3-Carbonylamino-5-cyclopentyl-1FI-pyrrole compounds having inhibitory activity against CDK2

Abstract

The present invention relates to compounds of formula (I) and their enantiomers and to pharmaceutically acceptable salts of formula (I) and said enantiomers, wherein R 1 , R 2 and R 3 As defined herein. The present invention further relates to pharmaceutical compositions comprising such compounds and salts, and to methods and uses of such compounds, salts and compositions for treating abnormal cell growth, including cancer, in a subject in need thereof. #imgabs0#

Description

[0001] Background of the invention. Field of the Invention

[0002] The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, to pharmaceutical compositions comprising such compounds and salts, and to uses thereof. The compounds, salts and compositions of the present invention can be used to treat abnormal cell growth, such as cancer, in a subject.

[0003] Description of the technology

[0004] Cyclin-dependent kinases (CDKs) and related serine / threonine protein kinases are important cellular enzymes that perform essential functions in regulating cell division and proliferation. CDKs 1-4, 6, 10, 11 have been reported to play a direct role in cell cycle progression, while CDKs 3, 5, and 7-9 may play an indirect role (e.g., through the activation of other CDKs, regulation of transcription or neuronal function). The CDK catalytic unit is activated by binding to regulatory subunits called cyclins, which are then phosphorylated. Cyclins can be divided into four major classes (G1, G1 / S, S, and M cyclins), and their expression levels vary at different points in the cell cycle. Cyclin B / CDK1, cyclin A / CDK2, cyclin E / CDK2, cyclin D / CDK4, cyclin D / CDK6, and possibly other heterodynes are important regulators of cell cycle progression.

[0005] Overexpression of CDK2 is associated with aberrant regulation of the cell cycle. The cyclin E / CDK2 complex plays an important role in the regulation of the G1 / S transition, histone biosynthesis, and centrosome duplication. Progressive phosphorylation of retinoblastoma (Rb) by cyclin D / Cdk4 / 6 and cyclin E / Cdk2 releases the G1 transcription factor E2F and promotes S phase entry. Activation of cyclin A / CDK2 during early S phase promotes phosphorylation of endogenous substrates, allowing DNA replication and inactivation of E2F, leading to completion of S phase (Asghar et al. The history and future of targeting cyclin- dependent kinases in cancer therapy , Nat. Rev. Drug. Discov. 2015;14(2):130-146).

[0006] Cyclin E, a regulatory cell cycle protein of CDK2, is often overexpressed in cancer. Cyclin E amplification or overexpression has long been associated with poor outcomes in breast cancer (Keyomarsi et al., Cyclin E and survival in patients with breast cancer. N Engl J Med.(2002) 347:1566-75). Cyclin E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells, and CDK2 inhibition has been reported to restore sensitivity to tamoxifen or CDK4 inhibitors in tamoxifen-resistant and CCNE2-overexpressing cells (Caldon et al., Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol. Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Early Adaptation and Acquired Resistance to CDK4 / 6 Inhibition in Estrogen Receptor-Positive BreastCancer, Cancer Res. (2016) 76: 2301-2313). It has also been reported that cyclin E amplification also promotes trastuzumab resistance in HER2+ breast cancer patients (Scaltriti et al. Cyclin E amplification / overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci. (2011) 108: 3761-6). It has also been reported that cyclin E overexpression plays a role in basal-like and triple negative breast cancer (TNBC) as well as inflammatory breast cancer (Elsawaf and Sinn, Triple Negative Breast Cancer: Clinical and Histological Correlations, Breast Care (2011) 6:273-278; Alexander et al., Cyclin E overexpression as abiomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8: 14897-14911).

[0007] Amplification or overexpression of cyclin E1 (CCNE1) has also been associated with poor outcome in ovarian, gastric, endometrial, and other cancers (Nakayama et al., Gene amplification CCNE1 is related to poorsurvival and potential therapeutic target in ovarian cancer, Cancer (2010)116: 2621-34; Etemadmoghadam et al., Resistance to CDK2 Inhibitors Is Associatedwith Selection of Polyploid Cells in CCNE1-Amplified Ovarian Cancer, Clin Cancer Res (2013) 19: 5960-71; Au-Yeung et al., Selective Targeting of Cyclin E1-Amplified High-Grade Serous Ovarian Cancer by Cyclin-Dependent Kinase 2 andAKT Inhibition, Clin. Cancer Res. (2017) 23:1862-1874; Ayhan et al., CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with apoor prognosis, Modern Pathology (2017) 30: 297-303; Ooi et al., Geneamplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situhybridization, Hum Pathol. (2017) 61: 58-67; Noske et al., Detection of CCNE1 / URI (19q12) amplification by in situhybridisation is common in high grade and type II endometrial cancer, Oncotarget (2017) 8: 14794-14805).

[0008] The small molecule inhibitor dinaciclib (MK-7965) inhibits CDK1, CDK2, CDK5, and CDK9 and is in clinical development for breast and hematological cancers. Celicib (roscovitine or CYC202), which inhibits CDK2, CDK7, and CDK9, has been studied in nasopharyngeal carcinoma and NSCLC and is currently being studied in combination with sapacitabine in patients with BRCA mutations. CYC065, which inhibits CDK2 and CDK9, is in early clinical development. Despite extensive efforts, to date there are no approved drugs that selectively target CDK2. Cicenas et al. Highlights of the LatestAdvances in Research on CDK Inhibitors. Cancers , (2014) 6:2224-2242.

[0009] There remains a need to discover CDK inhibitors with new activity profiles, such as selective CDK2 inhibitors, which can be used to treat cancer or other proliferative diseases or disorders. Specifically, CDK2 inhibitors can be used to treat CCNE1 or CCNE2 amplified tumors.

[0010] Brief description of the invention

[0011] The present invention provides, in part, compounds of formula (I) and pharmaceutically acceptable salts thereof. Such compounds can inhibit the activity of CDK (including CDK2), thereby affecting biological functions. In certain embodiments, the present invention provides compounds that are selective for CDK2. Pharmaceutical compositions and drugs are also provided, which contain compounds or salts of the present invention alone or in combination with additional anticancer therapeutic agents.

[0012] The present invention also provides, in part, methods of making the compounds, pharmaceutically acceptable salts and compositions of the present invention, as well as methods of using the foregoing.

[0013] In one aspect, the present invention provides a compound of formula (I):

[0014]

[0015] or a pharmaceutically acceptable salt thereof, wherein:

[0016] R 1Yes-L 1 -(5-10 membered heteroaryl) or -L 1 -(C6-C 12 aryl), wherein the 5-10 membered heteroaryl or C6-C 12 The aryl group is optionally substituted with one or more R 4 replace;

[0017] R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by one or more R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by one or more R 6 replace; or

[0018] R 2 and R 3 Together with the N-atom to which they are attached, they form a 4-6 membered heterocyclic group, the heterocyclic group optionally containing a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclic group is optionally replaced by one or more R 8 replace;

[0019] Each L 1 and L 2 is independently a bond or optionally substituted by one or more R 9 Substituted C1-C2 alkylene;

[0020] Each R 4 are independently F, Cl, OH, CN, NR 10 R 11 , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O)NR 10 R 11 、SO2R 12 、SO(=NH)R 12 or SO2NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 replace;

[0021] Each R 5 are independently OH, C1-C4 alkoxy or NR 10 R 11;

[0022] Each R 6 are independently F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 replace;

[0023] R 7 is H, C1-C4 alkyl or C(O)-C1-C4 alkyl;

[0024] Each R 8 are independently F, OH, C1-C4 alkyl, C1-C4 alkoxy or CN;

[0025] Each R 9 are independently F, OH or C1-C2 alkyl;

[0026] Each R 10 and R 11 are independently H or C1-C4 alkyl;

[0027] Each R 12 is C1-C4 alkyl or C3-C6 cycloalkyl;

[0028] Each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 ;

[0029] Each R 14 and R 15 are independently H or C1-C4 alkyl; and

[0030] q is 0, 1, or 2.

[0031] In another aspect, the present invention provides a compound of formula (II):

[0032]

[0033] or a pharmaceutically acceptable salt thereof, wherein:

[0034] R 1 , R 2 and R 3 As defined for formula (I).

[0035] In another aspect, the present invention provides a compound of formula (III):

[0036]

[0037] or a pharmaceutically acceptable salt thereof, wherein:

[0038] R 1 , R 2 and R 3 As defined for formula (I).

[0039] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention according to any formula described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0040] The present invention also provides methods and uses of treatment, which comprise administering the compound of the present invention or a pharmaceutically acceptable salt thereof to a subject.

[0041] In one aspect, the present invention provides a method for treating abnormal cell growth, particularly cancer, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be administered as a single agent, or can be administered in combination with other anti-cancer therapeutic agents, particularly with standard of care agents applicable to a particular cancer.

