CDK2 inhibitor and method of use thereof

Abstract

This invention provides a novel compound of formula (I) as a CDK2 inhibitor, which is useful for treating diseases or conditions mediated by CDK2, particularly cancer and other diseases caused by abnormal cell proliferation. Methods of preparation, pharmaceutical compositions, and methods of use are also included. JPEG2026514948000084.jpg43170

Description

[Background technology]

[0001] (Cross-reference of related applications) This application claims priority to PCT application number PCT / CN2023 / 090329 filed on 24 April 2023, U.S. application number 63 / 501,034 filed on 9 May 2023, PCT application number PCT / CN2023 / 127659 filed on 30 October 2023, and U.S. application number 63 / 615,863 filed on 29 December 2023, all of which are incorporated herein by reference in their entirety.

[0002] (Background of the invention) Cyclin-dependent kinases (CDKs) are serine / threonine kinases whose activity depends on cyclin, a regulatory subunit. Without cyclin, CDKs have little kinase activity; only the cyclin-CDK complex is the active kinase, although its activity can be further regulated by phosphorylation and other binding proteins. Based on the sequence of the kinase domain, CDKs belong to the CMGC group of kinases, along with mitogen-activated protein kinases (MAPKs), glycogen synthase kinase 3-beta (Gsk3β), members of the bispecific tyrosine-regulated kinase (DYRK) family, and CDK-like kinases (see Genome Biol. 2014; 15(6): 122). CDKs play crucial roles in many aspects of cell growth, proliferation, and transcriptional regulation in response to extracellular and intracellular signals. Evolutionary relationships between these CDK subfamilies have been identified, and it has been shown that CDK subfamilies can be classified into those that directly or indirectly regulate the cell cycle (CDK1-6, 11, and 14-18) or transcription (CDK7-13, 19, and 20) (see Pharmacol Ther. 2017 May; 173: 83-105).

[0003] CDKs are attractive pharmacological targets because they play a crucial role in regulating cell division, gene transcription, and other vital biological processes. Over the past two decades, there has been significant interest in developing CDK inhibitors. This focus initially stemmed from the observation that various CDK isoforms play a vital role in cancer cell proliferation through cell cycle dysregulation, a characteristic feature of cancer. The cell cycle involves cell growth (gap 1 or G1 stage), DNA copying (synthesis or S stage), preparation for division (gap 2 or G2 stage), and division (mitosis or M stage). At each checkpoint, various proteins are involved in a series of carefully coordinated biochemical reactions to ensure that cell division occurs under favorable conditions after sufficient growth and DNA replication. CDKs are the main driving force behind the cell cycle regulatory mechanism, promoting DNA synthesis and mitosis through the phosphorylation of key substrates. Consequently, abnormal activation of CDKs promotes cell cycle dysregulation and uncontrolled cell proliferation, leading to the development of malignant cancer. Currently, CDKs have been shown to control other processes, particularly various aspects of transcription (see Pharmacol Ther. 2017 May; 173: 83-105; Transcription. 2017; 8(2): 81-90). Therefore, CDK inhibitors may be able to treat a variety of diseases caused by CDK abnormalities, including cancer, autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, and infections.

[0004] Efforts to target the hyperactivity of CDKs in human cancers began with the purification of compounds from natural sources. Determination of their molecular properties and further biochemical and structural studies led to a deeper understanding of their inhibitory capabilities, enabling the rational design of structure-based CDK inhibitors. The first generation of CDK inhibitors developed were relatively nonspecific, known as pan-CDK inhibitors, and had certain limitations related to toxic side effects. Therefore, the development of second-generation CDK inhibitors with a narrower selectivity spectrum, offering the potential for higher efficacy and reduced side effects, was accelerated. CDK4 / 6 inhibitors were the first inhibitors approved by the FDA for clinical treatment. These inhibitors specifically inhibit CDK4 / 6 and have limited toxicity to normal cells. FDA-approved CDK4 / 6 inhibitors include palbociclib (Pfizer), ribociclib (Novartis), abemaciclib (Eli Lilly), and trilasiclib (G1 Therapeutics) (see J. Med. Chem. 2022, 65, 9, 6356-6389).

[0005] Like other family members, CDK2 activation requires binding to its cyclin-binding partner, either cyclin E or cyclin A. CDK2 activation leads to the phosphorylation of proteins involved in the initiation of DNA synthesis and the progression of the cell cycle from G1 to S phase (Cell Cycle 9:22, 4533-4541; November 15, 2010). In G1 / S phase, CDK4 and / or CDK6, complexed with cyclin D, first phosphorylate the retinoblastoma (Rb) protein. After E-type cyclins (cyclin E1 and cyclin E2, CCNE1 and CCNE2 genes) bind to CDK2, the CDK2 / cyclin E complex completes the phosphorylation of Rb, releasing and activating the transcriptional activity of the E2F family, thus advancing the cell to S phase. In addition to Rb protein phosphorylation, the activity of the CDK2 / cyclin E complex is required for MCM (minichromosome maintenance) proteins, which are essential for the initiation of replication. In late S phase, type A cyclins associated with CDK2 or CDK1 phosphorylate their substrates, such as MCM, Cdc7, or ribonucleotide reductase R2, thereby regulating the transition of the cell cycle from S phase to G2 phase (Oncogene. 2016 Mar 3; 35(9): 1170-1179).

[0006] The oncogenic activation of the CDK2 / cyclin complex is associated with abnormal regulation of the cell cycle, leading to replication stress and DNA damage, and consequently contributing to human carcinogenesis. Therefore, targeting the tumorigenic activity of the CDK2 / cyclin complex could be an attractive therapeutic strategy for cancer treatment. Despite considerable effort, no FDA-approved drugs targeting CDK2 exist to date. In this regard, the present invention provides a novel compound as a selective CDK2 inhibitor, a method for preparing the same, and its use in the treatment of CDK2-mediated diseases such as cancer or other proliferative disorders or conditions.

[0007] (Summary of the invention) The present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts, tautomers, or stereoisomers. Such compounds can inhibit the activity of CDKs, particularly CDK2. In some embodiments, the compounds can selectively inhibit the activity of CDK2, thereby demonstrating a favorable clinical outlook. Pharmaceutical compositions and methods for treating CDK2-mediated diseases using these compounds are also provided.

[0008] In one embodiment, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer thereof. [ka] During the ceremony, X is either CH or N; Z is either CH or N; Ring A consists of an aryl, heteroaryl, cycloalkyl, heterocyclyl, or aryl-condensed heterocyclyl, each of which has one R 1 and 1-4 R 2 The carbon atoms of the aryl condensed heterocyclyl are optionally and independently substituted, the carbon atoms of the aryl condensed heterocyclyl are optionally substituted with one oxo (=O), and the heteroatoms of the aryl condensed heterocyclyl are optionally substituted with one or two oxos; R 1 R 10 -S(O)2-, R 10 It is -S(O)2-NH- or -SF5; Each R 2 These are independently H, alkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -NO2, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, cycloalkyl, or heterocyclyl, wherein the cycloalkyl or heterocyclyl is one or more R 7 It is optionally replaced by; R 3is H, halo, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, alkenyl, alkynyl, -CN or cyanoalkyl; R 4 and R 6 are each independently H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxyl, (haloalkoxyl)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-N-R 9 R 9 、-CN, cyanoalkyl, cycloalkyl or heterocyclyl, said cycloalkyl or heterocyclyl being optionally substituted with one or more R 7 ; R 5 is H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxyl, (haloalkoxyl)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, said aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, -O-cycloalkyl, or -O-heterocyclyl being optionally substituted with one or more R 7 ; Each R 7 is independently alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxyl, (haloalkoxyl)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -CN, cyanoalkyl, oxo(=O), R 8 -S(O)2-, R 8 -O-C(=O)-, R 8 -C(=O)-O-, R 8-C(=O)-, cycloalkyl or heterocycline, wherein the cycloalkyl or heterocycline is one or more R 7 It is then optionally replaced; Each R 8 These are independently H, alkyl, or -NR 9 R 9 and; Each R 9 These are independently H, cycloalkyl, -alk-cycloalkyl, heterocyclyl, -alk-heterocyclyl, or alkyl; R 10 This includes H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, or -NR. 11 R 11 The cycloalkyl or heterocyclyl is one or more R 7 It is optionally replaced by; Each R 11 These are independently H, alkyl, cycloalkyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, hydroxyalkyl, alkoxyalkyl, -alk-OR 12 -alk-C(O)-OR 9 , or -alk-NR 9 R 9 The cycloalkyl, -alk-cycloalkyl, -alk-heterocyclyl, or heterocyclyl is one or more R 7 It is optionally replaced by, Each R 12 These are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl; Each of the heteroaryl and heterocyclyl compounds independently contains one or more ring-forming heteroatoms, each of which is independently oxygen, sulfur, or nitrogen; Each occurrence of the heterocyclyl is either saturated or partially unsaturated; Any of the H atoms in each alkyl group can be optionally replaced with deuterium (D).

[0009] In some preferred embodiments, the compound of formula (I) is the compound of formula (II): [ka] In the formula, rings A, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 This is the same as what is stipulated above.

[0010] In some embodiments, ring A is [ka] That is the case.

[0011] Hydroxyalkyls can be linear or branched, cyanoalkyls can be linear or branched, and cycloalkyls, cycloalkenyls, or heterocyclyls can be monocyclic or bicyclic.

[0012] In some embodiments, the compound of formula (I) is of formula (IIa), (IIb), (IIc), (IId), or (IIe), [ka] During the ceremony, Ring C is a crosslinked or spirodicyclic heterocycloalkyl group; Ring D is a 4- to 8-membered cycloalkyl or heterocyclyl condensed to an adjacent aryl group, and the cycloalkyl or heterocycloalkyl group is optionally substituted with one or two oxos. Y is N, O, or CH; however, if Y is O, R 1 It does not exist; M 1 and M 2 Each is independently either N or CH; R 1 , R 2 , R 3 , R 4 , R 5and R 6 This is the same as what is defined above.

[0013] In some embodiments, in formula (IIb), M 1 and M 2 It is CH.

[0014] In some embodiments, R 1 NHR 11 -S(O)2-, heterocyclyl-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 It is alkyl)-HN-S(O)2- or -SF5.

[0015] In some embodiments, the halo is F, Cl, or Br.

[0016] In some embodiments, R 2 is H, halo, haloalkyl, hydroxyl, alkyl, cycloalkyl or heterocyclyl, and cycloalkyl or heterocyclyl is one or more R 7 It is optionally replaced.

[0017] In some embodiments, R 3 The elements are H, halo, alkyl, haloalkyl, alkynyl, -CN, or cyanoalkyl.

[0018] In some embodiments, compound (I) is of formula (III): [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 This is the same as what is defined above.

[0019] Examples of exemplary compounds according to the present invention include, but are not limited to, the following: [ka] [ka] [ka] [ka] [ka] [ka]

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

[0021] Another aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one of the compounds described herein, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt thereof, a tautomer, or a stereoisomer, each mixed with one or more physiologically or pharmaceutically acceptable carriers or excipients.

[0022] In some other embodiments, such a pharmaceutical composition may include a second therapeutic agent. Examples of suitable second therapeutic agents, but are not limited to, CDK4 / 6 inhibitors (e.g., palbociclib, abemaciclib, ribociclib, or trilaciclib), estrogen receptor antagonists, hormone therapies (e.g., letrazole and fulvestrant), PARP inhibitors (e.g., olaparib), S-phase inhibitors (e.g., carboplatin, gemcitabine, cisplatin, topotecan), M-phase inhibitors (e.g., paclitaxel), and BCL-2 inhibitors (e.g., ABT-263).

