeOH (30 mL) and THF (30 mL), and stirred at 40 °C for 6 hours under H2 (40 Psi) atmosphere. The reaction mixture was filtered and concentrated to give N-methyl-4-[[4-[4-(3-oxocyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, a pale yellow solid, which was used directly in the next step without further purification. MS (ES-API positive): 481.0 (M+H)+. Step 4: 4-[[4-[4-(3-hydroxycyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0117] At -78°C, L-Selectride (1M, 541 mg) was added to a solution of N-methyl-4-[[4-[4-(3-oxocyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide (130.0 mg, 270.6 μmol) in THF (4 mL).0.2 μL) was stirred at a nitrogen atmosphere for 1 hour. The reaction mixture was quenched with water (8 mL), extracted with ethyl acetate, washed with brine, and concentrated. The residue was purified by rapid chromatography (eluent: 60% ethyl acetate / petroleum ether) to give compound 4-[[4-[4-(3-hydroxycyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, as a white solid. MS (ES-API positive): 483.2 (M+H)+. Step 5: 4-[[4-[4-(3-hydroxycyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0118] was treated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3·H2O)]; B%: 45%) to obtain Example 78 (retention time: 1.779 min) and Example 79 (retention time: 2.740 min), as white solids. MS (ES-API positive): 483.1 (M+H)+. Example 78: 1H NMR (400MHz, Methanol-d4) δ 8.86 (s, 1H), 8.36 (s, 1H), 8.01–7.92 (m, 2H), 7.84–7.79 (m, 2H), 7.75 (s, 1H), 4.53–4.41 (m, J = 2.6, 5.7Hz, 1H), 3.40–3.33 (m, 1H), 2.54 (s, 3H), 2.33–2.22 (m, 1H), 2.21–2.06 (m, 2H), 1.84–1.80 (m, 1H), 1.75–1.54 (m, 2H). Specification 30 / 78 pages 41 CN 121443596 A Example 79: 1H NMR (400MHz, Methanol-d4) δ 8.86 (s, 1H), 8.35 (s, 1H), 7.96 (d, J = 8.8Hz, 2H), 7.86–7.79 (m, 2H), 7.75 (s, 1H), 4.45–4.41 (m, 1H), 3.41–3.34 (m, 1H), 2.54 (s, 3H), 2.35–2.22 (m, 1H), 2.21–2.06 (m, 2H), 1.84–1.80 (m, 1H), 1.77–1.55 (m, 2H). Example 80: N-methyl-4-[[4-[4-(1-methyl-4-piperidinyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide Step 1: tert-butyl-4-(1-(2-((4-(N-methylaminosulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0119] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (388.7 mg, 1.3 mmol) and 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (500.0 mg, 1.0 mmol) in dioxane (10 mL) and water (2 mL), Na2CO3 (222.1 mg, 2.1 mmol) and Pd(dppf)Cl2 (76.7 mg, 104.8 μmol) were added. The mixture was degassed and purged three times with N2, then stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude tert-butyl 4-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate, a brown solid, which was used directly for the next step without further purification. MS (ES-API positive): 580.2(M+H)+. Step 2: Tert-butyl 4-(1-(2-((4-(N-methylaminosulfonyl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)-1H-pyrazol-4-yl)piperidine-1-carboxylate