[0042] In another aspect, the present invention provides a method of treating abnormal cell growth, particularly cancer, in a subject in need thereof, comprising administering to the subject an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional anti-cancer therapeutic agent, said amounts together being effective to treat the abnormal cell growth.

[0043] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating a subject in need of such treatment. In certain embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating abnormal cell growth, particularly cancer, in a subject.

[0044] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for treating abnormal cell growth, particularly cancer, in a subject.

[0045] In another aspect, the present invention provides a pharmaceutical composition for treating abnormal cell growth, particularly cancer, in a subject in need thereof, the pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0046] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament, particularly for use in the treatment of abnormal cell growth such as cancer.

[0047] In another aspect, the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating abnormal cell growth, such as cancer, in a subject.

[0048] In another aspect, the present invention provides a method for treating a disorder mediated by CDK2 in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to treat the disorder, particularly cancer.

[0049] Each embodiment of compounds of the invention described below may be combined with one or more other embodiments of compounds of the invention described herein that are not inconsistent with the embodiment with which it is combined.

[0050] In addition, each embodiment describing the invention below contemplates within its scope pharmaceutically acceptable salts of the compounds of the invention.Thus, the phrase "or a pharmaceutically acceptable salt thereof" is implicit in the description of all compounds described herein unless expressly indicated to the contrary. BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Figure 1 Propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H Single crystal X-ray structure of 5-pyrazol-5-yl] cyclopentyl ester monohydrate (Form 1).

[0053] Figure 2 Propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H PXRD spectrum of 5-pyrazol-5-yl]cyclopentyl ester monohydrate (Form 1). DETAILED DESCRIPTION OF THE INVENTION

[0055] The present invention can be more easily understood by reference to the following detailed description of preferred embodiments of the present invention and the examples included herein. It should be understood that the terms used herein are only used for the purpose of describing specific embodiments and are not intended to be limiting. It should be further understood that unless explicitly defined herein, the terms used herein should be given their conventional meanings known in the relevant art.

[0056] As used herein, the singular forms "a", "an" and "the" include plural forms unless otherwise indicated. For example, "a" or "an" substituent includes one or more substituents.

[0057] The invention described herein can be suitably practiced in the absence of any element not expressly disclosed herein. Thus, for example, in each instance herein, any one of the terms "comprising," "consisting essentially of," and "consisting of" may be replaced by any one of the other two terms.

[0058] "Alkyl" means a saturated monovalent aliphatic hydrocarbon radical, including straight and branched chain radicals having the specified number of carbon atoms. Alkyl substituents typically contain 1 to 12 carbon atoms ("C1-C 12 The term "alkyl" may be used interchangeably with the term "alkyl" or "Ci-Ci-alkyl" and may be any of a plurality of carbon atoms, typically 1 to 8 carbon atoms (a "C1-C8 alkyl"), or more typically 1 to 6 carbon atoms (a "C1-C6 alkyl"), 1 to 5 carbon atoms (a "C1-C5 alkyl"), 1 to 4 carbon atoms (a "C1-C4 alkyl"), or 1 to 2 carbon atoms (a "C1-C2 alkyl"). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl, and the like. Preferred C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, and tert-butyl. Preferred C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

[0059] The alkyl groups described herein as optionally substituted may be substituted with one or more substituents, as further defined by the claims herein. Unless otherwise indicated, such optional substituents are independently selected. To the extent that such substitutions are chemically meaningful, the total number of substituents may be equal to the total number of hydrogen atoms on the alkyl group. The optionally substituted alkyl groups typically contain 1-6 optional substituents, sometimes 1-5 optional substituents, 1-4 optional substituents, or preferably 1-3 optional substituents.

[0060] Exemplary substituents on the alkyl group include halogen, -OH, C1-C4 alkoxy or NR x R y , where each R x and R y is independently H or C1-C4 alkyl. It should be understood that NR x R y It is generally used herein to refer to an amino substituent as defined in the claims (e.g., NR 10 R 11 As an optional substituent R 5 part, or NR14 R 15 As an optional substituent R 13 In some cases, a substituted alkyl group is specifically named by reference to the substituent. For example, "haloalkyl" means an alkyl group having a specified number of carbon atoms, which is substituted with one or more halogen substituents, and typically contains 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, or 1-2 carbon atoms and 1, 2, or 3 halogen atoms (i.e., "C1-C5 haloalkyl", "C1-C4 haloalkyl", or "C1-C2 haloalkyl").

[0061] More specifically, the fluorinated alkyl group may be specifically referred to as a "fluoroalkyl" group (e.g., C1-C6, C1-C5, C1-C4 or C1-C2 fluoroalkyl), which is typically substituted with 1, 2 or 3 fluorine atoms. For example, C1-C4 fluoroalkyl groups include trifluoromethyl (-CF3), difluoromethyl (-CF2H), fluoromethyl (-CFH2), difluoroethyl (-CH2CF2H) and the like. Such groups may be further substituted with optional substituents as further described herein. Similarly, groups substituted with -OH, C1-C4 alkoxy or NR x R y Substituted alkyl groups may be referred to as "hydroxyalkyl," "alkoxyalkyl," or "aminoalkyl," in each case having the designated number of carbon atoms.

[0062] In certain embodiments of the invention, alkyl and fluoroalkyl are optionally substituted with one or more optional substituents, and preferably with 1-4, 1-3 or 1-2 optional substituents.

[0063] " Alkylene " used in this article represents a divalent hydrocarbon radical with a specified number of carbon atoms, which can link two other groups together. Such a group can be referred to as, for example, C1-C6 alkylene, C1-C4 alkylene, C1-C2 alkylene etc. In the case of a designation, alkylene can also be substituted by other groups, and can include one or more unsaturation (i.e., alkenylene or alkynylene groups) or rings. The open valence of alkylene need not be located at the opposite end of the chain. Branched chain alkylene can include-CH (Me)-,-CH2CH (Me)- and-C (Me)2-, which are also included in the scope of the term alkylene. When alkylene is described as optionally substituted, substituents include those as described herein. For example, C1-C2 alkylene can be methylene or ethylene.

[0064] "Alkoxy" means a monovalent -O-alkyl group, wherein the alkyl portion has a specified number of carbon atoms. Alkoxy groups typically contain 1-8 carbon atoms ("C1-C8 alkoxy"), or 1-6 carbon atoms ("C1-C6 alkoxy"), or 1-4 carbon atoms ("C1-C4 alkoxy"). For example, C1-C4 alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy (i.e., -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3), etc. Alkoxy groups may optionally be substituted with one or more halogen atoms and in particular one or more fluorine atoms, up to the total number of hydrogen atoms present on the alkyl portion. Such groups may be referred to as "haloalkoxy" (or, in the case of fluorine, more specifically "fluoroalkoxy") groups having the specified number of carbon atoms and substituted with one or more halogen substituents, typically such groups contain 1-6 carbon atoms, preferably 1-4 carbon atoms and sometimes 1-2 carbon atoms and 1, 2 or 3 halogen atoms (i.e., "C1-C6 haloalkoxy", "C1-C4 haloalkoxy" or "C1-C2 haloalkoxy"). More specifically, fluorinated alkyl groups may be specifically referred to as "fluoroalkoxy" groups, for example, C1-C6, C1-C4 or C1-C2 fluoroalkoxy, which are typically substituted with 1, 2 or 3 fluorine atoms. Thus, C1-C4 fluoroalkoxy includes, but is not limited to, trifluoromethyloxy (-OCF3), difluoromethyloxy (-OCF2H), fluoromethyloxy (-OCFH2), difluoroethyloxy (-OCH2CF2H), and the like.

[0065] "Cycloalkyl" means a non-aromatic saturated carbocyclic ring system containing a specified number of carbon atoms, which can be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system connected to the base molecule through the carbon atoms of the cycloalkyl ring. Typically, the cycloalkyl of the present invention contains 3-8 carbon atoms ("C3-C8 cycloalkyl"), preferably 3-7 carbon atoms ("C3-C7 cycloalkyl") or 3-6 carbon atoms ("C3-C6 cycloalkyl"). Representative examples of cycloalkyl rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, etc. Cycloalkyl can be optionally substituted, unsubstituted, or substituted by the groups described herein.

