Cyclopentylpyrazole CDK2 inhibitors

Abstract

Formula (I) Described herein are compounds of TIFF2024538694000310.tif25170 and pharma- ceutically acceptable salts thereof, pharmaceutical compositions containing them, and their uses and preparations.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 252,394, filed October 5, 2021, which is incorporated herein in its entirety. [Background technology]

[0002] background Throughout eukaryotes, the cell cycle is controlled by a family of cyclin-dependent kinases (CDKs). CDKs are activated by the binding of different regulatory cyclin proteins to promote cell cycle progression and many cell cycle-dependent events. Different cyclin partners are expressed at different points in the cell cycle to promote proliferation: cyclin D1 / 2 / 3 are expressed in G1, cyclin E1 / 2 are expressed in G1 / S, cyclin A2 is expressed during S / G2, and cyclin B1 / 2 / 3 are expressed during G2 / M. The human genome encodes 21 CDKs, but in most mammalian cell types, only a few - CDK1, CDK2, CDK4, CDK6 and CDK7 - have been shown to play a direct role in the cell cycle together with their cyclin partners. See, e.g., Luet al., Toxicological Sciences (2020) 177: 226-234 and Asghar et al., Nature Rev. (2015) 14: 130-146. CDK family members share high sequence homology, presenting a challenge for the development of isoform-selective small molecule inhibitors. See, e.g., Asghar et al., Nature Rev. (2015) 14: 130-146.

[0003] In general, the mammalian cell cycle requires the sequential activation of the three interphase CDKs 2, 4 and 6 to drive cells through interphase and then mitosis, which is controlled by CDK1. CDK4 / 6 are activated during G1 phase along with D-type cyclins, followed by increased expression of E-type cyclins that activate CDK2 to drive the G1 / S transition. CDK2 is activated by A-type cyclins to drive the transition from S phase to mitosis. CDK1 is first activated by A-type cyclins and then by B-type cyclins to drive the completion of the cell cycle through mitosis. Increased cell proliferation is a result of direct or indirect deregulation of this cell division cycle. See, for example, Lu et al., Toxicological Sciences (2020) 177: 226-234.

[0004] CDK4 / 6 inhibitors have been found to be useful in the treatment of cancer, but are also associated with negative side effects such as neutropenia. See, e.g., Thill and Schmidt Ther. Adv. Med. Oncol. (2018) 10:1-12. Gastrointestinal toxicity, such as from intestinal cell proliferation, has been associated with CDK1 inhibition, which may have a broader effect on all proliferating cells based on the results of mouse knockout studies. See, e.g., Lu et al., Toxicological Sciences (2020) 177:226-234; Santamaria et al., Nature (2007) 448:811-815. Deregulation of CDK2 has been shown to occur frequently in cancers such as breast cancer (see, e.g., Scaltriti et al., PNAS (2011) 108: 3761-3766, Akli et al., Cancer Res. (2011) 71: 3377-3386) and ovarian cancer (see, e.g., Yang et al., Oncotarget (2015) 6: 20801-20812), as well as many other cancers. There is also accumulating evidence that CDK2 deficiency or inhibition has no adverse effects on normal (non-cancerous tissues); see, for example, Barbacid et al., Cold Spring Harbor Symposia on Quantitative Biology (2005) 233-240, which describes that CDK2(- / -) and conditional null mice were viable and had no major cell cycle defects other than sterility, and Chauhan et al., Biochemical Journal (2016) 473:2783-2798, which similarly shows that a "kinase dead" mutant mouse model was also sterility-dead but showed normal mitotic cell cycle progression. Thus, there is a need to develop selective inhibitors of CDK2 that minimize inhibition of CDK4 / 6 and CDK1. Summary of the Invention

[0005] overview In one embodiment, a compound of formula (I): TIFF2024538694000002.tif25170 (in the formula, Ring A is a 6-membered heteroaryl having at least one N ring heteroatom and having 0-2 additional N ring heteroatoms; Each R 1 is independently 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -N(R 1a) (R 1b ), -C 1~6 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~8 cycloalkyl, 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or 5-membered heteroaryl having 1 or 2 heteroatoms, each independently N or O, each heterocycloalkyl and heteroaryl being selected from 0, 1, 2, or 3 R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 1c is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms which are each independently N and O; R 2 is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms, each independently being N or O, or C 1~6and alkylaryl, wherein said cycloalkyl, said heterocycloalkyl, and said aryl each independently represent 0, 1, 2, or 3 R 2a is substituted with a group; Each R 1d and R 2a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 3 is hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 4 is hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; and The subscript m is an integer 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0006] In another aspect, there is provided a pharmaceutical composition comprising a compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0007] In another aspect, there is provided a method of treating a CDK2-mediated disorder in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0008] In another aspect, there is provided a method for the manufacture of a medicament for treating a CDK2-mediated disorder in a human in need thereof, wherein a compound as described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein is used.

[0009] In another aspect, there is provided a use of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein, for the manufacture of a medicament for treating a CDK2-mediated disorder in a human.

[0010] In another aspect, there is provided a compound as described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in treating a CDK2-mediated disorder in a human in need of such treatment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description I. Overview Provided herein are cyclopentylpyrazole inhibitors of CDK2 of formula (I) or a pharma- ceutically acceptable salt thereof, pharmaceutical compositions thereof, and their uses for treating, and for the preparation of, diseases mediated by CDK2, such as, for example, cancer.

[0012] II. Definition Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.In addition, any method or material similar or equivalent to the method or material described herein can be used.In the description of this specification, the following terms are defined.

[0013] As used herein, "a," "an," or "the" not only includes aspects having one member, but also includes aspects having more than one member. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "the agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0014] "Alkyl" refers to a straight or branched chain saturated aliphatic group having the indicated number of carbon atoms. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. The abbreviation "Me" refers to the alkyl group methyl (-CH3).

[0015] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. With respect to the alkyl group, an alkoxy group is a C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further substituted with a variety of substituents described herein.

[0016] "Alkoxyalkyl" refers to a group having an alkyl component and an alkoxy component, where the alkyl component attaches the alkoxy component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene and is attached to the alkoxy component and to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent alkylene and is attached to the alkoxy component and to the point of attachment. 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The alkoxy moiety is as defined above. Examples of alkoxyalkyl groups include, but are not limited to, 2-ethoxy-ethyl, methoxymethyl.

[0017] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0018] "Haloalkyl" refers to an alkyl as defined above in which some or all of the hydrogen atoms have been replaced with halogen atoms. With respect to the alkyl group, a haloalkyl group is one having a C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or group in which all hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0019] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. With respect to an alkyl group, a haloalkoxy group is a C 1-6The alkoxy group can have any suitable number of carbon atoms, such as 1, 2, 3 or more halogens. If all hydrogens are replaced with halogens, such as fluorine, the compound is fully substituted, such as fully fluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0020] Cycloalkyl, heterocycloalkyl, aryl and heteroaryl bicyclic (fused, bridged or spirocyclic) or polycyclic (fused, bridged or spirocyclic) ring systems are defined based on the nature of the ring system and / or the attachment point. For example, if the entire bicyclic or polycyclic ring system is completely non-aromatic and contains at least one ring heteroatom, the ring system is a heterocycloalkyl bicyclic or polycyclic ring system. If the entire bicyclic or polycyclic ring system is completely aromatic and contains at least one ring heteroatom, the ring system is considered to be a heteroaryl bicyclic or polycyclic ring system. If the bicyclic or polycyclic ring system contains a mixture of non-aromatic and aromatic ring systems, it is the attachment point that determines the nature of the ring system, which is considered to be a cycloalkyl or heterocycloalkyl bicyclic or polycyclic ring system when attached to a non-aromatic cycloalkyl or heterocycloalkyl ring, and is considered to be an aryl or heteroaryl bicyclic or polycyclic ring system when attached to an aromatic aryl or heteroaryl ring.

[0021] "Cycloalkyl" refers to a non-aromatic saturated or partially unsaturated monocyclic, bicyclic or polycyclic ring system containing 3 to 12 ring carbon atoms and no heteroatom ring atoms. 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12Cycloalkyl groups can contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, bicyclo[1.1.1]pentane, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can be partially unsaturated, having one or more double or triple bonds within the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl groups can be saturated monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0022] "Heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic saturated or unsaturated monocyclic, bicyclic or polycyclic ring system having 3-12 ring carbons or heteroatoms, the ring system containing 1-4 ring heteroatoms selected from N, O and S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si and P. The heteroatoms may be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups can contain any number of ring atoms, for example, 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11 or 3-12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl group, such as 1, 2, 3 or 4, or 1-2, 1-3, 1-4, 2-3, 2-4 or 3-4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.

[0023] The heterocycloalkyl group can be linked through any position on the ring, for example, aziridine can be 1- or 2-aziridine, azetidine can be 1- or 2-azetidine, pyrrolidine can be 1-, 2-, or 3-pyrrolidine, piperidine can be 1-, 2-, 3-, or 4-piperidine, pyrazolidine can be 1-, 2-, 3-, or 4-pyrazolidine, imidazolidine can be 1-, 2-, 3-, or 4-imidazolidine, piperazine can be 1-, 2-, 3-, or 4-piperazine. the tetrahydrofuran may be 1- or 2-tetrahydrofuran, the oxazolidine may be 2-, 3-, 4- or 5-oxazolidine, the isoxazolidine may be 2-, 3-, 4- or 5-isothiazolidine, the thiazolidine may be 2-, 3-, 4- or 5-thiazolidine, the isothiazolidine may be 2-, 3-, 4- or 5-isothiazolidine, and the morpholine may be 2-, 3- or 4-morpholine.

[0024] When the heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocycloalkyl can also form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0025] "Aryl" refers to an aromatic ring system having any suitable number of ring carbon atoms and any suitable number of rings, but no heteroatom ring atoms. Aryl groups can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic or fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.*

[0026] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5-16 ring carbons and heteroatoms, with 1-5 of the ring atoms being heteroatoms selected from N, O and S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si and P. The heteroatoms may be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heteroaryl groups can contain any number of ring atoms, for example, 5-6, 5-8, 6-8, 5-9, 5-10, 5-11 or 5-12 ring members. Any suitable number of heteroatoms may be included in a heteroaryl group, such as 1, 2, 3, 4 or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4 or 3-5. Heteroaryl groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Heteroaryl groups can include groups such as pyridinones, such as pyridin-2-one, pyridin-3-one or pyridin-4-one, pyridazinones, such as pyridazin-3(2H)-one or pyridazin-4(1H)-one, pyrimidinones, such as pyrimidin-2(1H)-one or pyrimidin-4(3H)-one, and pyrazinones. Examples are shown of the respective tautomerizations. TIFF2024538694000003.tif142170

[0027] Heteroaryl groups can also be fused to an aromatic ring system, such as a phenyl ring, to form members that include, but are not limited to, benzopyrroles, such as indole and isoindole, benzopyridines, such as quinoline and isoquinoline, benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines, such as phthalazine and cinnoline, benzothiophenes, and benzofurans.

[0028] The heteroaryl group can be linked through any position on the ring. For example, pyrrole includes 1-, 2-, and 3-pyrrole, pyridine includes 2-, 3-, and 4-pyridine, imidazole includes 1-, 2-, 4-, and 5-imidazole, pyrazole includes 1-, 3-, 4-, and 5-pyrazole, triazole includes 1-, 4-, and 5-triazole, tetrazole includes 1- and 5-tetrazole, pyrimidine includes 2-, 4-, 5-, and 6-pyrimidine, pyridazine includes 3- and 4-pyridazine, 1,2,3-triazine includes 4- and 5-triazine, 1,2,4-triazine includes 3-, 5-, and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2- and 3-thiophene, furan includes 2- and and 3-furan, thiazoles include 2-, 4-, and 5-thiazoles, isothiazoles include 3-, 4-, and 5-isothiazoles, oxazoles include 2-, 4-, and 5-oxazoles, isoxazoles include 3-, 4-, and 5-isoxazoles, indoles include 1-, 2-, and 3-indole, isoindoles include 1- and 2-isoindole, quinolines include 2-, 3-, and 4-quinolines, isoquinolines include 1-, 3-, and 4-isoquinolines, quinazolines include 2- and 4-quinoazolines, cinnolines include 3- and 4-cinnolines, benzothiophenes include 2- and 3-benzothiophenes, and benzofurans include 2- and 3-benzofurans.

[0029] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having 5-8 ring members and 1-3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Some other heteroaryl groups include those having 9-12 ring members and 1-3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran and bipyridine. Still other heteroaryl groups include those having 5-6 ring members and 1-2 ring atoms containing N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole.

[0030] Some heteroaryl groups contain 5-10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine and cinnoline. Other heteroaryl groups contain 5-10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups contain 5-10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups contain 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.

[0031] "Substituted" or "substituting," as described in more detail herein, refers to the replacement of a hydrogen atom with a different (i.e., non-hydrogen) group. Subscripts n or m that are zero (0), and / or groups that are substituted with zero (0) substituents, are R 1 or R 4 The absence of a group (in the case of variables n or m) and / or the absence of a hydrogen replacement with a given list of substituents means that the hydrogen is not replaced.

[0032] "Treat", "treating" and "treatment" refer to any indicia of success in treating or ameliorating an injury, condition, symptom or symptom (e.g., pain), including any objective or subjective parameter, such as palliative; remission; attenuating symptoms or making the symptoms, injury, condition or symptom more tolerable to the patient; reducing the frequency or duration of the symptoms or symptoms; or, in some circumstances, preventing the onset of the symptoms. The treatment or amelioration of symptoms can be based on any objective or subjective parameter, including, for example, the results of a physical examination.

[0033] "Therapeutically effective amount or dose" or "therapeutically sufficient amount or dose" or "effective amount or dose" or "sufficient amount or dose" are used interchangeably to refer to a dose that produces the therapeutic effect for which it is administered. The exact dose will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques.

[0034] "Subject" refers to animals such as mammals, including but not limited to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In some embodiments, the subject is a human.

[0035] III.Compound Compounds of any one of formula (I) and pharma- ceutically acceptable salts are provided.

[0036] In some embodiments, the compound of formula (I): TIFF2024538694000004.tif25170 (in the formula, Ring A is a 6-membered heteroaryl having at least one N ring heteroatom and having 0-2 additional N ring heteroatoms; Each R 1 is independently 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -N(R 1a) (R 1b ), -C 1~6 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~8 cycloalkyl, 3-, 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or 5-membered heteroaryl having 1 or 2 heteroatoms, each independently N or O, each heterocycloalkyl and heteroaryl being selected from the group consisting of 0, 1, 2, or 3 R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 1c is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms which are each independently N and O; R 2 is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms, each independently being N or O, or C 1~6 and alkylaryl, wherein said cycloalkyl, said heterocycloalkyl, and said aryl each independently represent 0, 1, 2, or 3 R 2a is substituted with a group; Each R 1d and R 2a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 3 is hydrogen, C 1~6 Alkyl or C 1~6is haloalkyl; R 4 is hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; The subscript m is an integer 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0037] In some embodiments, the compound of formula (I): TIFF2024538694000005.tif25170 (in the formula, Ring A is TIFF2024538694000006.tif44170; Each R 1 is independently 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -N(R 1a) (R 1b ), -C 1~6 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~8 cycloalkyl, 3-, 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or 5-membered heteroaryl having 1 or 2 heteroatoms, each independently N or O, each heterocycloalkyl and heteroaryl being selected from the group consisting of 0, 1, 2, or 3 R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~6 Alkyl or C 1~6is haloalkyl; R 1c is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms which are each independently N and O; R 2 is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms, each independently being N or O, or C 1~6 and alkylaryl, wherein said cycloalkyl, said heterocycloalkyl, and said aryl each independently represent 0, 1, 2, or 3 R 2a is substituted with a group; Each R 1d and R 2a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 3 is hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 4 is hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; The subscript m is an integer 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0038] In some embodiments, TIFF2024538694000007.tif238170TIFF2024538694000008.tif58170 (in the formula, Each R 1 is independently 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -N(R 1a) (R 1b ), -C 1~6 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~8 cycloalkyl, 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or 5-membered heteroaryl having 1 or 2 heteroatoms, each independently N or O, each heterocycloalkyl and heteroaryl being selected from 0, 1, 2, or 3 R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 1c is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms which are each independently N and O; R 2 is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, 3-6 membered heterocycloalkyl having 1 or 2 heteroatoms, each independently being N or O, or C 1~6 and alkylaryl, wherein said cycloalkyl, said heterocycloalkyl, and said aryl each independently represent 0, 1, 2, or 3 R 2a is substituted with a group; Each R 1d and R 2a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 3 is hydrogen, C 1~6 Alkyl or C 1~6is haloalkyl; R 4 is hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; The subscript m is an integer 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0039] In some embodiments, the compound of formula (I): TIFF2024538694000009.tif25170 (in the formula, Ring A is a 6-membered heteroaryl having one N ring heteroatom and optionally having 1-2 additional N ring heteroatoms; Each R 1 is independently 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C 1~6 Haloalkoxy, -CN, -N(R 1a) (R 1b ), -C 1~6 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , C 3~8 cycloalkyl, 3-, 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or 5-membered heteroaryl having 1 or 2 heteroatoms, each independently N or O, each heterocycloalkyl and heteroaryl being selected from the group consisting of 0, 1, 2, or 3 R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 1c is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms which are each independently N and O; R 2 is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, or a 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms each independently being N or O, wherein the cycloalkyl and the heterocycloalkyl each independently have 0, 1, 2, or 3 R 2a is substituted with a group; Each R 1d and R 2a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 3 is hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 4 is hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; The subscript m is an integer 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0040] In some embodiments, the compound of formula (I): TIFF2024538694000010.tif25170 (in the formula, Ring A is a 6-membered heteroaryl having 1-2 additional N heteroatoms; Each R 1 is independently 1~6 Alkyl, C 1~6 Alkoxy, C 1~6 Hydroxyalkyl, C 2~6 Alkoxyalkyl, halogen, C 1~6 Haloalkyl, C1~6 Haloalkoxy, -CN, -N(R 1a) (R 1b ), -C 1~6 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , C 3~8 cycloalkyl, 3-, 4-, 5-, or 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or 5-membered heteroaryl having 1 or 2 heteroatoms, each independently N or O, each heterocycloalkyl and heteroaryl being selected from the group consisting of 0, 1, 2, or 3 R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 1c is a 3-6 membered heterocycloalkyl having 1-2 heteroatoms which are each independently N and O; R 2 is independently 1~6 Alkyl, C 1~6 Haloalkyl, C 3~8 cycloalkyl, or a 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms each independently being N or O, wherein the cycloalkyl and the heterocycloalkyl each independently have 0, 1, 2, or 3 R 2a is substituted with a group; Each R 1d and R 2a are independently hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 3 is hydrogen, C 1~6 Alkyl or C 1~6 is haloalkyl; R 4 is hydrogen, C 1~4 Alkyl, C2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; The subscript m is an integer 0 or 1. or a pharma- ceutically acceptable salt thereof.

