CDK2 inhibitors and methods of use thereof

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

Cross-references to related applications

[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, CDKs exhibit almost no kinase activity; they only become active kinases when cyclin binds to CDK to form a complex, and their activity can be further regulated by phosphorylation and other binding proteins. Based on their kinase domain sequences, CDKs belong to the CMGC kinase group, which also includes mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3β (Gsk3β), members of the bispecific tyrosine-regulated kinase (DYRK) family, and CDK-like kinases (see Genome Biol. 2014; 15(6):122). CDKs play a crucial role in various aspects of cell growth, proliferation, and transcriptional regulation in response to intracellular and extracellular signals. Studies on the evolutionary relationships among CDK subfamilies have revealed 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 their crucial regulatory role in key biological processes such as cell division and gene transcription, CDKs have become highly attractive pharmacological targets. 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 comprises four phases: cell enlargement (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, ensuring that cells divide only when they are sufficiently grown, have completed DNA replication, and under suitable conditions. CDKs are major drivers of cell cycle regulation mechanisms, promoting DNA synthesis and mitosis through phosphorylation of key substrates. Therefore, abnormal activation of CDKs can trigger cell cycle disturbances and uncontrolled cell proliferation, ultimately leading to malignant tumors. Existing research also indicates 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] To address the problem of CDK overactivation in human cancers, initial drug research focused on extracting active compounds from natural substances. Based on the analysis of the molecular structures of these compounds, combined with further biochemical and structural biology studies, researchers gained a deeper understanding of their inhibitory potential, enabling the rational design of CDK inhibitors based on structural information. First-generation CDK inhibitors had relatively low selectivity and were broad-spectrum inhibitors. Their limitations, such as toxic side effects, spurred the development of second-generation CDK inhibitors with higher selectivity. These specific inhibitors improved efficacy while reducing the risk of adverse reactions. CDK4 / 6 inhibitors were the first category to receive FDA approval for clinical treatment. These inhibitors 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 triasilib (G1 Therapeutics) (see J. Med. Chem. 2022, 65, 9, 6356-6389).

[0005] Similar to other CDK family members, CDK2 requires binding to cyclin chaperones (cyclin E or A) to activate. CDK2 activation triggers phosphorylation of proteins involved in the initiation of DNA synthesis and the G1-S phase of the cell cycle (Cell Cycle 9:22, 4533-4541; November 15, 2010). In 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 that bind to CDK2 or CDK1 regulate the transition of the cell cycle from S phase to G2 phase by phosphorylating their substrates (including MCM protein, Cdc7, ribonucleotide reductase R2, etc.) (Oncogene. 2016 Mar 3; 35(9): 1170-1179).

[0006] 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 development and progression of human tumors. Therefore, targeting and inhibiting the oncogenic activity of the CDK2 / cyclin complex has become a highly promising cancer treatment strategy. Despite significant investment in related research, no drug targeting CDK2 has yet been approved by the US FDA. In view of this, the present invention provides novel compounds that can serve as selective CDK2 inhibitors, their preparation methods, and their use in treating CDK2-mediated diseases (such as cancer or other proliferative disorders). 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 potential. This 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. in: 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 bound by an R. 1 and one to four Rs 2 Substitution; wherein the carbon atom of the aryl fused heterocyclic group is optionally substituted with one oxo (=O), and its heteroatom is optionally substituted with one or two oxo groups; R 1 For R 10 -S(O) 2 -、R 10 -S(O)2-NH- 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 It can be H, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkenyl, alkynyl, -CN or cyanoalkyl; R 4 With R 6 Each of the following can be independently H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-NR 9 R 9 -CN, cyanoalkyl, cycloalkyl, or heterocyclic group; wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R 7 replace; R 5 H, alkyl, halogen, haloalkyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -alk-NR 9 R 9 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 surrounded by one or more R 7 replace; Each R 7Independently 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 8 Independently H, alkyl or -NR 9 R 9 ; Each R 9 Independently, it can be H, cycloalkyl, -alk-cycloalkyl, heterocyclic, -alk-heterocyclic, or alkyl; R 10 It can be H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclic or -NR 11 R 11 ; wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R 7 replace; Each R 11 Independently, it can be H, alkyl, cycloalkyl, heterocyclic, -alk-cycloalkyl, -alk-heterocyclic, hydroxyalkyl, alkoxyalkyl, or -alk-OR. 12 -alk-C(O)-OR 9 or -alk-NR 9 R 9 ; wherein the cycloalkyl, -alk-cycloalkyl, -alk-heterocyclic or heterocyclic group is optionally surrounded by one or more R 7 replace; Each R 12 It can be independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclic; The heteroaryl and heterocyclic groups each contain one or more cyclic skeleton heteroatoms each time they appear, and each heteroatom is independently oxygen, sulfur or nitrogen; The heterocyclic group is either saturated or partially unsaturated each time it appears; and H in each alkyl group is optionally replaced by deuterium (D).