[0120] Palladium hydroxide (387.7 mg, 552.1 μmol, purity 20%) was added to a solution of tert-butyl 4-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (320.0 mg, 552.1 μmol) in MeOH (10 mL) and ethyl acetate (10 mL). The mixture was stirred at 20 °C for 16 hours under a N2 (50 psi) atmosphere. The reaction mixture was filtered and concentrated to give crude tert-butyl 4-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]piperidin-1-carboxylate, a brown solid, which could be used directly in the next step without further purification. MS (ES-API positive): 582.2(M+H)+. Step 3: N-methyl-4-[[4-[4-(4-piperidinyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0121] to tert-butyl 4-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol- ... (Instructions 31 / 78, page 42, CN 121443596 A)[4-yl]piperidin-1-carboxylate (265.0 mg, 455.6 μmol) was added to a solution of dioxane (1 mL) in 1 mL of HCl (4 M, dioxane solution, 1.1 mL). The mixture was degassed and purged three times with N2, followed by stirring at 20 °C for 2 hours. The reaction mixture was filtered and concentrated to give crude N-methyl-4-[[4-[4-(4-piperidinyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, a brown solid, which was used directly for the next step without further purification. MS (ES-API positive): 482.2(M+H)+. Step 4: N-Methyl-4-[[4-[4-(1-methyl-4-piperidinyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0122] To a solution of N-methyl-4-[[4-[4-(4-piperidinyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide (120.0 mg, 249.2 μmol) in MeOH (1 mL), NaBH3CN (47.0 mg, 747.7 μmol) and formaldehyde (60.7 mg, 747.7 μmol, purity 37%) were added. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (eluent: 33%–63% acetonitrile / water) to give N-methyl-4-[[4-[4-(1-methyl-4-piperidinyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, a white solid. MS (ES-API positive): 496.1 (M+H)+. 1HNMR (400MHz, Methanol-d4) δ8.87 (s, 1H), 8.41 (s, 1H), 7.96 (d, J=8.7Hz, 2H), 7.83 (d, J=7.4Hz, 3H), 3.82 (d, J=12.2Hz, 2H), 2.95-2.85 (m, 5H), 2.83-2.75 (m, 1H), 2.54 (s, 3H), 2.16-2.09 (m, 2H), 1.83-1.67 (m, 2H). Example 87: N-methyl-4-[[4-(4-pyrrolidone-1-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide Step 1: N-methyl-4-[[4-(4-nitropyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0123] Add Cs2CO3 (3.6 g, 5.5 mmol) to a mixture of 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (2.0 g, 5.5 mmol) and 4-nitro-1H-pyrazole (616.6 mg, 5.5 mmol) in DMF (30 mL).11.0 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into water (150 mL). The precipitate was filtered and dried to give the crude compound N-methyl-4-[[4-(4-nitropyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, a white solid. MS (ES-API positive): 444.0 (M+H)+. Step 2: 4-[[4-(4-aminopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0124] Pd / C (456.1 mg, 428.5 μmol, purity 10%) was added to a solution of N-methyl-4-[[4-(4-nitropyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide (1.9 g, 4.3 mmol) in THF (20 mL) and ethyl acetate (20 mL). The mixture was stirred at 25 °C for 4 hours under N2 (20 psi) atmosphere. After filtration, the mixture was concentrated under vacuum to give compound 4-[[4-(4-aminopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a white solid. MS (ES-API positive): 414.0 (M+H)+. Instructions for Use 32 / 78 pages 43 CN 121443596 A Step 3: N-methyl-4-[[4-(4-pyrrolidine-1-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0125] K2CO3 (66.9 mg, 483.8 μmol) was added to a solution of 4-[[4-(4-aminopyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (100.0 mg, 241.9 μmol) and 1,4-dibromobutane (78.4 mg, 362.9 μmol) in DMF (2 mL). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC (eluent: 50%–70% acetonitrile / water) to give N-methyl-4-[[4-(4-pyrrolidone-1-ylpyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide as a red solid. MS (ES-API positive): 468.0 (M+H)+. ¹H NMR (400 MHz, methanol-d₄) δ 8.81 (s, 1H), 8.00–7.95 (m, 3H), 7.83 (d, J = 8.8 Hz).2H), 7.69 (s, 1H), 3.29 (t, J=6.4Hz, 4H), 2.56 (s, 3H), 2.11-2.04 (m, 4H). Example 88: N-Methyl-4-[[4-[4-(2-oxopyrrolidone-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide Step 1: 4-Chloro-N-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]butyramide

[0126] TEA (0.1 mL, 967.6 μmol) was added to a mixture of 4-[[4-(4-aminopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (200.0 mg, 483.8 μmol) and 4-chlorobutyryl chloride (75.0 mg, 532.2 μmol) in THF (4 mL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–40% ethyl acetate / petroleum ether) to give compound 4-chloro-N-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]butyramide, as a yellow oil. MS (ES-API positive): 518.1 (M+H)+. Step 2: N-Methyl-4-[[4-[4-(2-oxopyrrolidone-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0127] Cs₂CO₃ (188.7 mg, 579.3 μmol) was added to a solution of 4-chloro-N-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]butyramide (200.0 mg, 386.2 μmol) in DMF (4 mL). The mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (eluting with 43%–63% acetonitrile / water) to give N-methyl-4-[[4-[4-(2-oxopyrrolidone-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, a white solid. MS (ES-API positive): 482.0 (M+H)+. 1H NMR (400 MHz, methanol-d4) δ 10.87 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.20 (s, 1H).1H), 8.03–7.94 (m, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.35 (q, J = 5.0 Hz, 1H), 3.82 (t, J = 7.1 Hz, 2H), 2.49–2.46 (m, 2H), 2.44–2.38 (m, 3H), 2.15 (q, J = 7.6 Hz, 2H). Examples 91 and 92: (R)-N-methyl-4-((4-(4-(pyrrolidin-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-(pyrrolidin-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide Step 1: tert-butyl 2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazole-4-yl]pyrrolidin-1-carboxylate

[0128] to 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (154.6 mg, 421.4 μg) Cs₂CO₃ (274.6 mg, 842.8 μmol) and tert-butyl 2-(1H-pyrazol-4-yl)pyrrolidine-1-carboxylate (100.0 mg, 421.4 μmol) were added to a solution in DMSO (1 mL). The mixture was stirred at 80 °C for 1 hour. The reaction mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give tert-butyl 2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate as a colorless oil. Subsequently, the compounds were purified by SFC (column: regis(s,s)whelk-o1 (250 mm × 25 mm × 10 μm); [CO2- EtOH]; B%: 50%) to obtain tert-butyl 2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate (isomer-1) and tert-butyl 2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate (isomer-2), both of which were colorless oils. The retention times were 1.527 min and 2.350 min, respectively. MS (ES-API positive): 568.1 (M+H)+.Step 2: (R)-N-methyl-4-((4-(4-(pyrrolidin-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-(pyrrolidin-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0129] HCl (4M, dioxane solution, 2.0 mL) was added to a solution of tert-butyl 2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (48.0 mg, 84.6 μmol) in dioxane (0.1 mL). The mixture was stirred at 25 °C for 1 hour. The mixture was then concentrated and purified by preparative HPLC (eluent: 22%–42% acetonitrile / water).