[0041] As should be understood herein, ring A is a monocyclic 6-membered heteroaryl ring having at least one N ring heteroatom and optionally 1-2 additional N ring heteroatoms. As used herein, "N ring heteroatom" is understood to be a nitrogen (N) heteroatom that is a member of a 6-membered ring system. In some embodiments, ring A is a monocyclic 6-membered heteroaryl ring having one N ring heteroatom. In some embodiments, ring A is a monocyclic 6-membered heteroaryl ring having two N ring heteroatoms. In some embodiments, ring A is a monocyclic 6-membered heteroaryl ring having three N ring heteroatoms. In some embodiments where m is 1 and valence permits, the at least one N ring heteroatom or the optionally present 1-2 additional heteroatoms are selected from the group R 4 In certain embodiments where m is 1 and valence permits, at least one N ring heteroatom is substituted with a group R 4 In certain embodiments where m is 1 and valence permits, at least one N ring heteroatom is substituted with a group R 4 and ring A contains one additional N ring heteroatom.

[0042] In some embodiments of Ring A, at least one N ring heteroatom is meta to the point of attachment. In some embodiments, at least one N ring heteroatom is para to the point of attachment. In some embodiments where Ring A has two N ring heteroatoms, the N atoms are meta and para to the point of attachment. In some embodiments, Ring A contains at least one N ring heteroatom meta to the point of attachment, and Ring A further contains an oxo (=O) group para to the point of attachment, and optionally Ring A further contains one additional N ring heteroatom.

[0043] In some embodiments, ring A is a 6-membered heteroaryl having one N ring heteroatom and optionally 1-2 additional N ring heteroatoms. In some embodiments, ring A is a 6-membered heteroaryl having at least one N ring heteroatom and 0-2 additional N ring heteroatoms. In some embodiments, ring A is a 6-membered heteroaryl having 1-3 N ring heteroatoms.

[0044] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000011.tif44170.

[0045] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000012.tif40170.

[0046] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000013.tif19170.

[0047] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000014.tif36170.

[0048] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000015.tif40170.

[0049] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000016.tif20170.

[0050] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000017.tif19170.

[0051] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000018.tif20170.

[0052] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000019.tif19170.

[0053] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000020.tif18170.

[0054] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has ring A having the structure: The compound has the following structure: TIFF2024538694000021.tif20170.

[0055] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has ring A having the structure: The compound has the following structure: TIFF2024538694000022.tif20170.

[0056] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has ring A having the structure: The compound has the following structure: TIFF2024538694000023.tif36170.

[0057] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has ring A having the structure: The compound has the following structure: TIFF2024538694000024.tif34170.

[0058] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has ring A having the structure: The compound has the following structure: TIFF2024538694000025.tif30170.

[0059] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has ring A having the structure: The compound has the following structure: TIFF2024538694000026.tif37170.

[0060] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which Ring A is pyridine, pyridazine, pyrimidine, pyrazine, triazine, pyridin-2-one, pyridazin-3-one, pyrimidin-2-one, or pyrazin-2-one.

[0061] In some embodiments, the compound of formula (Ia): The compound of formula TIFF2024538694000027.tif28170 or a pharma- ceutically acceptable salt thereof is provided.

[0062] In some embodiments, the compound of formula (Ia-1): The compound of formula TIFF2024538694000028.tif22170 or a pharma- ceutically acceptable salt thereof is provided.

[0063] In some embodiments, the compound of formula (Ia-2): The compound of formula TIFF2024538694000029.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0064] In some embodiments, the compound of formula (Ia-3): The compound of formula TIFF2024538694000030.tif22170 or a pharma- ceutically acceptable salt thereof is provided.

[0065] In some embodiments, the compound of formula (Ib): The compound of formula TIFF2024538694000031.tif27170 or a pharma- ceutically acceptable salt thereof is provided.

[0066] In some embodiments, the compound of formula (Ib-1): The compound of formula TIFF2024538694000032.tif24170 or a pharma- ceutically acceptable salt thereof is provided.

[0067] In some embodiments, the compound of formula (Ib-2): The compound of formula TIFF2024538694000033.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0068] In some embodiments, the compound of formula (Ic): The compound of formula TIFF2024538694000034.tif27170 or a pharma- ceutically acceptable salt thereof is provided.

[0069] In some embodiments, the formula (Ic-1): The compound of formula TIFF2024538694000035.tif28170 or a pharma- ceutically acceptable salt thereof is provided.

[0070] In some embodiments, the formula (Ic-2): The compound of formula TIFF2024538694000036.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0071] In some embodiments, the compound of formula (Ic-3): The compound of formula TIFF2024538694000037.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0072] In some embodiments, the compound of formula (Id): The compound of formula TIFF2024538694000038.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0073] In some embodiments, the compound of formula (Ie): The compound of formula TIFF2024538694000039.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0074] In some embodiments, the formula (If): The compound of formula TIFF2024538694000040.tif28170 or a pharma- ceutically acceptable salt thereof is provided.

[0075] In some embodiments, the formula (If-1): The compound of formula TIFF2024538694000041.tif22170 or a pharma- ceutically acceptable salt thereof is provided.

[0076] In some embodiments, the formula (If-2): The compound of formula TIFF2024538694000042.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0077] In some embodiments, the formula (If-3): The compound of formula TIFF2024538694000043.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0078] In some embodiments, the formula (If-4): The compound of formula TIFF2024538694000044.tif22170 or a pharma- ceutically acceptable salt thereof is provided.

[0079] In some embodiments, the compound of formula (Ig): The compound of formula TIFF2024538694000045.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0080] In some embodiments, the formula (Ig-1): The compound of formula TIFF2024538694000046.tif25170 or a pharma- ceutically acceptable salt thereof is provided.

[0081] In some embodiments, the formula (Ig-2): The compound of formula (I) is selected from the group consisting of: TIFF2024538694000047.tif29170, or a pharma- ceutically acceptable salt thereof.

[0082] In some embodiments, the formula (Ig-3): The compound of formula (I) is selected from the group consisting of: TIFF2024538694000048.tif29170, or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, the compound of formula (Ih): The compound of formula TIFF2024538694000049.tif27170 or a pharma- ceutically acceptable salt thereof is provided.

[0084] In some embodiments, the formula (Ih-1): The compound of formula TIFF2024538694000050.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0085] In some embodiments, the formula (Ih-2): The compound of formula TIFF2024538694000051.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0086] In some embodiments, the formula (Ih-3): The compound of formula TIFF2024538694000052.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0087] In some embodiments, the compound of formula (Ii): The compound of formula TIFF2024538694000053.tif27170 or a pharma- ceutically acceptable salt thereof is provided.

[0088] In some embodiments, the compound of formula (Ii-1): The compound of formula TIFF2024538694000054.tif23170 or a pharma- ceutically acceptable salt thereof is provided.

[0089] In some embodiments, the formula (Ii-2): The compound of formula TIFF2024538694000055.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0090] In some embodiments, the formula (Ii-3): The compound of formula TIFF2024538694000056.tif28170 or a pharma- ceutically acceptable salt thereof is provided.

[0091] In some embodiments, the formula (Ij): The compound of formula TIFF2024538694000057.tif27170 or a pharma- ceutically acceptable salt thereof is provided.

[0092] In some embodiments, the formula (Ij-1): The compound of formula TIFF2024538694000058.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0093] In some embodiments, the formula (Ij-2): The compound of formula TIFF2024538694000059.tif29170 or a pharma- ceutically acceptable salt thereof is provided.

[0094] In some embodiments, the formula (Ij-3): The compound of formula TIFF2024538694000060.tif25170 or a pharma- ceutically acceptable salt thereof is provided.

[0095] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000061.tif147170; Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3 or 4.

[0096] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000062.tif148170; Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3 or 4.

[0097] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000063.tif109170; Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4.

[0098] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000064.tif36170; Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4.

[0099] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000065.tif78170; Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4.

[0100] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000066.tif68170; Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; The subscript n is an integer 0, 1, 2, 3, or 4.

[0101] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000067.tif78170; Each R 1 But independently, C 1~4 Alkyl, C 1~3Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 is haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4.

[0102] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000068.tif73170.

[0103] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000069.tif30170.

[0104] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000070.tif37170.

[0105] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000071.tif69170.

[0106] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000072.tif32170.

[0107] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000073.tif37170.

[0108] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000074.tif37170; The subscript n is an integer 0, 1, 2, 3 or 4.

[0109] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000075.tif74170; The subscript n is an integer 0, 1, 2, 3 or 4.

[0110] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000076.tif38170; The subscript n is an integer 0, 1, 2, 3 or 4.

[0111] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000077.tif237170TIFF2024538694000078.tif78170.

[0112] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000079.tif79170.

[0113] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000080.tif37170.

[0114] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000081.tif110170.

[0115] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is The compound is TIFF2024538694000082.tif70170.

[0116] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C1~3 Hydroxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, wherein each heterocycloalkyl and heteroaryl is selected from the group consisting of zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy.

[0117] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , C 3~5cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy.

[0118] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -S(O)2R 1a , cyclopropyl, cyclobutyl, cyclopentyl, piperazine, morpholine, dioxane, pyrazole or imidazole, wherein the piperazine is selected from the group consisting of zero and one R 1d is replaced by; Each R 1a and R 1b is independently hydrogen or Me; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6haloalkyl or hydroxy.

[0119] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a) (R 1b ), -OR 1c , cyclopropyl, cyclobutyl, cyclopentyl, piperazine, morpholine, dioxane, pyrazole or imidazole, wherein the piperazine is selected from the group consisting of zero and one R 1d is replaced by; Each R 1a and R 1b is independently hydrogen or Me; R 1c is an azetidine or oxetane; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxyl.

[0120] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 1 are independently Me, -OCH3, -CH2OH, -CF3, -CN, -NH2, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -S(O)2CH3, TIFF2024538694000083.tif25170 is a compound.

[0121] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 1 are independently Me, Et, iPr, -OCH3, -CH2OH, -CH2CH2OCH3, -Cl, -CF3, -CH2CHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, TIFF2024538694000084.tif25170 is a compound.

[0122] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 4 is hydrogen or C 1~4 In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound having R 4 is hydrogen, Me, Et or iPr.

[0123] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound having R 4 In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which R is hydrogen, Me, Et, iPr, -CHCHOCH, or -CHCHF. 4 is hydrogen or Me.

[0124] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -S(O)2R 1a , C 3~5 cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, wherein each heterocycloalkyl and heteroaryl is selected from the group consisting of zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 is hydrogen or C 1~4 It is a compound that is alkyl.

[0125] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -OR 1c , C 3~5cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms each independently being N or O, or a 5-membered heteroaryl having two heteroatoms each independently being N, each heterocycloalkyl and heteroaryl being independently selected from zero or one R 1d is replaced by; Each R 1a and R 1b are independently hydrogen, C 1~3 Alkyl or C 1~3 is haloalkyl; R 1c is a 4-membered heterocycloalkyl having one N and one O heteroatom; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 A compound that is a haloalkyl.

[0126] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a )(R 1b ), -S(O)2R 1a , cyclopropyl, cyclobutyl, cyclopentyl, piperazine, morpholine, dioxane, pyrazole or imidazole, wherein the piperazine is selected from the group consisting of zero and one R 1d is replaced by; Each R 1a and R 1ba is independently hydrogen or Me; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 is hydrogen or C 1~4 It is a compound that is alkyl.

[0127] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Each R 1 But independently, C 1~4 Alkyl, C 1~3 Alkoxy, C 1~3 Hydroxyalkyl, C 2~4 Alkoxyalkyl, halogen, C 1~3 Haloalkyl, -CN, -N(R 1a )(R 1b ), -C 1~3 Alkyl-N(R 1a )(R 1b ), -C(O)N(R 1a) (R 1b ), -OR 1c , cyclopropyl, cyclobutyl, cyclopentyl, piperazine, morpholine, dioxane, pyrazole or imidazole, wherein the piperazine is selected from the group consisting of zero and one R 1d is replaced by; Each R 1a and R 1b a is independently hydrogen or Me; R 1c is an azetidine or oxetane; R 1d But hydrogen, C 1~6 Alkyl, halogen, C 1~6 haloalkyl or hydroxy; R 4 But hydrogen, C 1~4 Alkyl, C 2~4 Alkoxyalkyl or C 1~3 A compound that is a haloalkyl.

[0128] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 1 are independently Me, -OCH3, -CH2OH, -CF3, -CN, -NH2, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, -S(O)2CH3, TIFF2024538694000085.tif25170; R 4 is hydrogen or Me.

[0129] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 1 are independently Me, Et, iPr, -OCH3, -CH2OH, -CH2CH2OCH3, -Cl, -CF3, -CH2CHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -CH2N(CH3)2, -C(O)NHCH3, -C(O)N(CH3)2, TIFF2024538694000086.tif25170; R 4 is hydrogen or Me.

[0130] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Ring A is The compound is TIFF2024538694000087.tif248170TIFF2024538694000088.tif248170TIFF2024538694000089.tif68170.

[0131] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is Ring A is The compound is TIFF2024538694000090.tif238170TIFF2024538694000091.tif230170TIFF2024538694000092.tif135170.

[0132] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 2 But independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl with one heteroatom of N or O, C 1~4 and alkylaryl, wherein said cycloalkyl, said heterocycloalkyl, and said aryl each independently represent 0, 1, 2, or 3 R 2a is substituted with a group; Each R 2a But independently, C 1~3 Alkyl, C 1~3 haloalkyl or hydroxyl.

[0133] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 2 But independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, or a 4-, 5-, or 6-membered heterocycloalkyl having one heteroatom of N or O, wherein said cycloalkyl and said heterocycloalkyl each independently have 0, 1, 2, or 3 R 2a is substituted with a group; Each R 2a But independently, C 1~3 Alkyl, C 1~3 haloalkyl or hydroxyl.

[0134] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 2 But independently, C 1~4 Alkyl or C 3~6 cycloalkyl, said cycloalkyl being selected from zero or one R 2a is substituted with a group; R 2aBut, C 1~3 It is a compound that is alkyl.

[0135] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2 But independently, C 1~4 Alkyl, C 1~4 haloalkyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, tetrahydropyran, or phenylethyl, wherein the cyclopropyl and cyclobutyl are each independently selected from zero or one R 2a groups, each R 2a is Me, CF3, or -OH, and said azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, or tetrahydropyran are each independently substituted with zero or one Me group.

[0136] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2 But independently, C 1~4 Alkyl, C 1~4 haloalkyl, cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentyl, azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, or tetrahydropyran, wherein the cyclopropyl and cyclobutyl are each independently selected from zero or one R 2a groups, each R 2a is Me, CF3, or -OH, and said azetidine, pyrrolidine, piperidine, oxetane, tetrahydrofuran, or tetrahydropyran are each independently substituted with zero or one Me group.

[0137] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2 But independently, C 3~4alkyl, cyclopropyl, cyclobutyl or bicyclo[1.1.1]pentyl, wherein said cyclopropyl and cyclobutyl are each independently substituted with 0 or 1 Me groups.

[0138] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 2 are independently iPr, s-Bu, t-Bu, -CH(CH3)CF3, -CH(CH3)CH2CF3, -C(CH3)2CF2, TIFF2024538694000093.tif57170 is a compound.

[0139] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is R 2 Independently, iPr, s-Bu, t-Bu, -CH(CH3)CF3, TIFF2024538694000094.tif58170 is a compound.

[0140] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 2 But independently, t-Bu, TIFF2024538694000095.tif23170 is a compound.

[0141] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is 3 is hydrogen or C 1~3 In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound having R 3 In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein R 3 is hydrogen.

[0142] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein ring A is pyridine, pyridazine, pyrimidine, pyrazine, triazine, pyridin-2-one, pyridazin-3-one, pyrimidin-2-one, or pyrazin-2-one; R 2 But independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl, 4-, 5- or 6-membered heterocycloalkyl having one heteroatom of N or O or C 1~4 and alkylaryl, wherein said cycloalkyl, said heterocycloalkyl, and said aryl each independently represent 0, 1, 2, or 3 R 2a groups; each R 2a But independently, C 1~3 Alkyl, C 1~3 haloalkyl or hydroxyl.

[0143] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein ring A is pyridine, pyridazine, pyrimidine, pyrazine, triazine, pyridin-2-one, pyridazin-3-one, pyrimidin-2-one, or pyrazin-2-one; R 2 But independently, C 1~4 Alkyl, C 1~4 Haloalkyl, C 3~6 cycloalkyl or a 4-, 5-, or 6-membered heterocycloalkyl having one heteroatom of N or O, said cycloalkyl and said heterocycloalkyl each independently having 0, 1, 2, or 3 R 2a groups; each R 2a But independently, C 1~3 Alkyl, C 1~3 haloalkyl or hydroxyl.

[0144] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein ring A is pyridine, pyridazine, pyrimidine, pyrazine, triazine, pyridin-2-one, pyridazin-3-one, pyrimidin-2-one, or pyrazin-2-one; R 2 But independently, C 1~4 Alkyl or C 3~6 cycloalkyl, said cycloalkyl being selected from zero or one R 2a is substituted with a group; R 2a But, C 1~3 It is a compound that is alkyl.

[0145] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein Ring A is pyridine, pyridazine, pyrimidine, pyrazine, triazine, pyridin-2-one, pyridazin-3-one, pyrimidin-2-one, or pyrazin-2-one; R 3 is hydrogen.

[0146] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000096.tif37170; The subscript n is an integer 0, 1, 2, 3, or 4; R 3 is hydrogen.

[0147] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000097.tif249170TIFF2024538694000098.tif248170TIFF2024538694000099.tif68170;R 3 is hydrogen.

[0148] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000100.tif249170TIFF2024538694000101.tif248170TIFF2024538694000102.tif68170; R 2 Independently, iPr, s-Bu, t-Bu, -CH(CH3)CF3, TIFF2024538694000103.tif58170; R 3 is hydrogen.

[0149] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound wherein ring A is TIFF2024538694000104.tif238170TIFF2024538694000105.tif230170TIFF2024538694000106.tif135170; R 2 Independently, iPr, s-Bu, t-Bu, -CH(CH3)CF3, TIFF2024538694000107.tif58170; R 3 is hydrogen.

[0150] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is any one of the compounds listed in Table 1 or Table 2. [Table 1] TIFF2024538694000109.tif205170TIFF2024538694000110.tif251170TIFF2024538694000111.tif249170TIFF20245386 94000112.tif199170TIFF2024538694000113.tif210170TIFF2024538694000114.tif219170TIFF2024538694000115.tif 201170TIFF2024538694000116.tif207170TIFF2024538694000117.tif222170TIFF2024538694000118.tif222170TIFF2024538694000119.tif230170TIFF2024538694000120.tif213170TIFF2024538694000121.tif74170 or a pharma- ceutically acceptable salt thereof. [Table 2] TIFF2024538694000123.tif143170 or a pharma- ceutically acceptable salt thereof.

[0151] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof has the structure: TIFF2024538694000124.tif253170TIFF2024538694000125.tif55170 or a pharma- ceutically acceptable salt thereof.

[0152] In some embodiments, the compound has the formula: TIFF2024538694000126.tif38170, or a pharma- ceutically acceptable salt thereof.

[0153] In some embodiments, the compound has the formula: TIFF2024538694000127.tif34170, or a pharma- ceutically acceptable salt thereof.

[0154] In some embodiments, the compound has the formula: TIFF2024538694000128.tif38170, or a pharma- ceutically acceptable salt thereof.

[0155] In some embodiments, the compound has the formula: TIFF2024538694000129.tif34170, or a pharma- ceutically acceptable salt thereof.

[0156] In some embodiments, the compound has the formula: TIFF2024538694000130.tif42170, or a pharma- ceutically acceptable salt thereof.

[0157] In some embodiments, the compound has the formula: TIFF2024538694000131.tif37170, or a pharma- ceutically acceptable salt thereof.