[0009] In some preferred embodiments, the compound of formula (I) adopts formula (II): Among them, rings A and R 1 R 2 R3 R 4 R 5 and R 6 The definition is the same as described above.

[0010] In some implementations, 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) is adopted as formula (IIa), (IIb), (IIc), (IId), or (IIe): in The ring C is a bridged ring or a 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 group is optionally substituted with one or two oxo groups; Y is N, O, or CH; however, when Y is O, R 1 It does not exist; M 1 With M 2 Each is independently N or CH; and R 1 R 2 R 3 R 4 R 5 and R 6 The definition is the same as described above.

[0013] In some implementations, in formula (IIb), M 1 With M 2 All are CH.

[0014] In some implementations, R 1 For NHR 11 -S(O)2-, heterocyclic group -S(O)2-, C 1-6 Alkyl-S(O)2-, (C 1-6 Alkyl)2-NS(O)2-, (deuterated C) 1-6 Alkyl)2-NS(O)2-, C 1-6 Alkyl-S(O)2-NH-, (deuterated C) 1-6 Alkyl)-HN-S(O)2- or -SF5.

[0015] In some implementations, the halogen is F, Cl, or Br.

[0016] In some implementations, R 2 It is H, halogen, haloalkyl, hydroxyl, alkyl, cycloalkyl, or heterocyclic; wherein the cycloalkyl or heterocyclic group is optionally surrounded by one or more R 7 replace.

[0017] In some implementations, R 3 It can be H, halogen, alkyl, haloalkyl, alkynyl, -CN, or cyanoalkyl.

[0018] In some embodiments, the compound of formula (I) adopts formula (III): Where R 1 R 2 R 3 R 4 R 5 and R 6 The definition is the same as described above.

[0019] Without construing as limiting, exemplary compounds of the present invention include:

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

[0021] Another aspect of the invention provides pharmaceutical compositions, wherein each pharmaceutical composition comprises a therapeutically effective amount of the compound of the 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, abecilibicil, 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-263).

[0023] Another aspect of the present invention provides a treatment method for a disease or condition mediated by CDK2, comprising administering a therapeutically effective amount of the compound or pharmaceutical composition of the present invention to a subject in need.

[0024] In some implementations, the CDK2-mediated disease or condition is cancer or a disease caused by abnormal cell proliferation. Examples of cancer 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 present invention provides the use of the compounds described herein in the preparation of medicaments for treating diseases or conditions mediated by CDK2. Detailed Implementation

[0026] Preferred embodiments of the invention will now be described in detail, with further examples thereof. 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 in 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. definition

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

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

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

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

[0031] As used in this article, 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 "saturation" refers to a portion that does not include 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 the stated number of carbon atoms (e.g., C1-C1). 10 Or C 1-10 Alkyl groups. Whenever they appear in this document, numerical ranges (e.g., “1 to 10”) refer 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, up to a maximum of 10 carbon atoms, although this definition also covers the occurrence of the term “alkyl” without a specified numerical range. 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 linked to the parent molecule by a single bond. Unless otherwise stated in this specification, alkyl groups may optionally be substituted with one or more substituents.

[0035] When any H in an alkyl group is replaced by deuterium (D), the alkyl group is called a "deuterated alkyl group".

[0036] The term "alkylene" itself, or as part of other molecules, refers to a divalent group derived from an alkane, which can be straight-chain or branched. In this context, the prefix (e.g., C...)... 1-4 C 1-7 C 1-20 C 2-7 C 3-7 (etc.) indicates the number of carbon atoms or a range of carbon atoms. For example, the term "C" used in this article... 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms. Linear C 1-8 Examples of alkylene groups include, but are not limited to, -(CH2). n -, where n is an integer from 1 to 7, for example -CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-. Branched C 1-7Examples of 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 either 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 may be linear, 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, fused cycloalkyl, and spirocyclic cycloalkyl. In bridged 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 groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. The term "heterocyclic alkenyl" is a type of cycloalkenyl group as defined above, 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 cycloalkenyl and heterocyclic alkenyl groups 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 carbon atom 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 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 can be linked to a parent molecule portion via carbon atoms or heteroatoms in the group. Therefore, the term includes, but is not limited to, "heterocyclic alkyl," "heteroaryl," "bicyclic heterocycle," and "polycyclic heterocycle."

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

[0044] The term "haloalkyl" 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. "Fluoroalkyl" 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 substituents. For example, a fluoroethyl group may be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0045] 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).

[0046] 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, and n-hexoxy; while saturated branched alkoxy groups include isopropoxy, sec-butoxy, isobutoxy, tert-butoxy, and isopentoxy. Cyclic alkoxy groups are referred to herein as "cycloalkoxy". 1-4 "Alkoxy group" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Alkoxy groups can be attached to a molecule through one or two bonding sites.

[0047] As used herein, the term "alkoxyalkyl" refers to an alkyl group substituted with one, two, or three alkoxy groups.

[0048] 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" group may be substituted or unsubstituted.