[0130] The compound N-methyl-4-[[4-(4-pyrrolidone-2-ylpyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide was obtained as a white solid. Another isomer was prepared under similar conditions. MS (ES-API positive): 468.1 (M+H)+. Specification page 34 / 78 45 CN 121443596 A Example 91: 1H NMR (500MHz, CD3OD) δ 8.99-8.94 (m, 1H), 8.75-8.72 (m, 1H), 8.05-8.02 (m, 1H), 7.98-7.94 (m, 2H), 7.88-7.83 (m, 2H), 4.81-4.76 (m, 1H), 3.52-3.42 (m, 2H), 2.61-2.52 (m, 4H), 2.39-2.20 (m, 3H). Example 92: 1H NMR (400MHz, Methanol-d4) δ 8.96 (s, 1H), 8.79–8.70 (m, 1H), 8.03–8.02 (m, 1H), 7.98–7.95 (m, 2H), 7.88–7.83 (m, 2H), 4.82–4.77 (m, 1H), 3.53–3.42 (m, 2H), 2.60–2.53 (m, 4H), 2.37–2.21 (m, 3H). Examples 93 and 94: (R)-N-methyl-4-((4-(4-(pyrrolidin-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-(pyrrolidin-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide Step 1: tert-butyl3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyr

[0131] A mixture of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-2,5-dihydropyrrole-1-carboxylate (675.6 mg, 2.3 mmol) and 4-[[4-(4-iodopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (1.0 g, 1.9 mmol) in water (5 mL) and dioxane (15 mL) was mixed with Na2CO3 (606.5 mg, 5.7 mmol) and Pd(dppf)Cl2 (139.6 mg, 190.8 μmol). The mixture was stirred at 80 °C for 18 hours under a N2 atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were dried over Na₂SO₄ and concentrated. The residue was purified by rapid chromatography (eluent: 0%–45% ethyl acetate / petroleum ether) to give tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]-2,5-dihydropyrrole-1-carboxylate as a yellow solid. MS (ES-API positive): 566.2 (M+H)+. Step 2: Tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate

[0132] Pd / C (99.7 mg, 93.7 μmol, purity 10%) was added to a solution of tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]-2,5-dihydropyrrole-1-carboxylate (0.5 g, 937.1 μmol) in THF (5 mL) and ethyl acetate (5 mL). The mixture was stirred at 25 °C for 3 hours under a N2 (15 psi) atmosphere. The reaction mixture was filtered and concentrated. The residue was further purified by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm × 10 μm); [CO2-MeOH (0.1% NH3·H2O)]; B%: 50%) to give compound tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate (isomer-1) and compound tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate (isomer-2), both white solids. The retention times were 3.168 min and 3.168 min, respectively.3.851 minutes. MS (ES-API positive): 568.2 (M+H)+. Step 3: (R)-N-methyl-4-((4-(4-(pyrrolidine-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-(pyrrolidine-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0133] HCl (4M, dioxane solution, 2 mL) was added to a solution of tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (40.0 mg, 70.5 μmol) in dioxane. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (eluent: 25%–45% acetonitrile / water) to give N-methyl-4-[[4-(4-pyrrolidone-3-ylpyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, a white solid. Another isomer was prepared under similar conditions. MS (ES-API positive): 468.1 (M+H)+. Example 93: 1H NMR (400MHz, CD3OD) δ 8.92 (s, 1H), 8.55 (s, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.91 (s, 1H), 7.85 (d, J = 8.8Hz, 2H), 3.76 (dd, J = 7.9, 11.2Hz, 1H), 3.70–3.53 (m, 2H), 3.48–3.39 (m, 1H), 3.25 (dd, J = 9.5, 11.1Hz, 1H), 2.56 (s, 4H), 2.23–2.11 (m, 1H). Example 94: 1H NMR (400MHz, CD3OD) δ 8.96–8.83 (m, 1H), 8.55 (s, 1H), 7.97 (d, J = 8.8Hz, 2H), 7.91 (s, 1H), 7.85 (d, J = 8.8Hz, 2H), 3.83–3.71 (m, 1H), 3.68–3.53 (m, 2H), 3.47–3.40 (m, 1H), 3.25 (dd, J = 9.7, 11.0Hz, 1H), 2.56 (s, 4H), 2.25–2.06 (m, 1H). Example 103: 4-[[4-[4-(3-hydroxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide Step 1: N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0134] To a mixture of 4-[[4-(4-bromopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (0.4 g, 838.1 μmol) and 3-bromocyclobutanone (187.3 mg, 1.3 mmol) in DMA (10 mL), NiI₂ (52.4 mg, 167.6 μmol), TBAI (464.4 mg, 1.3 mmol), manganese (184.2 mg, 3.4 mmol), and pyridine-2,6-dimethylamidine (27.4 mg, 167.6 μmol) were added. The mixture was stirred at 60 °C for 4 hours under a nitrogen atmosphere. The reaction mixture was poured into water (30 mL) and extracted with EA (20 mL × 3). The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide, as a yellow oil. MS (ES-API positive): 467.2 (M+H)+. Instructions for Use, Pages 36 / 78, 47, CN 121443596 A, Step 2: 4-[[4-[4-(3-hydroxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0135] At -78°C, L-Selectride (343.0 μmol, 75.0 μL) was added to a solution of N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide (80.0 mg, 171.5 μmol) in THF (2 mL), and stirred for 1 hour under N2 atmosphere. The reaction mixture was quenched with water (4 mL) at -60°C, and stirred for 10 minutes after heating to 20°C. The mixture was extracted with ethyl acetate (5 mL × 3), washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC (eluent: 35%–65% acetonitrile / water) to give compound 4-[[4-[4-(3-hydroxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, as a white solid. MS (ES-API positive): 469.0 (M+H)+. 1HNMR (400MHz, Methanol-d4) δ8.87 (s, 1H), 8.36 (s, 1H), 7.96 (d, J=8.7Hz, 2H), 7.82(d, J=8.8Hz, 2H), 7.77(s, 1H), 4.19(q, J=7.5Hz, 1H), 3.02-2.90(m, 1H), 2.80-2.69(m, 2H), 2.54 (s, 3H), 2.05–1.94 (m, 2H). Examples 104 and 105: 4-((4-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Step 1: N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0136] Same as the previous example. Step 2: 4-[[4-[4-(3-hydroxy-3-methylcyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0137] At 0°C, MeMgBr (3M, 257.3μL) was added to a mixture of N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide (60.0 mg, 128.6 μmol) and CeCl3 (6.3 mg, 25.7 μmol) in THF (2 mL). The mixture was stirred at 0°C for 2 hours under a N2 atmosphere. At 0°C, the reaction mixture was quenched with saturated NH4Cl (6 mL) and extracted with ethyl acetate (5 mL × 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (eluent: 50%-70% acetonitrile / water) and then by preparative HPLC (eluent: 40%-60% acetonitrile / water).