[0158] In some embodiments, the compound has the formula: TIFF2024538694000132.tif37170, or a pharma- ceutically acceptable salt thereof.

[0159] In some embodiments, the compound has the formula: TIFF2024538694000133.tif32170, or a pharma- ceutically acceptable salt thereof.

[0160] In some embodiments, the compound has the formula: TIFF2024538694000134.tif30170, or a pharma- ceutically acceptable salt thereof.

[0161] In some embodiments, the compound has the formula: TIFF2024538694000135.tif37170, or a pharma- ceutically acceptable salt thereof.

[0162] In some embodiments, the compound has the formula: TIFF2024538694000136.tif34170, or a pharma- ceutically acceptable salt thereof.

[0163] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which ring A is a monocyclic 6-membered heteroaryl ring consisting of one N ring heteroatom.

[0164] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which ring A is a monocyclic 6-membered heteroaryl ring consisting of two N ring heteroatoms.

[0165] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which ring A is a monocyclic 6-membered heteroaryl ring consisting of 3 N ring heteroatoms.

[0166] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound Wherein m is 1.

[0167] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound of formula (I) or a pharma- ceutically acceptable salt thereof, wherein m is 1 and at least one N-ring heteroatom is a group R 4 and ring A contains one additional N ring heteroatom.

[0168] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is one in which at least one N-ring heteroatom is meta to the point of attachment.

[0169] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is one in which at least one N-ring heteroatom is para to the point of attachment.

[0170] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which ring A has two N ring heteroatoms, the two N atoms being meta and para to the point of attachment.

[0171] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is a compound in which at least one N ring heteroatom is meta to the point of attachment and Ring A further comprises an oxo (=O) group para to the point of attachment.

[0172] In some embodiments, the compounds of formula (I) or pharma- ceutically acceptable salts thereof are those in which ring A contains one additional N ring heteroatom.

[0173] In some embodiments, the compound of formula (I) is a compound of Example 1, Example 2, Example 3, Example 4, Example 5, Example 6, Example 7, Example 8, Example 9, Example 10, or Example 11, or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is a compound of Table G, Table H, Table I, Table J, Table K, Table L1, Table L2, Table M, or Table N (as provided in the Examples), or a pharma- ceutically acceptable salt thereof.

[0174] The compounds described herein may exist as salts. The present disclosure includes such salts, which may be pharma- ceutically acceptable salts. Examples of applicable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (e.g., (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate, and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds described herein contain a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphoric acid, dihydrogenphosphoric acid, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like.Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid.Certain compounds described herein contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts.

[0175] Other salts include the acid salt or base salt of the compound used in the method described herein.The examples of pharmaceutically acceptable salts are the salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid), the salts of organic acids (such as acetic acid, propionic acid, glutamic acid, citric acid), and the salts of quaternary ammonium (such as methyl iodide, ethyl iodide).It is understood that pharmaceutically acceptable salts are non-toxic.More information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0176] Pharmaceutically acceptable salts include salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein.When the compounds described herein contain relatively acidic functional groups, the neutral form of such compounds can be contacted with a sufficient amount of the desired base, either neat or in a suitable inert solvent, to obtain base addition salts.Examples of pharma-ceutically acceptable base addition salts include sodium salts, potassium salts, calcium salts, ammonium salts, organic amino salts or magnesium salts, or similar salts.When the compounds described herein contain relatively basic functional groups, the neutral form of such compounds can be contacted with a sufficient amount of the desired acid, either neat or in a suitable inert solvent, to obtain acid addition salts. Examples of pharma- ceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid or phosphorous acid, and the like, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galactunoric acid (see, e.g., Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain compounds described herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0177] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent forms of the compounds described in this invention.

[0178] Certain compounds described herein have asymmetric carbon atoms (optical centers) or double bonds; stereoisomeric forms and individual isomers that may be defined as (R)- or (S)- in terms of enantiomers, racemates, diastereomers, tautomers, geometric isomers, absolute stereochemistry, or (D)- or (L)- in terms of amino acids, are encompassed within the scope described herein. Compounds described herein do not include those known in the art to be too unstable to synthesize and / or isolate. The present disclosure is intended to include compounds in racemic and optically pure form. Optically active (R)- and (S)-isomers or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0179] Isomers include compounds that have the same number and kinds of atoms, and therefore the same molecular weight, but differ with regard to the structural or configuration of the atoms.

[0180] Unless otherwise stated, structures depicted herein are also intended to include all stereochemical forms of the structure, i.e., the R and S configurations of each asymmetric center. Accordingly, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.

[0181] Unless otherwise stated, the compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds described herein may contain, for example, deuterium ( 2 H), tritium ( 3 H), iodine-125(125 I), Fluorine-18( 18 F), Nitrogen-15( 15 N), oxygen-17( 17 O), oxygen-18( 18 O), Carbon-13( 13 C) or carbon-14 ( 14 The compound may be labeled with a radioactive or stable isotope, such as C. All isotopic variations of the compounds described herein, whether radioactive or not, are encompassed within the scope described herein.

[0182] IV. Pharmaceutical Formulations In some embodiments, a pharmaceutical composition is provided that includes any one of the compounds described herein and a pharma- ceutically acceptable excipient.

[0183] In some embodiments, a pharmaceutical composition is provided comprising a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable excipient.

[0184] The compounds described herein can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. The compounds described herein can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compounds described herein can also be administered by inhalation, for example, intranasally. Additionally, the compounds described herein can be administered transdermally. The compounds described herein can also be administered by intraocular, intravaginal, and intrarectal routes, including suppositories, insufflation, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). The present disclosure also provides pharmaceutical compositions comprising one or more pharma- ceutically acceptable carriers and / or excipients and either a compound of the present disclosure or a pharma- ceutically acceptable salt of a compound of the present disclosure.

[0185] For preparing pharmaceutical compositions from the compounds described herein, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents or encapsulating materials. Details regarding techniques for formulation and administration are fully described in the scientific and patent literature, see, for example, Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (see the latest edition of "Remington's").

[0186] In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with the carrier having the necessary binding properties and, if desired, additional additives in suitable proportions and compacted in the shape and size desired.

[0187] Powders, capsules and tablets preferably contain 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter and the like. The term "preparation" is intended to include formulations of the active compound, including encapsulating materials as carriers, in which the active ingredient, with or without other additives, is surrounded by the carrier, thus providing a capsule with the carrier. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid dosage forms suitable for oral administration.

[0188] Suitable solid additives are carbohydrate or protein fillers, including, but not limited to, sugars, including lactose, sucrose, mannitol or sorbitol; starches from corn, wheat, rice, potato or other plants; celluloses, such as methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose; gums, including gum arabic and tragacanth; and proteins, such as gelatin and collagen.If desired, disintegrants or solubilizers, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or its salt, such as sodium alginate, may be added.

[0189] Dragee cores are provided with suitable coatings such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may also contain suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical compositions described herein may also be used orally using, for example, push-fit capsules made of gelatin, as well as sealed soft capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain the compound of the present disclosure mixed with fillers or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the compound of the present disclosure may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0190] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0191] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0192] Aqueous solutions suitable for oral use can be prepared by dissolving active ingredient in water and adding suitable coloring, flavoring, stabilizing and thickening agents as required.Aqueous suspensions suitable for oral use can be prepared by dispersing finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic, and dispersing or wetting agents such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and partial esters derived from hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with fatty acids and partial esters derived from hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame, or saccharin. The preparations may be adjusted for osmolality.

[0193] Also included are solid form preparations that are intended to be converted immediately before use into liquid form preparations for oral administration.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0194] Oil suspensions can be formulated by suspending the compounds of the present disclosure in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin; or mixtures thereof. Oil suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. To provide a palatable oral preparation, sweeteners such as glycerol, sorbitol or sucrose can be added. These preparations can be preserved by the addition of antioxidants such as ascorbic acid. For an example of an injectable oil vehicle, see Minto, J.Pharmacol.Exp.Ther.281:93-102,1997. The pharmaceutical preparations described herein can also be in the form of oil-in-water emulsions. The oil phase can be the above-mentioned vegetable oil or mineral oil, or mixtures thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and gum tragacanth, naturally occurring phosphatides such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. Emulsions can also contain sweeteners and flavoring agents, as in the preparation of syrups and elixirs. Such preparations can also contain demulcents, preservatives or coloring agents.

[0195] The pharmaceutical compositions may be delivered by transdermal and topical routes, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0196] Pharmaceutical compositions can also be delivered as microspheres for sustained release in the body. For example, microspheres can be administered via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J.Biomater Sci.Polym.Ed.7:623-645,1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm.Res.12:857-863,1995); or as oral microspheres (see, e.g., Eyles, J.Pharm.Pharmacol.49:669-674,1997). Both transdermal and intradermal routes provide constant delivery over weeks or months.

[0197] The compounds of the present disclosure may be provided in pharmaceutical compositions as salts formed with acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. The salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, pH range 4.5-5.5, which is combined with a buffer prior to use.

[0198] The compounds of the present disclosure of the present invention may be provided in pharmaceutical compositions as salts formed with bases, including, but not limited to, cationic salts, such as alkali and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium, trimethylammonium, diethylammonium, and tris(hydroxymethyl)methylammonium salts.

[0199] In some embodiments, pharmaceutical compositions can be delivered by using liposomes that fuse with cell membrane or are engulfed in plasma membrane, i.e., by using ligands that are bound to liposomes or directly bound to oligonucleotides, which bind to cell surface membrane protein receptors and lead to endocytosis.By using liposomes, the delivery of GR regulators into target cells in vivo can be focused, especially when the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a specific organ.(See, for example, Al-Muhammed, J.Microencapsul.13:293-306,1996; Chonn, Curr.Opin.Biotechnol.6:698-708,1995; Ostro, Am.J.Hosp.Pharm.46:1576-1587,1989).

[0200] Pharmaceutical composition is preferably in unit dosage form.In this form, preparation is divided into unit doses containing appropriate amount of active ingredient.Unit dosage form can be packaged preparation, and the package contains separate amount of preparation, such as tablet, capsule, and powder in vial or ampoule in small packet.Also, unit dosage form can be capsule, tablet, cachet or lozenge itself, or any of these in packaged form in appropriate number.

[0201] The quantity of active ingredient in a unit dose preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 1000 mg, and most typically from 10 mg to 500 mg, according to the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0202] Dosing regimens also take into account pharmacokinetic parameters, i.e., rate of absorption, bioavailability, metabolism, clearance, etc., well known in the art (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; Remington's, most recently cited above). The current state of the art allows the clinician to determine the dosing regimen for each individual patient, GR and / or MR modulator, and disease or condition being treated.

[0203] Single or multiple doses of the pharmaceutical composition may be administered depending on the dosage and frequency required and tolerated by the patient. The composition should provide a sufficient amount of the active agent to effectively treat the disease state. Thus, in some embodiments, pharmaceutical compositions for oral administration of the compounds of the present disclosure are administered at about 0.5 to about 30 mg / kilogram body weight / day. In some embodiments, dosages of about 1 mg to about 20 mg / kg body weight / patient / day are used. Lower dosages can be used, particularly when the drug is administered to an anatomically isolated site such as the cerebrospinal fluid (CSF) space, as opposed to administration orally, into the bloodstream, into a body cavity, or into the lumen of an organ. Substantially higher dosages can be used in local administration. Actual methods for preparing formulations containing the compounds of the present disclosure for parenteral administration are known or apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, In “Receptor Mediated Antisteroid Action,” Agarwal, et al., eds., De Gruyter, New York (1987).

[0204] The compounds described herein may be used in a single pharmaceutical composition (by co-formulation) or in separate pharmaceutical compositions in combination with each other, with other active agents, or with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0205] In some embodiments, simultaneous administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours of the second active agent. Simultaneous administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other), or sequentially in any order. In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, the active agents and / or adjuncts can be linked or conjugated to each other.

[0206] After the pharmaceutical composition is formulated in one or more acceptable carriers, it can be placed in an appropriate container and labeled for treating the indicated condition. For administration of the compounds of the present disclosure, such labeling will include, for example, instructions regarding the amount, frequency and method of administration.

[0207] In some embodiments, the compositions of the present disclosure are useful for parenteral administration, such as intravenous (IV) administration or administration into the lumen of a body cavity or organ. Pharmaceutical compositions for administration generally comprise a solution of the compositions of the present disclosure dissolved in one or more pharma- ceutically acceptable carriers. Acceptable vehicles and solvents that can be used include water and Ringer's solution, isotonic sodium chloride. In addition, sterile, fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterile and generally free of undesirable substances. These preparations can be sterilized by conventional, well-known sterilization techniques. The preparations can contain pharma-ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, isotonicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. The concentration of the composition of the present disclosure in these preparations can vary widely and is selected mainly based on the volume of liquid, viscosity, body weight, etc., according to the particular mode of administration selected and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using these suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0208] In some embodiments, pharmaceutical compositions can be delivered by using liposomes that fuse with cell membranes or are engulfed in plasma membranes, i.e., by using ligands that are bound to liposomes or directly bound to oligonucleotides, which bind to cell surface membrane protein receptors and lead to endocytosis.By using liposomes, the delivery of the compositions of the present disclosure into target cells in vivo can be focused, especially when the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a specific organ. (See, for example, Al-Muhammed, J.Microencapsul.13:293-306,1996; Chonn, Curr.Opin.Biotechnol.6:698-708,1995; Ostro, Am.J.Hosp.Pharm.46:1576-1587,1989).

[0209] V. Method In some embodiments, there is provided a method of treating a disorder or condition in a human in need thereof, comprising administering to said human a therapeutically effective amount of a compound described herein or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0210] In some embodiments, there is provided a method of treating a CDK2-mediated disorder in a human in need thereof, comprising administering to the human a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0211] A method for manufacturing a medicament for treating a CDK2-mediated disorder in a human in need thereof, characterized in that a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or any one of the pharmaceutical compositions described herein, is used.

[0212] The use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for the manufacture of a medicament for the treatment in a human of a CDK2-mediated disorder.

[0213] A compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition as described herein, for use in treating a CDK2-mediated disorder in a human in need of such treatment.

[0214] In some embodiments, the disorder is cancer.Exemplary cancers include, but are not limited to, leukemia (e.g., acute myeloid leukemia), bladder cancer, brain cancer, breast cancer (e.g., hormone receptor positive breast cancer, triple negative breast cancer, HER2+ breast cancer), cervical cancer, colorectal cancer (e.g., including colon cancer and / or rectal cancer), endometrial cancer, esophageal cancer, gastric cancer (e.g., gastric adenocarcinoma), kidney cancer (e.g., renal cell carcinoma), liver cancer (e.g., hepatocellular carcinoma), lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), neuroblastoma, ovarian cancer (e.g., serous ovarian cancer), prostate cancer, skin cancer (e.g., melanoma), thyroid cancer, and uterine cancer (e.g., uterine carcinosarcoma).

[0215] In some embodiments, the cancer is ovarian cancer, gastric cancer, uterine cancer, esophageal cancer, lung cancer or breast cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer.

[0216] Since G1 / s specific cyclin-E1 is encoded by CCNE1 gene and CDK2 drives G1 / S transition, CDK2 inhibition will be useful in treating cancer with CCNE1 amplification or overexpression.Exemplary cancers with CCNE1 amplification or overexpression include, but are not limited to, ovarian cancer, gastric cancer, uterine cancer, esophageal cancer and breast cancer.In some embodiments, the cancer is breast cancer with CCNE1 amplification or overexpression.In some embodiments, the breast cancer with CCNE1 amplification or overexpression is hormone receptor positive (HR+).

[0217] In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is HR+ and the subject in need thereof is progressing on a CDK4 / 6 inhibitor. In some embodiments, the breast cancer is HER2+ and the subject is progressing on trastuzumab.

[0218] In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is non-small cell lung cancer (NSCLC) and the subject is progressing on an epidermal growth factor receptor (EGFR) inhibitor.

[0219] In certain embodiments, treatment may be administered after one or more symptoms have developed. Treatment may also be continued after symptoms have resolved, for example to prevent or delay the recurrence of symptoms.

[0220] (e.g., any one of the compounds described herein of formula (I) and (Ia)-(Ij) or a pharma- ceutically acceptable salt thereof) is an inhibitor of cyclin-dependent kinase 2 (CDK2). For example, the inhibitory constant (Ki) of the compounds described herein may be less than about 50 μM, or less than about 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 μM. The inhibitory constant (Ki) of the compounds described herein may be less than about 1,000 nM, or less than about 900, 800, 700, 600, 500, 400, 300, 200, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, or less than about 1 nM. The inhibition constants (Ki) of the compounds described herein can be less than about 1 nM, or less than about 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, or less than about 0.1 nM. As described herein.

[0221] (For example, the compounds described herein of any one of formulas (I) and (Ia)-(Ij) or pharma- ceutically acceptable salts thereof) may be selective inhibitors of cyclin-dependent kinase 2 (CDK2). For example, the CDK2 inhibition constant (Ki) of the compounds described herein may be at least 2-fold less than the inhibition constant of one or more of CDK1, CDK4 and CDK6, or at least 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100-fold less. The CDK2 inhibition constant (Ki) of the compounds described herein may also be at least 100-fold less than the inhibition constant of one or more of CDK1, CDK4 and CDK6, or at least 200, 300, 400, 500, 600, 700, 800, 900, 1000 or 10,000-fold less.

[0222] a) Cancer combination therapy The compounds described herein or their pharmaceutically acceptable salts can be used alone or in combination with other drugs for treatment.For example, the second drug of the pharmaceutical combination preparation or dosage regimen can have complementary activity to the compounds described herein so that they do not adversely affect each other.The compounds can be administered together in a single pharmaceutical composition or separately.In one embodiment, the compounds or their pharmaceutically acceptable salts can be administered together with chemotherapeutic agents to treat proliferative diseases and cancer.

[0223] The term "co-administration" refers to either simultaneous administration or separate sequential administration in any manner of the compound or salt thereof described herein and one or more additional active pharmaceutical ingredients, including chemotherapeutic agents.When administration is not simultaneous, the compounds are administered close to each other in time.Furthermore, it is not important whether the compounds are administered in the same dosage form, for example, one compound may be administered topically and another compound may be administered orally.

[0224] These additional agents can be administered separately from the compound-containing composition of the present invention as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form mixed with the compound described herein in a single composition. When administered as part of a multiple dose regimen, the two active agents can be presented simultaneously, sequentially, or within a period of each other, usually within 5 hours of each other.

[0225] As used herein, the term "combination", "combined" and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure.For example, the compounds described herein can be administered simultaneously or sequentially with another therapeutic agent, either in separate unit dosage forms or together in a single unit dosage form.Therefore, a single unit dosage form is provided that includes the compound of formula I, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

[0226] The amount of both the compound of the invention and the additional therapeutic agent (in compositions containing the additional therapeutic agent described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. In some embodiments, the compositions described herein are formulated to allow administration of a dosage of 0.01 to 100 mg / kg body weight / day of the inventive.

[0227] Typically, any agent active against the disease or condition being treated may be co-administered. Examples of such agents are described in Cancer Principles and Practice of Oncology, 6 by V. T. Davida and S. Hellman (editors). th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person skilled in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the disease involved.

[0228] In some embodiments, the methods of treatment comprise co-administration of a compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one chemotherapeutic agent.