[0049] 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 possessing a fully conjugated π-electron system. Non-limiting examples of unsubstituted heteroaryl groups 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 group may be substituted or unsubstituted.

[0050] As used herein, the term "aryl" 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.

[0051] As used herein, the term "hydroxyl group" or "hydroxyl group" refers to the -OH group.

[0052] 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. Therefore, the term "hydroxyalkyl" is intended to include monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and the like. In "hydroxyalkyl," the alkyl group may be linear (i.e., straight-chain or unbranched) or branched; accordingly, "hydroxyalkyl" includes both linear hydroxyalkyl and branched hydroxyalkyl.

[0053] 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, an alkylamino group is linked to a parent compound via its alkylene moiety. In "cyanoalkyl," the alkyl group may be linear (i.e., straight-chain or unbranched) or branched; correspondingly, "cyanoalkyl" includes both linear cyanoalkyl and branched cyanoalkyl.

[0054] As used herein, the term "-alk-" (used alone or in combination with other terms) represents an alkylene group, such as -alk-NR. 9 R 9 .

[0055] As used in this article, the term "oxo" (alone or in combination with other terms) refers to =O.

[0056] As used herein, the term "amino" or "amine" refers to -NH2. The term "alkylamino" refers to a group with the general formula -NHR, and "dialkylamino" refers to a group with the general formula -NRR', wherein R and R' are each independently alkyl.

[0057] As used in this article, the term "nitro" refers to -NO2.

[0058] As used in this article, the term "SO2" refers to sulfur dioxide, whose structural formula is:

[0059] As used in this article, the terms "-C(=O)-" or "-CO-" refer to structures with the following formulas: . group.

[0060] As used herein, the term "carboxyalkyl" refers to an alkyl group that is substituted with one, two, or three carboxyl groups.

[0061] 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" refer to a haloalkyl group that is attached to a parent molecule moiety via an oxygen atom. The term "(haloalkyl)oxyalkyl" refers to an alkyl group substituted with one, two, or three (haloalkyl)oxy groups.

[0062] As used in this article, the term "non-existent" means that the defined variable does not appear and is replaced by a chemical bond.

[0063] As used in this article, the term "bond" refers to a covalent connection between two atoms, which can be a single bond, a double bond, or a triple bond.

[0064] As used herein, the term "stereoisomer" refers to isomers that have the same molecular formula but differ in the spatial arrangement of atoms, not in the order of atomic bonding. 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 encompasses all possible stereoisomers, including substantially pure stereoisomers and mixtures thereof. Enantiomers and diastereomers are both stereoisomers. The term "enantiomer" refers to one of a pair of mirror-image molecular entities that are not superimposed. The term "diastereomer" refers to stereoisomers that are not mirror images of each other. The term "racemic mixture" or "racemic mixture" refers to a mixture of two enantiomers in equimolar amounts, wherein the mixture is optically inactive.

[0065] As used in this article, the term "chirality" refers to the property of a molecule that, due to its structural characteristics, cannot be perfectly superimposed on its mirror image.

[0066] As used herein, the term "tautomer" refers to two or more isomers of a compound that coexist in equilibrium and rapidly interconvert through the migration of atoms or groups within the molecule. Therefore, this disclosure is intended to cover all possible tautomers, even if the structural formula depicts only one of them.

[0067] 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 the case where the heterocyclic group is alkyl-substituted and the case where the heterocyclic group is not alkyl-substituted.

[0068] The term "pharmaceutically acceptable salt" refers to 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 effectively used for their intended purpose. 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 dioxide 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 (including naturally occurring substituted amine) salts, 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.

[0069] 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, methanesulfonic 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.

[0070] It should be understood that references to compounds of formula (I) in this document also refer to their pharmaceutically acceptable salts.

[0071] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or pharmaceutically acceptable salts or prodrugs thereof, 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.

[0072] The term "pharmaceuticalally acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of the compound. Examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycol.

[0073] As used herein, the term “therapeutic effective dose” refers to a dose of a compound that provides relief to one or more symptoms of the disease being treated. In cancer treatment, a therapeutic effective dose is 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.

[0074] As used herein, the terms “object” or “patient” are used interchangeably and refer to any animal object, including but not limited to humans, laboratory animals (such as primates, rats, and mice), livestock (such as cattle, sheep, goats, pigs, turkeys, and chickens), and domestic pets (such as dogs, cats, and rodents).

[0075] 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, they can be administered orally, parenterally, orally, sublingually, nasally, rectally, via patch, pump, or transdermally, with corresponding pharmaceutical compositions formulated accordingly. Parenterical administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and local administration modalities. Parenterical administration can be performed via continuous infusion over a selected time period. Isomer form

[0076] This invention provides a novel compound of formula (I) as a CDK2 inhibitor and its pharmaceutically acceptable salt.

[0077] It should be understood that certain Formula I compounds (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 Formula I compounds existing in any isomeric form or mixtures thereof, such as active single enantiomers, racemates, or any mixtures thereof. This invention aims to include all such isomeric forms of Formula (I) compounds.