[0023] A further aspect of the present invention provides a method for treating a subject suffering from a CDK2-mediated disease or disorder, the method comprising administering an effective amount of a compound or pharmaceutical composition described herein to a subject in need.

[0024] In some embodiments, the disease or disorder mediated by CDK2 is a disease caused by cancer or 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] A further aspect of the present invention provides the use of the compounds described herein for the manufacture of pharmaceuticals for the treatment of diseases or disorders mediated by CDK2. [Modes for carrying out the invention]

[0026] (Detailed description of the invention) Herein, preferred embodiments of the present invention are described in detail, and examples thereof are further explained. The present invention is described in conjunction with the preferred embodiments, but it should be understood that the present invention is not intended to be limited to these embodiments. On the contrary, the present invention is intended to cover substitutes, modifications, and equivalents that may fall within the spirit and scope of the present invention as defined by the claims. Furthermore, the detailed description of the present invention provides numerous specific details in order to enable a full understanding of the present invention. However, it will be apparent to those skilled in the art that the present invention can be carried out without these specific details. In other examples, well-known methods, procedures, components, and other features are not described in detail in order to avoid unnecessarily obscuring aspects of the present invention. definition

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

[0028] Unless otherwise specified, the following terms used in this specification and in the claims have the meanings set forth below.

[0029] As used herein, the term "or" includes both "and" and "or." In other words, the term "or" can be replaced with "and / or."

[0030] In defining various terms, for example, "X" and "Z" are used herein as general symbols representing various specific chemical elements.

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

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

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

[0034] As used herein, the term "alkyl" means, either by itself or as part of other substituents, unsaturated and containing a specified number of carbon atoms (e.g., C1-C1). 10 or C 1-10This refers to a linear (i.e., unbranched or linear) or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, having an alkyl group. Whenever a numerical range such as "1 to 10" is used herein, it refers to each integer within the specified range; for example, "1 to 10 carbon atoms" means that an alkyl group can consist of up to 10 carbon atoms, such as 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, etc. However, this definition also covers instances of the term "alkyl" where no numerical range is specified. Typical saturated linear or linear alkyl groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, and -n-hexyl; on the other hand, 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, and the like. Alkyls are bonded to the parent molecule by a single bond. Unless otherwise specified herein, alkyl groups may be optionally substituted with one or more substituents.

[0035] When any of the hydrogen atoms in an alkyl group are replaced with deuterium (D), that alkyl group becomes a deuterated alkyl group.

[0036] The term "alkylene" refers to a divalent radical derived from an alkane, which can be linear or branched, either by itself or as part of another molecule. In this context, the prefix (e.g., C) is used. 1-4 , C 1-7 , C 1-20 , C 2-7 , C 3-7 (etc.) indicates the number of carbon atoms or the range of carbon atoms. For example, the term "C" as used herein. 1-4 "Alkylene" refers to an alkylene group having 1 to 4 carbon atoms. 1-8 An example of an alkylene group is -(CH2) n-, where n is an integer from 1 to 7, including, but not limited to, -CH2-, -CH2CH2CH2-, and -CH2CH2CH2CH2-. Branch C 1-7 Examples 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” refers to an unsaturated branched or linear group having at least one carbon-carbon double bond, either by itself or as part of another substituent, derived by removing a hydrogen atom from a single carbon atom of the parent alkene. The group can be in either a cis or trans conformation with respect to the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl and propenyl.

[0038] As used herein, the term "alkynyl" refers to a carbon chain that contains at least one carbon-carbon triple bond, either by itself or as part of other substituents, and which may be linear, branched, or a combination thereof. Examples of alkynyls include ethynyl, propargyl, 3-methyl-1-pentynyl, and 2-heptynyl.

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

[0040] As used herein, the term "cycloalkenyl" refers to a non-aromatic carbon-carbon ring composed 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 "heterocycloalkenyl" refers to a type of cycloalkenyl group as defined above, in which at least one carbon atom in the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus, but is not limited to these. Cycloalkenyl and heterocycloalkenyl groups may be substituted or unsubstituted.

[0041] The term "heterocycloalkyl" is a type of cycloalkyl group as defined above, and is included in the meaning of the term "cycloalkyl," in which at least one carbon atom of the ring is replaced by a heteroatom such as nitrogen, oxygen, sulfur, or phosphorus, but not limited to these. Cycloalkyl groups and heterocycloalkyl groups may be substituted or unsubstituted.

[0042] As used herein, the terms “heterocyclic” or “heterocyclyl” refer to a group derived from a monocyclic, bridging bicyclic, fused bicyclic, spirocyclic, or polycyclic moiety that comprises at least one non-aromatic ring containing one or more ring-forming 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 another substituent, as defined). The heterocyclyl may be saturated or partially unsaturated. In certain embodiments, the heterocyclyl may contain 1 to 4 heteroatoms as ring members. The heterocyclyl groups of this disclosure may be bonded to the parent molecule via carbon atoms or heteroatoms in the group. Thus, the terms include, but are not limited to, “heterocycloalkyl,” “heteroaryl,” “bicyclic heterocyclic,” and “polycyclic heterocyclic.”

[0043] As used herein, the terms "halo" or "halogen" refer to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0044] The term "haloalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by halogens independently selected from fluoro, chloro, bromo, and iodine. "Fluoroalkyl" refers to an alkyl group as defined above in which one or more hydrogen atoms are replaced by fluoro atoms. Unless otherwise specified by a number, a haloalkyl group may contain as many halo atoms as chemically possible as substituents on the alkyl group. For example, fluoroethyl can be -CH2CF3, -CHF-CH3, or -CH2CH2F.

[0045] As used herein, the term "hydrogen" (or H) refers to its isotope deuterium (D or H). 2 H) and tritium ( 3 The compound of the present invention contains H), and one or any of the hydrogen atoms in the compound also contains deuterium (D or 2 H) and tritium ( 3 This means that it can be replaced with any of H).

[0046] As used herein, the terms "alkoxy" or "alkoxyl" refer to saturated linear or branched hydrocarbons bonded to an oxygen atom. Typical saturated linear alkoxys include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, and n-hextoxy, while saturated branched alkoxys include isopropoxyl, sec-butoxy, isobutoxy, tert-butoxy, and isopentoxy. Cyclic alkoxys are referred to herein as "cycloalkoxys." 1-4 "Alkoxy" refers to alkyl groups that have one, two, three, or four carbon atoms. Alkoxy can be bonded to a molecule by 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 polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group of 6 to 12 carbon atoms having a fully conjugated π-electron system. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl. 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 pairs of atoms) of 5 to 12 ring atoms, comprising 1, 2, 3, or 4 ring heteroatoms selected from N, O, or S, with the remaining ring atoms being C, and further having a fully conjugated π-electron system. Examples of unsubstituted heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrimidine, quinoline, isoquinoline, purine, triazole, tetrazole, triazine, carbazole, benzimidazole, benzoxazole, benzothiazole, indazole, and quinazoline. Heteroaryl groups may be substituted or unsubstituted.

[0050] As used herein, the term "arylene" refers to a bidentate ligand moiety obtained by removing two hydrogen atoms, one from each of two different aromatic ring atoms, from an aromatic compound, and (unless otherwise specified) this moiety has 3 to 20 ring atoms. Preferably, each ring has 5 to 7 ring atoms.

[0051] As used herein, the terms "hydroxyl" or "hydroxy" refer to the -OH group.

[0052] As used herein, the term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl substituent, either by itself or as part of another substituent. Therefore, the term "hydroxyalkyl" includes monohydroxyalkyl, dihydroxyalkyl, trihydroxyalkyl, and so on. In a "hydroxyalkyl" group, the alkyl can be linear (i.e., linear or unbranched) or branched alkyl, and therefore, the "hydroxyalkyl" group includes linear hydroxyalkyl and branched hydroxyalkyl groups.

[0053] As used herein, the terms “cyano” or “-CN” refer to a -CΞN group, and the terms “cyanoalkyl” or “-alk-CN” refer to an alkyl group having at least one -CN substituent. Generally, when a compound is bonded to an “-alk-CN” group, the alkylene portion of the “-alk-CN” group is bonded to the compound. In a “cyanoalkyl” group, the alkyl can be linear (i.e., linear or unbranched) or branched alkyl, and therefore, “cyanoalkyl” groups include linear cyanoalkyls and branched cyanoalkyls.

[0054] As used herein, the term "-alk-" (alone or in combination with other terms) refers to an alkylene group, e.g., -alk-NR 9 R 9 That is the case.

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

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

[0057] As used herein, the term "nitro" refers to -NO2.

[0058] The term "SO2" as used in this specification means [ka] This refers to sulfur dioxide having the following structure.

[0059] The terms "-C(=O)-" or "-CO-" used herein are: [ka] It refers to the basic structure of [something].

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

[0061] The groups defined above may include prefixes and / or suffixes that form substituents commonly used and more well known in this art. For example, the terms “haloalkoxy” or “(haloalkyl)oxy” refer to a haloalkyl group bonded to the parent molecule 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 herein, the term "does not exist" means that the defined variable does not exist and is replaced by a join.

[0063] As used herein, the term “bond” refers to a covalent bond between two atoms, and may include a single bond, a double bond, or a triple bond.

[0064] As used herein, the term “stereoisomer” refers to isomers of the same composition that differ only in the spatial arrangement of atoms, and not in the order of atomic linkage. Where a disclosed compound is named or described by structure without indicating stereochemistry, it is understood that the name or structure encompasses all possible stereoisomers, including essentially pure stereoisomers and combinations thereof. Enantiomers and diastereomers are examples of stereoisomers. The term “enantiomer” refers to one of a pair of molecular species that are mirror images of each other and cannot be superimposed. The term “diastereomer” refers to a stereoisomer that is not a mirror image of each other. The term “racemic compound” or “racemic mixture” refers to a composition consisting of equimolar amounts of two enantiomer species, the composition being optically inactive.

[0065] As used herein, the term "chiral" refers to a structural property of a molecule that makes it impossible to superimpose its mirror image onto another molecule.

[0066] As used herein, the term “tautomer” refers to each of two or more isomers of a compound that coexist in equilibrium and are readily exchanged by the movement of atoms or groups within the molecule. Therefore, this disclosure is intended to cover all possible tautomers, even if the structure shows only one of the tautomers.

[0067] The term "optional" or "optional" means that the event or situation described after it may occur, but is not necessarily required, and the description includes both cases in which the event or situation occurs and cases in which it does not. For example, "a heterocyclyl group optionally substituted with an alkyl group" means that an alkyl group may be present, but is not necessarily required, and the description includes both the situation in which the heterocyclyl group is substituted with an alkyl group and the situation in which the heterocyclyl group is not substituted with an alkyl group.

[0068] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids, that is suitable for use in contact with patient tissues within the bounds of sound medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications commensurate with a reasonable benefit / risk ratio, and that is effective for its intended use. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, iron(III), ferrous(II), lithium, magnesium, manganese salts, manganese, potassium, sodium, and zinc. Particularly preferred are salts of ammonium, calcium, magnesium, potassium, and sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydravamin, isopropylamine, lysine, methyl-glucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and others.

[0069] If the compound of the present invention is basic, the salt can be prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. Particularly preferred are citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.

[0070] In this specification, references to compounds of formula (I) are understood to include pharmaceutically acceptable salts.

[0071] The term "pharmaceutical composition" refers to a mixture of one or more of the compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, with other chemical components such as pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compound to an organism.

[0072] The term "pharmaceutically acceptable excipient" refers to an inert substance added to a pharmaceutical composition to further facilitate the administration of a 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 dose” refers to the amount of a compound administered that alleviates, to some extent, one or more symptoms of the disorder being treated. In relation to the treatment of cancer, a therapeutic dose refers to an amount that has the effect of (1) reducing the size of a tumor; (2) inhibiting tumor metastasis; (3) inhibiting tumor growth; and / or (4) alleviating one or more symptoms associated with cancer.