[0138] 4-((4-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide were obtained, both white solids. MS (ES-API positive): 483.1 (M+H)+. Example 104: ¹H NMR (400 MHz, Methanol-d⁴) δ 8.86 (s, ¹H), 8.37 (s, ¹H), 7.96 (d, J = 8.9 Hz, 2H), 7.87–7.79 (m, 2H), 7.75 (s, ¹H), 3.58 (q, J = 8.2 Hz, 1H), 2.58–2.50 (m, 5H), 2.22–2.13 (m, 2H), 1.35 (s, 3H). Example 105: ¹HNMR (400MHz, Methanol-d4) δ 8.86 (s, 1H), 8.36 (s, 1H), 7.96 (d, J = 8.9Hz, 2H), 7.87–7.81 (m, 2H), 7.79 (s, 1H), 3.06 (q, J = 8.9Hz, 1H), 2.54 (s, 3H), 2.51–2.45 (m, 2H), 2.23–2.14 (m, 2H), 1.44 (s, 3H). Example 106: 4-((4-(4-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Step 1: (3-bromocyclobutoxy)methylbenzene

[0139] CBr4 (5.6 g, 16.8 mmol) and PPh3 (4.4 g, 16.8 mmol) were added to a solution of 3-benzyloxycyclobutanol (2.0 g, 11.2 mmol) in DCM (20 mL). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–5% ethyl acetate / petroleum ether) to give the compound (3-bromocyclobutoxy)methylbenzene as a colorless oil. MS (ES-API positive): 241.1 (M+H)+. Step 2: Add TBAI (628.8 mg, 1.7 mmol) and NiI2 (59.8 mg, 1.4 mmol) to a solution of pyridine-2,6-dimethylamidine (44.5 mg, 272.4 μmol), (3-bromocyclobutoxy)methylbenzene (656.8 mg, 2.7 mmol) and 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (650.0 mg, 1.4 mmol) in DMA (7 mL). 272.4 μmol), manganese (299.3 mg, 5.5 mmol), and TFA (1.4 mmol, 101.2 μL). The mixture was stirred at 80 °C for 4 hours and then filtered. The filtrate was poured into water (15 mL), extracted with ethyl acetate (15 mL × 3), dried over Na2SO4, and concentrated. The crude product was purified by preparative HPLC (eluent: 0%–30% acetonitrile) to give compound 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazole-1-[4-[4-[4-(3-benzyloxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a yellow oil. MS (ES-API positive): 559.3 (M+H)+. Step 3: 4-((4-(4-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0141] Pd / C (57.2 mg, 53.7 μmol, purity 10%) was added to a solution of 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (300.0 mg, 537.1 μmol) in THF (5 mL) and MeOH (5 mL). The mixture was stirred at 25°C for 5 hours under a N2 (30 psi) atmosphere. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (eluting 44%–64% acetonitrile / water), and the product was further separated by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm × 10 μm); [CO2-i-PrOH (0.1% NH3H2O)]; B%: 50%) to give compound 4-((4-(4-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide, as a white solid (retention time: 1.562 min). MS (ES-API positive): 469.1 (M+H)+. 1HNMR (400MHz, Methanol-d4) δ8.88 (s, 1H), 8.42 (s, 1H), 7.98 (d, J=8.8Hz, 2H), 7.88-7.72(m, 3H), 4.62-4.42(m, 1H), 3.55-3.41(m, 1H), 2.56(s, 3H), 2.48-2.37(m, 4H). Instructions for Use, Pages 38 / 78, 49, CN 121443596 A, Example 116: 4-((5-(difluoromethyl)-4-(1H-pyrazol-1-yl)pyrimidin-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide, Step 1: 2,4-Dichloro-5-(difluoromethyl)pyrimidine

[0142] At 0°C, DAST (1.5 mL, 11.4 mmol) was added to a solution of 2,4-dichloropyrimidin-5-carboxaldehyde (1.0 g, 5.7 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by rapid chromatography (eluent: 10% ethyl acetate / petroleum ether) to give 2,4-dichloro-5-(difluoromethyl)pyrimidine as a white solid.¹H NMR (400 MHz, Chloroform-d) δ 8.81 (s, ¹H), 6.89 (t, J = 53.7 Hz, ¹H). Step 2: 2-Chloro-5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidine

[0143] ¹H-pyrazole (152.2 mg, 2.2 mmol) and K₂CO₃ (309.1 mg, 2.2 mmol) were added to a solution of 2,4-dichloro-5-(difluoromethyl)pyrimidine (445.0 mg, 2.2 mmol) in DMF (6 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water, extracted with ethyl acetate, and concentrated. The residue was purified by rapid chromatography (eluent: 10%-20% ethyl acetate / petroleum ether) to give 2-chloro-5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidine as a white solid. MS (ES-API positive): 231.1 (M+H)+. Step 3: 4-{[5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidin-2-yl]amino}-N-[5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazane-1-yl]benzenesulfonamide

[0144] to 2-chloro-5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidin (150.0 mg, 0 4-amino-N-[5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazane-1-yl]benzenesulfonamide (290.8 mg, 0.8 mmol), Pd2(dba)3 (178.7 mg, 0.2 mmol), Xantphos (150.5 mg, 0.3 mmol), and Cs2CO3 (275.5 mg, 0.8 mmol) were added to a solution of dioxane (6.0 mL). The reaction mixture was stirred at 90 °C for 1 hour under a nitrogen atmosphere. The mixture was extracted with ethyl acetate and then concentrated. The residue was purified by rapid chromatography (eluent: 30% ethyl acetate / petroleum ether) to give compound 4-{[5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidin-2-yl]amino}-N-[5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazane-1-yl]benzenesulfonamide, as a yellow solid. MS (ES-API positive): 567.2 (M+H)+. Step 4: 4-{[5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidin-2-yl]amino}-N-(2-hydroxyethyl)benzenesulfonamide

[0145] Add to a solution of 4-{[5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidin-2-yl]amino}-N-[5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazane-1-yl]benzenesulfonamide (226.0 mg, 0.4 mmol) in THF (5.0 mL)Add TBAF (4M, THF solution, 0.3 mL). Stir the reaction mixture at room temperature for 0.5 hours. Concentrate the reaction mixture under vacuum. Dilute the residue with water, extract with ethyl acetate, and concentrate. Purify the residue by rapid chromatography (eluent: 9% methanol / dichloromethane) to give compound 4-{[5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidin-2-yl]amino}-N-(2-hydroxyethyl)benzenesulfonamide, as a white solid. MS (ES-API positive): 411.0 (M+H)+. 1HNMR (400MHz, DMSO‑d6) δ10.66 (s, 1H), 8.91 (s, 1H), 8.71 (d, J=2.7Hz, 1H), 8.03 (d, J=1.6Hz, 1H), 7.95 (d, J=8.9Hz, 2H), 7.80 (dd, J=9.3, 7.3Hz, 3H), 7.46 (t, J=5.9Hz, 1H), 6.72 (dd, J=2.8, 1.6Hz, 1H), 4.70 (t, J=5.5Hz, 1H), 3.43-3.37 (m, 2H), 2.79 (q, J= 6.2Hz, 2H). Example 130: 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonylprop-1-ol Step 1: Methyl 3-(4-nitrophenyl)thiopropionate

[0146] At 0°C, KOH (1.9 g, 33.6 mmol) was added to a solution of 1-fluoro-4-nitrobenzene (3.4 g, 24.0 mmol) and methyl 3-mercaptopropionate (4.9 g, 40.8 mmol) in DMF (50 mL). The mixture was stirred at 80°C for 1 hour under a N2 atmosphere. The reaction mixture was quenched with ice water (120 mL), filtered, and recrystallized (via a methanol-water system) to give compound methyl 3-(4-nitrophenyl)thiopropionate, a pale yellow solid, which was used directly in the next step without further purification. Step 2: Methyl 3-(4-nitrophenyl)sulfonylpropionate

[0147] At 0°C, a solution of methyl 3-(4-nitrophenyl)thiopropionate (3.0 g, 12.4 mmol) in acetonitrile (300 mL) was added to a solution of Oxone (22.9 g, 37.3 mmol) in water (600 mL). The mixture was stirred at room temperature for 3 hours. At 0°C, the reaction mixture was quenched with saturated Na2SO3 aqueous solution (100 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was a pale yellow solid and was used directly for the next step without further purification. MS (ES-API positive): 296.2 (M+Na)+. Step 3: Methyl 3-(4-aminophenyl)sulfonylpropionate

[0148] Pd / C (779.0 mg, 0.7 mmol, 10% purity) was added to a solution of methyl 3-(4-nitrophenyl)sulfonylpropionate (2.0 g, 7.3 mmol) in MeOH (100 mL), and the mixture was stirred at room temperature for 16 hours under a N2 (40 psi) atmosphere. The reaction mixture was filtered and concentrated to give the desired compound as a pale yellow solid, which could be used directly for the next step without further purification. MS (ES-API positive): 261.2(M+H)+. Instructions for Use, Pages 40 / 78, No. 51, CN 121443596 A, Step 4: Methyl 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonyl propionate