[0066] The terms "heterocyclyl" or "heterocyclic" are used interchangeably to refer to a non-aromatic saturated ring system containing the specified number of ring atoms, which contains at least one heteroatom selected from N, O and S as a ring member, wherein the ring S atoms are optionally substituted with one or two oxo groups (i.e., S(O) q, wherein q is 0, 1 or 2) and wherein the heterocycle is attached to the base molecule via a ring atom (which may be C or N). Where expressly indicated, such heterocycles may be partially unsaturated. Heterocycles include spiro, bridged or fused rings formed with one or more other heterocycles or carbocycles, wherein such spiro, bridged or fused rings may themselves be saturated, partially unsaturated or aromatic to the extent that the unsaturation or aromaticity is chemically meaningful, provided that the point of attachment to the base molecule is an atom of the heterocycle portion of the ring system. Preferably, the heterocycle contains 1-4 atoms selected from N, O and S(O) q as ring members, and more preferably 1 to 2 ring heteroatoms, provided that such heterocyclic ring does not contain two adjacent oxygen atoms.

[0067] Heterocyclyl is unsubstituted or substituted with a suitable substituent as described herein. Such a substituent may be present on a heterocycle attached to the base molecule, or on a spirocycle, bridged ring or fused ring attached thereto. In addition, the ring N atom is optionally substituted with a group suitable for amines (e.g., alkyl, acyl, carbamoyl, sulfonyl, etc.).

[0068] As defined herein, heterocycle typically includes 3-8 membered heterocyclyls, and more preferably 4-7 or 4-6 membered heterocyclyls.

[0069] Illustrative examples of saturated heterocycles include, but are not limited to:

[0070]

[0071] .

[0072] In certain embodiments, the heterocyclic group contains 3-8 ring members, including carbon and non-carbon heteroatoms, and often 4-7 or 4-6 ring members. In certain embodiments, the substituents comprising a 4-7 membered heterocyclic ring are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl rings, each of which is optionally substituted as described herein to the extent that such substitution makes chemical sense.

[0073] In certain embodiments of the present invention, cycloalkyl and heterocyclyl are optionally substituted with one or more optional substituents as described herein.

[0074] It will be appreciated that, except where an oxo group is attached to S to form a sulfonyl group, or in the case of certain heteroaromatic rings such as triazole, tetrazole, oxadiazole, thiadiazole, triazine, etc., generally no more than two N, O or S atoms are attached in sequence.

[0075] "Aryl" or "aromatic" means an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having the well-known aromatic characteristics, wherein at least one ring contains a completely conjugated π-electron system. Typically, an aryl group contains 6-20 carbon atoms ("C6-C 20 aryl") as ring members, preferably 6 to 14 carbon atoms ("C6-C 14 aryl”) or more preferably 6 to 12 carbon atoms (“C6-C 12 Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl or heteroaryl ring or to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the base molecule on such a fused ring system is an atom of the aromatic portion of the ring system. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. Aryl groups are unsubstituted or substituted as further described herein.

[0076] Similarly, "heteroaryl" or "heteroaromatic" represents a monocyclic or fused bicyclic or polycyclic ring system with known aromaticity characteristics, which contains a specified number of ring atoms as defined above under "aryl", which includes at least one heteroatom selected from N, O and S as the ring members in the aromatic ring. Heteroatomic inclusion allows the aromaticity of 5-membered rings and 6-membered rings. Usually, heteroaryl contains 5-12 ring atoms ("5-12 yuan of heteroaryl"), and more preferably 5-10 ring atoms ("5-10 yuan of heteroaryl"). The heteroaryl ring is connected to the base molecule by the ring atoms of the heteroaromatic ring, thereby keeping aromaticity. Therefore, the 6-membered heteroaryl ring can be connected to the base molecule by the ring C atom, and the 5-membered heteroaryl ring can be connected to the base molecule by the ring C or N atom. Heteroaryl can also be fused to another aryl or heteroaryl ring, or to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the base molecule on such a fused ring system is an atom of the heteroaromatic portion of the ring system. Examples of unsubstituted heteroaryl include, but are not limited to, pyrazole, triazole, isoxazole, oxazole, thiazole, thiadiazole, imidazole, pyridine, pyrazine, indazole and benzimidazole. Other heteroaryl groups include pyrrole, furan, thiophene, oxadiazole, tetrazole, pyridazine, pyrimidine, benzofuran, benzothiophene, indole, quinoline, isoquinoline, purine, triazine, naphthyridine and carbazole. In common embodiments, 5- or 6-membered heteroaryl is a pyrazole, triazole, isoxazole, oxazole, thiazole, thiadiazole, imidazole, pyridine or pyrazine ring. Heteroaryl is unsubstituted or substituted as further described herein.

[0077] Aryl and heteroaryl groups described herein as optionally substituted may be substituted with one or more substituents, which are independently selected unless otherwise noted. To the extent that such substitutions are chemically meaningful and to the extent that aromaticity is maintained in the case of aryl and heteroaryl rings, the total number of substituents may be equal to the total number of hydrogen atoms on the aryl, heteroaryl or heterocyclyl group. An optionally substituted aryl or heteroaryl group typically contains 1-5 optional substituents, sometimes 1-4 optional substituents, preferably 1-3 optional substituents, or more preferably 1-2 optional substituents (as described herein).

[0078] Examples of monocyclic heteroaryl groups include, but are not limited to:

[0079]

[0080]

[0081] Illustrative examples of fused heteroaryl groups include, but are not limited to:

[0082]

[0083]

[0084]

[0085]

[0086] "Hydroxyl" means an OH group.

[0087] "Cyano" means a -C≡N group.

[0088] "Unsubstituted amino" refers to the group -NH2. Where amino is described as substituted or optionally substituted, the term includes -NR x R y A group of the form R x and R y Each is as further defined herein. For example, "alkylamino" means the group -NR x R y , where R x and R y One of the groups is an alkyl group and the other is H, and "dialkylamino" means -NR x R y , where R x and R y are all alkyl groups, wherein the alkyl group has the specified number of carbon atoms (e.g., -NH-C1-C4 alkyl or -N(C1-C4 alkyl)2). It should be understood that NR x Ry Typically used to represent an amino substituent as defined in the claims (e.g., NR 10 R 11 As an optional substituent R 5 part, or NR 14 R 15 As an optional substituent R 13 part).

[0089] "Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine (F, Cl, Br, I). Preferably, halogen refers to fluorine or chlorine (F or Cl).

[0090] "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

[0091] The terms "optionally substituted" and "substituted or unsubstituted" are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or that the group may have one or more non-hydrogen substituents (i.e., substituted). If not otherwise indicated, the total number of substituents that may be present is equal to the number of H atoms present in the unsubstituted form of the group being described. In the case where the optional substituents are attached via a double bond (such as an oxo (=O) substituent), the group takes up two available valences, so the total number of other substituents included is reduced by 2. In the case where the optional substituents are independently selected from the alternative list, the selected groups are the same or different. Throughout the disclosure, it is understood that the number and nature of the optional substituents will be limited to the extent that such substitutions make chemical sense.

[0092] Often, groups described herein as being optionally substituted with "one or more" substituents are optionally substituted with 1-4 such substituents, preferably optionally substituted with 1-3 such substituents, and more preferably optionally substituted with 1-2 such substituents. The description herein of a group "optionally substituted with one or more of the optional substituent list" can be replaced with "optionally substituted with 1-4 such optional substituents," "optionally substituted with 1-3 such optional substituents," "optionally substituted with 1-2 such optional substituents," "optionally substituted with 1, 2, 3 or 4 such optional substituents," "optionally substituted with 1, 2 or 3 such optional substituents," or "optionally substituted with 1 or 2 such optional substituents."

[0093] In one aspect, the present invention provides a compound of formula (I):

[0094]

[0095] or a pharmaceutically acceptable salt thereof, wherein:

[0096] R 1 Yes-L 1 -(5-10 membered heteroaryl) or -L 1 -(C6-C 12 aryl), wherein the 5-10 membered heteroaryl or C6-C 12 The aryl group is optionally substituted with one or more R 4 replace;

[0097] R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by one or more R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by one or more R 6 replace; or

[0098] R 2 and R 3 Together with the N-atom to which they are attached, they form a 4-6 membered heterocyclic group, the heterocyclic group optionally containing a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclic group is optionally replaced by one or more R 8 replace;

[0099] Each L 1 and L 2 is independently a bond or optionally substituted by one or more R 9 Substituted C1-C2 alkylene;

[0100] Each R 4 are independently F, Cl, OH, CN, NR 10 R 11 , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O)NR 10 R 11 、SO2R 12 、SO(=NH)R 12 or SO2NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 replace;

[0101] Each R5 are independently OH, C1-C4 alkoxy or NR 10 R 11 ;

[0102] Each R 6 are independently F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 replace;

[0103] R 7 is H, C1-C4 alkyl or C(O)-C1-C4 alkyl;

[0104] Each R 8 are independently F, OH, C1-C4 alkyl, C1-C4 alkoxy or CN;

[0105] Each R 9 are independently F, OH or C1-C2 alkyl;

[0106] Each R 10 and R 11 are independently H or C1-C4 alkyl;

[0107] Each R 12 is C1-C4 alkyl or C3-C6 cycloalkyl;

[0108] Each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 ;

[0109] Each R 14 and R 15 are independently H or C1-C4 alkyl; and

[0110] q is 0, 1, or 2.