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

[0075] The compounds taught herein can be administered to patients in various forms depending on the chosen route of administration, as will be understood by those skilled in the art. The compounds of the present invention can be administered, for example, orally, parenterally, orally, sublingually, nasally, rectally, by patch, pump, or transdermally, and the pharmaceutical compositions are formulated accordingly. Parenteral administration includes intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, and topical administration methods. Parenteral administration can be carried out by continuous infusion over a selected period of time. isomer

[0076] The present invention provides novel compounds of formula (I) or pharmaceutically acceptable salts thereof as CDK2 inhibitors. [ka]

[0077] It is understood that certain compounds of formula I (or their salts, prodrugs, or complexes) may exist and be isolated in the form of isomers, including tautomers, geometric isomers (i.e., cis or trans isomers), optical isomers (i.e., enantiomers and diastereomers), racemates, or any mixtures thereof. It should be understood that the present invention encompasses compounds of formula I in any isomeric form or mixture thereof, for example, an active single enantiomer, a racemate, or any mixture thereof. The present invention is intended to encompass all such isomeric forms of compounds of formula (I).

[0078] Furthermore, compounds of formula (I) (or their salts, prodrugs, or conjugates) may exhibit polymorphism or form solvates with water or organic solvents. The present invention also encompasses such polymorphic forms, any solvates thereof, or any mixtures thereof.

[0079] The following examples illustrate selected embodiments of the present invention and are not intended to limit the scope of the invention. Example 1: 2-(1-(5-Fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazol-4-yl)propan-2-ol

Chem.

[0080] To a solution of 2,4-dichloro-5-fluoropyrimidine (100.0 mg, 0.6 mmol) in DMSO (2 mL) were added ethyl 1H-pyrazole-4-carboxylate (125.9 mg, 0.9 mmol) and Et3N (0.25 mL, 1.8 mmol). The reaction mixture was stirred at 50 °C for 40 minutes. The mixture was extracted with ethyl acetate and concentrated in vacuo. The residue was purified by flash chromatography (eluting with 0% - 50% ethyl acetate in 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-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1H-pyrazole-4-carboxylate

[0081] To a solution of ethyl 1-(2-chloro-5-fluoropyrimidine-4-yl)pyrazole-4-carboxylate (70.0 mg, 0.3 mmol) in DMSO (1.5 mL), 1-(methylsulfonyl)piperidine-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 H2O. The aqueous layer was extracted with ethyl acetate and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether) to obtain ethyl 1-(5-fluoro-2-((1-(methylsulfonyl)piperidine-4-yl)amino)pyrimidine-4-yl)-1H-pyrazole-4-carboxylate as a white solid. MS (ES-API positive): 413.3 (M+H) + . Step 3: 2-(1-(5-fluoro-2-((1-(methylsulfonyl)piperidine-4-yl)amino)pyrimidine-4-yl)-1H-pyrazole-4-yl)propan-2-ol

[0082] To a solution of ethyl 1-(5-fluoro-2-((1-(methylsulfonyl)piperidine-4-yl)amino)pyrimidine-4-yl)-1H-pyrazole-4-carboxylate (54.0 mg, 0.1 mmol) in THF (1.0 mL), bromo(methyl)magnesium (1 M in THF, 0.4 mL) was added at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and at room temperature for 4.5 hours. The mixture was diluted with ethyl acetate and water, extracted with ethyl acetate, and concentrated under vacuum. The residue was purified by flash chromatography (eluting with 0% to 50% ethyl acetate in petroleum ether) to obtain 2-(1-(5-fluoro-2-((1-(methylsulfonyl)piperidine-4-yl)amino)pyrimidine-4-yl)-1H-pyrazole-4-yl)propan-2-ol as a yellow liquid. MS (ES-API positive): 399.3 (M+H) + . 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.35 (d, J=4.3 Hz, 1H), 7.86 (s, 1H), 3.99 - 3.93 (m, 1H), 3.71 (d, J=12.3 Hz, 2H), 2.97 (td, J=12.0, 2.1 Hz, 2H), 2.86 (s, 3H), 2.12 (dd, J=12.8, 3.0 Hz, 2H), 1.65 (ddd, J=12.7, 11.2, 4.0 Hz, 2H), 1.57 (s, 6H). Example 2: 4-((4-(4-(2-hydroxy-2-methylpropyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide [ka] Step 1: 4-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide

[0083] To a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (3.5 g, 16.1 mmol) in 2-methylpropan-2-ol (60 mL) and 1,2-dichloroethane (60 mL), ZnCl2 (2 M in THF, 8.9 mL) was carefully added over 20 minutes at 0°C, and the mixture was stirred at 0°C for 30 minutes. A solution of 4-amino-N-methylbenzenesulfonamide (3.0 g, 16.1 mmol) in 2-methylpropan-2-ol (30 mL) and 1,2-dichloroethane (30 mL) was added, followed by a solution of TEA (2.5 mL, 17.7 mmol) in 2-methylpropan-2-ol (30 mL) and 1,2-dichloroethane (30 mL) at 0°C. The reaction mixture was stirred at 0-20°C for 4 hours, and the solvent was removed under vacuum. The residue was suspended in water (20 mL), sonicated for 30 minutes, and then filtered. 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a yellow solid without 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] To a mixture of 4-[[4-Chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methylbenzenesulfonamide (0.9 g, 2.5 mmol) and K2CO3 (678.3 mg, 4.9 mmol) in DMF (10 mL), 4-Bromo-1H-pyrazole (432.8 mg, 2.9 mmol) was added at 15 °C. The reaction mixture was stirred at 15 °C for 16 hours. The reaction mixture was poured into H2O (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 with ethyl acetate and petroleum ether (1 / 10, V / V, 20 mL) and filtered. 4-[[4-(4-Bromopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methyl-benzenesulfonamide was obtained 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-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (100.0 mg, 209.5 μmol) and 1-bromo-2-methylpropan-2-ol (64.1 mg, 419.1 μmol) in DMA (1 mL), pyridine-2,6-dicarboxamidine (6.8 mg, 41.9 μmol), diiodonickel (13.1 mg, 41.9 μmol), Zn (54.8 mg, 838.1 μmol), and TBAI (116.1 mg, 314.3 μmol) were added. The mixture was degassed, purged three times with N2, and stirred at 80°C for 16 hours. The reaction mixture was filtered. The filtrate was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were dried with Na2SO4, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to obtain 4-[[4-[4-(2-hydroxy-2-methyl-propyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide as a brown solid. MS (ES-API positive): 471.0 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.42 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H), 7.74 (s, 1H), 2.71 (s, 2H), 2.54 (s, 3H), 1.24 (s, 6H). Example 11: 4-((4-(4-cyclopentyl-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide Example 12: 4-((4-(4-(cyclopento-1-en-1-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide [ka] Step 1: 4-((4-(4-(cyclopento-1-en-1-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide

[0086] To a solution of 4-[[4-(4-iodopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (450.0 mg, 858.4 μmol) and cyclopenten-1-ylboronic acid (144.1 mg, 1.3 mmol) in H2O (2 mL) and dioxane (4 mL), Pd(dppf)Cl2 (125.6 mg, 171.7 μmol) and Na2CO3 (181.9 mg, 1.7 mmol) were added. 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 x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether) to obtain compound 4-[[4-[4-(cyclopenten-1-yl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide as a brown solid. MS (ES-API positive): 465.2 (M+H) + . 1 H NMR (500 MHz, CD3OD) δ 8.87 (s, 1H), 8.44 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=8.9 Hz, 2H), 7.84-7.80 (m, 2H), 6.14 (t, J=2.1 Hz, 1H), 2.69-2.65 (m, 2H), 2.55 (d, J=2.6 Hz, 1H), 2.54 (s, 3H), 2.53-2.49 (m, 1H), 2.08-2.01 (m, 2H). Step 2: 4-((4-(4-cyclopentyl-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide

[0087] To a solution of 4-[[4-[4-(cyclopentylpyrazole-1-yl)]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (50.0 mg, 107.6 μmol) in THF (5 mL) and ethyl acetate (5 mL), Pd / C (22.9 mg, 21.5 μmol, purity 10%) was added. The reaction mixture was stirred with 20 psi of H2 at 20°C for 2 hours. The mixture was filtered and concentrated. The residue was purified by preparative HPLC (eluting with 70% to 90% acetonitrile in water) to obtain compound 4-[[4-(4-cyclopentylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide as a white solid. MS (ES-API positive): 467.1 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.86 (s, 1H), 8.34 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8 Hz, 2H), 7.74 (s, 1H), 3.04 (t, J=8.2 Hz, 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-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide [ka] Step 1: 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0088] This is the same as Example 2. Step 2: N-methyl-4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0089] Cs2CO3 (35.5 g, 109.0 mmol) was added to a solution of 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-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 (elution with 40% to 70% acetonitrile in water). Compound N-methyl-4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a yellow solid. MS (ES-API positive): 399.0 (M+H) + . 1 H NMR (400 MHz, CD3OD) δ 8.89 (s, 1H), 8.57 (d, J=2.7 Hz, 1H), 7.96 (d, J=8.7 Hz, 2H), 7.88-7.76 (m, 3H), 6.61 (dd, J=1.6, 2.6 Hz, 1H), 2.54 (s, 3H). Example 32: 2-(ethyldioxo-λ6-sulfanyl)-6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptane [ka] Step 1: 2-Methylpropan-2-yl 6-{[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptan-2-carboxylate

[0090] tZnCl2 (5.2 mL, 5.2 mmol) was added to a mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (766.5 mg, 3.5 mmol) in a BuOH:DCE = 1:1 (10 mL) solution at 0°C for 0.5 hours. t A mixture of 2-methylpropan-2-yl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (500.0 mg, 2.4 mmol) in BuOH:DCE=1:1 (10 mL) was added, followed by the addition of TEA (0.4 mL, 2.6 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours and concentrated under vacuum. The residue was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluting with 23%-30% ethyl acetate in petroleum ether) to obtain 2-methylpropan-2-yl 6-{[4-chloro-5-(trifluoromethyl)pyrimidine-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-Methylpropan-2-yl 6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3,3]heptan-2-carboxylate

[0091] A mixture of 2-methylpropan-2-yl 6-{[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptan-2-carboxylate (630.0 mg, 1.6 mmol) in DMF (7 mL) was mixed with 1H-pyrazole (218.4 mg, 3.2 mmol) and K2CO3 (665.0 mg, 4.8 mmol). The reaction mixture was stirred at 80°C for 16 hours and concentrated under vacuum. The residue was diluted with H2O and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution with 50% to 55% ethyl acetate in petroleum ether) to obtain 2-methylpropan-2-yl 6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptan-2-carboxylate as a white solid. MS (ES-API positive): 425.2 (M+H) + . Step 3: 6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3,3]heptane

[0092] A mixture of 2-methylpropan-2-yl 6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptan-2-carboxylate (50.0 mg, 0.1 mmol) in DCM (0.5 mL) was mixed with TFA (0.5 mL, 6.5 mmol). The reaction mixture was stirred at 35°C for 8 hours and concentrated under vacuum. The residue was used directly in the next step without further purification. MS (ES-API positive): 325.2 (M+H) + . Step 4: 2-(ethyldioxo-λ6-sulfanyl)-6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptane

[0093] A mixture of 6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptane (38.2 mg, 0.1 mmol) in DCM (0.5 mL) was mixed with TEA (0.3 mL, 2.1 mmol) and stirred for 15 minutes. Ethanesulfonyl chloride (15.1 mg, 0.1 mmol) was added and stirred for a further 2 hours. The mixture was diluted with H2O and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash chromatography (elution with 55-60% ethyl acetate in petroleum ether) to obtain 2-(ethyldioxo-λ6-sulfanyl)-6-{[4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino}-2-azaspiro[3.3]heptane as a white solid. MS (ES-API positive): 417.2 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 8.76 - 8.36 (m, 3H), 7.90 (d, J=5.6 Hz, 1H), 6.65 - 6.57 (m, 1H), 4.37 - 4.24 (m, 1H), 3.95 (d, J=10.2 Hz, 2H), 3.82 (s, 2H), 3.07 (t, J=7.3 Hz, 2H), 2.60 (s, 2H), 2.23 (dd, J=14.7, 6.4 Hz, 2H), 1.20 (t, J=7.4 Hz, 3H). Example 36: 4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide [ka] Step 1: N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide

[0094] 9.4 g, 53.8 mmol of 2-((tert-butyldimethylsilyl)oxy)ethane-1-amine and 14.9 g, 140.4 mmol of Na2CO3 were added to a mixture of H2O (150 mL) and DCM (150 mL) at 0°C with 10.4 g, 46.8 mmol of 4-nitrobenzenesulfonyl chloride. The reaction mixture was stirred at 30°C for 2 hours. The mixture was diluted with DCM and saturated NaHCO3 solution. The organic layer was separated, washed with brine, and concentrated under vacuum to obtain the crude compound N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide as a white solid without further purification. MS (ES-API positive): 361.1 (M+H) + . Step 2: 4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide

[0095] To a solution of N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-nitrobenzenesulfonamide in EtOH (150 mL) and H2O (100 mL), Fe (20.9 g, 374.4 mmol) and NH4Cl (37.6 g, 701.9 mmol) were added. 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 flash chromatography (elution with 3% to 16% methanol in dichloromethane) to obtain 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)pyrimidine-2-yl)amino)benzenesulfonamide

[0096] tTo a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (14.5 g, 66.7 mmol) in BuOH (110 mL) and DCE (110 mL), ZnCl2 (73.3 mL, 73.3 mmol) was added at 0°C and the mixture was stirred at 0°C for 1 hour. DCE (110 mL) and t A solution of 4-amino-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide (11.0 g, 33.3 mmol) in BuOH (110 mL) was added dropwise at 0°C, followed by the dropwise addition of TEA (7.0 mL, 50.0 mmol). The reaction mixture was stirred at 30°C for 24 hours. The solvent was removed and the mixture was diluted with ethyl acetate and brine. The organic layer was separated and concentrated under vacuum. The resulting residue was purified by flash chromatography (elution with 66% ethyl acetate in petroleum ether) to obtain N-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-((4-chloro-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide as a pale yellow solid. MS (ES-API positive): 512.1 (M+H) + . Step 4: 4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-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)pyrimidine-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 flash chromatography (eluting with 80% to 100% ethyl acetate in petroleum ether) to obtain compound 4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-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-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide

[0098] To a solution of 4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-(2-((tert-butyldimethylsilyl)oxy)ethyl)benzenesulfonamide (13.6 g, 25.1 mmol) in THF (100 mL), TBAF (62.9 mL, 62.9 mmol) 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 flash chromatography (elution with 7% methanol in dichloromethane) to obtain the crude compound 4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide as a white solid. MS (ES-API positive): 429.1 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.01 (s, 1H), 8.62 (d, J=2.8 Hz, 1H), 8.13-7.88 (m, 3H), 7.80 (d, J=8.5 Hz, 2H), 7.50 (t, J=6.0 Hz, 1H), 6.71 (s, 1H), 4.70 (t, J=5.6 Hz, 1H), 3.40-3.38 (m, 2H), 2.80 (q, J=6.2 Hz, 2H). Example 42: 1,1-Dioxo-N-[4-Pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]-2,3-Dihydro-1,2-Benzothiazole-5-amine [ka] Step 1: 1,1-Dioxo-2,3-Dihydro-1,2-Benzothiazole-5-amine

[0099] A mixture of 5-amino-1,1-dioxo-1,2-benzothiazole-3-one (500.0 mg, 2.5 mmol) in concentrated HCl (5 mL) was mixed with Zn (1.6 g, 25.0 mmol). The mixture was stirred at 25°C for 2 hours. Saturated NaHCO3 solution was added until the pH reached 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 obtain compound 1,1-dioxo-2,3-dihydro-1,2-benzothiazole-5-amine as a yellow solid without further purification. MS (ES-API positive): 185.0 (M+H) + . Step 2: 1,1-Dioxo-N-[4-Pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]-2,3-Dihydro-1,2-Benzothiazole-5-amine

[0100] To a solution of 2-chloro-4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine (202.4 mg, 814.3 μmol) and 1,1-dioxo-2,3-dihydro-1,2-benzothiazole-5-amine (150.0 mg, 814.3 μmol) in dioxane (2 mL), TsOH (140.2 mg, 814.3 μmol) was added. The mixture was stirred at 100 °C for 2 hours, filtered, and concentrated to obtain the residue. The residue was purified by preparative HPLC (elution with 35%-55% acetonitrile in water). The crude product was ground with DCM and MeOH (10 mL, v / v=5 / 1) at 25 °C for 20 minutes. The turbid solution was filtered and washed with DCM and MeOH (5 mL x 3, v / v = 5 / 1) to obtain compound 1,1-dioxo-N-[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]-2,3-dihydro-1,2-benzothiazole-5-amine as a white solid. MS (ES-API positive): 396.9 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90-10.74 (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=5.0 Hz, 2H). Example 49: 4-[[4-[4-(1-cyano-1-methyl-ethyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide [ka] Step 1: 4-iodo-1-tetrahydropyran-2-ylpyrazole

[0101] 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) was mixed with 4-methylbenzenesulfonic acid (490.3 mg, 2.6 mmol) and stirred at 25°C for 16 hours. The reaction mixture was diluted with H2O (40 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (eluted with 0% to 25% ethyl acetate in petroleum ether) to obtain compound 4-iodo-1-tetrahydropyran-2-ylpyrazole 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-dioxaborolan-2-yl)isoxazole (925.7 mg, 4.8 mmol), and cataCXiumA Pd G3 (288.1 mg, 395.6 μmol) in H2O (10 mL) and dioxane (30 mL). The mixture was stirred at 100 °C for 16 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether). The compound 2-(1-tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile was obtained as a yellow oil. MS (ES-API positive): 192.4 (M+H) + . Step 3: 2-Methyl-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)propannitrile

[0103] To a solution of 2-(1-tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile (200.0 mg, 1.1 mmol) in THF (3 mL), NaH (92.0 mg, 2.3 mmol, purity 60.0%) was added at 0°C. After gas generation ceased, CH3I (296.9 mg, 2.1 mmol) was added dropwise at 0°C, and the mixture was stirred at 0-25°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution with 0%-50% ethyl acetate in petroleum ether). Compound 2-methyl-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)propanenitrile was obtained as a yellow oil. MS (ES-API positive): 220.1 (M+H) + . Step 4: 2-Methyl-2-(1H-pyrazole-4-yl)propanenitrile

[0104] 2-methyl-2-(1-tetrahydropyran-2-ylpyrazole-4-yl)propanenitrile (120.0 mg, 547.2 μmol) was added to a 2 mL solution of HCl in dioxane. The mixture was stirred at 50°C for 2 hours. The reaction mixture was concentrated under vacuum, and the residue was obtained as a yellow oil without further purification. MS (ES-API positive): 136.3 (M+H) + . Step 5: 4-[[4-[4-(1-cyano-1-methyl-ethyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0105] To a solution of 2-methyl-2-(1H-pyrazole-4-yl)propanenitrile (50.0 mg, 369.9 μmol) and 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (135.7 mg, 369.9 μmol) in DMSO (2 mL), Cs2CO3 (241.0 mg, 739.8 μmol) was added. The mixture was stirred at 40°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (elution with 60%-80% acetonitrile in water). Compound 4-[[4-[4-(1-cyano-1-methyl-ethyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a white solid. MS (ES-API positive): 466.1 (M+H) + . 1 ¹H NMR (400 MHz, methanol-d4): δ 8.92 (s, 1H), 8.63 (s, 1H), 8.04-7.92 (m, 3H), 7.82 (d, J=8.8 Hz, 2H), 2.54 (s, 3H), 1.77 (s, 6H). Example 51: 4-[[4-[4-(1-cyanocyclopropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide [ka] Step 1: 4-[[4-[4-(cyanomethyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0106] To a mixture of 4-[[4-(4-iodopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-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-dioxaborolan-2-yl)isoxazole (446.4 mg, 2.3 mmol) in H2O (4 mL) and dioxane (16 mL), cataCXiumA Pd G3 (138.9 mg, 190.8 μmol) was added. The mixture was stirred under N2 at 100°C for 16 hours. The reaction mixture was added to H2O (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 100% ethyl acetate in petroleum ether). Compound 4-[[4-[4-(cyanomethyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a brown solid. MS (ES-API positive): 437.9 (M+H) + . Step 2: 4-[[4-[4-(1-cyanocyclopropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0107] To a solution of 4-[[4-[4-(cyanomethyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (150.0 mg, 342.9 μmol) in DMSO (1.8 mL), diphenyl(vinyl)sulfonium trifluoromethanesulfonate (150.0 mg, 413.9 μmol) was added. The mixture was stirred at 20°C for 2 minutes. DBU (157.5 mg, 1.0 mmol) was added, and the mixture was stirred at 20°C for a further 18 hours. The reaction mixture was added to H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (elution with 42%-62% acetonitrile in water). Compound 4-[[4-[4-(1-cyanocyclopropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a yellow solid. MS (ES-API positive): 464.1 (M+H) + . 1 ¹H NMR (400 MHz, methanol-d4) δ values: 8.93 (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)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide [ka] Step 1: 1-Tetrahydropyran-2-yl-4-vinylpyrazole

[0108] To a solution of 4-iodo-1-tetrahydropyran-2-ylpyrazole (3.2 g, 11.5 mmol) and potassium trifluoro(vinyl)borane (2.3 g, 17.3 mmol) in dioxane (30 mL) and H2O (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 H2O (40 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 35% ethyl acetate in petroleum ether). Compound 1-tetrahydropyran-2-yl-4-vinylpyrazole was obtained as a yellow oil. MS (ES-API positive): 178.2 (M+H) + . Step 2: 4-(2,2-difluorocyclopropyl)-1-tetrahydropyran-2-ylpyrazole