[0149] To a solution of methyl 3-(4-aminophenyl)sulfonyl propionate (1.0 g, 2.1 mmol) in ACN (16 mL), add TsOH·H2O (784.0 mg, 2.1 mmol) and 2-chloro-4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidine (1.0 g, 2.1 mmol). The mixture is stirred at 80 °C for 2 hours. The reaction mixture is concentrated and diluted with NaHCO3 (20 mL). The combined organic layers are washed with brine, dried over Na2SO4, filtered, and concentrated. The residue is purified by rapid chromatography (eluent: 0%–33% ethyl acetate / petroleum ether) to give the desired compound as a yellow solid. MS (ES-API positive): 456.0 (M+H)+. Step 5: 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonylpropionate

[0150] At -78°C, LAH (2.5M, 0.5mL) was added to a mixture of methyl 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonylpropionate (600.0mg, 1.3mmol) in THF (5mL), and stirred at -40°C for 1 hour. At 0°C, the reaction mixture was quenched with Na2SO4·10H2O (0.6g), filtered, and concentrated. The residue was subjected to preparative HPLC (eluting with 35%–53% acetonitrile / water) to give 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonylprop-1-ol, a white solid. MS (ES-API positive): 428.3 (M+H)+. ¹H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.01 (s, 1H), 8.63 (d, J = 2.6 Hz, 1H), 8.07–7.94 (m, 3H), 7.88 (d, J = 8.8 Hz, 2H), 6.70 (d, J = 2.5 Hz, 1H), 3.41 (t, J = 6.2 Hz, 2H), 3.33–3.14 (m, 2H), 1.76–1.61 (m, 2H). Example 136: N-(2-hydroxyethyl)-5-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-2-sulfonamide Step 1: 5-bromo-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyridine-2-sulfonamide

[0151] TEA (7.8 mmol, 1.0 mL) was added to a solution of 5-bromopyridine-2-sulfonyl chloride (1.0 g, 3.9 mmol) and 2-[tert-butyl(dimethyl)silyl]oxyethylamine (820.0 mg, 4.7 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with DCM (15 mL × 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give compound 5-bromo-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyridine-2-sulfonamide, as a white solid. MS (ES-API positive): 396.8, 394.8 (M+H)+. Step 2: N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-2-sulfonamide

[0152] A mixture of 5-bromo-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyridine-2-sulfonamide (400.0 mg, 1.0 mmol), 4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-amine (232.0 mg, 1.0 mmol), Xantphos (120.0 mg, 0.2 mmol), Pd2(dba)3 (93.0 mg, 0.1 mmol), and Cs2CO3 (667.0 mg, 2.0 mmol) in dioxane (4 mL) was degassed and purged three times with H2. The mixture was stirred at 100 °C for 16 hours. The reaction mixture was quenched with water (10 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid chromatography (eluent: 0%–50% ethyl acetate / petroleum ether) to give compound N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-2-sulfonamide, as a white solid. MS (ES-API positive): 544.1 (M+H)+. Step 3: N-(2-hydroxyethyl)-5-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-2-sulfonamide

[0153] At 0 °C, TBAF (1 M, 221.0 μL) was added to a solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-2-sulfonamide (100.0 mg, 184.0 μmol) in THF (1 mL), and the mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with water (5 mL) and then extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was ground with ethyl acetate (5 mL) at room temperature for 10 minutes and then filtered. The filter cake was purified by preparative HPLC (eluent: 31%–51% acetonitrile / water) to obtain N-(2-hydroxyethyl)-5-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyridine-2-sulfonamide, a white solid. MS (ES-API positive): 430.1 (M+H)+. 1HNMR (500MHz, DMSO‑d6) δ11.01 (s, 1H), 9.12‑8.91 (m, 2H), 8.60 (d, J=2.6Hz, 1H), 8.43 (d, J=2.4Hz, 1H), 8.06-7.89 (m, 2H), 7.69 (s, 1H), 6.71 (d, J=2.6Hz, 1H), 4.66 (t, J= 5.6Hz, 1H), 3.37 (q, J=6.4Hz, 2H), 2.98-2.92 (m, 2H). Example 138: ((4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine Step 1: tert-butyl((4-nitrophenyl)sulfonyl)glycine ester

[0154] At 0°C, Na2CO3 (358.7 mg, 3.4 mmol) and 4-nitrobenzenesulfonyl chloride (500.0 mg, 2.3 mmol) were added to a mixture of 2-methylpropyl-2-ylaminoacetate (355.2 mg, 2.7 mmol) in DCM (6 mL) and water (6 mL). The reaction mixture was stirred at room temperature for 1.5 hours, extracted with DCM, and concentrated to obtain the residue, which was used directly in the next step without further purification. Step 2: Tert-Butyl ((4-Aminophenyl)sulfonyl)glycine ester

[0155] Iron (503.9 mg, 9.0 mmol) was added to a mixture of tert-butyl ((4-nitrophenyl)sulfonyl)glycine ester (713.7 mg, 2.3 mmol) and NH4Cl (1.2 g, 22.6 mmol) in EtOH (9 mL) and water (6 mL). The reaction mixture was stirred at 65 °C for 8 hours. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was extracted with ethyl acetate and concentrated. ResidueThe residue was purified by rapid chromatography (eluent: 66% ethyl acetate / petroleum ether) to give tert-butyl((4-aminophenyl)sulfonyl)glycine ester as a yellow solid. MS (ES-API negative): 285.1 (M+H)+. Step 3: Tert-butyl((4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine ester