[0111] The compounds of formula (I) are characterized by a cis relationship between the substituents at the 1- and 3-positions of the cyclopentyl ring. The compounds of formula (I) may be present with cis relative configurations at the 1- and 3-positions (i.e., ( 1R,3S )or( 1S,3R )) or a mixture in the form of cis enantiomers, such as ( 1R,3S )and( 1S,3R )'s racemic mixture.

[0112] In the compound of formula (I), R 1 Yes-L1 -(5-10 membered heteroaryl) or -L 1 -(C6-C 12 aryl), wherein the 5-10 membered heteroaryl or C6-C 12 The aryl group is optionally substituted with one or more R 4 replace.

[0113] In certain embodiments, R 1 Yes-L 1 -(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 In certain such embodiments, the 5-10 membered heteroaryl is pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl or benzimidazolyl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 In certain embodiments, the 5-10 membered heteroaryl is optionally substituted with one or more R 4 In a specific embodiment, the 5-10 membered heteroaryl is optionally substituted with one or more R 4 In other embodiments, the 5-10 membered heteroaryl is optionally substituted with one or more R 4 In other embodiments, the 5-10 membered heteroaryl is isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl or benzimidazolyl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 In certain embodiments, the 5-10 membered heteroaryl is optionally substituted with one or more R 4 In a specific embodiment, the 5-10 membered heteroaryl is optionally substituted with one or more R 4 In other embodiments, the 5-10 membered heteroaryl is thiazolyl, thiadiazolyl or imidazolyl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 In other embodiments, the 5-10 membered heteroaryl is pyridyl, pyrazinyl, indazolyl or benzimidazolyl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 In certain embodiments of each of the foregoing, the 5-10 membered heteroaryl is optionally substituted by 1, 2, 3 or 4 R 4 In certain embodiments of each of the foregoing, the 5-10 membered heteroaryl is optionally substituted with 1 or 2 R 4 replace.

[0114] In other embodiments, R 1Yes-L 1 -(C6-C 12 aryl), wherein the C6-C 12 The aryl group is optionally substituted with one or more R 4 In certain such embodiments, the C6-C 12 Aryl is optionally substituted with one or more R 4 In certain embodiments of each of the foregoing, the C6-C 12 The aryl group is optionally substituted with 1, 2, 3 or 4 R 4 In certain embodiments of each of the foregoing, the C6-C 12 The aryl group is optionally substituted with 1 or 2 R 4 replace.

[0115] In the compound of formula (I), L 1 is a bond or optionally one or more R 9 In certain such embodiments, the L 1 is a bond or is optionally substituted by 1, 2, 3 or 4 R 9 In certain such embodiments, L 1 is a bond or optionally 1 or 2 R 9 In certain such embodiments, L 1 is a bond, a methylene group or an ethylene group. In certain such embodiments, L 1 is a bond or a methylene group. In certain embodiments of each of the foregoing, L 1 is a bond. In other embodiments of each of the foregoing, L 1 is optionally replaced by one or more R 9 In certain such embodiments, the L 1 is optionally replaced by 1, 2, 3 or 4 R 9 In certain such embodiments, the L 1 is optionally replaced by 1 or 2 R 9 In certain such embodiments, L 1 is methylene or ethylene (ie, -CH2 or -CH2CH2-). In certain embodiments, L 1 It is a methylene group.

[0116] In the compound of formula (I), R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L 2 -(C3-C7 cycloalkyl) or -L 2-(4-7 membered heterocyclyl), wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by one or more R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by one or more R 6 Replacement; or R 2 and R 3 Together with the N-atom to which they are attached, they form a 4-6 membered heterocyclic group, the heterocyclic group optionally containing a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclic group is optionally replaced by one or more R 8 replace.

[0117] In certain embodiments, R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by one or more R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by one or more R 6 In certain such embodiments, the C1-C6 alkyl and C1-C6 fluoroalkyl groups are optionally substituted by 1, 2, 3 or 4 R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by 1, 2, 3 or 4 R 6 In certain such embodiments, the C1-C6 alkyl and C1-C6 fluoroalkyl groups are optionally substituted with 1 or 2 R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by 1 or 2 R 6 replace.

[0118] In certain embodiments, R 2 and R 3 are independently H, C1-C6 alkyl or C1-C6 fluoroalkyl, wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl is optionally substituted by one or more R 5 In certain such embodiments, each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by 1, 2, 3 or 4 R 5 In certain such embodiments, each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by 1 or 2 R 5 In certain embodiments, R 2 and R 3are independently H, C1-C6 alkyl or C1-C6 fluoroalkyl. 2 is H and R 3 is C1-C6 alkyl or C1-C6 fluoroalkyl. 2 is H and R 3 is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH2CH2CH3, CH(CH3)CH2CH3, CH2CH(CH3)2, or C(CH3)3.

[0119] In other embodiments, R 2 and R 3 Independently H, -L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C3-C7 cycloalkyl and 4-7 membered heterocyclyl is optionally substituted by one or more R 6 In certain such embodiments, R 2 is H and R 3 Yes-L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C3-C7 cycloalkyl and 4-7 membered heterocyclyl is optionally substituted by one or more R 6 In certain embodiments, R 2 is H and R 3 Yes-L 2 -(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl is optionally substituted by one or more R 6 In certain embodiments of each of the foregoing, each of the C3-C7 cycloalkyl and 4-7 membered heterocyclyl groups is optionally substituted by 1, 2, 3 or 4 R 6 In certain embodiments of each of the foregoing, each of the C3-C7 cycloalkyl and 4-7 membered heterocyclyl groups is optionally substituted by 1 or 2 R 6 In certain such embodiments, each R 6 It is CH3.

[0120] In the compound of formula (I), L 2 is a bond or optionally one or more R 9 In certain such embodiments, the L 2 is a bond or is optionally substituted by 1, 2, 3 or 4 R 9 In certain such embodiments, L 2 is a bond or optionally 1 or 2 R 9In certain such embodiments, L 2 is a bond, a methylene group or an ethylene group. In certain such embodiments, L 2 is a bond or a methylene group. In certain embodiments of each of the foregoing, L 2 is a bond. In other embodiments of each of the foregoing, L 2 is optionally replaced by one or more R 9 In certain such embodiments, L 2 is optionally replaced by 1, 2, 3 or 4 R 9 In certain such embodiments, L 2 is optionally replaced by 1 or 2 R 9 In certain such embodiments, L 2 is methylene or ethylene (ie, -CH2 or -CH2CH2-). In certain embodiments, L 2 It is a methylene group.

[0121] In certain embodiments, R 2 and R 3 Together with the N-atom to which they are attached, they form a 4-6 membered heterocyclic group, the heterocyclic group optionally containing a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclic group is optionally replaced by one or more R 8 substituted, and wherein q is 0, 1 or 2. In certain such embodiments, the 4-6 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 R 8 In certain such embodiments, the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R 8 replace.

[0122] In certain such embodiments, R 2 and R 3 Together with the N-atom to which they are attached, they form an optionally substituted 4-6 membered heterocyclic group, which optionally contains a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each optionally substituted by one or more R 8 In certain such embodiments, R 2 and R 3 Together with the N-atom to which they are attached, they form an azetidinyl or pyrrolidinyl group, each optionally substituted by one or more R 8In a specific embodiment, R 2 and R 3 Together with the N-atom to which they are attached, they form a 8 In certain embodiments of each of the foregoing, the 4-6 membered heterocyclyl is optionally substituted by 1, 2, 3 or 4 R 8 In certain embodiments of each of the foregoing, the 4-6 membered heterocyclyl is optionally substituted by 1 or 2 R 8 In certain such embodiments, each R 8 It is CH3.

[0123] In the compound of formula (I), each R 4 are independently F, Cl, OH, CN, NR 10 R 11 , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O)NR 10 R 11 、SO2R 12 、SO(=NH)R 12 or SO2NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 In certain embodiments, each R 4 is independently C1-C4 alkyl or C1-C4 alkoxy, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 In certain such embodiments, each R 13 In certain embodiments of each of the foregoing, each C1-C4 alkyl and C1-C4 fluoroalkyl is optionally replaced by 1, 2, 3 or 4 R 13 In certain embodiments of each of the foregoing, each C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted with 1 or 2 R 13 In a specific embodiment, each R 4 (or by R 13 Replaced by R 4 ) are independently CH3, OCH3 or CH2OCH3.

[0124] In the compound of formula (I), each R 5 are independently OH, C1-C4 alkoxy or NR 10 R 11 In certain such embodiments, each R 5 independently OH, OCH3, NH2, NHCH3 or N(CH3)2.