[0229] The term "chemotherapeutic agent" refers to an agent useful in the treatment of cancer, including radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212and radioisotopes of Lu); proliferation inhibitors; anti-microtubule agents; platinum analogues; topoisomerase II inhibitors; antimetabolites; topoisomerase I inhibitors; hormones and hormone analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; pro-apoptotic agents; cell cycle signaling inhibitors; nitrogen mustards; alkylating agents; toxoids or taxanes; aromatase inhibitors; pigment protein enediyne antibiotic chromophores; mitomycins; antihormones; antiandrogens; protein kinase inhibitors; lipid kinase inhibitors; antisense oligonucleotides; tyrosine kinase inhibitors; Raf-1 inhibitors; EGFR inhibitors; camptothecins; anthracycline antibiotics; nucleoside metabolism inhibitors, and other CDK inhibitors.

[0230] Exemplary chemotherapeutic agents include lapatinib (Tykerb (R) , GSK572016, Glaxo Smith Kline) or gefitinib (Iressa (R) EGFR inhibitors such as thiotepa, cytoxan (R) alkylating agents such as cyclophosphamide or chlorambucil; camptothecins such as topotecan, irinotecan; nitrogen mustards such as chlorambucil, chromafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembitine, phenesterine, prednimustine, trophosfamide or uracil mustard; neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores; adriamycin (R)anthracycline antibiotics such as doxorubicin; mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, lodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, or zorubicin; antimetabolites such as methotrexate, 5-fluorouracil (5-FU), or hydroxyurea; taxol (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), or abraxane (R) (Cremophor free), an albumin engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.) and taxotere (R) Toxoids or taxanes such as (docetaxel; Sanofi-Aventis); Gemzar (R) Nucleoside metabolic inhibitors such as (gemcitabine); cisplatin, carboplatin, oxaliplatin (ELOXATIN (R)、Sanofi ); etoposide (VP-16); capecitabine (Xeloda) (R) retinoids, such as retinoic acid; antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators / degraders (SERDs), such as tamoxifen (Nolvadex) (R) ;including tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxyfene, ketoxyfene, LY117018, onapristone, fairstone (R) (toremifine citrate), fulvestrant, brilantrant, elacestrant or giledestrant (GDC-9545); letrozole, exemestane, anastozole, aminoglutethimide, MEGASE (R)(megestrol acetate), formestanie, fadrozole or rivisor (R) aromatase inhibitors, such as valproate (vorozole), which inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands; antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide goserelin, buserelin, tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retionic acid or fenretinide; antisense oligonucleotides, which inhibit the expression of genes in signaling pathways involved in abnormal cell growth, such as PKC-alpha, Ralf and H-Ras; erlotinib (Tarceva); (R) , Genentech / OSI Pharm.); CDK4 / 6 inhibitors such as palbociclib, ribociclib or abemaciclib; and antibodies such as alemtuzumab (Campath), bevacizumab (Avastin®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (Vectibix®, Amgen), rituximab (Rituxan®, Genentech / Biogen Idec), pertuzumab (Omnitarg®, 2C4, Genentech), trastuzumab (Herceptin®, Genentech), tositumomab (Bexar, Corixia), gemtuzumab ozogamicin (Mylotarg®, Wyeth) and antibody conjugates thereof.

[0231] Additionally, the chemotherapeutic agents include pharma- ceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, as well as combinations of two or more thereof.

[0232] In some embodiments, the compounds described herein can be administered in combination with a CDK4 / 6 inhibitor, such as palbociclib, ribociclib, or abemaciclib, for the treatment of breast cancer, for example.

[0233] In other embodiments, the compounds described herein can be administered with an aromatase inhibitor, such as letrozole, exemestane, or anastozole, for example, for the treatment of breast cancer.

[0234] In yet other embodiments, the compounds described herein may be administered in combination with a selective estrogen receptor degrader (SERD), such as fulvestrant, brilantrant, elacestrant, or giledestrant (GDC-9545), for example, for the treatment of breast cancer.

[0235] In some embodiments, the compounds described herein can be administered in combination with a CDK4 / 6 inhibitor and a selective estrogen receptor degrader (SERD), e.g., for the treatment of breast cancer (e.g., HR2+ breast cancer).

[0236] In yet other embodiments, the compounds described herein can be administered in combination with an antibody such as trastuzumab (Herceptin®, Genentech), e.g., for the treatment of breast cancer (e.g., HER+ breast cancer).

[0237] In yet other embodiments, the compounds described herein may be administered in combination with toxoids or taxanes (such as paclitaxel, albumin engineered nanoparticle formulations of paclitaxel and docetaxel / doxetaxel) and / or platinum analogs (such as cisplatin, carboplatin and oxaliplatin), for example, for the treatment of ovarian cancer. EXAMPLES

[0238] VI. Working Examples General Experimental Details All solvents and commercially available reagents were used as received unless otherwise stated. When products were purified by chromatography on silica gel, this was done using either glass columns manually packed with silica gel (Kieselgel 60, 220-440 mesh, 35-75 μm) or Isolute SPE Si II cartridges. "Isolute SPE Si cartridge" refers to a prepacked polypropylene column containing unbonded activated silica with irregular particles with an average size of 50 μm and a nominal porosity of 60 Å (angstroms). When an Isolute® SCX2 cartridge was used, "Isolute® SCX-2 cartridge" refers to a prepacked polypropylene column containing a non-endcapped propylsulfonic acid functionalized silica strong cation exchange sorbent.

[0239] Nuclear magnetic resonance spectroscopy (NMR) analysis method 1 H NMR spectra were recorded at ambient temperature unless otherwise stated using one of the following: Bruker AVIII 400 MHz with 2 RF channels, 5 mm Prodigy BBI (Broadband Inverse Ag-P detectable) probe; Bruker Avance 400 MHz with 2 RF channels, 5 mm Prodigy BBFO (Broadband Inverse Ag-P detectable) probe; Bruker Nanobay 400 MHz, 5 mm Prodigy BBFO probe. br=broad; s=singlet; d=doublet; t=triplet; q=quartet; m=multiplet.

[0240] High pressure liquid chromatography / liquid chromatography-mass spectrometry (HPLC / LC-MS) analytical method HPLC / LC-MS chromatograms were recorded using one of the following instruments and conditions:

[0241] LC-MS method 1 Shimadzu LCMS-2020, Waters Acquity BEH C18-reversed phase column (50 mm × 2.1 mm × 1.7 μm), A: water + 0.1% formic acid; B: elution with acetonitrile; detection: MS, ELS, UV (100 μL split into MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray atmospheric pressure ionization. [Table A]

[0242] LC-MS method 2 Shimadzu LCMS-2020, Waters Acquity BEH C18-reversed phase column (50 mm × 2.1 mm × 1.7 μm), A: water + 0.1% trifluoroacetic acid; B: elution with acetonitrile; detection: MS, ELS, UV (100 μL split into MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray atmospheric pressure ionization. [Table B]

[0243] LC-MS method 3 Shimadzu LCMS-2020, Waters Acquity BEH C18-reversed phase column (50 mm × 2.1 mm × 1.7 μm), A: water + 0.1% ammonium hydroxide; B: elution with acetonitrile; detection: MS, ELS, UV (100 μL split into MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray atmospheric pressure ionization. [Table C]

[0244] LC-MS method 4 Agilent 1290 UHPLC; Phenomenex XB C18 column (50 mm x 2.1 mm x 1.7 μm), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid; detection: MS, ELS, UV at 220 nm and 254 nm (100 μL split into MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray atmospheric pressure ionization. [Table D]

[0245] LC-MS method 5 Agilent 1290 UHPLC; Agilent Zorbax Eclipse XDB C18 column (100 mm x 3.0 mm x 3.5 μm), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid; detection: MS, ELS, UV at 220 nm and 254 nm (100 μL split to MS with in-line UV detector); MS ionization method: electrospray (positive and negative ions). ES-API = electrospray atmospheric pressure ionization. [Table E] HPLC purification procedure [Table F] TIFF2024538694000143.tif104170

[0246] Preparation of intermediates Intermediate A. 3-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole TIFF2024538694000144.tif77170SEM = 2-(trimethylsilyl)ethoxymethyl; TBS = tert-butyldimethylsilyl; dppf = 1,1'-bis(diphenylphosphino)ferrocene; THF = tetrahydrofuran; DCM = dichloromethane Step 1: 3,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. To a solution of 3,5-dibromo-1H-pyrazole (10.0 g, 44 mmol) in tetrahydrofuran (100 mL) was slowly added sodium hydride (60%, 3.5 g, 89 mmol). The mixture was stirred at 20° C. for 30 min, and then 2-(trimethylsilyl)ethoxymethyl chloride (9.4 mL, 53 mmol) was added. The resulting mixture was stirred at 25° C. for 1 h and quenched by the addition of water (200 mL). The mixture was extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate:petroleum ether) to give 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (11.6 g, 73%). 1 H NMR (400MHz, CDCl3) δ6.38-6.33(s,1H),5.45(s,2H),3.66-3.62(m,2H),0.94-0.90(m,2H),0.00(s,9H).

[0247] Step 2: 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopent-2-enone. A mixture of 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (7.5 g, 21 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (4.4 g, 21 mmol), cesium carbonate (20.9 g, 63 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride (1.5 g, 2.2 mmol) in 1,4-dioxane (150 mL) and water (30 mL) was stirred at 100° C. for 30 minutes under nitrogen atmosphere. The mixture was cooled to ambient temperature, diluted with ethyl acetate (400 mL), washed with brine (400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate:petroleum ether) to give 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopent-2-enone (3.6 g, 48%). LCMS (ES-API, m / z): 357.1 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ6.73(s,1H),6.66(s,1H),5.50(s,2H),3.68-3.64(m, 2H), 2.99-2.97(m, 2H), 2.57-2.55(m, 2H), 0.92-0.88(m, 2H), 0.00(s, 9H).

[0248] Step 3: 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanone. A mixture of 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopent-2-enone (3.0 g, 8.4 mmol) and rhodium (10% on carbon, 3.4 g, 0.84 mmol) in tetrahydrofuran (30 mL) was stirred under hydrogen atmosphere (15 psi) at ambient temperature for 2 hours and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate:petroleum ether) to give 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanone (2.3 g, 76%). 1 H NMR (400MHz, CDCl3): δ6.17(s,1H),5.43(d,J=2.4Hz,2H),3.60-3.56(m,3H),2.74-2.69(m,1 H),2.49-2.46(m,2H),2.34-2.28(m,2H),2.04-2.02(m,1H),0.91-0.87(m,2H),0.00(s,9H).

[0249] Step 4: 3-(3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol. To a solution of 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanone (2.3 g, 6.4 mmol) in tetrahydrofuran (40 mL) was added lithium tri-sec-butylborohydride (1.0 M in tetrahydrofuran, 7.7 mL, 7.7 mmol) at −78° C. under nitrogen atmosphere. The mixture was stirred at −78° C. for 2 hours and then poured into water (50 mL). The mixture was extracted with ethyl acetate (2×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate:petroleum ether) to give 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol (2.1 g, 91%). LCMS (ES-API, m / z): 363.1 [M+H] + .

[0250] Step 5: 3-Bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole. To a solution of 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol (2.1 g, 5.8 mmol) and imidazole (1.6 g, 23 mmol) in dichloromethane (30 mL) was added tert-butyldimethylchlorosilane (1.3 g, 8.7 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% ethyl acetate:petroleum ether) to give 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (2.3 g, 83%). LCMS (ES-API, m / z): 475.2 [M+H] + .

[0251] Intermediate B. (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate TIFF2024538694000145.tif60170Cbz = carboxybenzyl;DIEA = N,N-diisopropylethylamine Step 1: Benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butylcarbamoyl)oxy)-cyclopentyl)-1H-pyrazol-5-yl)carbamate. The starting material, (4-nitrophenyl)[(1R,3S)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl]carbonate, can be prepared according to the procedure provided in Example 1 of WO202157652. To a solution of (4-nitrophenyl)[(1R,3S)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl]carbonate (60 g, 114 mmol) in tetrahydrofuran (420 mL) was added N,N-diisopropylethylamine (74.2 g, 574 mmol) and 2-methylpropan-2-amine (10.9 g, 149 mmol). The mixture was stirred at 25 °C for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to give benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (90 g, 84.9%).

[0252] Step 2: (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate. To a solution of benzyl benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (30 g, 65.7 mmol) in tetrahydrofuran (90 mL) and ethyl acetate (90 mL) was added palladium (10% on carbon, 5.5 g). The mixture was stirred under hydrogen atmosphere (15 psi) at 25° C. for 16 hours and filtered. The filtrate was concentrated to dryness under reduced pressure to give (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate (16 g, 74.1%). 1 H NMR (400 MHz, methanol-d4) δ 5.46 (s, 1H), 5.04 (br s, 1H), 3.05-2.92 (m, 1H), 2.50-2.37 (m, 1H), 2.04-1.65 (m, 5H), 1.61 (s, 9H), 1.36-1.25 (m, 9H).

[0253] Intermediate C. (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentanol TIFF2024538694000146.tif21170Cbz=Carboxybenzyl To a solution of benzyl N-[2-tert-butyl-5-[(1S,3R)-3-hydroxycyclopentyl]pyrazol-3-yl]carbamate (5.0 g, 13.99 mmol) in tetrahydrofuran (30 mL) and ethyl acetate (30 mL) was added palladium (10% on carbon, 3.0 g). The mixture was stirred under hydrogen atmosphere (15 psi) at 25° C. for 16 h and filtered. The filtrate was concentrated to dryness under reduced pressure to give (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentanol (3.0 g, 96%). LCMS (ES-API, M / Z): 224.2 [M+H] + .

[0254] General Procedures and Examples The stereochemical configurations of the cyclopentanyl rings of Examples 2, 2L, 3E, 4, 4A, 4K, 4E were determined by X-ray crystallography. The configurations of all other Examples were assigned by analogy. General Procedure 1 TIFF2024538694000147.tif177170TBAF = tetrabutylammonium fluoride;DMAP = 4-dimethylaminopyridine;DIEA = N,N-diisopropylethylamine;MeOH = methanol;THF = tetrahydrofuran;Chiral SFC = chiral supercritical fluid chromatography;DCM = dichloromethane

[0255] Example 1. (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate The title compound was prepared according to General Procedure 1 below. TIFF2024538694000148.tif115170

[0256] Step 1: 5-((5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one. A mixture of [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (180 mg, 0.21 mmol), 5-amino-1-methylpyridin-2(1H)-one (522 mg, 4.2 mmol), 3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (Intermediate A) (1.00 g, 2.1 mmol) and cesium carbonate (2100 mg, 6.3 mmol) in 1,4-dioxane (15 mL) was stirred at 90° C. under a nitrogen atmosphere for 16 hours and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-2% methanol:ethyl acetate) to give 5-((5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one (1.00 g, 92%). LCMS (ES-API, m / z): 519.3 [M+H] + .

[0257] Step 2: 5-((5-(3-hydroxycyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one. To a solution of 5-((5-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one (1.0 g, 1.9 mmol) in tetrahydrofuran (15 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 2.9 mL, 2.9 mmol). The reaction was stirred at 25° C. for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol:dichloromethane) to give 5-((5-(3-hydroxycyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one (750 mg, 96%). LCMS (ES-API, m / z): 405.3 [M+H] + .

[0258] Step 3: 5-((5-((1S,3R)-3-hydroxycyclopentyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one. A racemic mixture containing the title compound and its enantiomer (750 mg, 1.8 mmol) was purified by purification procedure F (chiral supercritical fluid chromatography (SFC)) using 0.1% ammonium hydroxide-30% ethanol-carbon dioxide to give 5-((5-((1S,3R)-3-hydroxycyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one (peak 1, retention time = 4.912 min) (220 mg, 29%). LCMS(ES-API,M / Z):405.3[M+H] + .

[0259] Step 4: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 5-((5-((1S,3R)-3-hydroxycyclopentyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)amino)-1-methylpyridin-2(1H)-one (160 mg, 0.40 mmol) in dichloromethane (4 mL) was added 4-nitrophenyl chloroformate (199 mg, 0.99 mmol), pyridine (0.16 mL, 2.0 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.04 mmol). The mixture was stirred at 25° C. for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol:ethyl acetate) to give (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (90 mg, 40%). LCMS (ES-API, m / z): 570.2 [M+H] + .

[0260] Step 5: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. To a solution of (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (90 mg, 0.16 mmol) in tetrahydrofuran (4 mL) was added N,N-diisopropylethylamine (0.08 mL, 0.5 mmol) and tert-butylamine (0.02 mL, 0.2 mmol). The reaction was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (TLC) (10% methanol:ethyl acetate) to give (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (60 mg, 75%). LCMS (ES-API, m / z): 504.3 [M+H] + .

[0261] Step 6: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. To a solution of (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (40 mg, 0.08 mmol) in methanol (5 mL) was added hydrochloric acid (1.0 M in methanol, 2.0 mL, 2.0 mmol). The solution was stirred at 60° C. for 16 h and adjusted to pH=8 with aqueous ammonium hydroxide. The mixture was concentrated under reduced pressure. The residue was purified by purification procedure A using 0.05% ammonium hydroxide-acetonitrile in water (28-58%) to give (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (5.9 mg, 19%). LCMS (ES-API, M / Z): 374.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d6): δ11.59(s,1H),7.94(s,1H),7.86(s,1H),7.33-7.30(m,1H),6.77(s,1H),6.34(d,J=9.6Hz,1H),5.4 7(s,1H),4.95(s,1H),3.38(s,3H),3.02-2.98(m,1H),2.41-2.38(m,1H),1.99-1.87(m,2H),1.71-1.55(m,3H),1.20(s,9H). General Procedure 2 TIFF2024538694000149.tif69170XPhos Pd G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate

[0262] Example 2. (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate The title compound was prepared according to General Procedure 2 below. TIFF2024538694000150.tif71170

[0263] Step 1: (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. 6-Bromo-2-methyl-3(2H)-pyridazinone can be prepared according to the procedure provided in Example 2 of WO202157652.

[0264] A mixture of cesium carbonate (158 mg, 0.49 mmol), [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (50 mg, 0.16 mmol), (2-dicyclohexylphosphino-2',4',6'-tri-isopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (14 mg, 0.02 mmol) and 6-bromo-2-methyl-3(2H)-pyridazinone (61 mg, 0.32 mmol) in 1,4-dioxane (3 mL) was stirred at 100° C. under nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (TLC) (ethyl acetate) to give (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (53 mg, 80%). LCMS (ES-API, m / z): 417.3 [M+H] + .

[0265] Step 2: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (80 mg, 0.19 mmol) in formic acid (3.7 mL) was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was purified by purification procedure B using 0.05% ammonium hydroxide-10 mM ammonium bicarbonate-acetonitrile (30-60%) in water to give (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (40 mg, 57%). LCMS (ES-API, m / z): 361.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.91(s,1H),9.18(s,1H),7.30-7.28(m,1H),6.96-6.94(m,1H),6.82(d,J=9.6Hz,1H),6.23(s,1H),4.99-4.98( m,1H),3.60-3.55(m,1H),3.52(s,3H),3.34-3.04(m,1H),2.47-2.44(m,1H),2.01-1.90(m,2H),1.72-1.60(m,3H),1.02(d,J=6.4Hz,6H).