[0156] Tert-butyl((4-aminophenyl)sulfonyl)glycine ester (115.1 mg, 0.4 mmol), Pd2(dba)3 (110.5 mg, 0.1 mmol), Xantphos (93.1 mg, 0.2 mmol), and K2CO3 (61.1 mg, 0.4 mmol) were added to the mixture of 2-chloro-4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidine (100.0 mg, 0.4 mmol) in dioxane (2 mL). The reaction mixture was stirred at 85 °C for 1.5 hours under a N2 atmosphere. After filtration, the mixture was extracted with ethyl acetate and concentrated. The residue was purified by rapid chromatography (eluent: 50%–66% ethyl acetate / petroleum ether) to give tert-butyl((4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine ester as a yellow solid. MS (ES-API positive): 499.2 (M+H)+. Step 4: ((4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine

[0157] TFA (0.5 mL, 6.5 mmol) was added to a mixture of tert-butyl((4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine ester (144.0 mg, 0.2 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was diluted with water, extracted with DCM and IPA (v / v = 3:1), and concentrated under vacuum. The residue was purified by C18 chromatography (eluent: 52% acetonitrile / water) to give ((4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)sulfonyl)glycine, a white solid. MS (ES-API positive): 443.0 (M+H)+. 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.59 (d, J = 2.7 Hz, 1H), 7.95 (d, J = 8.8 Hz, 2H), 7.85 (dt, J = 6.1, 2.2 Hz, 3H), 6.62 (dd, J = 2.8, 1.6 Hz, 1H), 3.66 (s, 2H). Example DescriptionBook 43 / 78 pages 54 CN 121443596 A Instruction Manual 44 / 78 pages 55 CN 121443596 A Instruction Manual 45 / 78 pages 56 CN 121443596 A Instruction Manual 46 / 78 pages 57 CN 121443596 A Instruction Manual 47 / 78 pages 58 CN 121443596 A Instruction Manual 48 / 78 pages 59 CN 121443596 A Instruction Manual 49 / 78 pages 60 CN 121443596 A Instruction Manual 50 / 78 pages 61 CN 121443596 A Instruction Manual 51 / 78 pages 62 CN 121443596 A Instruction Manual 52 / 78 pages 63 CN 121443596 A Instruction Manual 53 / 78 pages 64 CN 121443596 A Instruction manual pages 54 / 78, page 65: CN 121443596 A; Instruction manual pages 55 / 78, page 66: CN 121443596 A; Instruction manual pages 56 / 78, page 67: CN 121443596 A; Instruction manual pages 57 / 78, page 68: CN 121443596 A; Instruction manual pages 58 / 78, page 69: CN 121443596 A; Instruction manual pages 59 / 78, page 70: CN 121443596 A; Instruction manual pages 60 / 78, page 71: CN 121443596 A; Instruction manual pages 61 / 78, page 72: CN 121443596 A; Instruction manual pages 62 / 78, page 73: CN 121443596 A; Instruction manual pages 63 / 78, page 74: CN 121443596 A; Instruction manual pages 64 / 78, page 75: CN 121443596 A Instruction manual, pages 65 / 78, 76 CN 121443596 A; Instruction manual, pages 66 / 78, 77 CN 121443596 A; Instruction manual, pages 67 / 78, 78 CN 121443596 A; Instruction manual, pages 68 / 78, 79 CN 121443596 A; Instruction manual, pages 69 / 78, 80 CN 121443596 A; Example A: Assay of Cyclin-Dependent Kinase Activity

[0158] Cyclin-dependent kinase activity was determined by a continuous ATP coupling method, wherein ADP produced by kinase-catalyzed phosphorylation was converted into phosphoenolpyruvate by pyruvate kinase / lactate dehydrogenase (PK / LDH).(PEP) and NADH are reconverted into ATP. The assay system (see Table 1) includes one of the following kinases (CDK1 / cyclin B1, CDK2 / cyclin E1, CDK4 / cyclin D3 or CDK6 / cyclin D3, added at the specified concentration), the ATP concentration of the corresponding kinase Km value, the conpeptide substrate, and the ATP coupling system composed of PEP, NADH and PK / LDH. The reaction was carried out in a reaction buffer of 20 mM Tris (pH 7.5), 50 mM NaCl, 0.5 mM DTT and 0.04% BSA, and the fluorescence decay of NADH under 340 nm excitation light and 460 nm emission light was continuously recorded. The reaction rate was obtained by linear regression analysis of the reaction time trajectory.

[0159] In the inhibition assay, the compound was first serially diluted from 10 μM to 0.05 nM at a ratio of 1:3 with 10× reaction buffer. Then, a CDK kinase was added to the compound solution and incubated for 15 minutes. Finally, the ATP coupling system components were added to start the reaction. The final reaction system was a 1× reaction assay buffer containing 1% DMSO. The reaction rate as a function of compound concentration was fitted using a four-variable IC50 equation to determine the half-maximal inhibitory concentration (IC50) of the compound. The inhibition constant (Ki) was obtained by fitting the same data using a quadratic / Morrison equation. Data analysis was performed using the commercial software Graphpad Prism. Table 1. Composition and conditions of the CDK activity assay system

[0160] Table 2 below lists the CDK inhibitory activity data for representative compounds. Exemplary results are presented in the form of calculated IC50 values. A: IC50 ≤ 10 nM B: IC50 > 10 nM and IC50 < 100 nM C: IC50 ≥ 100 nM Table 2. Representative CDK inhibitory activity data (Repeated 7 times)