[0078] 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.

[0079] The following examples illustrate some implementations of the present 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 Step 1: Ethyl 1-(2-chloro-5-fluoropyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[0080] 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

[0081] To a solution of 1-(2-chloro-5-fluoropyrimidin-4-yl)pyrazol-4-carboxylate (70.0 mg, 0.3 mmol) in DMSO (1.5 mL), 1-(methanesulfonyl)piperidin-4-amine (69.2 mg, 0.4 mmol) and Et3N (0.1 mL, 0.8 mmol) were added. 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 1-(5-fluoro-2-((1-(methanesulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-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

[0082] At 0 °C, methyl magnesium bromide (1 M, 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-yl)prop-2-ol (54.0 mg, 0.1 mmol) in 1.0 mL of THF. The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 4.5 h. 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 as a yellow liquid. MS (ES-API positive): 399.3 (M+H) + . 1 HNMR (400MHz, CD3OD) δ8.38 (s, 1H), 8.35 (d, J=4.3Hz, 1H), 7.86 (s, 1H), 3.99-3.93 (m, 1H), 3.71 (d, J=12.3Hz, 2H), 2.9 7 (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 Step 1: 4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0083] At 0 °C, ZnCl2 (2M, THF solution, 8.9 mL) was slowly added over 20 minutes to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.5 g, 16.1 mmol) in 2-methylprop-2-ol (60 mL) and 1,2-dichloroethane (60 mL), and the mixture was 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 obtain 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, a yellow solid requiring 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

[0084] At 15 °C, 4-bromo-1H-pyrazole (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 stirred in ethyl acetate and petroleum ether (1 / 10, V / V, 20 mL) and then filtered to give 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide as an off-white solid. MS (ES-API positive): 476.9, 478.9 (M+H) + . Step 3: 4-((4-(4-(2-hydroxy-2-methylpropyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0085] To a solution of 4-[[4-(4-bromopyrazol-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), pyridine-2,6-dimethylamidine (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) were added. The mixture was degassed and purged three times with N2, followed by stirring 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) + . 1 HNMR (400MHz, CD3OD) δ 8.87 (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-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide Step 1: 4-((4-(4-(cyclopent-1-en-1-yl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide

[0086] 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, a brown solid. MS (ES-API positive): 465.2 (M+H) + . 1 HNMR (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

[0087] Pd / C (22.9 mg, 21.5 μmol, purity 10%) was added to a solution of 4-[[4-[4-(cyclopent-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 reaction mixture was 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 as a white solid. MS (ES-API positive): 467.1 (M+H) +. 1 HNMR (400MHz, CD3OD) δ8.86 (s, 1H), 8.34 (s, 1H), 7.96 (d, J = 8.8Hz, 2H), 7.81 (d, J = 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 Step 1: 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0088] Same as Example 2. Step 2: N-methyl-4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0089] 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 (eluent: 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) + . 1 HNMR (400MHz, CD3OD) δ8.89 (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-λ) 6 -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

[0090] At 0°C, 2,4-dichloro-5-(trifluoromethyl)pyrimidine (766.5 mg, 3.5 mmol) was subjected to... t ZnCl2 (5.2 mL, 5.2 mmol) was added to a mixture of BuOH 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. t A mixture of BuOH and DCE (1:1, 10 mL) and TEA (0.4 mL, 2.6 mmol). The reaction mixture was 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-yl6-{[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-yl6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane-2-carboxylate

[0091] 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), 1H-pyrazole (218.4 mg, 3.2 mmol) and K₂CO₃ (665.0 mg, 4.8 mmol) were added. The reaction mixture was stirred at 80 °C for 16 h 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: 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

[0092] 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-λ) 6 -thioalkyl)-6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane

[0093] 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-λ) 6 -Thioalkyl)-6-{[4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-azaspiro[3.3]heptane, is a white solid. MS (ES-API positive): 417.2 (M+H) + . 1 HNMR (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 Step 1: N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide

[0094] 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 give the crude compound N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide, a white solid, which required no further purification. MS (ES-API positive): 361.1 (M+H) + . Step 2: 4-Amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide

[0095] Iron (20.9 g, 374.4 mmol) and NH₄Cl (37.6 g, 701.9 mmol) were added to a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide in EtOH (150 mL) and water (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

[0096] At 0°C, 2,4-dichloro-5-(trifluoromethyl)pyrimidine (14.5 g, 66.7 mmol) was subjected to... tZnCl2 (73.3 mL, 73.3 mmol) was added to solutions of BuOH (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) was added dropwise to solutions of DCE (110 mL) and DCE (110 mL) at 0 °C. t To the solution in BuOH (110 mL), TEA (7.0 mL, 50.0 mmol) was added. The reaction mixture was stirred at 30 °C for 24 hours. After removing the solvent, the mixture 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) + . Step 4: 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide

[0097] 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), 1H-pyrazole (3.6 g, 53.5 mmol) and K₂CO₃ (11.1 g, 80.2 mmol) were added, and the mixture was stirred at 35 °C for 18 hours. The reaction mixture was 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 give compound 4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide, as 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

[0098] To a solution of 13.6 g (25.1 mmol) of 4-((4-(1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide in 100 mL of THF, 62.9 mL (62.9 mmol) of TBAF was added, 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) + . 1 HNMR (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 = 8.5 Hz, 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

[0099] 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 as a yellow solid, requiring 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

[0100] TsOH (140.2 mg, 814.3 μmol) was added to a solution of 2-chloro-4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidine (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 minutes. The suspension was filtered and then 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-benzisothiazol-5-amine, which was a white solid. MS (ES-API positive): 396.9 (M+H) + . 1 HNMR (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

[0101] 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), 4-methylbenzenesulfonic acid (490.3 mg, 2.6 mmol) was added, 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 the compound 4-iodo-1-tetrahydropyran-2-yl-pyrazole as a yellow oil. MS (ES-API positive): 278.9 (M+H) + . Step 2: 2-(1-Tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile

[0102] 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-ylpyrazol-4-yl)acetonitrile, as a yellow oil. MS (ES-API positive): 192.4 (M+H) + . Step 3: 2-Methyl-2-(1-tetrahydropyran-2-ylpyrazol-4-yl)propionitrile

[0103] At 0 °C, NaH (92.0 mg, 2.3 mmol, 60% purity) was added to a solution of 2-(1-tetrahydropyran-2-ylpyrazol-4-yl)acetonitrile (200.0 mg, 1.1 mmol) in THF (3 mL). After complete gas release, 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 compound 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

[0104] 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 required no 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

[0105] 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 (eluent: 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, which was a white solid. MS (ES-API positive): 466.1 (M+H)+ . 1 HNMR (400MHz, Methanol-d4) δ 8.92 (s, 1H), 8.63 (s, 1H), 8.04-7.92 (m, 3H), 7.82 (d, J = 8.8Hz, 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

[0106] To a mixture of 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-dioxaborhexacyclopentan-2-yl)isoxazole (446.4 mg, 2.3 mmol) in water (4 mL) and dioxane (16 mL), cataCXiumA Pd G₃ (138.9 mg, 190.8 μmol) was added. The mixture was stirred at 100 °C for 16 hours under a nitrogen 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, 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, 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

[0107] Diphenyl(vinyl)sulfonamide (150.0 mg, 342.9 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 (eluting with 42%-62% acetonitrile / water) to give compound 4-[[4-[4-(1-cyanocyclopropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, which was a yellow solid. MS (ES-API positive): 464.1 (M+H) + . 1 HNMR (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

[0108] To a mixture of 3.2 g (11.5 mmol) of 4-iodo-1-tetrahydropyran-2-yl-pyrazole and 2.3 g (17.3 mmol) of potassium trifluoro(vinyl)borate in dioxane (30 mL) and water (3 mL), Na₂CO₃ (3.7 g, 34.5 mmol) and Pd(dppf)Cl₂ (1.3 g, 1.7 mmol) were added. 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 as a yellow oil. MS (ES-API positive): 178.2 (M+H) + . Step 2: 4-(2,2-difluorocyclopropyl)-1-tetrahydropyran-2-yl-pyrazole

[0109] To a solution of 1-tetrahydropyran-2-yl-4-vinylpyrazole (790.0 mg, 4.4 mmol) in toluene (8 mL), (bromodifluoromethyl)trimethylsilane (1.1 g, 5.3 mmol) and TBAB (142.9 mg, 443.2 μmol) were added. The mixture was stirred at 110 °C for 1 hour. (bromodifluoromethyl)trimethylsilane (1.1 g, 5.3 mmol) was added again. The mixture was stirred at 110 °C for another 1 hour. The reaction mixture was poured into 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. 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

[0110] A 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)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0111] 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 residues were separated by SFC (column: DAICL CHIRALPAK IG (250 mm × 30 mm × 10 μm); [CO2-MeOH (0.1% NH3·H2O)]; B%: 40%) to obtain Example 52 (retention time: 1.373 min) and Example 53 (retention time: 1.716 min). The samples were purified by preparative HPLC (eluent: 55%-75% acetonitrile / water) to obtain Examples 52 and 53, which were white solids. MS (ES-API positive): 474.4 (M+H) + . Example 52: 1 HNMR (400MHz, Methanol-d4) δ8.91 (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 53: 1 HNMR (400MHz, Methanol-d4) δ8.91 (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

[0112] At 0 °C, H₂SO₄ (8.0 mmol, 0.4 mL) was added dropwise to a solution of 4-[[4-[4-(2-hydroxy-2-methylpropyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (85.0 mg, 180.7 μmol) in 0.9 mL of 2-chloroacetonitrile. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was 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, a white solid requiring 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