[0109] To a solution of 1-tetrahydropyran-2-yl-4-vinylpyrazole (790.0 mg, 4.4 mmol) in toluene (8 mL), [bromo(difluoro)methyl]-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. Then, [bromo(difluoro)methyl]-trimethylsilane (1.1 g, 5.3 mmol) was added. The mixture was stirred at 110°C for another 1 hour. The reaction mixture was poured into H2O (10 ml) and extracted with ethyl acetate (10 ml x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 35% ethyl acetate in petroleum ether). Compound 4-(2,2-difluorocyclopropyl)-1-tetrahydropyran-2-ylpyrazole was obtained 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-ylpyrazole (400.0 mg, 1.8 mmol) in HCl (4 M in dioxane, 0.4 mL) was stirred at 25°C for 1 hour. The reaction mixture was concentrated and purified by flash chromatography (elution with 0% to 25% ethyl acetate solution in petroleum ether). Compound 4-(2,2-difluorocyclopropyl)-1H-pyrazole was obtained as a white solid. MS (ES-API positive): 144.1 (M+H) + . Step 4: 4-[[4-[4-(2,2-difluorocyclopropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0111] To a solution of 4-(2,2-difluorocyclopropyl)-1H-pyrazole (250.0 mg, 1.7 mmol) and 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (954.3 mg, 2.6 mmol) in DMSO (4 mL), Cs2CO3 (1.7 g, 5.2 mmol) was added. 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 x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by SFC (column: DAIEL CHIRALPAK IG (250mm × 30mm × 10μm); [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). Examples 52 and 53 were obtained as white solids by preparative HPLC (elution in 55% to 75% acetonitrile in water). MS (ES-API positive): 474.4 (M+H) + . Example 52: 1 ¹H NMR (400 MHz, methanol-d4): δ 8.91 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.90-7.75 (m, 3H), 2.83 (dt, J=7.7, 12.2 Hz, 1H), 2.56 (s, 3H), 2.04-1.91 (m, 1H), 1.52-1.47 (m, 1H). Example 53: 1 ¹H NMR (400 MHz, methanol-d4): δ 8.91 (s, 1H), 8.50 (s, 1H), 7.98 (d, J=8.8 Hz, 2H), 7.90-7.75 (m, 3H), 2.83 (dt, J=7.7, 12.2 Hz, 1H), 2.56 (s, 3H), 2.04-1.91 (m, 1H), 1.52-1.47 (m, 1H). Example 72: 4-[[4-[4-(2-hydroxy-1,1,2-trimethylpropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide [ka] Step 1: 2-Chloro-N-[1,1-dimethyl-2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]ethyl]acetamide

[0112] To a solution of 4-[[4-[4-(2-hydroxy-2-methylpropyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (85.0 mg, 180.7 μmol) in 2-chloroacetonitrile (0.9 mL), H2SO4 (8.0 mmol, 0.4 mL) was added dropwise at 0°C. The mixture was stirred at 20°C for 1 hour. The reaction product was treated with ice water (8 mL) and aqueous NaHCO3 to a pH of approximately 8. The mixture was extracted with ethyl acetate (10 mL x 3). The resulting organic layers were combined, dried over Na2SO4, filtered, and concentrated to obtain the crude compound 2-chloro-N-[1,1-dimethyl-2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]ethyl]acetamide as a white solid without purification. MS (ES-API positive): 546.2 (M+H) + . Step 2: 4-[[4-[4-(2-amino-2-methyl-propyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0113] To a solution of 2-chloro-N-[1,1-dimethyl-2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]ethyl]acetamide (90.0 mg, 164.8 μmol) in EtOH (6 mL) and AcOH (1.0 mL), thiourea (25.1 mg, 329.7 μmol) was added. The mixture was stirred at 85°C for 1 hour. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (elution with 23% to 43% acetonitrile in water). Compound 4-[[4-[4-(2-amino-2-methyl-propyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a white solid. MS (ES-API positive): 470.1 (M+H) + . 1¹H NMR (400 MHz, methanol-d4): δ 8.91 (s, 1H), 8.51 (s, 1H), 8.00-7.89 (m, 2H), 7.87-7.76 (m, 3H), 2.91 (s, 2H), 2.54 (s, 3H), 1.40 (s, 6H). Examples 74 and 75: 4-[[4-[4-[(1S,2R)-2-hydroxycyclopentyl]pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide and 4-[[4-[4-[(1R,2S)-2-hydroxycyclopentyl]pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide [ka] Step 1: 4-[[4-[4-[trans-2-hydroxycyclopentyl]pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0114] To a mixture of pyridine-2,6-dicarboxamidine (34.2 mg, 209.5 μmol), 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-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), Zn (274.0 mg, 4.2 mmol), TBAI (580.5 mg, 1.6 mmol), diiodonickel (65.5 mg, 209.5 μmol), and N,N-diethylethanamine hydrochloride (144.2 mg, 1.1 mmol) were added. The mixture was stirred under N2 at 80°C for 4 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution with 0% to 70% ethyl acetate in petroleum ether). Compound 4-[[4-[4-[trans-2-hydroxycyclopentyl]pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a white solid. MS (ES-API positive): 483.1 (M+H) + . Step 2: 4-[[4-[4-[(1S,2R)-2-hydroxycyclopentyl]pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide & 4-[[4-[4-[(1R,2S)-2-hydroxycyclopentyl]pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0115] The residue was purified using SFC (column: DAISEL CHIRALPAK IC (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3H2O)]; B%: 40%). Examples 74 (retention time: 2.294 min) and 75 (retention time: 3.013 min) were obtained as white solids. MS (ES-API positive): 483.1 (M+H) + . Example 74: 1 H NMR (400 MHz, CD3OD) δ 8.87 (s, 1H), 8.43 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.89-7.76 (m, 3H), 4.07 (q, J=6.8 Hz, 1H), 2.92 (q, J=7.8 Hz, 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 (400 MHz, CD3OD) δ 8.86 (s, 1H), 8.42 (s, 1H), 7.96 (d, J=8.9 Hz, 2H), 7.87-7.74 (m, 3H), 4.07 (q, J=6.8 Hz, 1H), 2.92 (q, J=7.8 Hz, 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-(4-((1S,2S)-2-hydroxycyclopentyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1R,2R)-2-hydroxycyclopentyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide [ka] Step 1: 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide This is the same as step 1 of Examples 74 and 75. Step 2: 2-(1-(2-((4-(N-methylsulfamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-4-yl)cyclopentyl 4-nitrobenzoate

[0116] To a solution of 4-nitrobenzoic acid (69.3 mg, 414.5 μmol) and 4-[[4-[4-(2-hydroxycyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-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 x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether). The compound [2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]cyclopentyl]4-nitrobenzoate was obtained as a white solid. MS (ES-API positive): 632.2 (M+H) + . Step 3: 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide & 4-((4-(4-(2-hydroxycyclopentyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide

[0117] To a solution of [2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]cyclopentyl]4-nitrobenzoate (180.0 mg, 285.0 μmol) in THF (2 mL) and H2O (0.4 mL), LiOH·H2O (59.8 mg, 1.4 mmol) was added. The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated. The residue was purified by preparative HPLC (eluting with 38%-58% acetonitrile in water). MS (ES-API positive): 483.2 (M+H) + . Step 4: The product was separated using SFC (column: DAISEL CHIRALPAK AD (250 mm × 30 mm × 10 μm); [CO2-EtOH (0.1% NH3H2O)]; B%: 60%). Example 76 (retention time: 1.055 min) and Example 77 (retention time: 2.025 min) were obtained as white solids. MS (ES-API positive): 483.2 (M+H) + . Example 76: 1 ¹H NMR (400 MHz, methanol-d4) δ 8.76 (s, 1H), 8.35 (s, 1H), 7.87 (d, J=8.8 Hz, 2H), 7.75-7.70 (m, 2H), 7.69 (s, 1H), 4.19-4.12 (m, 1H), 2.95-2.83 (m, 1H), 2.02-1.79 (m, 4H), 1.76-1.59 (m, 2H) Example 77: 1 ¹H NMR (400 MHz, methanol-d4): δ 8.88 (s, 1H), 8.47 (s, 1H), 7.99 (d, J=8.7 Hz, 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-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1S,3S)-3-hydroxycyclopentyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide [ka] Step 1: [1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]boronic acid

[0118] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 g, 6.0 mmol) in DMF (30 mL), Cs2CO3 (3.6 g, 10.9 mmol) and 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (2.0 g, 5.5 mmol) were added at 20°C. The mixture was stirred at 20°C for 60 hours. The reaction mixture was poured into H2O (150 mL). The pH was adjusted to 7.0 using 2N aq.HCl. The crude product was filtered to obtain [1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]boronic acid as a pale yellow solid, which was used in the next step without purification. MS (ES-API positive): 443.0 (M+H) + . Step 2: N-methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0119] To a mixture of [1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-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 under N2 at 30°C for 16 hours. The reaction mixture was poured into H2O (30 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 65% ethyl acetate in petroleum ether). The compound N-methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a pale yellow solid. MS (ES-API positive): 479.0 (M+H) + . Step 3: N-methyl-4-[[4-[4-(3-oxocyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0120] To a solution of N-methyl-4-[[4-[4-(3-oxocyclopenten-1-yl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide (600.0 mg, 1.2 mmol) in MeOH (30 mL) and THF (30 mL), Pd / C (253.6 mg, 238.3 μmol, purity 10.0%) was added and the mixture was stirred at 40°C for 6 hours under H2 (40 psi). The reaction mixture was filtered and concentrated to obtain N-methyl-4-[[4-[4-(3-oxocyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide as a pale yellow solid, which was used directly without further purification. MS (ES-API positive): 481.0 (M+H)+ . Step 4: 4-[[4-[4-(3-hydroxycyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0121] To a solution of N-methyl-4-[[4-[4-(3-oxocyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide (130.0 mg, 270.6 μmol) in THF (4 mL), L-selectide (1 M, 541.2 μL) was added at -78 °C and the mixture was stirred under N2 for 1 hour. The reaction mixture was quenched with H2O (8 mL), extracted with ethyl acetate, washed with brine, and concentrated. The residue was purified by flash chromatography (elution with 60% ethyl acetate in petroleum ether). Compound 4-[[4-[4-(3-hydroxycyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methyl-benzenesulfonamide was obtained as a white solid. MS (ES-API positive): 483.2 (M+H) + . Step 5: 4-[[4-[4-(3-hydroxycyclopentyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0122] Using SFC (column: DAISEL CHIRALPAK IG (250mm × 30mm × 10μm); CO2-EtOH (0.1% NH3·H2O); B%: 45%), Examples 78 (retention time: 1.779 min) and 79 (retention time: 2.740 min) were obtained as white solids. MS (ES-API positive): 483.1 (M+H) + . Example 78: 1H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.36 (s, 1H), 8.01-7.92 (m, 2H), 7.84-7.79 (m, 2H), 7.75 (s, 1H), 4.53 - 4.41 (m, J=2.6, 5.7 Hz, 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: 1 H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.35 (s, 1H), 7.96 (d, J=8.8 Hz, 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-piperidyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide [ka] Step 1: tert-butyl 4-(1-(2-((4-(N-methylsulfamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0123] To a mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (388.7 mg, 1.3 mmol) and 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (500.0 mg, 1.0 mmol), Na2CO3 (222.1 mg, 2.1 mmol) and Pd(dppf)Cl2 (76.7 mg, 104.8 μmol) were added. The mixture was degassed, purged three times with N2, and stirred at 80°C for 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. The crude product tert-butyl 4-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate was obtained as a brown solid and used in the next step without further purification. MS (ES-API positive): 580.2 (M+H) + . Step 2: tert-butyl 4-(1-(2-((4-(N-methylsulfamoyl)phenyl)amino)-5-(trifluoromethyl)pyrimidine-4-yl)-1H-pyrazole-4-yl)piperidine-1-carboxylate