[0266] Example 2T: (1R,3S)-3-(3-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate TIFF2024538694000151.tif70170 Step 1: (1R,3S)-3-(1-(tert-butyl)-5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate. A mixture of [(1R,3S)-3-(5-amino-1-tert-butyl-pyrazol-3-yl)cyclopentyl]N-isopropylcarbamate (60 mg, 0.19 mmol), 2-chloro-3-methylpyrazine (30 mg, 0.23 mmol), cesium carbonate (190 mg, 0.58 mmol) and methanesulfonate (2-dicyclohexylphosphino-2',6'-di-i-propoxy-1,1'-biphenyl) (2'-amino-1,1'-biphenyl-2-yl) palladium(II) (16 mg, 0.02 mmol) in 1,4-dioxane (3 mL) was stirred under nitrogen atmosphere at 100° C. for 16 hours. Water (10 mL) was added to the mixture, which was then extracted with ethyl acetate (3×10 mL) and water (20 mL). The combined organic layers were washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (100% ethyl acetate in petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (88 mg, 86%). LCMS (ES-API, m / z): 401.3 [M+H] + .

[0267] Step 2: (1R,3S)-3-(3-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate (88 mg, 0.22 mmol) in formic acid (3 mL) was stirred at 90° C. for 16 h. The mixture was concentrated under reduced pressure and purified by preparative TLC (100% ethyl acetate in petroleum ether) to give the crude product (30 mg). The crude product was purified by purification procedure S using 0.05% ammonium hydroxide in water and 10 mM ammonium bicarbonate-acetonitrile (30-60%) to give (1R,3S)-3-(3-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (6.9 mg, 9%). LCMS (ES-API, M / Z): 345.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.02(br s,1H),8.54(br s,1H),7.94(s,1H),7.77(s,1H),6.95-6.94(m,1H),6.38(br s,1H),5.00(br s,1H),3.58-3.55(m,1H),3.05(br s,1H),2.50-2.46(m,1H),2.45(s,3H),2.01-1.86(m,2H),1.74-1.63(m,3H),1.02(br d,J=5.6Hz,6H).

[0268] Other compounds were synthesized following the general procedure and Example 2, as shown in Table G below. [Table G] TIFF2024538694000153.tif231170TIFF2024538694000154.tif252170TIFF2024538694000155.tif255170TIFF2024 538694000156.tif255170TIFF2024538694000157.tif249170TIFF2024538694000158.tif237170TIFF2024538694000 159.tif255170TIFF2024538694000160.tif215170TIFF2024538694000161.tif252170TIFF2024538694000162.tif255170TIFF2024538694000163.tif255170TIFF2024538694000164.tif236170TIFF2024538694000165.tif90170General Procedure 3 TIFF2024538694000166.tif106170BrettPhos = 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl;Ac = acetyl;iBuOH = isobutyl alcohol;DMAP = 4-dimethylaminopyridine;DCM = dichloromethane;THF = tetrahydrofuran;DIEA = N,N-diisopropylethylamine

[0269] Example 3: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate The title compound was prepared according to General Procedure 3 below. TIFF2024538694000167.tif79170

[0270] Step 1: (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentan-1-ol. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentanol (Intermediate C) (28.4 g, 127 mmol), 3-chloropyridazine hydrochloride (16.0 g, 106 mmol), 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-tri-isopropyl-1,1'biphenyl (11.4 g, 21.2 mmol), palladium(II) acetate (2.38 g, 10.6 mmol) and sodium carbonate (33.7 g, 318 mmol) in isobutyl alcohol was stirred at 60° C. for 12 hours under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 1-2% methanol:dichloromethane) to give (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentan-1-ol (25.0 g, 65%). 1 H NMR(400MHz,DMSO-d6)δ8.66(s,1H),8.60(br s,1H),7.40-7.36(m,1H),6.75-6.73(br s,1H),5.98(s,1H),4.58-4.57(br s, 1H), 4.15-4.14 (m, 1H), 2.95-2.90 (m, 1H), 2.50-2.49 (m, 1H), 1.57-1.51 (m, 5H), 1.50 (s, 9H).

[0271] Step 2: (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of (1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentanol (2.0 g, 6.6 mmol) in dichloromethane (15 mL) and tetrahydrofuran (15 mL) was added 4-nitrophenyl chloroformate (2.7 g, 13 mmol), pyridine (1.6 mL, 20 mmol) and 4-dimethylaminopyridine (81 mg, 0.66 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate:petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (3.0 g, 97%). LCMS (ES-API, m / z): 467.2 [M+H] + .

[0272] Step 3: (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (400 mg, 0.86 mmol) in tetrahydrofuran (10 mL) was added N,N-diisopropylethylamine (0.90 mL, 5.1 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (154 mg, 1.3 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (TLC) (ethyl acetate, Rf=0.5) to give (1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentyl]N-(1-bicyclo[1.1.1]pentanyl)carbamate (110 mg, 31%). LCMS (ES-API, m / z): 411.2 [M+H] + .

[0273] Step 4: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A solution of (1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentyl]N-(1-bicyclo[1.1.1]pentanyl)carbamate (110 mg, 0.27 mmol) in formic acid (10 mL) was stirred at 90° C. for 5 h and concentrated under reduced pressure. The residue was purified by purification procedure C using 0.05% ammonium hydroxide in water and 10 mM ammonium bicarbonate-acetonitrile (20-50%) to give (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (40 mg, 42%). LCMS (ES-API, m / z): 355.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ11.95(s,1H),9.52(s,1H),8.59(s,1H),7.79(s,1H),7.55-7.52(m,1H),7.41-7.37(m,1H), 6.20(s,1H),5.00(s,1H),3.08-3.04(m,1H),2.47-2.34(m,2H),2.07-1.99(m,2H),1.89(s,6H),1.84-1.60(m,3H).

[0274] Example 3A: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate TIFF2024538694000168.tif36170 Step 1: [(1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentyl]N-(1-methylcyclopropyl)carbamate. A solution of (4-nitrophenyl)[(1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentyl]carbonate (280 mg, 0.60 mmol), N,N-diisopropylethylamine (0.63 mL, 3.6 mmol) and 1-methylcyclopropanamine hydrochloride (77 mg, 0.72 mmol) in tetrahydrofuran (10 mL) was stirred at 25° C. for 16 hours. The mixture was concentrated to dryness, diluted with ethyl acetate (30 mL), washed with 1M sodium hydroxide solution (30 mL), brine (50 mL) and the organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (100% ethyl acetate in petroleum ether, Rf=0.4) to give [(1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentyl]N-(1-methylcyclopropyl)carbamate (30 mg, 13%). LCMS (ES-API, M / Z): 399.2 [M+H] + .

[0275] Step 2: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate. A solution of [(1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentyl]N-(1-methylcyclopropyl)carbamate (30 mg, 0.08 mmol) in formic acid (5 mL) was stirred at 90° C. for 5 h. The mixture was concentrated to remove formic acid and adjusted to pH=8 by addition of ammonium hydroxide. The crude product was purified by purification procedure Q using 0.05% ammonium hydroxide in water and 10 mM ammonium bicarbonate-acetonitrile (18-48%) to give (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (9.8 mg, 37%). LCMS (ES-API, m / z): 343.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.93(s,1H),9.51(s,1H),8.58(d,J=3.6Hz,1H),7.55-7.40(m,1H),7.39-7.36(m,2H),6.20(s,1H),5.00(br s,1H),3.05-3.03(m,1H),2.47-2.45(m,1H),2.07-1.84(m,2H),1.72-1.59(m,3H),1.23(s,3H),0.59(br s,2H),0.47(br s,2H).

[0276] Other compounds were synthesized following the general procedure and Example 3, as shown in Table H below. [Table H] TIFF2024538694000170.tif197170TIFF2024538694000171.tif202170TIFF2024538694000172.tif115170*Examples 3B, 3C: Carbamate N-substituent stereochemical configurations were arbitrarily assigned General Procedure 4 TIFF2024538694000173.tif79170RuPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) methanesulfonate; TBSCl = tert-butyldimethylchlorosilane

[0277] Example 4: (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate The title compound was prepared according to General Procedure 4 below. TIFF2024538694000174.tif31170

[0278] Step 1: (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate (Intermediate B) (200 mg, 0.62 mmol), 3-bromo-2-methylpyridine (0.14 mL, 1.2 mmol), cesium carbonate (606 mg, 1.9 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (52 mg, 0.06 mmol) in 1,4-dioxane (10 mL) was stirred at 100°C under nitrogen atmosphere for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate:petroleum ether) to give (1R,3S)-3-[1-tert-butyl-5-[(2-methyl-3-pyridyl)amino]pyrazol-3-yl]cyclopentyl-N-tert-butylcarbamate (200 mg, 78%). LCMS (ES-API, m / z): 414.2 [M+H] + .

[0279] Step 2: (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. A solution of (1R,3S)-3-[1-tert-butyl-5-[(2-methyl-3-pyridyl)amino]pyrazol-3-yl]cyclopentyl-N-tert-butylcarbamate (200 mg, 0.48 mmol) in formic acid (5 mL) was stirred at 60° C. for 16 h and concentrated under reduced pressure. The residue was purified by purification procedure D using 0.225% formic acid-acetonitrile (15-45%) in water to give (1R,3S)-3-(3-((4-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (45 mg, 26%). LCMS(ES-API,m / z):358.1[M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.11(s,1H),8.14(s,1H),8.05(d,J=8.4Hz,1H),7.83-7.82(m,1H),7.45(s,1H),7.06-7.03(m,1H),6.76(s, 1H),5.77(s,1H),4.97(s,1H),3.08-3.01(m,1H),2.46-2.44(m,1H),2.43(s,3H),2.02-1.89(m,2H),1.75-1.58(m,3H),1.20(s,9H).

[0280] Example 4K: (1R,3S)-3-(3-(pyridazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate TIFF2024538694000175.tif66170 Step 1: (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-4-ylamino)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate (200 mg, 0.62 mmol), 4-chloropyridazine (85 mg, 0.74 mmol), potassium phosphate (395 mg, 1.86 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (39 mg, 0.06 mmol) and tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.04 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. for 16 hours under nitrogen atmosphere. Methanol (10 mL) was added to the reaction. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-4-ylamino)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate (75 mg, 30%). LCMS (ES-API, M / Z): 401.3 [M+H] + .

[0281] Step 2: (1R,3S)-3-(3-(pyridazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-4-ylamino)-1H-pyrazol-3-yl)cyclopentyl tert-butylcarbamate (75 mg, 0.19 mmol) in formic acid (3 mL) was stirred at 60° C. for 16 h. The mixture was concentrated to remove formic acid and the crude product was purified by purification procedure O using 0.225% formic acid in water-acetonitrile (11-41%) to give (1R,3S)-3-(3-(pyridazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (13.1 mg, 19.5%). LCMS(ES-API,M / Z):345.0[M+H] + ; 1 HNMR(400MHz,DMSO-d6)δ12.10(s,1H),9.38(s,1H),8.97(s,1H),8.68(d,J=6.0Hz,1H),8.14(s,1H),7.58-7.56(m,1H),6.76(br s,1H),5.76(s,1H),4.97(s,1H),3.11-3.04(m,1H),2.47-2.43(m,1H) ,2.03-2.01(m,1H),1.91-1.89(m,1H),1.73-1.59(m,3H),1.20(s,9H).

[0282] Other compounds were synthesized following the general procedure and Example 4, as shown in Table I below. [Table I] TIFF2024538694000177.tif207170TIFF2024538694000178.tif218170TIFF2024538694000179.tif202170TIFF2024538694000180.tif165170TIFF2024538694000181.tif223170General Step 5 TIFF2024538694000182.tif61170DPPA = diphenylphosphoryl azide; TEA = trimethylamine; PhCH3 = toluene

[0283] Example 5: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1-(trifluoromethyl)cyclopropyl)carbamate The title compound was prepared according to general procedure 5 below. TIFF2024538694000183.tif70170

[0284] Step 1: (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl(1-(trifluoromethyl)cyclopropyl)carbamate. A mixture of 1-(trifluoromethyl)cyclopropanecarboxylic acid (100 mg, 0.65 mmol), triethylamine (0.11 mL, 0.78 mmol) and diphenylphosphoryl azide (0.15 mL, 0.71 mmol) in toluene (5 mL) was heated at 100° C. for 1 h, followed by the addition of (1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentanol (prepared by the method of Example 2, Step 3) (391 mg, 1.30 mmol). The resulting mixture was stirred at 100° C. for an additional 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-60% ethyl acetate:petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl(1-(trifluoromethyl)cyclopropyl)carbamate (120 mg, 41%). LCMS (ES-API, m / z): 453.1 [M+H] + .

[0285] Step 2: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1-(trifluoromethyl)cyclopropyl)carbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-(pyridazin-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl(1-(trifluoromethyl)cyclopropyl)carbamate (100 mg, 0.22 mmol) in formic acid (2 mL) was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was purified by purification procedure D using 0.225% formic acid-acetonitrile (20-45%) in water to give (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1-(trifluoromethyl)cyclopropyl)carbamate (30 mg, 34%). LCMS (ES-API, m / z): 397.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.00(s,1H),9.53(s,1H),8.59-8.58(m,1H),8.16-8.11(m,1H),7.52-7.50(m,1H),7.41-7.37(m,1 H),6.19(s,1H),5.03(s,1H),3.08-3.04(m,1H),2.04-1.90(m,2H),1.75-1.61(m,3H),1.20-1.18(m,2H),1.17-1.03(m,2H).

[0286] Example 5A: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl ((S)-1,1,1-trifluoropropan-2-yl)carbamate TIFF2024538694000184.tif71170 Step 1: (1R,3S)-3-(1-(tert-butyl)-3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1,1,1-trifluoropropan-2-yl)carbamate. A mixture of 3,3,3-trifluoro-2-methyl-propanoic acid (150 mg, 1.06 mmol), triethylamine (0.18 mL, 1.27 mmol) and diphenylphosphoryl azide (0.25 mL, 1.16 mmol) in toluene (5 mL) was heated at 100° C. for 1 h, followed by the addition of (1R,3S)-3-[1-tert-butyl-5-(pyridazin-3-ylamino)pyrazol-3-yl]cyclopentanol (318 mg, 1.06 mmol). The resulting mixture was stirred at 100° C. for an additional 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% ethyl acetate in petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1,1,1-trifluoropropan-2-yl)carbamate (130 mg, 28%). LCMS (ES-API, M / Z): 441.3 [M+H] + .

[0287] Step 2: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1,1,1-trifluoropropan-2-yl)carbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1,1,1-trifluoropropan-2-yl)carbamate (130 mg, 0.3000 mmol) in formic acid (2.67 mL) was stirred at 90° C. for 2 h. After concentration, the residue was adjusted to pH=8 by addition of ammonium hydroxide. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-6% methanol in dichloromethane) to give (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1,1,1-trifluoropropan-2-yl)carbamate (80 mg, 71%) LCMS (ES-API, M / Z): 385.1 [M+H] + .

[0288] Step 3: (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl ((S)-1,1,1-trifluoropropan-2-yl)carbamate. The title compound (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl(1,1,1-trifluoropropan-2-yl)carbamate (80 mg, 0.21 mmol) was purified by purification procedure T (SFC separation) using 0.1% ammonium hydroxide-40% ethanol-carbon dioxide to give (1R,3S)-3-(3-(pyridazin-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl((S)-1,1,1-trifluoropropan-2-yl)carbamate (25.5 mg, 31%) (peak 1, retention time = 4.454 min). LCMS (ES-API, M / Z): 385.0 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ11.97(br s,1H),9.53(s,1H),8.59-8.58(m,1H),7.85(d,J=8.8Hz,1H),7.51(d,J=7.6Hz,1H),7.41-7.38(m,1H),6.21(s,1H),5.07(br s,1H),4.29-4.24(m,1H),3.09-3.05(m,1H),2.55-2.50(m,1H),2.05-1.91(m,2H),1.77-1.62(m,3H).1.22(br d,J=6.8Hz,3H).

[0289] Other compounds were synthesized following the general procedure and Example 5, as shown in Table J below. [Table J] TIFF2024538694000186.tif99170* Examples 5A, 5B: Stereochemical configuration of arbitrarily assigned carbamate N-substituents General Procedure 6 TIFF2024538694000187.tif128170TBAF=Tetra-n-butylammonium fluoride;THF=Tetrahydrofuran;TBS=tert-butyldimethylsilyl;DCM=Dichloromethane;TEA=Trimethylamine;DMAP=4-Dimethylaminopyridine;XantPhos Pd G3=[(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate;t-AmOH=tert-amyl alcohol (2-methylbutan-2-ol)

[0290] Example 6: (1R,3S)-3-(5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate The title compound was prepared according to General Procedure 6 below. TIFF2024538694000188.tif80170

[0291] Step 1: 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-methylpyridazin-3(2H)-one. 6-Bromo-2-methyl-3(2H)-pyridazinone can be prepared according to the procedure provided in Example 11 of WO202157652.

[0292] A mixture of 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (1.38 g, 4.1 mmol), 6-bromo-2-methyl-3(2H)-pyridazinone (975 mg, 4.9 mmol), cesium carbonate (3.99 g, 12 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (815 mg, 0.82 mmol) in 2-methyl-2-butanol (20 mL) was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% (25% methanol:75% isopropyl acetate:heptane) to give 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-methylpyridazin-3(2H)-one (854 mg, 47%). LCMS (ES-API, m / z): 446.2 [M+H] + .

[0293] Step 2: 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-methylpyridazin-3(2H)-one. To a solution of 6-((1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)amino)-2-methylpyridazin-3(2H)-one (854 mg, 1.9 mmol) in tetrahydrofuran (5 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 2.3 mL, 2.3 mmol). The reaction was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-70% (25% methanol:75% isopropyl acetate:heptane) to give 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-methylpyridazin-3(2H)-one (595 mg, 92%). LCMS (ES-API, m / z): 332.1 [M+H] + .

[0294] Step 3: (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of 6-((1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)amino)-2-methylpyridazin-3(2H)-one (595 mg, 1.8 mmol) in dichloromethane (18 mL) was added 4-nitrophenyl chloroformate (470 mg, 2.3 mmol), pyridine (380 μL, 4.7 mmol) and 4-dimethylaminopyridine (22 mg, 0.18 mmol). The mixture was stirred at 25° C. for 16 h and then concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% (25% methanol:75% isopropyl acetate):heptane) to give (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (714 mg, 80%). LCMS (ES-API, m / z): 497.2 [M+H] + .

[0295] Step 4: (1R,3S)-3-(5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (66.1 mg, 0.13 mmol) in formic acid (1 mL) was stirred at 90° C. for 2 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The crude residue containing (1R,3S)-3-(5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate was used directly in the following step without purification.

[0296] Step 5: (1R,3S)-3-(5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of (1R,3S)-3-(5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (57 mg, 0.13 mmol) in tetrahydrofuran (1.3 mL) was added triethylamine (70 μL, 0.52 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (65 mg, 0.52 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by purification procedure H using 0.1% formic acid-acetonitrile in water to give (1R,3S)-3-(5-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (12.3 mg, 25%). LCMS (ES-API, m / z): 385.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.90(br,s,1H),9.16(s,1H),7.74(s,1H),7.28(d,J=9.8Hz,1H),6.82(d,J=9.8Hz,1H),6.23(s,1H),4. 99(m,1H),3.52(s,3H),3.05(m,1H),2.44(m,1H),2.34(m,1H),2.02(m,1H),1.89(s,6H),1.87(m,1H),1.72(m,2H),1.61(m,1H).