[0113] 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 as a white solid. MS (ES-API positive): 470.1 (M+H) + . 1 HNMR (400MHz, 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

[0114] 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 extracted with ethyl acetate (50 mL × 3). 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: 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

[0115] The residue was passed through an SFC (column: DAICL CHIRALPAK IC (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3H2O)]; B%: 40%) to obtain Example 74 (retention time: 2.294 min) and Example 75 (retention time: 3.013 min), as a white solid. MS (ES-API positive): 483.1 (M+H) + . Example 74: 1 H NMR (400MHz, CD3OD) δ8.87 (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: 1 H NMR (400MHz, CD3OD) δ8.86 (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-methylbenzenesulfonamide Step 1: 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide 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-nitrobenzene ester

[0116] 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), PPh3 (326.2 mg, 1.2 mmol) and DIAD (251.5 mg, 1.2 mmol) were added. 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-nitrobenzoate, as 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

[0117] LiOH·H₂O (59.8 mg, 1.4 mmol) was added to a solution of [2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]cyclopentyl]4-nitrobenzene (180.0 mg, 285.0 μmol) in THF (2 mL) and water (0.4 mL). 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: DAICL CHIRALPAK AD (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3H2O)]; B%: 60%) to obtain Example 76 (retention time: 1.055 min) and Example 77 (retention time: 2.025 min), which were white solids. MS (ES-API positive): 483.2 (M+H)+ . Example 76: 1 HNMR (400MHz, Methanol-d4) δ8.76 (s, 1H), 8.35 (s, 1H), 7.87 (d, J=8.8Hz, 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: 1 HNMR (400MHz, Methanol-d4) δ8.88 (s, 1H), 8.47 (s, 1H), 7.99 (d, J=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-((1R,3R)-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]boronic acid

[0118] At 20 °C, Cs₂CO₃ (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 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron-4-yl)pyrimidin-4-yl]boronic acid in DMF (30 mL). 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-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]boronic acid, a pale yellow solid, which could 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

[0119] 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 nitrogen 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, a pale yellow solid. MS (ES-API positive): 479.0 (M+H) + . Step 3: N-methyl-4-[[4-[4-(3-oxocyclopentyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0120] Pd / C (253.6 mg, 238.3 μmol, purity 10%) was added to a solution of N-methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)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 the mixture was stirred at 40 °C for 6 hours under a H2 (40 Psi) atmosphere. The reaction mixture was filtered and concentrated to give N-methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)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

[0121] At -78 °C, L-Selectride (1 M, 541.2 μL) 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), and the mixture was stirred for 1 hour under a nitrogen atmosphere. 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

[0122] The samples were treated with SFC (column: DAICL 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), which were white solids. MS (ES-API positive): 483.1 (M+H) + . Example 78: 1 HNMR (400MHz, Methanol-d4) δ8.86 (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). Example 79: 1HNMR (400MHz, Methanol-d4) δ8.86 (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-pyrazol-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0123] 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-bromopyrazol-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, followed by stirring 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 obtain 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 could be used directly in 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

[0124] 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]piperidine-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]piperidine-1-carboxylate as a brown solid, which was used directly for 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

[0125] HCl (4M, 1.1 mL, dioxane solution) was added to a solution of tert-butyl-4-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]piperidin-1-carboxylate (265.0 mg, 455.6 μmol) in dioxane (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

[0126] 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, 37% purity) 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 as a white solid. MS (ES-API positive): 496.1 (M+H) + . 1 HNMR (400MHz, Methanol-d4) δ 8.87 (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

[0127] Cs₂CO₃ (3.6 g, 11.0 mmol) was added 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). 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-nitropyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide as 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

[0128] 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 a 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 as a white solid. MS (ES-API positive): 414.0 (M+H) + . Step 3: N-methyl-4-[[4-(4-pyrrolidone-1-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0129] K₂CO₃ (66.9 mg, 483.8 μmol) was added to a solution of 4-[[4-(4-aminopyrazol-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, which was a red solid. MS (ES-API positive): 468.0 (M+H) + . 1 HNMR (400MHz, Methanol-d4) δ 8.81 (s, 1H), 8.00-7.95 (m, 3H), 7.83 (d, J=8.8Hz, 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

[0130] 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

[0131] 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 (eluent: 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 as a white solid. MS (ES-API positive): 482.0 (M+H) + . 1HNMR (400MHz, Methanol-d4) δ10.87 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.20 (s, 1H), 8.03-7.94 (m, 2H), 7.76 (d, J=8. 7Hz, 2H), 7.35 (q, J=5.0Hz, 1H), 3.82 (t, J=7.1Hz, 2H), 2.49-2.46 (m, 2H), 2.44-2.38 (m, 3H), 2.15 (q, J=7.6Hz, 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-(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]pyrazol-4-yl]pyrrolidine-1-carboxylate

[0132] 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 of 4-[[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (154.6 mg, 421.4 μmol) 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, which is 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-(4-(pyrrolidin-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0133] A solution of tert-butyl 2-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate (48.0 mg, 84.6 μmol) in dioxane (0.1 mL) was added to HCl (4 M, dioxane solution, 2.0 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).