[0124] To a solution of tert-butyl 4-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (320.0 mg, 552.1 μmol) in MeOH (10 mL) and ethyl acetate (10 mL), dihydroxypalladium (387.7 mg, 552.1 μmol, purity 20.0%) was added. The mixture was stirred at 20°C for 16 hours under H2 (50 psi). The reaction mixture was filtered and concentrated. The crude product tert-butyl 4-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]piperidine-1-carboxylate was obtained as a brown solid and used in the next step without further purification. MS (ES-API positive): 582.2 (M+H) + . Step 3: N-methyl-4-[[4-[4-(4-piperidyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0125] To a solution of tert-butyl 4-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]piperidine-1-carboxylate (265.0 mg, 455.6 μmol) in dioxane (1 mL), HCl (4 M in dioxane, 1.1 mL) was added. The mixture was degassed, purged three times with N2, and stirred at 20°C for 2 hours. The reaction mixture was filtered and concentrated. The crude product N-methyl-4-[[4-[4-(4-piperidyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a brown solid and used in the next step without further purification. MS (ES-API positive): 482.2 (M+H) + . Step 4: N-methyl-4-[[4-[4-(1-methyl-4-piperidyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0126] To a solution of N-methyl-4-[[4-[4-(4-piperidyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide (120.0 mg, 249.2 μmol) in MeOH (1 mL), NaBH3CN (47.0 mg, 747.7 μmol) and formaldehyde (60.7 mg, 747.7 μmol, purity 37.0%) 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 (elution with 33% to 63% acetonitrile in water). Compound N-methyl-4-[[4-[4-(1-methyl-4-piperidyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a white solid. MS (ES-API positive): 496.1 (M+H) + . 1 H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.41 (s, 1H), 7.96 (d, J=8.7 Hz, 2H), 7.83 (d, J=7.4 Hz, 3H), 3.82 (d, J=12.2 Hz, 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-pyrroridine-1-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide [ka] Step 1: N-Methyl-4-[[4-(4-nitropyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0127] 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) was added Cs2CO3 (3.6 g, 11.0 mmol). The mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into water (150 mL). The precipitate was filtered and dried. The crude compound N-methyl-4-[[4-(4-nitropyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide was obtained 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-methyl-benzenesulfonamide

[0128] 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) was added Pd / C (456.1 mg, 428.5 μmol, purity 10.0%). The mixture was stirred at 25 °C for 4 hours under 20 psi H2. The mixture was filtered and concentrated in vacuo. The compound 4-[[4-(4-aminopyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methyl-benzenesulfonamide was obtained as a white solid. MS (ES-API positive): 414.0 (M+H) + . Step 3: N-Methyl-4-[[4-(4-pyrrolidin-1-ylpyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

[0129] 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), K2CO3 (66.9 mg, 483.8 μmol) was added. The mixture was stirred at 80 °C for 2 hours. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (eluting with 50% - 70% acetonitrile in water). The compound N-methyl-4-[[4-(4-pyrrolidin-1-ylpyrazol-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide was obtained as a red solid. MS (ES-API positive): 468.0 (M+H) + . 1 H NMR (400 MHz, methanol-d4) δ 8.81 (s, 1H), 8.00 - 7.95 (m, 3H), 7.83 (d, J = 8.8 Hz, 2H), 7.69 (s, 1H), 3.29 (t, J = 6.4 Hz, 4H), 2.56 (s, 3H), 2.11 - 2.04 (m, 4H). Example 88: N-Methyl-4-[[4-[4-(2-oxopyrrolidin-1-yl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide

Chemical Structure

[0130] A mixture of 4-[[4-(4-aminopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (200.0 mg, 483.8 μmol) and 4-chlorobutanoyl chloride (75.0 mg, 532.2 μmol) in THF (4 mL) was mixed with TEA (0.1 mL, 967.6 μmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 40% ethyl acetate in petroleum ether). The compound 4-chloro-N-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]butanamide was obtained as a yellow oil. MS (ES-API positive): 518.1 (M+H) + . Step 2: N-methyl-4-[[4-[4-(2-oxopyrrolidine-1-yl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0131] To a solution of 4-chloro-N-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]butanamide (200.0 mg, 386.2 μmol) in DMF (4 mL), Cs2CO3 (188.7 mg, 579.3 μmol) was added. The mixture was stirred at 60°C for 2 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (eluting with 43%-63% acetonitrile in water). The compound N-methyl-4-[[4-[4-(2-oxopyrrolidine-1-yl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a white solid. MS (ES-API positive): 482.0 (M+H) + . 1 H NMR (400 MHz, methanol-d4) δ 10.87 (s, 1H), 8.98 (s, 1H), 8.89 (s, 1H), 8.20 (s, 1H), 8.03-7.94 (m, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.35 (q, J=5.0 Hz, 1H), 3.82 (t, J=7.1 Hz, 2H), 2.49-2.46 (m, 2H), 2.44-2.38 (m, 3H), 2.15 (q, J=7.6 Hz, 2H). Examples 91 and 92: (R)-N-methyl-4-((4-(4-(pyrroridine-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-((pyrroridine-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka] Step 1: tert-butyl 2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate

[0132] To a solution of 4-[[4-chloro-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (154.6 mg, 421.4 μmol) in DMSO (1 mL), Cs2CO3 (274.6 mg, 842.8 μmol) and tert-butyl 2-(1H-pyrazole-4-yl)pyrrolidine-1-carboxylate (100.0 mg, 421.4 μmol) were added. The mixture was stirred at 80°C for 1 hour. The reaction mixture was added to H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether). The compound tert-butyl 2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate was obtained as a colorless oil. The residue was purified by SFC (column: Regis(s,s) Whelk-o1 (250mm × 25mm × 10μm); [CO2-EtOH]; B%: 50%). The compound tert-butyl 2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (isomer-1) was obtained as a colorless oil, and tert-butyl 2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (isomer-2) was also obtained as a colorless oil. The retention times were 1.527 minutes and 2.350 minutes, respectively. MS (ES-API positive): 568.1 (M+H) + . Step 2: (R)-N-methyl-4-((4-(4-((pyrroridine-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-((pyrroridine-2-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

[0133] To a solution of tert-butyl 2-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (48.0 mg, 84.6 μmol) in dioxane (0.1 mL), HCl (4 M in dioxane, 2.0 mL) was added. The mixture was stirred at 25°C for 1 hour. The mixture was concentrated and purified by preparative HPLC (eluting at acetonitrile concentrations of 22% to 42% in water).

[0134] The compound N-methyl-4-[[4-(4-pyrroridine-2-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a white solid. Other isomers were obtained under similar conditions. MS (ES-API positive): 468.1 (M+H) + . Example 91: 1 H NMR (500 MHz, CD3OD) δ 8.99-8.94 (m, 1H), 8.75-8.72 (m, 1H), 8.05-8.02 (m, 1H), 7.98-7.94 (m, 2H), 7.88-7.83 (m, 2H), 4.81-4.76 (m, 1H), 3.52-3.42 (m, 2H), 2.61-2.52 (m, 4H), 2.39-2.20 (m, 3H). Example 92: 1¹H NMR (400 MHz, methanol-d4) δ values: 8.96 (s, 1H), 8.79-8.70 (m, 1H), 8.03-8.02 (m, 1H), 7.98-7.95 (m, 2H), 7.88-7.83 (m, 2H), 4.82-4.77 (m, 1H), 3.53-3.42 (m, 2H), 2.60-2.53 (m, 4H), 2.37-2.21 (m, 3H). Examples 93 and 94: (R)-N-methyl-4-((4-(4-(pyrroridine-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-((pyrroridine-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide [ka] Step 1: tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]-2,5-dihydropyrrole-1-carboxylate

[0135] To a mixture of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydropyrrole-1-carboxylate (675.6 mg, 2.3 mmol) and 4-[[4-(4-iodopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (1.0 g, 1.9 mmol) in H2O (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 an N2 atmosphere. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (25 mL x 3). The combined organic phase was dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (elution with 0% to 45% ethyl acetate in petroleum ether). The compound tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]-2,5-dihydropyrrole-1-carboxylate was obtained as a yellow solid. MS (ES-API positive): 566.2 (M+H) + . Step 2: tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate

[0136] To a solution of tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]-2,5-dihydropyrrole-1-carboxylate (0.5 g, 937.1 μmol) in THF (5 mL) and ethyl acetate (5 mL), Pd / C (99.7 mg, 93.7 μmol, purity 10.0%) was added. The mixture was stirred at 25°C for 3 hours under an H2 (15 psi) atmosphere. The reaction mixture was filtered and concentrated. The residue was further purified by SFC (column: DAIEL CHIRALPAK IG (250 mm × 30 mm × 10 μm); [CO2-MeOH (0.1% NH3·H2O)]; B%: 50%). The compound tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (isomer-1) was obtained as a white solid. The compound tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (isomer-2) was obtained as a white solid. The retention times were 3.168 minutes and 3.851 minutes, respectively. MS (ES-API positive): 568.2 (M+H) + . Step 3: (R)-N-methyl-4-((4-(4-((pyrroridine-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide and (S)-N-methyl-4-((4-(4-((pyrroridine-3-yl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)benzenesulfonamide

[0137] To a solution of tert-butyl 3-[1-[2-[4-(methylsulfamoyl)anilino]-5-(trifluoromethyl)pyrimidine-4-yl]pyrazole-4-yl]pyrrolidine-1-carboxylate (40.0 mg, 70.5 μmol) in dioxane, HCl (4 M in dioxane, 2 mL) was added. The mixture was stirred at 20°C for 2 hours. The reaction mixture was filtered and concentrated. The residue was purified by preparative HPLC (elution with 25% to 45% acetonitrile in water). Compound N-methyl-4-[[4-(4-pyrrolidine-3-ylpyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide was obtained as a white solid. Other isomers were obtained under similar conditions. MS (ES-API positive): 468.1 (M+H) + . Example 93: 1 H NMR (400 MHz, CD3OD) δ 8.92 (s, 1H), 8.55 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.91 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 3.76 (dd, J=7.9, 11.2 Hz, 1H), 3.70-3.53 (m, 2H), 3.48-3.39 (m, 1H), 3.25 (dd, J=9.5, 11.1 Hz, 1H), 2.56 (s, 4H), 2.23-2.11 (m, 1H). Example 94: 1 H NMR (400 MHz, CD3OD) δ 8.96-8.83 (m, 1H), 8.55 (s, 1H), 7.97 (d, J=8.8 Hz, 2H), 7.91 (s, 1H), 7.85 (d, J=8.8 Hz, 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, 11.0 Hz, 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-methyl-benzenesulfonamide

Chem.

[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-dicarboxamidine (27.4 mg, 167.6 μmol) were added. The mixture was stirred at 60 °C for 4 h under N2. The reaction mixture was poured into H2O (30 mL) and extracted with EA (15 mL × 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (eluting with 0% - 50% ethyl acetate in petroleum ether). Compound N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzenesulfonamide was obtained as a yellow oil. MS (ES-API positive): 467.2(M+) + . Step 2: 4-[[4-[4-(3-Hydroxycyclobutyl)pyrazol-1-yl]-5-(trifluoromethyl)pyrimidin-2-yl]amino]-N-methyl-benzenesulfonamide

[0139] To a solution of N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide (80.0 mg, 171.5 μmol) in THF (2 mL), L-selectide (343.0 μmol, 75.0 μL) was added at -78 °C and the mixture was stirred under N2 for 1 hour. The reaction mixture was quenched with H2O (4 mL) at -60 °C, then heated to 20 °C and stirred for 10 minutes. The mixture was extracted with ethyl acetate (5 mL x 3), washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (elution with 35%-65% acetonitrile in water). Compound 4-[[4-[4-(3-hydroxycyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a white solid. MS (ES-API positive): 469.0 (M+H) + . 1 H NMR (400 MHz, methanol-d4) δ 8.87 (s, 1H), 8.36 (s, 1H), 7.96 (d, J=8.7 Hz, 2H), 7.82 (d, J=8.8 Hz, 2H), 7.77 (s, 1H), 4.19 (q, J=7.5 Hz, 1H), 3.02-2.90 (m, 1H), 2.80-2.69 (m, 2H), 2.54 (s, 3H), 2.05-1.94 (m, 2H). Examples 104 and 105: 4-((4-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide [ka] Step 1: N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide

[0140] This is the same as the previous example. Step 2: 4-[[4-[4-(3-hydroxy-3-methylcyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0141] A mixture of N-methyl-4-[[4-[4-(3-oxocyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]benzenesulfonamide (60.0 mg, 128.6 μmol) and CeCl3 (6.3 mg, 25.7 μmol) in THF (2 mL) was mixed with MeMgBr (3 M, 257.3 μL) at 0 °C. The mixture was stirred under N2 at 0 °C for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution (6 mL) at 0 °C and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (eluting with 50%-70% acetonitrile in water), followed by preparative HPLC (eluting with 40%-60% acetonitrile in water).