[0125] In the compound of formula (I), each R 6 are independently F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 In certain embodiments, each R 6 is independently C1-C4 alkyl or C1-C4 alkoxy, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 In certain embodiments of each of the foregoing, each C1-C4 alkyl group is optionally substituted with 1, 2, 3 or 4 R 13 In certain embodiments of each of the foregoing, each C1-C4 alkyl group is optionally substituted with 1 or 2 R 13 In certain such embodiments, R 13 is CH3 or OCH3. In certain embodiments, each R 6 is independently CH3, OCH3 or CH2OCH3. In certain embodiments, each R 6 is independently CH3.

[0126] In the compound of formula (I), R 7 is H, C1-C4 alkyl or C(O)-C1-C4 alkyl. 7 It is H, CH3 or C(O)CH3.

[0127] In the compound of formula (I), each R 8 is independently F, OH, C1-C4 alkyl, C1-C4 alkoxy or CN. In certain embodiments, each R 8 is independently F, OH, CH3, OCH3 or CN. In a specific embodiment, each R 8 It is CH3.

[0128] In the compound of formula (I), each R 9 is independently F, OH or C1-C2 alkyl. 9 is F, OH or CH3. In certain embodiments, R 9 is F, OH or CH3. In certain embodiments, L 1 and L 2 is a bond or an unsubstituted C1-C2 alkylene group and R 9 Does not exist.

[0129] In the compound of formula (I), each R10 and R 11 is independently H or C1-C4 alkyl. In certain embodiments, each R 10 and R 11 are independently H or CH3.

[0130] In the compound of formula (I), each R 12 is C1-C4 alkyl or C3-C6 cycloalkyl. In a specific embodiment, each R 12 It is CH3, CH2CH3, CH2CH2CH3, CH(CH3)2 or cyclopropyl.

[0131] In the compound of formula (I), each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 In certain embodiments, each R 13 are independently OH, OCH3 or NR 14 R 15 , where R 14 and R 15 is independently H or CH3. In a specific embodiment, each R 13 independently OH, OCH3, NH2, NHCH3 or N(CH3)2.

[0132] In the compound of formula (I), each R 14 and R 15 are independently H or C1-C4 alkyl. In certain embodiments, R 14 and R 15 are independently H or CH3.

[0133] In certain embodiments, the compound of Formula (I) has the absolute stereochemistry as shown in Formula (II):

[0134]

[0135] or a pharmaceutically acceptable salt thereof, wherein:

[0136] R 1 , R 2 and R 3 As defined for formula (I).

[0137] In certain embodiments, the compound of Formula (I) has the absolute stereochemistry as shown in Formula (III):

[0138]

[0139] or a pharmaceutically acceptable salt thereof, wherein:

[0140] R 1 , R 2 and R 3 As defined for formula (I).

[0141] The compounds of formula (II) and (III) retain a cis relationship between the substituents at the 1- and 3-positions of the cyclopentyl ring, but are presented as the indicated enantiomers in substantially enantiomerically pure form.

[0142] Each aspect and embodiment described herein with respect to formula (I) also applies to compounds of formula (II) or (III).

[0143] In certain embodiments, the present invention provides a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein:

[0144] R 1 is optionally replaced by 1 or 2 R 4 Replaced by -L 1 -(5-10 membered heteroaryl);

[0145] R 2 and R 3 are independently H, C1-C6 alkyl, -L 2 -(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl is optionally substituted by one R 6 replace;

[0146] Each L 1 and L 2 is independently a bond or a methylene group;

[0147] Each R 4 are independently F, Cl, OH, CN, NR 10 R 11 , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O)NR 10 R 11 、SO2R 12 、SO(=NH)R 12 or SO2NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally replaced by one R 13 replace;

[0148] Each R 6 are independently F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR 10 R 11, wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally replaced by one R 13 replace;

[0149] Each R 10 and R 11 are independently H or C1-C4 alkyl;

[0150] Each R 12 is C1-C4 alkyl or C3-C6 cycloalkyl; and

[0151] Each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 .

[0152] In other embodiments, the present invention provides a compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein:

[0153] R 1 is optionally replaced by 1 or 2 R 4 Replaced by -L 1 -(5-10 membered heteroaryl);

[0154] R 2 and R 3 is independently H, C1-C6 alkyl or C3-C7 cycloalkyl optionally substituted with one C1-C4 alkyl;

[0155] L 1 are independently a bond or a methylene group; and

[0156] Each R 4 Independently is C1-C4 alkyl optionally substituted by OH or C1-C4 alkoxy.

[0157] In other embodiments, the present invention provides compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof having two or more of the following features:

[0158] R 1 Yes-L 1 -(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace;

[0159] R 2 and R 3 are independently H or C1-C6 alkyl;

[0160] L 1 is a bond or a C1-C2 alkylene group;

[0161] Each R 4is independently C1-C4 alkyl, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 replace;

[0162] Each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 ;and

[0163] Each R 14 and R 15 are independently H or C1-C4 alkyl.

[0164] In certain such embodiments, the present invention provides compounds of Formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following features:

[0165] R 1 is optionally replaced by one or more R 4 Replaced by -L 1 -(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl is pyrazolyl;

[0166] R 2 It is H;

[0167] R 3 is a C1-C6 alkyl group, preferably a C1-C4 alkyl group;

[0168] L 1 is the key;

[0169] Each R 4 is independently C1-C4 alkyl, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 replace;

[0170] Each R 13 are independently OH, OCH3 or NR 14 R 15 ;and

[0171] Each R 14 and R 15 are independently H or CH3.

[0172] In other embodiments, the present invention provides compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof having two or more of the following features:

[0173] R 1 Yes-L 1 -(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace;

[0174] R 2 and R 3 Independently H or -L 2 -(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl is optionally substituted by one or more R 6 replace;

[0175] L 1 is a bond or a C1-C2 alkylene group;

[0176] L 2 is a bond or a C1-C2 alkylene group;

[0177] Each R 4 is independently C1-C4 alkyl, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 replace;

[0178] Each R 6 are independently F, OH or C1-C4 alkyl;

[0179] Each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 ;and

[0180] Each R 14 and R 15 are independently H or C1-C4 alkyl.

[0181] In other embodiments, the present invention provides compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof having two or more of the following features:

[0182] R 1 is optionally replaced by one or more R 4 Replaced by -L 1 -(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl is isoxazolyl;

[0183] L 1 is C1-C2 alkylene;

[0184] R 2 It is H;

[0185] R 3 is optionally replaced by one or more R 6 Replaced by -L 2 -(C3-C7 cycloalkyl);

[0186] L 2 is the key;

[0187] Each R 4is independently C1-C4 alkyl, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 replace;

[0188] Each R 6 are independently F, OH or C1-C4 alkyl;

[0189] Each R 13 are independently OH, C1-C4 alkoxy or NR 14 R 15 ;and

[0190] Each R 14 and R 15 are independently H or C1-C4 alkyl.

[0191] In another aspect, the present invention provides a compound selected from the compounds exemplified in Examples 1-649 inclusive, or a pharmaceutically acceptable salt thereof.

[0192] In another aspect, the present invention provides a compound selected from the group consisting of:

[0193] Propylcarbamic acid (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0194] Propan-2-ylcarbamic acid (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0195] Ethylcarbamic acid (1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0196] (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0197] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0198] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0199] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0200] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester;

[0201] (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate (isomer A);

[0202] (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate (isomer B);

[0203] Tert-butylcarbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0204] 2,2-Dimethylazetidine-1-carboxylic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0205] Propan-2-ylcarbamic acid (1R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester;

[0206] (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester;

[0207] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0208] (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl ester;

[0209] Tert-butylcarbamic acid (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl ester; and

[0210] (1-Methylcyclobutyl)carbamic acid R ,3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester;

[0211] or a pharmaceutically acceptable salt thereof.

[0212] In another aspect, the present invention provides a compound selected from the group consisting of:

[0213] Propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H-pyrazol-5-yl]cyclopentyl ester; and

[0214] Propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester;

[0215] or a pharmaceutically acceptable salt thereof.

[0216] In another aspect, the present invention provides propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl] cyclopentyl ester or a pharmaceutically acceptable salt thereof.

[0217] In another aspect, the present invention provides propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl] cyclopentyl ester.

[0218] In another aspect, the present invention provides propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl] cyclopentyl ester.