[0134] 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) + . Example 91: 1 HNMR (500MHz, CD3OD) δ8.99-8.94(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: 1 H NMR (400MHz, Methanol-d4) δ8.96 (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-(pyrrolid-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-(4-(pyrrolid-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide Step 1: tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]-2,5-dihydropyrrole-1-carboxylate

[0135] To 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), Na₂CO₃ (606.5 mg, 5.7 mmol) and Pd(dppf)Cl₂ (139.6 mg, 190.8 μmol) were added. The mixture was stirred at 80 °C for 18 hours under a nitrogen atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL × 3). The combined organic phases were concentrated after drying with Na₂SO₄. 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

[0136] 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 then 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 tert-butyl 3-[1-[2-[4-(methylaminosulfonyl)phenylamino]-5-(trifluoromethyl)pyrimidin-4-yl]pyrazol-4-yl]pyrrolidine-1-carboxylate (isomer-1) and 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 3.851 min, respectively. MS (ES-API positive): 568.2 (M+H) + . Step 3: (R)-N-methyl-4-((4-(4-(pyrrolid-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-(4-(pyrrolid-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzenesulfonamide

[0137] HCl (4M, 2 mL, dioxane solution) 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-pyrrolidine-3-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide as a white solid. Another isomer was prepared under similar conditions. MS (ES-API positive): 468.1 (M+H) + . Example 93: 1 H NMR (400MHz, CD3OD) δ8.92 (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: 1 HNMR (400MHz, CD3OD) δ8.96-8.83 (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

[0138] 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, which was a yellow oil. MS (ES-API positive): 467.2 (M+H) + . Step 2: 4-[[4-[4-(3-hydroxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0139] 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 2 mL of THF, and the mixture was stirred for 1 hour under a nitrogen atmosphere. The reaction mixture was quenched with water (4 mL) at -60°C, and then heated to 20°C and stirred for 10 minutes. 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) + . 1 HNMR (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-((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 Step 1: N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0140] Same as previous example. Step 2: 4-[[4-[4-(3-hydroxy-3-methylcyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0141] MeMgBr (3M, 257.3 μL) 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) at 0 °C. The mixture was stirred at 0 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was quenched with saturated NH4Cl (6 mL) at 0 °C and then 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) followed by further preparative HPLC (eluent: 40%–60% acetonitrile / water).

[0142] 4-((4-(((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)-N-methylbenzenesulfonamide, both white solids, were obtained. MS (ES-API positive): 483.1 (M+H) + . Example 104: 1 H NMR (400MHz, Methanol-d4) δ8.86 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=8.9Hz, 2H), 7.87-7.79 (m, 2H), 7.75 (s, 1H), 3.58 (q, J=8.2Hz, 1H), 2.58-2.50 (m, 5H), 2.22-2.13 (m, 2H), 1.35 (s, 3H). Example 105: 1 H NMR (400MHz, Methanol-d4) δ8.86 (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

[0143] 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: 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide

[0144] 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-bromopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (650.0 mg, 1.4 mmol) in DMA (7 mL), TBAI (628.8 mg, 1.7 mmol), NiI2 (59.8 mg, 272.4 μmol), manganese (299.3 mg, 5.5 mmol), and TFA (1.4 mmol, 101.2 μL) were added. 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 obtain compound 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide, which is 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

[0145] 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 then filtered and concentrated. The residue was purified by preparative HPLC (eluting with 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) + . 1 HNMR (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). 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

[0146] 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. 1¹H 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

[0147] To a solution of 2,4-dichloro-5-(difluoromethyl)pyrimidine (445.0 mg, 2.2 mmol) in DMF (6 mL), 1H-pyrazole (152.2 mg, 2.2 mmol) and K₂CO₃ (309.1 mg, 2.2 mmol) were added, 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-silazhex-1-yl]benzenesulfonamide

[0148] To a solution of 2-chloro-5-(difluoromethyl)-4-(pyrazol-1-yl)pyrimidine (150.0 mg, 0.7 mmol) in dioxane (6.0 mL), 4-amino-N-[5-methyl-4,4-di(propyl-2-yl)-3-oxa-4-silazhex-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. 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-silazhex-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

[0149] 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-silazhex-1-yl]benzenesulfonamide (226.0 mg, 0.4 mmol) in THF (5.0 mL), TBAF (4 M, THF solution, 0.3 mL) was added. The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was concentrated under vacuum. The residue was diluted with water, extracted with ethyl acetate, and concentrated. The residue was purified 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) + . 1 HNMR (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

[0150] 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 nitrogen atmosphere. The reaction mixture was quenched with ice water (120 mL), filtered, and recrystallized (via a methanol-water system) to give methyl 3-(4-nitrophenyl)thiopropionate, a pale yellow solid, which could be used directly in the next step without further purification. Step 2: Methyl 3-(4-nitrophenyl)sulfonylpropionate