[0142] 4-((4-(4-((1s,3s)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide and 4-((4-(4-((1r,3r)-3-hydroxy-3-methylcyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide were obtained as white solids. MS (ES-API positive): 483.1 (M+H) + . Example 104: 1¹H NMR (400 MHz, methanol-d4): δ 8.86 (s, 1H), 8.37 (s, 1H), 7.96 (d, J=8.9 Hz, 2H), 7.87-7.79 (m, 2H), 7.75 (s, 1H), 3.58 (q, J=8.2 Hz, 1H), 2.58-2.50 (m, 5H), 2.22-2.13 (m, 2H), 1.35 (s, 3H). Example 105: 1 H NMR (400 MHz, methanol-d4) δ 8.86 (s, 1H), 8.36 (s, 1H), 7.96 (d, J=8.9 Hz, 2H), 7.87-7.81 (m, 2H), 7.79 (s, 1H), 3.06 (q, J=8.9 Hz, 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-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide [ka] Step 1: (3-bromocyclobutoxy)methylbenzene

[0143] To a solution of 3-benzyloxycyclobutanol (2.0 g, 11.2 mmol) in DCM (20 mL), CBr4 (5.6 g, 16.8 mmol) and PPh3 (4.4 g, 16.8 mmol) were added. 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 x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0%-5% ethyl acetate in petroleum ether). The compound (3-bromocyclobutoxy)methylbenzene was obtained as a colorless oil. MS (ES-API positive): 241.1(M+) + . Step 2: 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide

[0144] To a solution of pyridine-2,6-dicarboxamidine (44.5 mg, 272.4 μmol), (3-bromocyclobutoxy)methylbenzene (656.8 mg, 2.7 mmol), and 4-[[4-(4-bromopyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-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 x 3), dried over Na2SO4, and then concentrated. The crude product was purified by preparative HPLC (elution with 0% to 30% acetonitrile in water). Compound 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide was obtained as a yellow oil. MS (ES-API positive): 559.3 (M+H) + . Step 3: 4-((4-(4-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide

[0145] To a solution of 4-[[4-[4-(3-benzyloxycyclobutyl)pyrazole-1-yl]-5-(trifluoromethyl)pyrimidine-2-yl]amino]-N-methylbenzenesulfonamide (300.0 mg, 537.1 μmol) in THF (5 mL) and MeOH (5 mL), Pd / C (57.2 mg, 53.7 μmol, 10.0% purity) was added. The mixture was stirred at 25°C for 5 hours under 30 psi H2. The reaction mixture was filtered and then concentrated. The residue was purified by preparative HPLC (eluting with 44%-64% acetonitrile in water) to obtain the desired compound. Further separation by SFC (column: DAIEL CHIRALPAK IC (250 mm × 30 mm × 10 μm); [CO2-i-PrOH (0.1% NH3H2O)]; B%: 50%) yielded compound 4-((4-(4-((1r,3r)-3-hydroxycyclobutyl)-1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)-N-methylbenzenesulfonamide as a white solid (retention time: 1.562 min). MS (ES-API positive): 469.1 (M+H) + . 1 ¹H NMR (400 MHz, methanol-d4): δ 8.88 (s, 1H), 8.42 (s, 1H), 7.98 (d, J=8.8 Hz, 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-pyrazole-1-yl)pyrimidine-2-yl)amino)-N-(2-hydroxyethyl)benzenesulfonamide [ka] Step 1: 2,4-Dichloro-5-(difluoromethyl)pyrimidine

[0146] To a solution of 2,4-dichloropyrimidine-5-carbaldehyde (1.0 g, 5.7 mmol) in DCM (10 mL), DAST (1.5 mL, 11.4 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 2 hours and then concentrated. The residue was purified by flash chromatography (elution with 10% ethyl acetate in petroleum ether) to obtain 2,4-dichloro-5-(difluoromethyl)pyrimidine as a white solid. 1 ¹H NMR (400 MHz, chloroform-d): δ 8.81 (s, 1H), 6.89 (t, J=53.7 Hz, 1H). Step 2: 2-Chloro-5-(difluoromethyl)-4-(pyrazole-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 then concentrated. The residue was purified by flash chromatography (elution with 10-20% ethyl acetate in petroleum ether) to obtain 2-chloro-5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine as a white solid. MS (ES-API positive): 231.1 (M+H) + . Step 3: 4-{[5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine-2-yl]amino}-N-[5-methyl-4,4-di(propa-2-yl)-3-oxa-4-silahexa-1-yl]benzenesulfonamide

[0148] To a solution of 2-chloro-5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine (150.0 mg, 0.7 mmol) in dioxane (6.0 mL), 4-amino-N-[5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silahexyl]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 under N2 at 90°C for 1 hour. The mixture was extracted with ethyl acetate and then concentrated. The residue was purified by flash chromatography (elution with 30% ethyl acetate in petroleum ether) to obtain 4-{[5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine-2-yl]amino}-N-[5-methyl-4,4-di(propa-2-yl)-3-oxa-4-silahexa-1-yl]benzenesulfonamide as a yellow solid. MS (ES-API positive): 567.2 (M+H) + . Step 4: 4-{[5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine-2-yl]amino}-N-(2-hydroxyethyl)benzenesulfonamide

[0149] To a solution of 4-{[5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine-2-yl]amino}-N-[5-methyl-4,4-di(propan-2-yl)-3-oxa-4-silahexa-1-yl]benzenesulfonamide (226.0 mg, 0.4 mmol) in THF (5.0 mL), TBAF (4 M in THF, 0.3 mL) was added. The reaction mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with H2O, extracted with ethyl acetate, and then concentrated. The residue was purified by flash chromatography (elution with 9% methanol in dichloromethane) to obtain 4-{[5-(difluoromethyl)-4-(pyrazole-1-yl)pyrimidine-2-yl]amino}-N-(2-hydroxyethyl)benzenesulfonamide as a white solid. MS (ES-API positive): 411.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.91 (s, 1H), 8.71 (d, J=2.7 Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.95 (d, J=8.9 Hz, 2H), 7.80 (dd, J=9.3, 7.3 Hz, 3H), 7.46 (t, J=5.9 Hz, 1H), 6.72 (dd, J=2.8, 1.6 Hz, 1H), 4.70 (t, J=5.5 Hz, 1H), 3.43 - 3.37 (m, 2H), 2.79 (q, J=6.2 Hz, 2H). Example 130: 3-[4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]phenyl]sulfonylpropan-1-ol [ka] Step 1: Methyl 3-(4-nitrophenyl)sulfanylpropanoate

[0150] To a solution of 1-fluoro-4-nitrobenzene (3.4 g, 24.0 mmol) and methyl 3-sulfanylpropanoate (4.9 g, 40.8 mmol) in DMF (50 mL), KOH (1.9 g, 33.6 mmol) was added at 0°C. The mixture was stirred under N2 at 80°C for 1 hour. The reaction mixture was quenched with ice water (120 mL), filtered, and recrystallized (methanol and water). The compound methyl 3-(4-nitrophenyl)sulfanylpropanoate was obtained as a pale yellow solid and was used directly in the next step without further purification. Step 2: Methyl 3-(4-nitrophenyl)sulfonylpropanoate

[0151] A solution of oxon (22.9 g, 37.3 mmol) in H2O (600 mL) was added at 0°C to a solution of methyl 3-(4-nitrophenyl)sulfanylpropanoate (3.0 g, 12.4 mmol) in acetonitrile (300 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched at 0°C with saturated Na2SO3 aq. (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was obtained as a pale yellow solid and was used directly in the next step without further purification. MS (ES-API positive): 296.2 (M+Na) + . Step 3: Methyl 3-(4-aminophenyl)sulfonylpropanoate

[0152] To a solution of methyl 3-(4-nitrophenyl)sulfonylpropanoate (2.0 g, 7.3 mmol) in MeOH (100 mL), Pd / C (779.0 mg, 0.7 mmol, purity 10.0%) was added and the mixture was stirred at room temperature under H2 (40 psi) for 16 hours. The reaction mixture was filtered and concentrated to obtain the desired compound as a pale yellow solid, which was used directly in the next step without further purification. MS (ES-API positive): 261.2 (M+H) + . Step 4: Methyl 3-[4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]phenyl]sulfonylpropanoate

[0153] To a solution of methyl 3-(4-aminophenyl)sulfonylpropanoate (1.0 g, 2.1 mmol) in acetonitrile (16 mL), TsOH·H2O (784.0 mg, 2.1 mmol) and 2-chloro-4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine (1.0 g, 2.1 mmol) were added. The mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated and diluted with aqueous NaHCO3 (20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 33% ethyl acetate in petroleum ether). The desired compound was obtained as a yellow solid. MS (ES-API positive): 456.0 (M+H) + . Step 5: 3-[4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]phenyl]sulfonylpropan-1-ol

[0154] To a solution of methyl 3-[4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]phenyl]sulfonylpropanoate (600.0 mg, 1.3 mmol) in THF (5 mL), LAH (2.5 M, 0.5 mL) was added at -78 °C 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 purified by preparative HPLC (eluting with 35% to 53% acetonitrile in water) to obtain 3-[4-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]phenyl]sulfonylpropan-1-ol as a white solid. MS (ES-API positive): 428.3 (M+H) + . 1H NMR (400 MHz, DMSO-d6) δ 10.94 (s, 1H), 9.01 (s, 1H), 8.63 (d, J=2.6 Hz, 1H), 8.07-7.94 (m, 3H), 7.88 (d, J=8.8 Hz, 2H), 6.70 (d, J=2.5 Hz, 1H), 3.41 (t, J=6.2 Hz, 2H), 3.33-3.14 (m, 2H), 1.76-1.61 (m, 2H). Example 136: N-(2-hydroxyethyl)-5-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]pyridine-2-sulfonamide [ka] Step 1: 5-Bromo-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyridine-2-sulfonamide

[0155] To a solution of 5-bromopyridine-2-sulfonyl chloride (1.0 g, 3.9 mmol) and 2-[tert-butyl(dimethyl)silyl]oxyethaneamine (820.0 mg, 4.7 mmol) in DCM (15 mL), TEA (7.8 mmol, 1.0 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction product was extracted with DCM (15 mL x 2), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether). Compound 5-bromo-N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]pyridine-2-sulfonamide was obtained 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-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-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-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-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 N2. 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 x 3). The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (elution with 0% to 50% ethyl acetate in petroleum ether). Compound N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]pyridine-2-sulfonamide was obtained as a white solid. MS (ES-API positive): 544.1 (M+H) + . Step 3: N-(2-hydroxyethyl)-5-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]pyridine-2-sulfonamide