Claims

1. A compound of Formula (I), wherein X is CH or N; Z is CH or N; Rings A is aryl, heteroaryl, cycloalkyl, heterocyclyl, or aryl-fused heterocyclyl, each of which is optionally and independently substituted with one R 1 to four R 2 substituents; wherein the carbon atoms of said aryl-fused heterocyclyl are optionally substituted with one oxo, and the heteroatoms thereof are optionally substituted with one or two oxo; R 1 -S(O)2-R 10 -NH-S(O)2-R 10 or -SF5; Each R 2 Independently, it is H, alkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -NO2, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, cycloalkyl, or heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R 7 replace; R 3 H, halogen, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, -CN, or cyanoalkyl; R 4 with R 6 each independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-N(R 9 R 9 , -CN, cyanoalkyl, cycloalkyl, or heterocyclyl; wherein said cycloalkyl or heterocyclyl is optionally substituted with one or more R 7 substituents; R 5 H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -alk-N(R 9 R 9 , aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, -O-cycloalkyl, or -O-heterocyclyl; wherein said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, -O-cycloalkyl, or -O-heterocyclyl is optionally substituted with one or more R 7 ; Each R 7 Independently alkyl, halogen, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -CN, cyanoalkyl, oxo (=O), R 8 -S(O)2-、R 8 -OC(=O)-、R 8 -C(=O)-O-、R 8 -C(=O)-, cycloalkyl or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally further influenced by one or more R 7 replace; each R is independently H, alkyl, or -NR 8 is independently H, alkyl, or -NR 9 R 9 ; Each R 9 Independently, it is H, cycloalkyl, -alk-cycloalkyl, or alkyl; R 10 H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, or -NR 11 R 11 ; wherein said cycloalkyl or heterocyclyl is optionally substituted with one or more R 7 substituents; each R is independently H, alkyl, cycloalkyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, hydroxyalkyl, -alk-O-R 11 12 9 9 R is H, alkyl, cycloalkyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, hydroxyalkyl, -alk-O-R 9 ; wherein said cycloalkyl, -alk-cycloalkyl, -alk-heterocyclyl or heterocyclyl is optionally substituted with one or more R 7 ;​​​ Each R 12 It can be independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclic; the heteroaryl and heterocyclyl independently comprise one or more ring skeletal heteroatoms, each heteroatom independently being oxygen, sulfur, or nitrogen; the heterocyclyl at each occurrence is saturated or partially unsaturated; and each H in the alkyl is optionally substituted with deuterium (D); or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

2. The compound of claim 1, wherein ring A is 3. The compound of claim 1 or 2, wherein the hydroxyalkyl is linear or branched hydroxyalkyl.

4. The compound of claim 1 or 2, wherein the cyanoalkyl is linear or branched cyanoalkyl.

5. The compound of claim 1 or 2, wherein the cycloalkyl, cycloalkenyl, or heterocyclyl of ring A is monocyclic or bicyclic.

6. The compound of claim 1, wherein X is N.

7. The compound of claim 1, wherein Z is N.

8. The compound of claim 1, wherein the compound is of Formula (II): wherein the definition of ring A is the same as in claim 1.

9. The compound of claim 1, wherein the compound is of Formula (IIa), (IIb), (IIc), (IId), or (IIe): wherein ring C is a bridged or spiro bicyclic heterocycloalkyl; ring D is a 4-8 membered cycloalkyl or heterocyclyl fused to the adjacent aryl; optionally, ring D is substituted with one or two oxo; Y is N, O or CH; and when Y is O, R 1 absent; M 1 with M 2 each independently N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are defined as in claim 1.

10. The compound of any one of claims 1 to 9, wherein R 1 is NHR 11 -S(O)2-, heterocyclyl-S(O)2-, C 1-6 alkyl-S(O)2-, (C 1-6 alkyl)2-N-S(O)2-, (deuterated C 1-6 alkyl)2-N-S(O)2-, (deuterated C 1-6 alkyl)-HN-S(O)2-, C 1-6 alkyl-S(O)2-NH-, or -SF5.

11. The compound of any one of claims 1 to 10, wherein R 2 is H, halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, or heterocyclyl; wherein the cycloalkyl or heterocyclyl is optionally substituted with one or more R 7 .

12. The compound of any one of claims 1 to 11, wherein R 3 is H, halogen, alkyl, haloalkyl, alkynyl, -CN, or cyanoalkyl.

13. The compound of any one of claims 1-12, wherein the halogen is F, CI, or Br.

14. The compound of claim 1, wherein the compound is of Formula (III) wherein R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in claim 1.

15. The compound of any one of claims 1-14, wherein the compound is selected from the following compounds:

16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-15, and a pharmaceutically acceptable carrier or excipient.

17. The pharmaceutical composition of claim 16, further comprising a second therapeutic agent.

18. The pharmaceutical composition of claim 17, wherein the second therapeutic agent is a CDK4 / 6 inhibitor, an estrogen receptor antagonist, a hormonal therapy drug, a PARP inhibitor, a S-phase inhibitor, a M-phase inhibitor, or a BCL-2 inhibitor.

19. A method of treating a disease or disorder mediated by CDK2 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-15 or a pharmaceutical composition of any one of claims 16-18.

20. The method of claim 19, wherein the disease or disorder mediated by CDK2 is cancer.

21. The method of claim 20, wherein the cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, pancreatic cancer, melanoma, prostate cancer, glioblastoma, or sarcoma.

22. Use of a compound of any one of claims 1-15 in the manufacture of a medicament for treating a disease mediated by CDK2.