[0219] In certain embodiments, the present invention provides propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl] cyclopentyl ester monohydrate (Form 1). In certain such embodiments, the monohydrate (Form 1) is characterized by a powder X-ray diffraction (PXRD) pattern (2θ) comprising the following peaks:

[0220] (a) 1, 2, 3, 4, 5 or more peaks selected from the peaks in Table 1 (measured in °2θ±0.2°2θ); (b) 1, 2, 3, 4 or 5 peaks selected from 10.4, 11.7, 12.9, 18.2 and 24.2 (measured in °2θ±0.2°2θ); (c) any two peaks selected from 10.4, 11.7, 12.9, 18.2 and 24.2 (measured in °2θ±0.2°2θ); (d) any three peaks selected from 10.4, 11.7, 12.9, 18.2 and 24.2 (measured in °2θ±0.2°2θ); (e) any four peaks selected from 10.4, 11.7, 12.9, 18.2 and 24.2 (measured in °2θ±0.2°2θ); (f) peaks at 10.4, 11.7, 12.9, 18.2 and 24.2 (measured in °2θ±0.2°2θ); (g) 1 peak at 10.4, and 1, 2, 3 or 4 peaks selected from 11.7, 12.9, 18.2 and 24.2 (in ° 2θ ± 0.2 ° 2θ); (h) 1 peak at 11.7, and 1, 2, 3 or 4 peaks selected from 10.4, 12.9, 18.2 and 24.2 (in ° 2θ ± 0.2 ° 2θ); (i) 1 peak at 12.9, and 1, 2, 3 or 4 peaks selected from 10.4, 11.7, 18.2 and 24.2 (in ° 2θ ± 0.2 ° 2θ); (j) 1 peak at 18.2, and 1, 2, 3 or 4 peaks selected from 10.4, 11.7, 12.9 and 24.2 (in ° 2θ ± 0.2 ° 2θ); (k) 1 peak at 24.2, and 1, 2, 3 or 4 peaks selected from 10.4, 11.7, 12.9 and 18.2 (in ° 2θ ± 0.2 ° 2θ); or (l) substantially the same as the peaks at Figure 2 The same peaks at 2θ values ​​are shown in .

[0221] In another embodiment, the present invention provides (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl) cyclopentyl ester or a pharmaceutically acceptable salt thereof.

[0222] In another embodiment, the present invention provides (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester.

[0223] In another embodiment, the present invention provides (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester.

[0224] In one embodiment, the present invention provides a compound having the following structure:

[0225]

[0226] or a pharmaceutically acceptable salt thereof.

[0227] In another specific embodiment, the present invention provides a compound having the following structure:

[0228]

[0229] or a pharmaceutically acceptable salt thereof.

[0230] In preferred embodiments, the compounds of the invention are selective inhibitors of CDK2, i.e., they have a lower inhibition constant (e.g., Ki or IC) for CDK2 relative to other enzyme targets. 50 ). Emerging data suggest that GSK3β inhibition may be associated with gastrointestinal toxicity, which has been observed with some CDK inhibitors. Compounds that are selective inhibitors of CDK2 relative to GSK3β may offer an improved safety profile, improved dosing schedules (e.g., by reducing the need for dose reductions or dosing holidays), and / or enhanced overall efficacy due to the potential for higher doses, application of continuous dosing regimens, and / or extended overall treatment duration. Similarly, selective inhibitors of CDK2 may have a reduced risk of certain hematologic toxicities that have been reported to be associated with inhibition of CDK6.

[0231] In certain embodiments, the compounds of the invention are selective for CDK2 relative to CDK1. In certain such embodiments, the compounds exhibit at least a 10-fold selectivity for CDK2 relative to CDK1. In other embodiments, the compounds exhibit at least a 20-fold selectivity for CDK2 relative to CDK1. In specific embodiments, the compounds exhibit at least a 30-fold selectivity for CDK2 relative to CDK1.

[0232] In certain embodiments, the compounds of the invention are selective for CDK2 relative to CDK4 and / or CDK6. In certain such embodiments, the compounds exhibit at least a 10-fold selectivity for CDK2 relative to CDK4 and / or CDK6. In other embodiments, the compounds exhibit at least a 20-fold selectivity for CDK2 relative to CDK4 and / or CDK6. In specific embodiments, the compounds exhibit at least a 30-fold selectivity for CDK2 relative to CDK4 and / or CDK6.

[0233] In certain embodiments, the compounds of the invention are selective for CDK2 relative to GSK3β. In certain such embodiments, the compounds exhibit at least a 10-fold selectivity for CDK2 relative to GSK3β. In other embodiments, the compounds exhibit at least a 20-fold selectivity for CDK2 relative to GSK3β. In specific embodiments, the compounds exhibit at least a 30-fold selectivity for CDK2 relative to GSK3β.

[0234] "Pharmaceutical composition" means a mixture of one or more compounds of the present invention or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof as an active ingredient and at least one pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent.

[0235] In one aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the pharmaceutical composition comprises two or more pharmaceutically acceptable carriers and / or excipients.

[0236] In certain embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent. In certain such embodiments, the combination provides an additive, greater than additive, or synergistic anti-cancer effect.

[0237] The term "additive" is used to mean that the result of the combination of two compounds, components, or targeting agents is no greater than the sum of each compound, component, or targeting agent alone.

[0238] The term "synergistic effect" or "synergistic" is used to refer to that the result of the combination of two compounds, components, or targeting agents is greater than the sum of each compound, component, or targeting agent alone. This improvement in the disease, condition, or disorder being treated is a "synergistic" effect. A "synergistic amount" is the amount of a combination of two compounds, components, or targeting agents that produces a synergistic effect, and "synergistic" is as defined herein.

[0239] Determine the synergistic interaction between one or two components, by administering the components within different dosage ranges and / or dosage ratios to patients in need of treatment, the optimal range of the effect and the absolute dosage range of each component of the effect can be ultimately measured. However, observations of synergy in in vitro or in vivo models can predict the effects in humans and other species, and as described herein, there are in vitro or in vivo models to measure synergistic effects. The results of such studies can also be used to predict effective doses and plasma concentration ratio ranges and the absolute doses and plasma concentrations required in humans and other species, for example, by applying pharmacokinetic and / or pharmacodynamic methods.

[0240] Unless otherwise indicated, all references herein to compounds of the invention include references to salts, solvates, hydrates and complexes thereof, and solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers and isotopically labeled forms thereof.

[0241] The compounds of the present invention may exist in the form of pharmaceutically acceptable salts, such as acid addition salts and base addition salts of compounds of one of the formulas provided herein. The term "pharmaceutically acceptable salts" as used herein refers to salts that retain the biological effectiveness and properties of the parent compound. Unless otherwise indicated, the phrase "pharmaceutically acceptable salts" as used herein includes salts of acidic or basic groups that may be present in compounds of the formulae disclosed herein.

[0242] For example, the compound of the present invention of basic nature can form multiple salts with various inorganic and organic acids. Although such salt must be pharmaceutically acceptable for use to animals, it is often necessary in practice to initially separate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt, and then the latter is simply converted back to the free base compound by treating with an alkaline agent, and subsequently the latter free base is converted into a pharmaceutically acceptable acid addition salt. By treating the base compound with a substantially equivalent amount of selected inorganic acid or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol, the acid addition salt of the base compound of the present invention can be prepared. After evaporating the solvent, the required solid salt is obtained. By adding a suitable inorganic acid or organic acid in the solution, the required acid salt can also be precipitated from the solution of the free base in an organic solvent.

[0243] Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts (i.e., salts containing a pharmacologically acceptable anion), such as the following salts: hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrose, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)] (i.e., pamoate).

[0244] Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1,4-dioate, calcium edetate, dextrorotatory camphorsulfonate, carbonate, chloride, hexanoate, octanoate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edislyate, etopoate, esylate, ethylsuccinate, formate, fumarate, glucoheptonate, gluconate, glutamate, glycolate, glycolyl p-aminophenylarsonic acid salt, heptanoate, hexyne-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride , gamma-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, metaphosphate, methane-sulfonate, methylsulfate, monohydrogen phosphate, mucate, naphthalenesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (pamoate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, 8-chlorotheophylline, toluenesulfonate, triethiodode, and valerate.

[0245] Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0246] In addition to the above-mentioned acids, the compounds of the present invention including a basic group such as an amino group can form pharmaceutically acceptable salts with various amino acids.

[0247] Alternatively, useful compounds of acidic nature may be able to form alkali salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, and particularly sodium and potassium salts. These salts are all prepared by conventional techniques. Chemical bases used as reagents to prepare pharmaceutically acceptable alkali salts of the present invention are those that form non-toxic alkali salts with the acidic compounds herein. These salts can be prepared by any suitable method, for example, by treating free acids with inorganic or organic bases such as amines (primary, secondary or tertiary amines), alkali metal hydroxides or alkaline earth metal hydroxides, etc. These salts can also be prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation, and then preferably evaporating the resulting solution to dryness under reduced pressure. Alternatively, they can also be prepared as follows: a lower alkanol solution of an acidic compound and a desired alkali metal alkoxide are mixed together, and then the resulting solution is evaporated to dryness in the same manner as before. In either case, it is preferred to use a stoichiometric amount of reagent to ensure the completeness of the reaction and the maximum yield of the desired final product.