[0297] Example 6C: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate TIFF2024538694000189.tif39170 To a solution of (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (950 mg, 2.16 mmol) in tetrahydrofuran (15 mL) was added N,N-diisopropylethylamine (1.4 g, 10.79 mmol) and tert-butylamine (315.5 mg, 4.31 mmol). The reaction was cooled to 50° C. for 1 hour. o C for 16 h. The mixture was concentrated under reduced pressure and purified by column chromatography (silica gel, 100-200 mesh, 0-5% methyl alcohol in dichloromethane) to give the crude product (200 mg). The crude product was purified by purification procedure U using 0.05% ammonium hydroxide in water and 10 mM ammonium bicarbonate-acetonitrile (30-60%) to give (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyridazin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (105 mg, 18%). LCMS (ES-API, m / z): 375.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.91(br s,1H),9.19(s,1H),7.30(br d,J=9.8Hz,1H),6.85-6.79(m,2H),6.24(s,1H),4.98(br s,1H),3.52(s,3H),3.06-3.02(m,1H),2.45-2.43(m,1H),1.92-1.89(m,2H),1.72-1.60(m,3H),1.21(s,9H).

[0298] Other compounds were synthesized following the general procedure and Example 6, as shown in Table K below. [Table K] TIFF2024538694000191.tif252170TIFF2024538694000192.tif51170General Step 7 TIFF2024538694000193.tif158170DMAP = 4-Dimethylaminopyridine;XantPhos Pd G3 = [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate;TEA = trimethylamine;Cbz = carboxybenzyl;THF = tetrahydrofuran;EtOH = ethanol;t-AmOH = tert-amyl alcohol (2-methylbutan-2-ol);DCM = dichloromethane

[0299] Example 7: (1R,3S)-3-(3-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate The title compound was prepared according to General Procedure 7 below. TIFF2024538694000194.tif84170

[0300] Step 1: Benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. Benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate can be prepared according to the procedure provided for the preparation of synthetic intermediates in WO202157652.

[0301] To a solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (500 mg, 1.4 mmol) in dichloromethane (14 mL) was added 4-nitrophenyl chloroformate (367 mg, 1.8 mmol), pyridine (290 μL, 3.6 mmol) and 4-dimethylaminopyridine (17 mg, 0.14 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-30% (25% methanol:75% isopropyl acetate:heptane) to give benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (730 mg, 100%). LCMS (ES-API, m / z): 523.2 [M+H] + .

[0302] Step 2: Benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((1-methylcyclopropyl)carbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (730 mg, 1.4 mmol) in tetrahydrofuran (16 mL) was added triethylamine (890 μL, 6.4 mmol) and 1-methylcyclopropanamine hydrochloride (706 mg, 6.4 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-80% isopropyl acetate:heptane) to give benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((1-methylcyclopropyl)carbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (635 mg, 99%). LCMS (ES-API, m / z): 455.2 [M+H] + .

[0303] Step 3: (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate. A solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((1-methylcyclopropyl)carbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (656 mg, 1.4 mmol) and palladium on carbon (5 wt%, 614 mg, 0.29 mmol) in ethanol (10 mL) was stirred under a hydrogen atmosphere (15 psi) at 25° C. for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to give (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (471 mg, 100%). LCMS (ES-API, m / z): 321.1 [M+H] + .

[0304] Step 4: (1R,3S)-3-(1-(tert-butyl)-5-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (52 mg, 0.16 mmol), 5-bromo-N,N,6-trimethylpicolinamide (43 mg, 0.18 mmol), cesium carbonate (157 mg, 0.48 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (32 mg, 0.032 mmol) in 2-methyl-2-butanol (800 μL) was stirred at 100° C. under nitrogen atmosphere for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-90% (25% methanol:75% isopropyl acetate):heptane) to give (1R,3S)-3-(1-(tert-butyl)-5-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (40.4 mg, 52%). LCMS (ES-API, m / z): 483.2 [M+H] + .

[0305] Step 5: (1R,3S)-3-(3-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (40 mg, 0.084 mmol) in formic acid (1 mL) was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was purified by purification procedure I using 0.1% formic acid-acetonitrile in water to give (1R,3S)-3-(3-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (17 mg, 46%). LCMS (ES-API, m / z): 427.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.90(br,s,1H),8.15(br,s,1H),7.74(s,1H),7.33 (d,J=8.5Hz,2H),5.82(s,1H),4.99(m,1H),3.06(s,3H),3.01(m,1H),2.96(s ,3H),2.45(s,3H),2.43(m,1H),2.05-1.98(m,1H),1.98-1.82(m,1H),1.74- 1.65(m,2H),1.58(m,1H),1.23(s,3H),0.63-0.51(m,2H),0.55-0.42(m,2H).

[0306] Example 7A: (1R,3S)-3-(5-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate TIFF2024538694000195.tif42170 Step 1: (1R,3S)-3-(1-(tert-butyl)-5-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (52 mg, 0.16 mmol), 5-bromo-N,6-dimethylpicolinamide (44 mg, 0.19 mmol), cesium carbonate (157 mg, 0.48 mmol) and [(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (32 mg, 0.032 mmol) in 2-methyl-2-butanol (860 μL) was stirred at 100° C. under a nitrogen atmosphere for 16 hours and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-100% isopropyl acetate:heptane) to give (1R,3S)-3-(1-(tert-butyl)-5-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (40.4 mg, 54%). LCMS (ES-API, m / z): 469.2 [M+H] + .

[0307] Step 2: (1R,3S)-3-(5-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (40 mg, 0.086 mmol) in formic acid (1 mL) was stirred at 90° C. for 2 h and concentrated under reduced pressure. The residue was purified by purification procedure H using 0.1% formic acid-acetonitrile in water to give (1R,3S)-3-(5-((2-methyl-6-(methylcarbamoyl)pyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate (16 mg, 44%). LCMS (ES-API, m / z): 413.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ11.95(s,1H),8.26(q,J=4.8Hz,1H),8.23-8.16(m,1H),7.86(s,1H) ),7.72(d,J=8.5Hz,1H),7.33(s,1H),5.85(s,1H),5.10-4.92(m,1H),3.11-3.01(m,1H),2. 79(d,J=4.9Hz,3H),2.50(s,3H),2.49-2.40(m,1H),2.06-1.97(s,1H),1.98-1.82(m,1H),1 .77-1.64(m,2H),1.63-1.52(s,1H),1.23(s,3H),0.59(q,J=4.4Hz,2H),0.51-0.42(m,2H).

[0308] Other compounds were synthesized according to the general procedure and Example 7, as shown in Table L1 below. [Table L1] TIFF2024538694000197.tif146170TIFF2024538694000198.tif233170General Step 8 TIFF2024538694000199.tif136170Py=pyridine;DMAP=4-dimethylaminopyridine;DIEA=N,N-diisopropylethylamine;RuPhos Pd G3=(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate;TBSCl=tert-butyldimethylchlorosilane

[0309] Example 8. (1R,3S)-3-(3-((6-(dimethylcarbamoyl)-2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate The title compound was prepared according to General Procedure 8 below. TIFF2024538694000200.tif181170

[0310] Step 1: Benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl N-[2-tert-butyl-5-[(1S,3R)-3-hydroxycyclopentyl]pyrazol-3-yl]carbamate (Intermediate C) (5.0 g, 13.99 mmol) and imidazole (3.81 g, 55.95 mmol) in dichloromethane (80 mL) at 0° C., tert-butyldimethylchlorosilane (3.16 g, 20.98 mmol) was then added. The mixture was stirred at 25° C. for 16 hours. TLC (30% ethyl acetate in petroleum ether, Rf=0.5) showed the reaction was complete. The resulting solution was diluted with water (50 mL) and extracted with ethyl acetate (2×40 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give the crude product, which was purified by column chromatography (silica gel, 100-200 mesh, 5% ethyl acetate in petroleum ether) to give benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (5.7 g, 86.4%). LCMS (ES-API, M / Z): 472.2 [M+H]+.

[0311] Step 2: 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine. To a solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (5.7 g, 12.08 mmol) in ethyl acetate (40 mL) and tetrahydrofuran (20 mL) was added palladium (10% on carbon, 2.57 g). The mixture was stirred under hydrogen atmosphere (15 psi) at 20° C. for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (3.6 g, 88.3%). LCMS (ES-API, M / Z): 338.4 [M+H]+.

[0312] Step 3: N-(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)-2-methylpyridin-3-amine. To a solution of 1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-amine (500 mg, 1.48 mmol) in 1,4-dioxane (10 mL) was added 3-bromo-2-methylpyridine (509 mg, 2.96 mmol), cesium carbonate (1447.8 mg, 4.44 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) methanesulfonate (123.9 mg, 0.15 mmol). The mixture was stirred at 100° C. under N for 16 h and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 20% ethyl acetate in petroleum ether) to give N-(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)-2-methylpyridin-3-amine (600 mg, 94.5%). LCMS (ES-API, M / Z): 429.3 [M+H]+.

[0313] Step 4: (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl formate. A mixture of N-(1-(tert-butyl)-3-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)-2-methylpyridin-3-amine (300 mg, 0.70 mmol) in formic acid (8.0 mL, 212.04 mmol) was stirred at 25° C. for 16 hours and concentrated. The residue was concentrated to give (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl formate (220 mg, 91.8%). LCMS(ES-API,M / Z):343.3[M+H]+.

[0314] Step 5: (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentanol. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl formate (220.0 mg, 0.64 mmol) in methanol (10 mL) and water (5 mL) was added lithium hydroxide hydrate (81.0 mg, 1.93 mmol). The reaction mixture was stirred at 25° C. for 1 h and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 80% ethyl acetate in petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentanol (195 mg, 96.5%). LCMS (ES-API, M / Z): 315.0 [M+H]+.

[0315] Step 6: (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentanol (85.0 mg, 0.27 mmol) and 4-nitrophenyl chloroformate (109.0 mg, 0.54 mmol) in dichloromethane (10 mL) was added pyridine (0.07 mL, 0.81 mmol) and 4-dimethylaminopyridine (3.3 mg, 0.03 mmol). The mixture was stirred at 25° C. for 3 h and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 10% methanol in dichloromethane) to give (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (70.0 mg, 54%). LCMS (ES-API, M / Z): 480.2 [M+H] +.

[0316] Step 7: (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-3-yl)amino)-1H-pyrazol-3-yl)cyclopentyl(4-nitrophenyl)carbonate (200.0 mg, 0.42 mmol) in formic acid (5.0 mL, 132.52 mmol) was stirred at 75° C. for 16 hours and concentrated to give crude (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (150 mg, 85%). LCMS(ES-API,M / Z):424.0[M+H] + .

[0317] Step 8: (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate. To a solution of 3-methyloxetan-3-amine hydrochloride (65.7 mg, 0.53 mmol) in tetrahydrofuran (5 mL) was added (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (150.0 mg, 0.35 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.06 mmol). The mixture was stirred at 25° C. for 16 h and concentrated. The residue was purified by purification procedure J using 0.225% formic acid-acetonitrile (5-35%) in water to give (1R,3S)-3-(3-((2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate (16.2 mg, 12.2%). 1H NMR(400MHz,DMSO-d6)δ11.90(br,1H),8.15(s,1H),8.05(d,J=4.0Hz,1H),7.82(d,J=7.2Hz,1H),7.62(br s,1H),7.45(s,1H),7.08-7.03(m,1H),5.77(s,1H),5.05(br s,1H),4.63(br s,2H),4.25-4.18(m,2H),3.07-3.01(m,1H),2.46(s,1H),2.43(s,3H) ,2.05-2.01(m,1H),1.96-1.90(m,1H),1.79-1.57(m,3H),1.47(s,3H). LCMS(ES-API,M / Z):372.1[M+H] + .

[0318] Example 8B: (1R,3S)-3-(3-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl (3-methyloxetan-3-yl)carbamate TIFF2024538694000201.tif75170 Step 1: (1R,3S)-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate. To a solution of benzyl(5-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (4.0 g, 8.58 mmol), 3-methyloxetan-3-amine hydrochloride (1.6 g, 12.86 mmol) in tetrahydrofuran (40 mL) was added N,N-diisopropylethylamine (4.48 mL, 25.73 mmol). The mixture was stirred at 25° C. for 16 h. The reaction was dulited with 10% aqueous sodium hydroxide (20 mL) and then extracted with ethyl acetate (3×30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-55% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate (2.1 g, 58%). LCMS (ES-API, m / z): 415.4 [M+H] + .

[0319] Step 2: (1R,3S)-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate. To a solution of (1R,3S)-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate (1.0 g, 2.41 mmol) in tetrahydrofuran (10 mL) and ethyl acetate (20 mL) was added palladium (10% on carbon, 0.5 g). The mixture was stirred at 25° C. under a hydrogen atmosphere (15 psi) for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-100% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate (1.0 g, 99%). LCMS (ES-API, M / Z): 281.2 [M+H] + .

[0320] Step 3: (1R,3S)-3-(3-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate. A solution of (1R,3S)-3-(3-(((benzyloxy)carbonyl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate (100 mg, 0.36 mmol), 2-chloro-3-methylpyrazine (50 mg, 0.39 mmol), sodium tert-butoxide (69 mg, 0.71 mmol) in 2-methyl-2-propanol (5 mL). A mixture of [9-[dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]-5-phosphanyl]-8-aza-94-palladatricyclo[8.4.0.02,7]tetradeca-1(10),2(7),3,5,11,13-hexaen-9-yl]methanesulfonate (30 mg, 0.04 mmol) and [9-[dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]-5-phosphanyl]-8-aza-94-palladatricyclo[8.4.0.02,7]tetradeca-1(10),2(7),3,5,11,13-hexaen-9-yl]methanesulfonate (30 mg, 0.04 mmol) was stirred under nitrogen atmosphere at 100° C. for 4 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was then purified by preparative TLC (100% ethyl acetate in petroleum ether) to give crude product (20 mg), which was further purified by purification procedure R using 0.225% formic acid-acetonitrile (30-60%) in water to give (1R,3S)-3-(3-((3-methylpyrazin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl(3-methyloxetan-3-yl)carbamate (18.8 mg, 15%). LCMS (ES-API, m / z): 373.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.62(br s,1H),7.95(d,J=2.8Hz,1H),7.78(d,J=2.8Hz,1H),7.64(br s,1H),6.34(s,1H),5.02(br s,1H),4.56-4.55(m,2H),4.24(d,J=6.4Hz,2H),3.08-3.04(m,1H),2.48-2 .46(m,1H),2.45(s,3H),2.04-1.83(m,2H),1.69-1.63(m,3H),1.47(s,3H).

[0321] Other compounds were synthesized following the general procedure and Example 8, as shown in Table L2 below. [Table L2] General Procedure 9 TIFF2024538694000203.tif78170DIEA = N,N-Diisopropylethylamine; RuPhos Pd G3 = (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate

[0322] Example 9. (1R,3S)-3-(3-((2-methylpyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate The title compound was prepared according to General Procedure 9 below. TIFF2024538694000204.tif70170

[0323] Step 1: (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of (4-nitrophenyl)[(1R,3S)-3-[5-(benzyloxycarbonylamino)-1-tert-butyl-pyrazol-3-yl]cyclopentyl]carbonate (8100 mg, 15.5 mmol) in tetrahydrofuran (80 mL) was added N,N-diisopropylethylamine (8.1 mL, 46.5 mmol) and bicyclo[1.1.1]pentan-1-amine; hydrochloride (2781 mg, 23.2 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 25-35% ethyl acetate in petroleum ether) to give (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (5000 mg, 69.1%). LCMS (ES-API, M / Z): 467.2 [M+H] + .

[0324] Step 2: (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of (1R,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (4.0 g, 8.57 mmol) in ethyl acetate (40 mL) and tetrahydrofuran (20 mL) was added palladium (10% on carbon, 1.82 g). The mixture was stirred under hydrogen atmosphere (15 psi) at 20° C. for 16 hours and filtered. The filtrate was concentrated under reduced pressure to give crude (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (2.3 g, 80.7%). 1H NMR(400MHz,CDCl3)δ5.48(s,1H),5.13(br s,2H),3.79(br,1H),3.13(br s,1H),2.53-2.48(m,1H),2.41(s,1H),2.03(br s, 6H), 1.91-1.86 (m, 3H), 1.77-1.71 (m, 2H), 1.65 (s, 9H). LCMS(ES-API, M / Z):333.3[M+H] + .

[0325] Step 3: (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (50.0 mg, 0.15 mmol), 4-bromo-2-methylpyridine (0.02 mL, 0.1800 mmol), potassium phosphate (96 mg, 0.45 mmol) and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(ii) methanesulfonate (12.6 mg, 0.02 mmol) in 2-methyl-2-butanol (4 mL) was stirred at 100 °C for 16 h under N and concentrated. The residue was purified by column chromatography (silica gel, 100-200 mesh, 30% ethyl acetate in petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-5-((2-methylpyridin-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (55 mg, 86.3%). LCMS (ES-API, M / Z): 424.3 [M+H] + .

[0326] Step 4: (1R,3S)-3-(3-((2-methylpyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A solution of (1R,3S)-3-(1-(tert-butyl)-5-((3-methylpyridin-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (40.0 mg, 0.09 mmol) in formic acid (1.0 mL, 26.5 mmol) was stirred at 60° C. for 16 h and concentrated. The residue was purified by purification procedure K using 0.225% formic acid-acetonitrile (20–50%) in water to give (1R,3S)-3-(3-((2-methylpyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (4.5 mg, 12.3%). 1 H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.23(br s,1H),8.04(d,J=6.0Hz,1H),7.77(br s,1H),7.11(s,1H),7.05(d,J=5.6Hz,1H),5.72(s,1H),4.99(br s,1H),3.08-3.03(m,1H),2.48-2.44(m,1H),2.33(s,3H),2.08-2.03(m,1H),2.03-1.97(m,1H),1.89(br s,6H),1.71-1.60(m,3H). LCMS(ES-API, M / Z):368.1[M+H] + .

[0327] Example 9A: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate TIFF2024538694000205.tif82170 Step 1: 2-Chloro-3-methyl-pyrimidin-4-one. To a solution of 2-chloropyrimidin-4-ol (500 mg, 3.83 mmol) in N,N-dimethylformamide (10 mL) was added lithium carbonate (570 mg, 7.66 mmol) and iodomethane (0.48 mL, 7.66 mmol). The mixture was stirred at 25 °C for 2 h. The mixture was extracted with ethyl acetate (3 × 20 mL) and water (10 mL) and washed with brine (3 × 30 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-20% ethyl acetate in petroleum ether) to give 2-chloro-3-methyl-pyrimidin-4-one (300 mg, 54%). 1 H NMR (400MHz, CDCl3) δ7.74(d,J=6.4Hz,1H),6.42(d,J=6.4Hz,1H),3.68(s,3H).

[0328] Step 2: (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A mixture of (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (300 mg, 0.90 mmol), 2-chloro-3-methyl-pyrimidin-4-one (196 mg, 1.35 mmol), potassium phosphate (575 mg, 2.71 mmol), (R)-(+)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (56 mg, 0.09 mmol) and tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol) in 1,4-dioxane (10 mL) was stirred at 100° C. for 16 hours under nitrogen atmosphere. Methanol (10 mL) was added to the reaction and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel, 100-200 mesh, 0-50% ethyl acetate in petroleum ether) to give (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (113 mg, 28%). LCMS (ES-API, m / z): 441.2 [M+H] + .