[0157] To a solution of N-[2-[tert-butyl(dimethyl)silyl]oxyethyl]-5-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]pyridine-2-sulfonamide (100.0 mg, 184.0 μmol) in THF (1 mL), TBAF (1 M, 221.0 μL) was added at 0°C and the mixture was stirred at this temperature for 1 hour. The reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (10 mL x 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 filtered. The filtered cake was purified by preparative HPLC (eluting with 31% to 51% acetonitrile in water) to obtain N-(2-hydroxyethyl)-5-[[4-pyrazole-1-yl-5-(trifluoromethyl)pyrimidine-2-yl]amino]pyridine-2-sulfonamide as a white solid. MS (ES-API positive): 430.1 (M+H) + . 1 H NMR (500 MHz, DMSO-d6) δ 11.01 ( s, 1H), 9.12-8.91 (m, 2H), 8.60 (d, J=2.6 Hz, 1H), 8.43 (d, J=2.4 Hz, 1H), 8.06-7.89 (m, 2H), 7.69 ( s, 1H), 6.71 (d, J=2.6 Hz, 1H), 4.66 (t, J=5.6 Hz, 1H), 3.37 (q, J=6.4 Hz, 2H), 2.98-2.92 (m, 2H). Example 138: ((4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)sulfonyl)glycine [ka] Step 1: tert-butyl ((4-nitrophenyl)sulfonyl)glycinate

[0158] A mixture of 2-methylpropan-2-ylaminoacetate (355.2 mg, 2.7 mmol) in DCM (6 mL) and H2O (6 mL) was mixed with Na2CO3 (358.7 mg, 3.4 mmol) and 4-nitrobenzenesulfonyl chloride (500.0 mg, 2.3 mmol) at 0°C. The reaction mixture was stirred at room temperature for 1.5 hours, extracted with DCM, and concentrated to obtain the residue, which was used in the next step without further purification. Step 2: tert-butyl ((4-aminophenyl)sulfonyl)glycinate

[0159] Fe (503.9 mg, 9.0 mmol) was added to a mixture of tert-butyl((4-nitrophenyl)sulfonyl)glycinate (713.7 mg, 2.3 mmol) and NH4Cl (1.2 g, 22.6 mmol) in EtOH (9 mL) and H2O (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 flash chromatography (elution with 66% ethyl acetate in petroleum ether) to obtain tert-butyl((4-aminophenyl)sulfonyl)glycinate as a yellow solid. MS (ES-API negative): 285.1 (M+H) + . Step 3: tert-butyl ((4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)sulfonyl)glycinate

[0160] To a mixture of 2-chloro-4-(pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine (100.0 mg, 0.4 mmol) in dioxane (2 mL), tert-butyl ((4-aminophenyl)sulfonyl)glycinate (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 under N2 at 85°C for 1.5 hours. The mixture was filtered, extracted with ethyl acetate, and then concentrated. The residue was purified by flash chromatography (elution with 50% to 66% ethyl acetate in petroleum ether) to obtain tert-butyl ((4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)aminophenyl)sulfonyl)glycinate as a yellow solid. MS (ES-API positive): 499.2 (M+H) + . Step 4: ((4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)sulfonyl)glycine

[0161] A mixture of ((4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)sulfonyl)glycinate (144.0 mg, 0.2 mmol) in DCM (2 mL) was mixed with TFA (0.5 mL, 6.5 mmol) and 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 (eluted with 52% acetonitrile in water) to obtain ((4-((4-(1H-pyrazole-1-yl)-5-(trifluoromethyl)pyrimidine-2-yl)amino)phenyl)sulfonyl)glycine as a white solid. MS (ES-API positive): 443.0 (M+H) + . 1H NMR (400 MHz, methanol-d4) δ 8.90 (s, 1H), 8.59 (d, J=2.7 Hz, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.85 (dt, J=6.1, 2.2 Hz, 3H), 6.62 (dd, J=2.8, 1.6 Hz, 1H), 3.66 (s, 2H). (Examples) JPEG2026514948000042.jpg236170JPEG2026514948000043.jpg226170JPEG2026514948000044.jpg234170JPEG2026 514948000045.jpg235170JPEG2026514948000046.jpg227170JPEG2026514948000047.jpg207170JPEG202651494800 0048.jpg215170JPEG2026514948000049.jpg205170JPEG2026514948000050.jpg234170JPEG2026514948000051.jpg 226170JPEG2026514948000052.jpg220170JPEG2026514948000053.jpg235170JPEG2026514948000054.jpg218170JP EG2026514948000055.jpg165170JPEG2026514948000056.jpg231170JPEG2026514948000057.jpg206170JPEG202651 4948000058.jpg221170JPEG2026514948000059.jpg239170JPEG2026514948000060.jpg233170JPEG20265149480000 61.jpg245170JPEG2026514948000062.jpg236170JPEG2026514948000063.jpg210170JPEG2026514948000064.jpg221170JPEG2026514948000065.jpg222170JPEG2026514948000066.jpg229170JPEG2026514948000067.jpg87170 Example A: Cyclin-dependent kinase activity assay

[0162] Cyclin-dependent kinase activity assays are measured by a serial ATP coupling assay, in which ADP produced by kinase-catalyzed phosphorylation is reconverted to ATP by pyruvate kinase / lactate dehydrogenase (PK / LDH) catalyzed by phosphoenolpyruvate (PEP) and NADH. The assay solution (see Table 1) contains one kinase at a specified concentration, including CDK1 / cyclin B1, CDK2 / cyclin E1, CDK4 / cyclin D3, and CDK6 / cyclin D3, and the K of the kinase. m The assay consists of ATP, copeptides, and ATP coupling systems of PEP, NADH, and PK / LDH in the corresponding components. The assay was performed in a reaction buffer of 20 mM Tris (pH 7.5) containing 50 mM NaCl, 0.5 mM DTT, and 0.04% BSA, and the results were continuously monitored using NADH fluorescence decrease with excitation light at 340 nm and emission light at 460 nm. The reaction rate was obtained by linear regression analysis of the resulting reaction time curves.

[0163] In the inhibition assay, the compound was first serially diluted from 10 μM to 0.05 nM in a 1:3 ratio using 10x reaction buffer. Next, one CDK kinase was added to the compound solution and incubated for 15 minutes. Finally, the ATP coupling system composition was introduced into the resulting solution to initiate the reaction. The final reaction mixture was in a 1x concentration reaction assay buffer containing 1% DMSO. The semi-maximal inhibitory concentration (IC) of the compound was measured. 50 ) plots reaction rate and compound concentration using 4 variables IC 50 The inhibitory constant (Ki) was determined by fitting the same plot to a quadratic / Morrison equation. The data was analyzed using the commercially available software Graphpad Prism. JPEG2026514948000068.jpg135170

[0164] Table 2 below shows the CDK inhibitory activity of representative compounds. Exemplary results are calculated IC50. 50 It is shown as a value. A:IC 50 ≤10nM B:IC 50 >10nM and IC 50 <100nM C:IC 50 ≥100nM JPEG2026514948000069.jpg255153JPEG2026514948000070.jpg255133JPEG2026514948000071.jpg255133JPEG2026514948000072.jpg255158

Claims

1. Compound of formula (I), 【Chemistry 1】 [In the formula, X is either CH or N; Z is either CH or N; Ring A is an aryl, heteroaryl, cycloalkyl, heterocyclyl, or aryl-condensed heterocyclyl, each of which has one R １ and 1 to 4 R ２ The carbon atoms of the aryl condensed heterocyclyl are optionally and independently substituted, the carbon atoms of the aryl condensed heterocyclyl are optionally substituted with one oxo, and the heteroatoms of the aryl condensed heterocyclyl are optionally substituted with one or two oxos; R １ is -S(O) ２ -R １０ ,-NH-S(O) ２ -R １０ or -SF ５ And; Each R ２ is independently H, alkyl, -CN, cyanoalkyl, amino, alkylamino, dialkylamino, -NO ２ , halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxyl, (haloalkoxyl)alkyl, alkoxyalkyl, cycloalkyl or heterocyclyl, wherein said cycloalkyl or heterocyclyl is optionally substituted with one or more R ７ ; R ３ is H, halo, alkyl, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, alkoxyalkyl, alkenyl, alkynyl, -CN, or cyanoalkyl; R ４ and R ６ Each of these is independently H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -alk-N-R ９ R ９ , -CN, cyanoalkyl, cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is one or more R ７ It is optionally replaced by; R ５ H, alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, 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 the aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, -O-cycloalkyl, or -O-heterocyclyl is one or more R ７ It is optionally replaced by; Each R ７ These are independently alkyl, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkoxyl, haloalkoxy, (haloalkoxy)alkyl, alkoxyalkyl, amino, alkylamino, dialkylamino, -CN, cyanoalkyl, oxo(=O), R ８ -S(O) ２ -, R ８ -O-C(=O)-, R ８ -C(=O)-O-, R ８ -C(=O)-, cycloalkyl or heterocycline, wherein the cycloalkyl or heterocycline is one or more R ７ It is then optionally replaced; Each R ８ These are independently H, alkyl, or -NR ９ R ９ And; Each R ９ These are independently H, cycloalkyl, -alk-cycloalkyl, or alkyl; R １０ H, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl or -NR １１ R １１ The cycloalkyl or heterocyclyl is one or more R ７ It is optionally replaced by; Each R １１ These are independently H, alkyl, cycloalkyl, heterocyclyl, -alk-cycloalkyl, -alk-heterocyclyl, hydroxyalkyl, -alk-O-R １２ , -alk-C(O)-OR ９ or -alk-N-R ９ R ９ The cycloalkyl, -alk-cycloalkyl, -alk-heterocyclyl, or heterocyclyl is one or more R ７ It is optionally replaced by, Each R １２ These are independently H, alkyl, cycloalkyl, haloalkyl, or heterocyclyl; Each of the heteroaryl and heterocyclyl compounds independently contains one or more ring-forming heteroatoms, each of which is independently oxygen, sulfur, or nitrogen; Each occurrence of the heterocyclyl is saturated or partially unsaturated; One of the hydrogen atoms in each alkyl group can be optionally replaced with deuterium (D). or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

2. Ring A is, 【Chemistry 2】 The compound according to claim 1.

3. The compound according to claim 1 or 2, wherein the hydroxyalkyl is a linear or branched hydroxyalkyl.

4. The compound according to claim 1 or 2, wherein the cyanoalkyl is a linear or branched cyanoalkyl.

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

6. The compound according to claim 1, wherein X is N.

7. The compound according to claim 1, wherein Z is N.

8. The compound in question is of formula (II): 【Transformation 3】 The compound according to claim 1, wherein ring A is the same as that defined in claim 1.

9. The compound is of formula (IIa), (IIb), (IIc), (IId), or (IIe): 【Chemistry 4】 During the ceremony, Ring C is a crosslinked or spirodicyclic heterocycloalkyl group; Ring D is a 4- to 8-membered cycloalkyl or heterocyclyl condensed to an adjacent aryl, and optionally, ring D is substituted with one or two oxos; Y is N, O, or CH; if Y is O, R １ It does not exist; M １ and M ２ Each is independently N or CH; R １ , R ２ , R ３ , R ４ , R ５ and R ６ The compound according to claim 1, wherein the compound is the same as in claim 1.

10. R １ 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 -, (Deuterized C １－６ Alkyl) ２ -N-S(O) ２ -, (Deuterized C １－６ Alkyl)-HN-S(O) ２ -, C １－６ Alkyl-S(O) ２ -NH- or -SF ５ The compound according to any one of claims 1 to 9.

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

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

13. The compound according to any one of claims 1 to 12, wherein the halo is F, Cl, or Br.

14. The aforementioned compound is of formula (III), 【Transformation 5】 In the formula, R １ , R ２ , R ３ , R ４ , R ５ and R ６ The compound according to claim 1, wherein is the same as that defined in claim 1.

15. The compound is selected from the following, according to any one of claims 1 to 14: 【Transformation 6】 【Transformation 7】 【Transformation 8】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound described in any one of claims 1 to 15 and a pharmaceutically acceptable carrier or excipient.

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

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

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

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

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

22. Use of the compound according to any one of claims 1 to 15 for the manufacture of a pharmaceutical product for treating a CDK2-mediated disorder.

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