[0151] 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 aqueous Na₂SO₃ 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 could be used directly for the next step without further purification. MS (ES-API positive): 296.2 (M+Na) + . Step 3: Methyl 3-(4-aminophenyl)sulfonylpropionate

[0152] 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) + . Step 4: Methyl 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonylpropionate

[0153] TsOH·H₂O (784.0 mg, 2.1 mmol) and 2-chloro-4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidine (1.0 g, 2.1 mmol) were added to a solution of methyl 3-(4-aminophenyl)sulfonylpropionate (1.0 g, 2.1 mmol) in ACN (16 mL). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated and diluted with NaHCO₃ (20 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, and concentrated. The residue was 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]sulfonylprop-1-ol

[0154] At -78°C, LAH (2.5 M, 0.5 mL) was added to a mixture of methyl 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonyl propionate (600.0 mg, 1.3 mmol) in THF (5 mL), and the mixture was stirred at -40°C for 1 hour. The reaction mixture was quenched with Na₂SO₄·10H₂O (0.6 g) at 0°C, filtered, and concentrated. The residue was subjected to preparative HPLC (eluent: 35%–53% acetonitrile / water) to give 3-[4-[[4-pyrazol-1-yl-5-(trifluoromethyl)pyrimidin-2-yl]amino]phenyl]sulfonyl prop-1-ol as a white solid. MS (ES-API positive): 428.3 (M+H) + . 1 HNMR (400MHz, DMSO-d6) δ10.94 (s, 1H), 9.01 (s, 1H), 8.63 (d, J=2.6Hz, 1H), 8.07-7.94 (m, 3H), 7.88 ( d, J=8.8Hz, 2H), 6.70 (d, J=2.5Hz, 1H), 3.41 (t, J=6.2Hz, 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

[0155] 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 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 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

[0156] 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 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

[0157] 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, which was 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

[0158] 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 a residue, which was used directly for the next step without further purification. Step 2: tert-butyl((4-aminophenyl)sulfonyl)glycine ester

[0159] 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. The 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

[0160] To a mixture of 2-chloro-4-(pyrazol-1-yl)-5-(trifluoromethyl)pyrimidine (100.0 mg, 0.4 mmol) in dioxane (2 mL), 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. The reaction mixture was stirred at 85 °C for 1.5 h under a nitrogen 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

[0161] 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 as a white solid. MS (ES-API positive): 443.0 (M+H) + . 1 HNMR (400MHz, Methanol-d4) δ8.90 (s, 1H), 8.59 (d, J=2.7Hz, 1H), 7.95 (d, J=8. 8Hz, 2H), 7.85 (dt, J=6.1, 2.2Hz, 3H), 6.62 (dd, J=2.8, 1.6Hz, 1H), 3.66 (s, 2H). Example Example A: Assay of cyclin-dependent kinase activity

[0162] Cyclin-dependent kinase activity was measured using a continuous ATP-coupled assay, in which ADP, produced by kinase-catalyzed phosphorylation, is converted back into ATP by pyruvate kinase / lactate dehydrogenase (PK / LDH) through the consumption of phosphoenolpyruvate (PEP) and NADH. The assay system (see Table 1) included one of the following kinases (CDK1 / cyclin B1, CDK2 / cyclin E1, CDK4 / cyclin D3, or CDK6 / cyclin D3, added at specified concentrations) and the corresponding kinase K. mThe values ​​of ATP concentration, conopeptide substrate, and ATP coupling system consisting of PEP, NADH, and PK / LDH were determined. 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. The fluorescence decay of NADH under 340 nm excitation and 460 nm emission light was continuously recorded. The reaction rate was obtained by linear regression analysis of the reaction time trajectory.

[0163] In the inhibition assay, the compound was first serially diluted from 10 μM to 0.05 nM at a 1:3 ratio using 10× reaction buffer. A CDK kinase was then added to the compound solution, and the mixture was incubated for 15 minutes. Finally, the ATP-coupled system components were added to initiate the reaction. The final reaction system was 1× reaction assay buffer containing 1% DMSO. The data on the reaction rate as a function of compound concentration were plotted using a four-variable IC50 assay. 50 The equation was fitted to determine the half-maximal inhibitory concentration (IC50) of the compound. 50 Suppression constant (K) i This was obtained by fitting the same data using a quadratic / Morrison equation. Data analysis was performed using the commercial software Graphpad Prism. The suppression constant (K) was... i This was obtained by fitting the same data using a quadratic / Morrison equation. Data analysis was performed using the commercial software GraphpadPrism. Table 1. Composition and conditions of the CDK activity assay system

[0164] Table 2 below lists the CDK inhibitory activity data for representative compounds. Exemplary results are presented with calculated IC50 values. 50 Presented in value form. A: IC 50 ≦10nM B: IC 50 >10nM and IC 50 <100nM C:IC 50 ≥100nM Table 2. Representative CDK inhibitory activity data

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.

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