[0329] Step 3: (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A mixture of (1R,3S)-3-(1-(tert-butyl)-5-((1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-3-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (113 mg, 0.26 mmol) in formic acid (5 mL) was stirred at 80° C. for 16 hours. The mixture was concentrated under reduced pressure and the residue was purified by purification procedure N using 0.05% ammonium hydroxide in water and 10 mM ammonium bicarbonate-acetonitrile (30-60%) to give (1R,3S)-3-(3-((1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (38 mg, 38%). LCMS (ES-API, m / z): 385.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ12.2(br s,1H),9.14(br s,1H),7.77(s,1H),7.60(s,1H),5.78(s,1H),5.52(s,1H),4.79(s,1H) ,3.26(s,3H),3.08-3.04(m,1H),2.50-2.34(m,2H),2.07-1.55(m,11H).

[0330] Other compounds were synthesized following the general procedure and Example 9, as shown in Table M below. [Table M] TIFF2024538694000207.tif197170TIFF2024538694000208.tif183170TIFF2024538694000209.tif202170TIFF2024538694000210.tif186170TIFF2024538694000211.tif120170General Procedure 10 TIFF2024538694000212.tif85170Cbz = carboxybenzyl;DIEA = N,N-diisopropylethylamine;tBu-XPhos Pd G3 = [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0331] Example 10. (1R,3S)-3-(3-((4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate The title compound was prepared according to general procedure 10 below. TIFF2024538694000213.tif119170DIEA=N,N-Diisopropylethylamine

[0332] Step 1: Benzyl (5-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate. A solution of benzyl (1-(tert-butyl)-3-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (4.0 g, 7.65 mmol) in formic acid (30 mL, 795.13 mmol) was stirred at 75° C. for 16 h and concentrated to give crude benzyl (5-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (3.0 g, 84%). LCMS(ES-API, M / Z):467.0[M+H] + .

[0333] Step 2: Benzyl (3-((1S,3R)-3-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate. To a solution of benzyl (5-((1S,3R)-3-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-3-yl)carbamate (3.0 g, 6.43 mmol) in tetrahydrofuran (20 mL) was added bicyclo[1.1.1]pentan-1-amine; hydrochloride (1.5 g, 12.86 mmol) and N,N-diisopropylethylamine (3.4 mL, 19.03 mmol). The mixture was stirred at 25° C. for 16 h and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 55% ethyl acetate in petroleum ether) to give benzyl (3-((1S,3R)-3-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (2.3 g, 87.1%). LCMS (ES-API, M / Z): 411.3 [M+H] + .

[0334] Step 3: (1R,3S)-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of benzyl (3-((1S,3R)-3-((bicyclo[1.1.1]pentan-1-ylcarbamoyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (1.15 g, 2.8 mmol) in ethyl acetate (15 mL) and tetrahydrofuran (8 mL) was added palladium (10% on carbon, 0.60 g). The mixture was stirred under hydrogen atmosphere (15 psi) at 20° C. for 16 hours and filtered. The filtrate was concentrated to give (1R,3S)-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (1.10 g). 1H NMR(400MHz,DMSO-d6)δ11.08(br s,1H),7.75(m,1H),5.18(s,1H),4.95(br s,1H),4.45(br s, 1H), 2.91-2.84 (m, 1H), 2.42-2.34 (m, 2H), 1.95-1.73 (m, 9H), 1.69-1.47 (m, 3H). LCMS(ES-API, M / Z):277.2[M+H] + .

[0335] Step 4: (1R,3S)-3-(3-((4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A mixture of (1R,3S)-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (150.0 mg, 0.54 mmol), 5-bromo-4-methoxy-1-methyl-pyridin-2-one (142.0 mg, 0.65 mmol), cesium carbonate (530.6 mg, 1.63 mmol) and t-BuXPhos Phos palladium(II) biphenyl-2-amine mesylate (43.0 mg, 0.05 mmol) in 2-methyl-2-propanol (10 mL) was stirred at 80° C. under nitrogen for 16 h and concentrated. The residue was purified first by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) and then by purification procedure L using 0.05% ammonium hydroxide-10 mM ammonium bicarbonate in water-acetonitrile (20-50%) to give (1R,3S)-3-(3-((4-methoxy-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (11.6 mg, 5%). 1H NMR(400MHz,DMSO-d6)δ11.58(br s,1H),8.16(s,1H),7.76(br s,1H),7.16(s,1H),5.86(s,1H),5.65(s,1H),4.98(m,1H),3.82(s,3H),3.34(s,3H),3.01-2.97(m, 1H), 2.44-2.42 (m, 1H), 2.38-2.35 (m, 1H), 2.03-1.98 (m, 1H), 1.89-1.81 (m, 7H), 1.68-1.65 (m, 3H). LCMS(ES-API, M / Z):414.1[M+H] + .

[0336] Example 10D: (1R,3S)-3-(3-((6-cyano-2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate TIFF2024538694000214.tif39170To a mixture of 5-bromo-6-methyl-pyridine-2-carbonitrile (266 mg, 1.35 mmol), (1R,3S)-3-(3-amino-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (300 mg, 1.13 mmol), cesium carbonate (1101 mg, 3.38 mmol) and potassium iodide (224 mg, 1.35 mmol) in 2-methyl-2-butanol (6 mL), [2-(2-aminophenyl)phenyl]methylsulfonyloxy-palladium dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (102 mg, 0.11 mmol) was added. The reaction was stirred at 100° C. under nitrogen atmosphere for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-3% methyl alcohol in dichloromethane) to give (1R,3S)-3-(3-((6-cyano-2-methylpyridin-3-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (110 mg, 25%). LCMS (ES-API, m / z): 383.3 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ12.10(br s,1H),8.27-8.24(m,2H),7.67(d,J=8.4Hz,1H),6.77(br s,1H),5.91(d,J=2.0Hz,1H),4.98(br s,1H),3.09-3.05(m,1H),2.48(s,1H),2.47-2.45(m,1H),2.04-1.90(m,2H),1.75-1.95(m,3H),1.75-1.58(m,3H),1.20(s,9H). General Procedure 11 TIFF2024538694000215.tif142170SEM = 2-(trimethylsilyl)ethoxymethyl; Ac = acetyl; (S)-DTBM-SEGPHOS = (S)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole; Me = methyl; THF = tetrahydrofuran; SFC = supercritical fluid chromatography; P y = pyridine;DMAP = 4-dimethylaminopyridine;DCM = dichloromethane;DIEA = N,N-diisopropylethylamine;tBuBrettPhos-Pd-G3 = 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate;TFA = trifluoroacetic acid

[0337] Example 11: (1R,3S)-3-(3-((3-cyclopropylpyridazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate TIFF2024538694000216.tif138170AcOH = acetic acid;Pd(dppf)Cl2 = [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);Ac = acetyl;(S)-DTBM-SEGPHOS = (S)-(+)-5,5'-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4'-bi-1,3-benzodioxole;Me = methyl;THF = tetrahydrofuran;SF C = Supercritical Fluid Chromatography; Py = Pyridine; DMAP = 4-Dimethylaminopyridine; DCM = Dichloromethane; DIEA = N,N-Diisopropylethylamine; tBuBrettPhos-Pd-G3 = 2-(Di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; TFA = Trifluoroacetic acid Step 1: 3-Bromopyridazin-4-amine. To a solution of pyridazin-4-amine (5.0 g, 52.58 mmol) in acetic acid (50 mL) was added bromine (2.42 mL, 47.32 mmol). The reaction was stirred at 25° C. for 2 h. The mixture was adjusted to pH=10 with aqueous sodium hydroxide (2 M) and then extracted with dichloromethane (3×50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-80% ethyl acetate in petroleum ether) to give 3-bromopyridazin-4-amine (1.0 g, 11%). 1 H NMR (400MHz, DMSO-d6) δ 8.49 (d, J = 5.6 Hz, 1H), 6.73 (d, J = 5.6 Hz, 1H), 6.65 (br s, 2H).

[0338] Step 2: 3-Cyclopropylpyridazin-4-amine. A mixture of 3-bromopyridazin-4-amine (900 mg, 5.17 mmol), cesium carbonate (6.7 g, 20.69 mmol), cyclopropylboronic acid (4.0 g, 46.55 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (380 mg, 0.52 mmol) in 1,4-dioxane (20 mL) and water (4 mL) was stirred at 100° C. for 16 h under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (50 mL) and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in ethyl acetate) to give 3-cyclopropylpyridazin-4-amine (400 mg, 57%). 1 H NMR (400MHz, DMSO-d6) δ 8.32 (d, J = 5.6 Hz, 1H), 6.54 (d, J = 5.6 Hz, 1H), 6.33 (br s, 2H), 2.13-2.09 (m, 1H), 0.97-0.91 (m, 4H).

[0339] Step 3: (S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanone. To a solution of 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopent-2-enone (3.0 g, 8.40 mmol), [4-[5-bis(3,5-di-tert-butyl-4-methoxy-phenyl)phosphanyl-1,3-benzodioxol-4-yl]-1,3-benzodioxol-5-yl]-bis(3,5-di-tert-butyl-4-methoxy-phenyl)phosphane (1.0 g, 0.84 mmol) in toluene (80 mL) was added copper(II) acetate (150 mg, 0.84 mmol) and dimethoxy(methyl)silane (2.18 mL, 16.79 mmol). The reaction was stirred at 40° C. under nitrogen for 16 h. Water (20 mL) was added to the mixture, followed by tetrabutylammonium fluoride (5 mL, 1M in tetrahydrofuran). The reaction mixture was stirred for 30 minutes and then extracted with ethyl acetate (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanone (3.0 g, 99%). The crude product was used directly in the next step.

[0340] Step 4: (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol. To the above solution of (S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanone (3.0 g, 8.35 mmol) in tetrahydrofuran (50 mL) was added tri-sec-butylborohydride (10.02 mL, 10.02 mmol) (1M in tetrahydrofuran) dropwise at −60° C. under nitrogen atmosphere. The mixture was stirred at −60° C. under nitrogen atmosphere. oThe mixture was stirred at C for 2 h. The mixture was poured into water (100 mL) and stirred for 30 min. The aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol (1.9 g, 64%), which was further separated by purification procedure M (chiral SFC) with 0.1% ammonium hydroxide-25% ethanol-carbon dioxide to give (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol (816 mg, 43%, retention time = 4.056 min). LCMS (ES-API, M / Z): 361.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ6.23(s,1H),5.38(s,2H),4.45(br s,1H),3.61-3.47(m,2H),3.28-3.17(m,1H),2.52-2.42(m,1H),2.18-2.06(m,1H),1.96-1.85( m,2H),1.73-1.63(m,1H),1.63-1.59(m,1H),1.29-1.16(m,1H),0.91-0.85(m,2H),0.00(s,9H).

[0341] Step 5: (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate. To a solution of (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentanol (3.0 g, 8.3 mmol) in dichloromethane (30 mL) was added N,N-dimethylpyridin-4-amine (101 mg, 0.83 mmol), pyridine (2.0 g, 24.91 mmol) and 4-nitrophenyl carbonochloridate (2.5 g, 12.45 mmol). The mixture was stirred at 25° C. for 16 h. The reaction was quenched by the addition of saturated aqueous ammonium chloride (200 mL) and then extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-15% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (4.2 g, 96%). LCMS (ES-API, M / Z): 526.1 [M+H] + .

[0342] Step 6: (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (1000 mg, 1.90 mmol) in tetrahydrofuran (5 mL) was added bicyclo[1.1.1]pentan-1-amine hydrochloride (341 mg, 2.85 mmol) and N,N-diisopropylethylamine (0.99 mL, 5.70 mmol). The reaction was stirred at 25° C. for 16 h. The mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with 1 M aqueous sodium hydroxide (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-35% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (600 mg, 67%). LCMS (ES-API, M / Z): 470.0 [M+H] + .

[0343] Step 7: (1R,3S)-3-(3-((3-cyclopropylpyridazin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. A mixture of (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (80 mg, 0.17 mmol), 3-cyclopropylpyridazin-4-amine (34 mg, 0.26 mmol), cesium carbonate (222 mg, 0.68 mmol) and [2-(2-aminophenyl)phenyl]methyl methanesulfonate ditert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane (13 mg, 0.02 mmol) in 1,4-dioxane (5 mL) was stirred at 100° C. for 16 h under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with brine (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (10% methanol in dichloromethane) to give (1R,3S)-3-(3-((3-cyclopropylpyridazin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (15 mg, 17%). LCMS (ES-API, M / Z): 525.3 [M+H] + .

[0344] Step 8: (1R,3S)-3-(3-((3-cyclopropylpyridazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate. To a solution of [(1R,3S)-3-[5-[(3-cyclopropylpyridazin-4-yl)amino]-2-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]cyclopentyl]N-(1-bicyclo[1.1.1]pentanyl)carbamate (15 mg, 0.03 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.1 mL). The reaction was stirred at 25° C. for 16 h. The reaction mixture was adjusted to pH=7 by adding aqueous ammonia (37%, 3 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by purification procedure G using 10 mM ammonium bicarbonate in 0.05% ammonium hydroxide-water-acetonitrile (30-60%) to give (1R,3S)-3-(3-((3-cyclopropylpyridazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl bicyclo[1.1.1]pentan-1-ylcarbamate (1.1 mg, 9.4%). LCMS (ES-API, M / Z): 395.1 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.05 (br s, 1H), 7.59 (br s, 1H), 6.05 (s, 1H), 5.19-5.14 (m, 1H), 3.23-3.19 (m, 1H), 2.58-2.37 (m, 1H), 2.21-2.19 (m, 2H), 2.18-2.0 (m, 10H), 1.14-1.10 (m, 4H).

[0345] Example 11A: (1R,3S)-3-(3-((3-methylpyridazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate TIFF2024538694000217.tif96170 Step 1: 3-Methylpyridazin-4-amine. A solution of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (8.03 mL, 28.74 mmol), 3-bromopyridazin-4-amine (2.0 g, 11.49 mmol), cesium carbonate (14.9 g, 45.98 mmol) and dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (841 mg, 1.15 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was stirred at 100° C. for 16 hours under nitrogen atmosphere. Ethyl acetate (50 mL) and methanol (50 mL) were added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in ethyl acetate) to give 3-methylpyridazin-4-amine (700 mg, 56%). 1 HNMR (400MHz, DMSO-d6) δ8.38 (d, J = 6.0 Hz, 1H), 6.55 (d, J = 6.0 Hz, 1H), 6.14 (br s, 2H), 2.36 (s, 3H).

[0346] Step 2: (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. To a solution of 3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl(4-nitrophenyl)carbonate (800 mg, 1.52 mmol) in tetrahydrofuran (15 mL) was added N,N-diisopropylethylamine (0.79 mL, 4.56 mmol) and tert-butylamine (0.48 mL, 4.56 mmol). The reaction was stirred at 25° C. for 16 hours. Ethyl acetate (50 mL) was added and the organic layer was washed with aqueous sodium hydroxide (15 mL, 1 M), brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-30% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (270 mg, 39%). LCMS (ES-API, M / Z): 460.2 [M+H] + .

[0347] Step 3: (1R,3S)-3-(3-((3-methylpyridazin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. A solution of (1R,3S)-3-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (400 mg, 0.87 mmol), 3-methylpyridazin-4-amine (237 mg, 2.17 mmol), methanesulfonate 2-di-t-butylphosphino-3,6-dimethoxy-2'-4'-6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (74 mg, 0.09 mmol) and cesium carbonate (1.1 g, 3.47 mmol) in 1,4-dioxane (15 mL) was stirred under nitrogen atmosphere at 100° C. for 16 hours. Ethyl acetate (100 mL) was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography (silica gel, 100-200 mesh, 0-5% methanol in ethyl acetate) to give (1R,3S)-3-(3-((3-methylpyridazin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (210 mg, 50%). LCMS (ES-API, M / Z): 489.3 [M+H] + .

[0348] Step 4: (1R,3S)-3-(3-((3-methylpyridazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate. To a solution of (1R,3S)-3-(3-((3-methylpyridazin-4-yl)amino)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (210 mg, 0.43 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (2 mL). The reaction was stirred at 25° C. for 16 h. The reaction mixture was adjusted to pH=7 by adding aqueous ammonia (37%, 3 mL). After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 100-200 mesh, 0-10% methanol in dichloromethane) to give the crude product (150 mg), which was further purified by purification procedure P (SFC separation) with 0.1% ammonium hydroxide-40% ethyl alcohol-carbon dioxide to give (1R,3S)-3-(3-((3-methylpyridazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate (137 mg, 87%). LCMS (ES-API, M / Z): 359.0 [M+H] + ; 1 H NMR (400MHz, DMSO-d6) δ12.15(br s,1H), 8.61(d,J=5.6Hz,1H),8.31(s,1H),7.83(d,J=6.0Hz,1H),6.76(br s,1H),5.92(s,1H). 4.98(br s,1H),3.09-3.05(m,1H),2.56(s,3H),2.48-2.46(m,1H),2.04-1.90(m,2H),1.76-1.59(m,3H),1.20(s,9H).

[0349] As shown in Table N below, other compounds can be synthesized following the general procedure and Example 10 or the general procedure and Example 11. [Table N] TIFF2024538694000219.tif207170TIFF2024538694000220.tif217170

[0350] Assay Method Enzyme assays Cyclin-dependent kinase 1 / cyclin A2 (CDK1-cycA2), cyclin-dependent kinase 2 / cyclin E1 (CDK2-cycE1), cyclin-dependent kinase 4 / cyclin D3 (CDK4-cycD3) and cyclin-dependent kinase 6 / cyclin D3 (CDK6-cycD3) enzyme assays were performed as described below. K was then calculated using the Morrison tight-binding model (Morrison, JF, Biochim. Biophys. Acta. 185:269-296 (1969); William, JW and Morrison, JF, Meth. Enzymol., 63:437-467 (1979)) modified for ATP-competitive inhibition, K = Kapp (1 + [ATP] / Kmpp). i value was determined.

[0351] (i)CDK1-cycA2 TR-FRET(LANCE(R)) Dose responses of compounds dissolved in DMSO are created in 384-well microplates using an Echo acoustic dispenser. A volume of 5 μL of enzyme mix is ​​added to the wells and pre-incubated with the compounds for 30 minutes. A volume of 5 μL of substrate mix is ​​added to the enzyme and compounds and allowed to react for 90 minutes at room temperature. Final concentrations are as follows: 0.625 nM CDK1, 50 nM Ulight-4E-BP1 substrate and 20 μM ATP (Km=16 μM). Buffer conditions are 50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM TCEP, 0.05% BGG and 0.01% Brij 35. Reactions are quenched with 5 μL of EDTA in detection buffer (15 mM [EDTA final]). Finally, 5 μL of TR-FRET detection mix is ​​added to the quenched reaction containing europium-labeled anti-phospho-4E-BP1. After 60 min incubation, 20 uL of the total reaction is read on an Envision plate reader (ex320, dual em615 / 665). Signal is the ratio of acceptor fluorescence to donor fluorescence. Inhibition constants are calculated via the Morrison equation. The enzyme source for CDK1-cycA2 is ProQinase, catalog number: 0134-0054-1.