[0248] Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of the compounds of the invention that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to, those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucosamine-(meglumine), and lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.

[0249] Hemisalts of acids and bases can also be formed, for example hemisulphate and hemicalcium salts.

[0250] For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention and for interconverting salt and free base forms are known to those skilled in the art.

[0251] The salts of the present invention can be prepared according to methods known to those skilled in the art. Pharmaceutically acceptable salts of the compounds of the present invention can be readily prepared by mixing the compound with a solution of an acid or base as appropriate. The salt can precipitate from the solution and can be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to almost non-ionized.

[0252] It will be appreciated by those skilled in the art that the compounds of the present invention in the form of free bases with basic functional groups can be converted into acid addition salts by treating with a stoichiometric excess of an appropriate acid. The acid addition salts of the compounds of the present invention can be converted back into the corresponding free bases by treating with a stoichiometric excess of a suitable base (such as potassium carbonate or sodium hydroxide), usually in the presence of an aqueous solvent and at a temperature of about 0°C to 100°C. The free base form can be separated in a conventional manner, for example, by extraction with an organic solvent. In addition, the acid addition salts of the compounds of the present invention can be interchanged by utilizing the differential solubility of the salt, the volatility or acidity of the acid, or by treating with an appropriately loaded ion exchange resin. For example, the interchange may be affected by the following factors: the salt of the compound of the present invention reacts with a slightly stoichiometric excess of an acid, the pK of the acid being lower than the acid component of the starting salt. The conversion is usually carried out at a temperature between about 0°C and the boiling point of the solvent used as the medium for the procedure. Similar exchanges may be carried out with base addition salts, usually by the intermediate intermediate of the free base form.

[0253] The compounds of the present invention may exist in unsolvated and solvated forms. When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry, independent of humidity. However, when the solvent or water is weakly bound (such as in channel solvates and hygroscopic compounds), the water / solvent content will depend on humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term 'solvate' is used herein to describe a molecular complex comprising a compound of the present invention and one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term 'hydrate' is used. Pharmaceutically acceptable solvates according to the present invention include hydrates and solvates in which the solvent of crystallization can be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.

[0254] Also included within the scope of the present invention are complexes such as clathrates, drug-host inclusion complexes, wherein, in contrast to the above-mentioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs containing two or more organic and / or inorganic components in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized or non-ionized. For a review of such complexes, see Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975), the disclosure of which is incorporated herein by reference in its entirety.

[0255] The present invention also relates to prodrugs of compounds of the formula provided herein. Therefore, certain derivatives of the compounds of the present invention, which may have little or no pharmacological activity themselves, may be converted into compounds of the present invention when administered to a patient, for example, by hydrolytic cleavage. Such derivatives are referred to as 'prodrugs'. For further information on the application of prodrugs, see 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (EB Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety.

[0256] For example, prodrugs according to the invention can be produced by replacing appropriate functional groups present in the compounds of the invention with certain groups known to the person skilled in the art as 'pro-moieties', as described, for example, in "Design of Prodrugs" by HBundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety.

[0257] Some non-limiting examples of prodrugs according to the present invention include:

[0258] (i) in case the compound contains a carboxylic acid function (-COOH), an ester thereof, for example, by replacing the hydrogen with a (C1-C8)alkyl group;

[0259] (ii) in case the compound contains an alcohol function (-OH), an ether thereof, for example, by replacing the hydrogen with a (C1-C6)alkanoyloxymethyl group or with a phosphate ether group; and

[0260] (iii) In case the compound contains a primary or secondary amino function (-NH2 or -NHR, where R≠H), its amide, for example, by replacing one or both hydrogens with a suitable metabolically labile group such as amide, carbamate, urea, phosphonate, sulfonate, etc.

[0261] Further examples of replacement groups according to the foregoing embodiments and examples of other prodrug types can be found in the aforementioned references.Finally, certain compounds of the invention may themselves act as prodrugs of other compounds of the invention.

[0262] Also included within the scope of the present invention are metabolites of the compounds of the formulae described herein, ie, compounds formed in vivo following administration of the drug.

[0263] In addition to the cis relationship between the substituents at the 1- and 3-positions of the cyclopentyl ring in formulae (I), (II) and (III), the compounds of the formulae provided herein may have an additional asymmetric carbon atom as defined by R 1 , R 2 and R 3 Substituents or moieties of optional substituents attached to these groups. At such additional asymmetric centers, solid lines are used to indicate that all possible stereoisomers are included at that carbon atom, while solid lines or dotted wedges indicate that only the isomer shown is intended to be included at such stereocenters, unless otherwise indicated. Compounds of the formulae herein may include substituents containing cis and trans geometric isomers, rotamers, atropisomers, conformers, and tautomers of the compounds of the invention, including compounds that exhibit more than one type of isomerism.

[0264] Also included are acid addition salts or base addition salts in which the counterion is optically active, for example, d-lactate or l-lysine, or racemic, for example, dl-tartrate or dl-arginine.

[0265] When any racemate is crystallized, two different types of crystals are possible. The first type is the racemic compound (true racemate) described above, in which one homogeneous form of crystal is produced, which contains equimolar amounts of the two enantiomers. The second type is a racemic mixture or conglomerate, in which two forms of crystal are produced in equimolar amounts, each containing a single enantiomer.

[0266] Compounds of the present invention can show tautomerism and structural isomerism. For example, the compound can exist in several tautomeric forms, including enol and imine forms and ketone and enamine forms, and geometric isomers and mixtures thereof. All such tautomeric forms are included in the scope of compounds of the present invention. Tautomers exist as mixtures of tautomeric sets in solution. In solid forms, usually a tautomer is dominant. Even if a tautomer can be described, the present invention includes all tautomers of the compounds of the formula provided.

[0267] In addition, some compounds of the invention may form atropisomers (e.g., substituted biaryls). Atropisomers are conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or greatly slowed (this is a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetric). The interconversion of atropisomers is slow enough to allow separation and isolation under predetermined conditions. The energy barrier to thermal racemization can be determined by steric hindrance to free rotation of one or more bonds forming a chiral axis.

[0268] Where the compounds of the invention contain an alkenyl or alkenylene group, geometric cis / trans (or Z / E) isomers are possible. Cis / trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.

[0269] Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

[0270] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, for example an alcohol, or with an acid or base such as tartaric acid or 1-phenylethylamine in the case where the compound contains an acidic or basic group. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers converted into the corresponding pure enantiomer by means well known to those skilled in the art.

[0271] The chiral compounds of the present invention (and chiral precursors thereof) can be obtained in an enantiomerically enriched form using chromatography (usually HPLC) on an asymmetric resin using a mobile phase consisting of a hydrocarbon, usually heptane or hexane, containing 0-50%, usually 2-20% isopropanol and 0-5% alkylamine, usually 0.1% diethylamine. The eluent is concentrated to obtain an enriched mixture.

[0272] Aggregates of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by EL Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.

[0273] The enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which indicates the extent to which a sample contains one enantiomer in a greater amount than the other enantiomer. A racemic mixture has 0% ee, while a single, completely pure enantiomer has 100% ee. Similarly, diastereomeric purity can be described in terms of diastereomeric excess (de). "Enantiomerically pure" or "substantially enantiomerically pure" as used herein refers to a compound that contains one enantiomer of the compound and is substantially free of the opposite enantiomer of the compound. A typical enantiomerically pure compound contains greater than about 95% by weight of one enantiomer of the compound and less than about 5% by weight of the opposite enantiomer of the compound, preferably greater than about 97% by weight of one enantiomer of the compound and less than about 3% by weight of the opposite enantiomer of the compound, more preferably greater than about 98% by weight of one enantiomer of the compound and less than about 2% by weight of the opposite enantiomer of the compound, and even more preferably greater than about 99% by weight of one enantiomer of the compound and less than about 1% by weight of the opposite enantiomer of the compound.

[0274] The present invention also includes isotopically labeled compounds which are identical to those depicted in one of the provided formulae, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

[0275] Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed.

[0276] Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H. 3 H. 13 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Certain isotopically labeled compounds of the invention, for example, wherein a radioactive isotope (such as 3 H and 14 C) are useful in drug and / or substrate tissue distribution assays. Because of their ease of preparation and detectability, tritiated (i.e.,3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred. Further, heavier isotopes (such as deuterium, i.e., 2 H) substitution may result in certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in certain circumstances. Isotopically labeled compounds of the invention may generally be prepared as follows: carrying out the procedures disclosed in the following schemes and / or examples and preparations by replacing a non-isotopically labeled reagent with an isotopically labeled reagent.