[0352] (ii)CDK2-cycE1 TR-FRET(LANCE(R)) An Echo acoustic dispenser is used to create a dose response of compounds dissolved in DMSO in a 384-well microplate. A volume of 5 μL of the enzyme mix is ​​added to the wells and pre-incubated with the compounds for 30 minutes. A volume of 5 μL of the substrate mix is ​​added to the enzyme and compounds and allowed to react for 90 minutes at room temperature. The final concentrations are as follows: 0.625 nM CDK2, 50 nM Ulight-MBP substrate and 100 μM ATP (K m= 103 μM). Buffer conditions are 50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM TCEP, 0.05% BGG and 0.01% Brij 35. The reaction is quenched with 5 μL of EDTA in detection buffer (15 mM [EDTA final]). Finally, 5 μL of TR-FRET detection mix is ​​added to the quenched reaction containing europium-labeled anti-phospho-MBP1. After 60 minutes of incubation, 20 μL of the total reaction is read on an Envision plate reader (ex320, dual em615 / 665). The signal is the ratio of acceptor fluorescence to donor fluorescence. The inhibition constant is calculated via the Morrison equation. The enzyme source of CDK2-cycE1 is ProQinase, catalog number: 0050-0055-1.

[0353] (iii)CDK4-cycD3 TR-FRET(LANCE(R)) Dose responses of compounds dissolved in DMSO are created in 384-well microplates using an Echo acoustic dispenser. A volume of 5 μL of enzyme mix is ​​added to the wells and pre-incubated with the compounds for 30 minutes. A volume of 5 μL of substrate mix is ​​added to the enzyme and compounds and allowed to react for 90 minutes at room temperature. Final concentrations are as follows: 3 nM CDK4, 50 nM Ulight-4E-BP1 substrate and 500 μM ATP (Km=699 μM). Buffer conditions are 50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM TCEP, 0.05% BGG and 0.01% Brij 35. Reactions are quenched with 5 μL of EDTA in detection buffer (15 mM [EDTA final]). Finally, 5 μL of TR-FRET detection mix is ​​added to the quenched reaction containing europium-labeled anti-phospho-4E-BP1. After 60 min incubation, 20 μL of the total reaction is read on an Envision plate reader (ex320, dual em615 / 665). Signal is the ratio of acceptor fluorescence to donor fluorescence. Inhibition constants are calculated via the Morrison equation. The enzyme source of CDK4-cycD3 is Carna Biosciences, catalog number: 04-105.

[0354] (iv)CDK6-cycD3 TR-FRET(LANCE(R)) Dose responses of compounds dissolved in DMSO are generated in 384-well microplates using an Echo acoustic dispenser. A volume of 5 μL of enzyme mix is ​​added to the wells and pre-incubated with the compounds for 30 min. A volume of 5 μL of substrate mix is ​​added to the enzyme and compounds and allowed to react for 60 min at room temperature. Final concentrations are as follows: 0.625 nM CDK6, 50 nM Ulight-4E-BP1 substrate and 1000 μM ATP (Km=959 μM). Buffer conditions are 50 mM HEPES, pH 7.5, 10 mM MgCl2, 2 mM TCEP, 0.05% BGG and 0.01% Brij 35. The reaction is quenched with 5 μL of EDTA in detection buffer (15 mM [EDTA final]). Finally, 5 μL of TR-FRET detection mix is ​​added to the quenched reaction containing europium-labeled anti-phospho-4E-BP1. After 60 min incubation, 20 uL of the total reaction is read on an Envision plate reader (ex320, dual em615 / 665). Signal is the ratio of acceptor fluorescence to donor fluorescence. Inhibition constants are calculated via the Morrison equation. Enzyme source of CDK4-cycD3 is Carna Biosciences, catalog number: 04-107.

[0355] Cell proliferation assay (i) OVISE and SKOV-3 EdU incorporation cell proliferation assays Ovarian cancer cell proliferation is measured by the incorporation of EdU (5-ethynyl-2'-deoxyuridine) into newly synthesized DNA. CDK2-dependent proliferation is determined using OVISE (JCRB1043, CCNE1 amplified) and CDK4 / 6-dependent effects are determined in CCNE1 non-amplified SKOV-3 (ATCC HTB-77).

[0356] Cells are plated in 384-well plates in RPMI medium supplemented with 10% FBS. Compounds are added at the desired concentrations with a final DMSO content of 0.5% and cells are incubated for 16 hours at 37°C / 5% CO2. EdU (Life Technologies) is added to a final concentration of 0.5 μM and incubation is continued for 8 hours, followed by fixation with 4% paraformaldehyde. EdU incorporated in chromosomal DNA is labeled with Alexa Flour 488 dye using Click-It kit reagents according to the manufacturer's instructions (Invitrogen-C10351) and total nuclear DNA is stained with HCS NuclearMask Blue (Invitrogen). Images are acquired using a Yokogawa CQ1 imaging cytometer with a 10x objective. Images are analyzed to count the total number of nuclei (NuclearMask Blue, ex405nm / em447nm) and the number of EdU-positive nuclei (ex488nm / em525nm). IC for inhibition of cell division 50 is determined by fitting the percentage of EdU positive cells as a function of compound dose using a four-parameter logistic model.

[0357] (ii) p-H3 HCT-116 mitotic release cell proliferation assay Inhibition of cellular CDK1 is determined by the release of cells from nocodazole-induced mitotic arrest, as measured by the reduction of phospho-histone H3. Histone H3 (Ser10) levels are detected in cell lysates by generating a fluorescence resonance energy transfer (FRET) signal between two antibodies, phospho-histone H3 Cryptate (acting as the donor) and phospho-histone H3 d2 (acting as the acceptor).

[0358] HCT116 cells are seeded at 20,000 cells / well in Falcon 96-well plates in RPMI 1640 medium supplemented with 10% FBS and 1% L-glutamine. Plates are left overnight at 37°C / 5% CO2. The next morning, nocodazole is diluted in complete medium and 5 μL is added to each test well and positive control well for a final concentration of 500 nM. Plates are then incubated for 16 hours at 37°C / 5% CO2. Using an Echo acoustic dispenser, dose responses of compounds dissolved in DMSO are generated in 96-well microplates and these compounds are diluted to 10 times the desired assay concentration using assay medium (RPMI 1640 medium supplemented with 10% FBS and 1% L-glutamine). 10 μL of diluted compounds are then transferred to the cell plate (final DMSO concentration 0.1%). Cell plates are then incubated for 4 hours at 37°C in 5% CO2. Prepare cell lysis buffer on ice using reagents from the Phospho-Histone H3 (Ser10) Cell Kit (Cisbio-64HH3PEG). Discard the supernatant from the cell plate and add 80 μL of supplemented cell lysis buffer (1:99 dilution of blocking reagent and 1× cell lysis buffer provided in the kit) to each of the experimental wells. Allow the cell lysis reaction to proceed at room temperature with vigorous shaking for 30 minutes. Prepare a 384-well HTRF (homogeneous time-resolved fluorescence) plate by adding 2 μL of each diluted antibody (phospho-histone H3 Cryptate antibody and phospho-histone H3 d2 antibody diluted 19:1 in detection buffer) and 12 μL of supplemented cell lysis buffer to each well in the HTRF plate. Add 4 μL of cell lysate to the prepared HTRF plate, which is then sealed and allow the reaction to proceed at room temperature for a minimum of 2 hours. Read fluorescence on a Perkin Elmer Envision (wavelengths of 665 nm and 620 nm).

[0359] Compound Activity Data The compounds described herein were tested for activity against the above assays. As can be seen from Table O below, all of the compounds tested had activity below 2 micromolar against CDK2, with the majority exhibiting activity below 10 nM, and many of them exhibiting nanomolar activity below 1 nM. See, for example, compounds 2, 2E, 2F, 2H, 2I, 2L-2O, 2R, 2T, 2V, 2CC, 4, 4B, 4D, 4K, 6, 6A-6C, and 7, which exhibit activity below 1 nM. In addition, all of the compounds tested exhibited selectivity for CDK2 over CDK1 and CDK4. See, for example, the selectivity fold (FS) for CDK1 / CDK2 and CDK4 / CDK2 enzyme assay data, and the selectivity fold (FS) for SKOV-3 / OVISE cell assay data (measuring CDK4 / 6 relative to CDK2). Many compounds showed greater than 30-fold selectivity for CDK2 over CDK1 (see, e.g., selectivity fold enzyme data for compounds 1, 2, 2A-2C, 2E, 2G, 2T-2V, 2Y, 2Z, 2CC-2EE, 4, 4A, 4B, 4D, 4E, 4G, 4H, 4J, 4K, 6, 6A, 6C, 7), and greater than 100-fold selectivity for CDK2 over CDK4 (see, e.g., selectivity fold enzyme data for compounds 2, 2B, 2F, 2H, 2K-2M, 2O, 2R, 2T-2V, 2Z, 2AA, 2CC, 4, 4A-4D, 4K, 6-6C).

[0360] The compounds described herein contain an amine (-NH-) linker. The activity of compounds containing an acetamide linker (-NH-C(=O)-CH2-; see Comparative Agent A) and an amide linker (-NH-C(=O)-; see Comparative Agent B) was compared with the exemplary compound 4K containing an amine (-HN-) linker. See Table P. The CDK2 potency of amine compound 4K shares nanomolar activity with acetamide comparative agent A (compare 0.45nM to 0.17nM), both of which are more CDK2 potent than amide comparative agent B (1.0nM), but compound 4K is at least 3-fold more CDK2 selective than CDK4 / 6, as evidenced by SKOV-3 / OVISE selectivity fold cell assay data. As evidenced by the pH3 / OVISE cell assay data (measuring CDK1 relative to CDK2), compound 4K was also at least 3-fold selective for CDK2 over CDK1: compare compound 4K (2.1-fold selective) versus comparator A (0.78-fold selective) and comparator B (0.31-fold selective). The (+) symbol in Table P indicates a desirable increased selectivity fold for the exemplary compound 4K compared to both comparators.

[0361] In addition to the amine (-NH-) linker, the compounds described herein contain a 6-membered (monocyclic) heteroaryl ring A containing at least one N heteroatom and, optionally, one or two additional N heteroatoms.

[0362] As can be seen from Table Q, comparator C, which has a 5-membered pyrazole ring A, has greater than 10 nanomolar CDK2 activity (32 nM in the enzyme assay) and less than 10-fold selectivity over CDK4 and CDK4 / 6 (9.1-fold over CDK4 in the enzyme assay and greater than 3.6-fold over CDK4 / 6 in the cellular assay). In contrast, comparator C, which has a 6-membered heteroaryl ring A and isopropyl R provided in Table Q, has greater than 10 nanomolar CDK2 activity (32 nM in the enzyme assay) and less than 10-fold selectivity over CDK4 and CDK4 / 6 in the cellular assay. 2Many of the comparable exemplary compounds containing the group exhibit a 1.9-fold to over 300-fold improvement in potency against CDK2 as measured by enzyme assay (see CDK2 enzyme assay data comparing the CDK2 activity of Comparator C at 32 nM to that of the test compounds) and increased selectivity fold for CDK2 over CDK4. Similar improvements in potency and selectivity are observed in cellular assays. The (+) symbol in Table Q indicates a desirable increased selectivity fold between Comparator C and the comparative exemplary compounds.

[0363] As can be seen from Table R, Comparator D, which has a bicyclic 6,7-dihydro-5H-cyclopenta[b]pyridinyl ring A, is more potent against CDK2 (2.7 nM in the enzyme assay) than the 5-membered pyrazole Comparator C (32 nM in the enzyme assay), whereas the 6-membered heteroaryl ring A and tert-butyl R 2 It has lower potency against CDK2 cells and lower selectivity for CDK2 over both CDK1 or CDK4 compared to the majority of exemplary compounds containing the group. The (+) symbols in Table R indicate a desirable fold increase in selectivity of the exemplary compound compared to the comparator D.

[0364] As can be seen from Table S, the comparative agent E with phenyl ring A is more potent against CDK2 (0.52 nM in enzyme assay) than the comparative agent C with 5-membered ring A (32 nM in enzyme assay) and the comparative agent D with bicyclic ring A (2.7 nM in enzyme assay). As shown in exemplary compounds 1, 2A, 4, 4A, 4C, 4D, 4E, 4H, 4I, 4K and 6C, the inclusion of additional N-ring heteroatoms in the ring system, particularly in the meta or para positions relative to the point of attachment, generally results in increased selectivity for CDK2 compared to CDK4, as evidenced by the SKOV-3 / OVISE selectivity fold cell assay data. Furthermore, many of the compounds that follow this trend have also been shown to be more potent CDK2 cell inhibitors compared to the comparative agent E, as evidenced by the CDK2 OVISE cell assay data for compounds 2A, 4, 4D, 4E, 4H, 4K and 6C. The (+) sign in Table S indicates the desired increased selectivity fold of the exemplary compounds compared to the comparative agent E.

[0365] The data provided herein demonstrate that having a shorter amine linker is preferred over a longer linker, resulting in increased potency and selectivity. The data further demonstrate that having a 6-membered monocyclic heteroaryl ring results in more potent and selective CDK2 inhibitors compared to compounds containing smaller (5-membered) or larger (bicyclic) heteroaryl ring A. Finally, the data demonstrate improved potency and / or selectivity by including a nitrogen (N) ring heteroatom in the aromatic monocyclic ring system of ring A, especially when at least one of the N ring heteroatoms is in the meta or para position relative to the point of attachment. [Table O] TIFF2024538694000222.tif255170TIFF2024538694000223.tif134170 [Table P] [Table Q] TIFF2024538694000226.tif246170TIFF2024538694000227.tif247170TIFF2024538694000228.tif246170TIFF2024538694000229.tif246170TIFF2024538694000230.tif246170TIFF2024538694000231.tif246170TIFF2024538694000232.tif246170TIFF2024538694000233.tif236170TIFF2024538694000234.tif246170TIFF2024538694000235.tif246170

Table R

Table S

[0366] Other embodiments Although the foregoing disclosure has been described in some detail by way of illustration and example for clarity of understanding, those skilled in the art will understand that certain changes and modifications may be implemented within the scope of the appended claims.Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.In the event of any inconsistency between this application and the references provided herein, this application shall prevail.

Claims

1. Formula (I): (In the formula, Ring A is a 6-membered heteroaryl having at least one N ring heteroatom and having 0-2 additional N ring heteroatoms; Each R １ are independently １～６ Alkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C ２～６ Alkoxyalkyl, halogen, C １～６ Haloalkyl, C １～６ Haloalkoxy, —CN, —N(R １ａ） (R １ｂ ), -C １～６ Alkyl-N(R １ａ ) (R １ｂ ), -C(O)N(R １ａ ) (R １ｂ ), -O-R １ｃ , -S(O) ２ R １ａ , C ３～８ cycloalkyl, 3- to 6-membered heterocycloalkyl each having 1 or 2 heteroatoms independently of N or O, or 5-membered heteroaryl each having 1 or 2 heteroatoms independently of N or O, and each heterocycloalkyl and heteroaryl is selected from the group consisting of 0, 1, 2, or 3 R １ｄ is substituted with; Each R １ａ and R １ｂ are independently hydrogen, C １～６ Alkyl or C １～６ haloalkyl; R １ｃ are each independently a 3- to 6-membered heterocycloalkyl having 1-2 heteroatoms of N and O; R ２ are independently １～６ Alkyl, C １～６ Haloalkyl, C ３～８ cycloalkyl, 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, or C １～６ alkylaryl, and cycloalkyl, heterocycloalkyl, and aryl each independently represent 0, 1, 2, or 3 R ２ａ substituted with a group; Each R １ｄ and R ２ａ are independently hydrogen, C １～６ Alkyl, halogen, C １～６ haloalkyl or hydroxy; R ３ is hydrogen, C １～６ Alkyl or C １～６ haloalkyl; R ４ is hydrogen, C １～４ Alkyl, C ２～４ Alkoxyalkyl or C １～３ haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; The subscript m is an integer 0 or 1. or a pharmaceutically acceptable salt thereof.

2. Ring A is a 6-membered heteroaryl having one N ring heteroatom and optionally 1-2 additional N ring heteroatoms; Each R １ But independently, C １～６ Alkyl, C １～６ Alkoxy, C １～６ Hydroxyalkyl, C ２～６ Alkoxyalkyl, halogen, C １～６ Haloalkyl, C １～６ Haloalkoxy, —CN, —N(R １ａ） (R １ｂ ), -C １～６ Alkyl-N(R １ａ ) (R １ｂ ), -C(O)N(R １ａ ) (R １ｂ ), -O-R １ｃ , C ３～８ cycloalkyl, 3- to 6-membered heterocycloalkyl each having 1 or 2 heteroatoms independently of N or O, or 5-membered heteroaryl each having 1 or 2 heteroatoms independently of N or O, and each heterocycloalkyl and heteroaryl is selected from the group consisting of 0, 1, 2, or 3 R １ｄ is substituted with; Each R １ａ and R １ｂ are independently hydrogen, C １～６ Alkyl or C １～６ haloalkyl; R １ｃ are each independently a 3- to 6-membered heterocycloalkyl having 1-2 heteroatoms of N and O; R ２ But independently, C １～６ Alkyl, C １～６ Haloalkyl, C ３～８ cycloalkyl, or 3- to 6-membered heterocycloalkyl having 1 or 2 heteroatoms, each independently N or O, and the cycloalkyl and heterocycloalkyl each independently contain 0, 1, 2, or 3 R ２ａ substituted with a group; Each R １ｄ and R ２ａ are independently hydrogen, C １～６ Alkyl, halogen, C １～６ haloalkyl or hydroxy; R ３ But hydrogen, C １～６ Alkyl or C １～６ haloalkyl; R ４ But hydrogen, C １～４ Alkyl, C ２～４ Alkoxyalkyl or C １～３ haloalkyl; The subscript n is an integer 0, 1, 2, 3, or 4; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the subscript m is an integer 0 or 1.

3. Ring A is 2. The compound of claim 1, wherein:

4. Each R １ But independently, C １～４ Alkyl, C １～３ Alkoxy, C １～３ Hydroxyalkyl, halogen, C １～３ Haloalkyl, —CN, —N(R １ａ ) (R １ｂ ), -C １～３ Alkyl-N(R １ａ ) (R １ｂ ), -C(O)N(R １ａ ) (R １ｂ ), -S(O) ２ R １ａ , C ３～５ cycloalkyl, a 6-membered heterocycloalkyl having two heteroatoms, each independently N or O, or a 5-membered heteroaryl having two heteroatoms, each independently N, wherein each heterocycloalkyl and heteroaryl is selected from the group consisting of zero or one R １ｄ is substituted with; Each R １ａ and R １ｂ are independently hydrogen, C １～３ Alkyl or C １～３ haloalkyl; R １ｄ But hydrogen, C １～６ Alkyl, halogen, C １～６ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is haloalkyl or hydroxy.

5. R ４ is hydrogen or C １～４ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is 1 or 2;

6. Ring A is 2. The compound of claim 1, wherein:

7. R ２ But independently, C １～４ Alkyl or C ３～６ cycloalkyl, which is a cycloalkyl group having zero or one R ２ａ substituted with a group; R ２ａ is C １～３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: R is 1 or 2;

8. R ２ are independently iPr, s-Bu, t-Bu, -CH(CH ３ )CF ３ , -CH(CH ３ ) CH ２ CF ３ , -C(CH ３ ) ２ CF ２ , 2. The compound of claim 1, wherein:

9. 2. The compound of claim 1 selected from Table 1 or Table 2, or a pharmaceutically acceptable salt thereof.

10. below:

2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.

12. A medicament for treating a CDK2-mediated disorder, comprising a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.

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