[0277] The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products or mixtures thereof. They can be obtained, for example, in the form of solid plugs, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave or radio frequency drying can be used for this purpose.

[0278] Treatments and uses

[0279] The present invention further provides methods and uses of treatment comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof, alone or in combination with other therapeutic or palliative agents.

[0280] In one aspect, the present invention provides a method for treating abnormal cell growth in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0281] In another aspect, the present invention provides a method for treating abnormal cell growth in a subject in need thereof, the method comprising administering to the subject an amount of a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with an amount of an additional therapeutic agent (e.g., an anti-cancer therapeutic agent) that together are effective to treat the abnormal cell growth.

[0282] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in treating abnormal cell growth in a subject.

[0283] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for treating abnormal cell growth in a subject.

[0284] In another aspect, the present invention provides a pharmaceutical composition for treating abnormal cell growth in a subject in need thereof, the pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

[0285] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use as a medicament, particularly for use in the treatment of abnormal cell growth.

[0286] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating abnormal cell growth in a subject.

[0287] In common embodiments of the methods provided herein, the abnormal cell growth is cancer.The compounds of the invention can be administered as a single agent, or can be administered in combination with other anti-cancer therapeutics, particularly with standard of care agents applicable to the particular cancer.

[0288] In certain embodiments, the provided methods produce one or more of the following effects: (1) inhibiting cancer cell proliferation; (2) inhibiting cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibiting cancer cell metastasis; or (5) inhibiting angiogenesis.

[0289] In another aspect, the present invention provides a method for treating a disorder mediated by CDK2 in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to treat the disorder, particularly cancer.

[0290] In certain aspects and embodiments of the compounds, compositions, methods and uses described herein, the compounds of the invention are more selective for CDK2 than other CDKs, particularly CDK1. In certain embodiments, the compounds of the invention are more selective for CDK2 than CDK4 and / or CDK6. In other aspects and embodiments, the compounds of the invention are more selective for CDK2 than glycogen synthase kinase 3β (GSK3β). The compounds of the invention include compounds of any formula described herein or pharmaceutically acceptable salts thereof.

[0291] In another aspect, the present invention provides a method of inhibiting the proliferation of cancer cells in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell proliferation.

[0292] In another aspect, the present invention provides a method of inhibiting cancer cell invasiveness in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell invasiveness.

[0293] In another aspect, the present invention provides a method of inducing apoptosis of cancer cells in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to induce apoptosis.

[0294] In another aspect, the present invention provides a method of inhibiting metastasis of cancer cells in a subject, the method comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit cell metastasis.

[0295] In another aspect, the present invention provides a method of inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to inhibit angiogenesis.

[0296] In the common embodiments of the methods provided herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC, SCLC, squamous cell carcinoma or adenocarcinoma), esophageal cancer, head and neck cancer, colorectal cancer, renal cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e., gastric) cancer or thyroid cancer. In other embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer or gastric cancer.

[0297] In other embodiments, the cancer is breast cancer, including, for example, ER-positive / HR-positive, HER2-negative breast cancer; ER-positive / HR-positive, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In certain embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer that exhibits primary or acquired resistance to CDK4 / CDK6 inhibition. In certain embodiments, the breast cancer is advanced or metastatic breast cancer. In certain embodiments of each of the foregoing, the breast cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0298] In certain embodiments of the methods provided herein, the abnormal cell growth is a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In certain embodiments of the methods provided herein, the subject is identified as having a cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0299] In certain embodiments, the cancer is selected from breast cancer and ovarian cancer. In certain such embodiments, the cancer is breast cancer or ovarian cancer characterized by amplification or overexpression of CCNE1 and / or CCNE2. In certain such embodiments, the cancer is: (a) breast cancer or ovarian cancer; (b) characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In certain embodiments, the cancer is ovarian cancer.

[0300] In certain embodiments, the compounds of the present invention are administered as first-line therapy. In other embodiments, the compounds of the present invention are administered as second (or subsequent) line therapy. In certain embodiments, the compounds of the present invention are administered as second (or subsequent) line therapy after treatment with endocrine therapy agents and / or CDK4 / CDK6 inhibitors. In certain embodiments, the compounds of the present invention are administered as second (or subsequent) line therapy after treatment with endocrine therapy agents (e.g., aromatase inhibitors, SERMs, or SERDs). In certain embodiments, the compounds of the present invention are administered as second (or subsequent) line therapy after treatment with CDK4 / CDK6 inhibitors. In certain embodiments, the compounds of the present invention are administered as second (or subsequent) line therapy after treatment with one or more chemotherapy regimens (e.g., including taxanes or platinum agents). In certain embodiments, the compounds of the present invention are administered as second (or subsequent) line therapy after treatment with HER2 targeting agents (e.g., trastuzumab).

[0301] As used herein, an "effective dose" or "effective amount" of a drug, compound, or pharmaceutical composition is an amount sufficient to affect any one or more beneficial or desired (including biochemical, histological, and / or behavioral) symptoms of a disease, its complications, and intermediate pathological phenotypes presented during the course of disease progression. For therapeutic uses, a "therapeutically effective amount" means an amount of a compound administered that alleviates to some extent one or more symptoms of the disorder being treated. With respect to the treatment of cancer, a therapeutically effective amount means an amount that has the following effects: (1) reduces the size of a tumor, (2) inhibits (that is, slows to some extent, preferably stops) tumor metastasis, (3) inhibits (that is, slows to some extent, preferably stops) tumor growth or tumor invasiveness, (4) alleviates to some extent (or, preferably, eliminates) one or more signs or symptoms associated with cancer, (5) reduces the dose of other drugs required to treat the disease, and / or (6) enhances the effect of another drug, and / or (7) delays the progression of the disease in a patient.

[0302] The effective dose may be administered in one or more administrations. For purposes of the present invention, the effective dose of a drug, compound, or pharmaceutical composition is an amount sufficient to accomplish a preventive or therapeutic treatment, either directly or indirectly. As understood in a clinical context, the effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition.

[0303] "Tumor" when applied to a subject diagnosed with or suspected of having cancer means a malignant or potentially malignant neoplasm or mass of tissue of any size, and includes primary tumors and secondary neoplasms. Solid tumors are abnormal growths or masses of tissue that usually do not contain cysts or areas of fluid. Examples of solid tumors are sarcomas, carcinomas, and lymphomas. Leukemias (cancers of the blood) do not usually form solid tumors (National Cancer Institute, Dictionary of CancerTerms).

[0304] "Tumor burden" or "tumor load" refers to the total amount of tumor material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined by a variety of methods known in the art, for example, using calipers, or when in vivo using imaging techniques, such as ultrasound, bone scans, computed tomography (CT), or magnetic resonance imaging (MRI) scans.

[0305] The term "tumor size" refers to the overall size of a tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by a variety of methods known in the art, for example, by measuring the size of the tumor after removal from a subject (e.g., using calipers), or using imaging techniques (e.g., bone scans, ultrasound, CR or MRI scans) while in vivo.

[0306] As used herein, "subject" refers to a human or animal subject. In certain preferred embodiments, the subject is a human.

[0307] As used herein, the term "treating" cancer means administering a compound of the invention to a subject having cancer or diagnosed with cancer to achieve at least one positive therapeutic effect, such as a reduced number of cancer cells, a reduced tumor size, a reduced rate of cancer cell infiltration into surrounding organs, or a reduced rate of tumor metastasis or tumor growth, reversal of the disorder or condition to which such terms apply, or one or more symptoms of such disorders or conditions, alleviation of the disorder or condition to which such terms apply, or one or more symptoms of such disorders or conditions, inhibition of progression of the disorder or condition to which such terms apply, or prevention of the disorder or condition to which such terms apply, or one or more symptoms of such disorders or conditions. As used herein, the term "treating" means the act of treating as defined immediately above as "treating," unless otherwise indicated. The term "treatment" also includes adjuvant and neoadjuvant treatment of a subject.

[0308] For the purposes of the present invention, beneficial or desired clinical results include, but are not limited to, one or more of the following: reduction (or destruction) of proliferation of neoplastic or cancerous cells; inhibition of metastatic or neoplastic cells; shrinkage or reduction of tumor size; alleviation of cancer; reduction of symptoms caused by cancer; improvement of quality of life of those suffering from cancer; reduction of the dose of other drugs required to treat cancer; delaying the development of cancer; curing cancer; overcoming one or more resistance mechanisms of cancer; and / or prolonging the survival of cancer patients. Positive treatment effects of cancer can be measured in many ways (see, e.g., WA Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl 1: 1S-10S (2009). For example, with respect to tumor growth inhibition (T / C), according to the National Cancer Institute (NCI) criteria, a T / C of less than or equal to 42% is the lowest level of anti-tumor activity. A T / C of <10% is considered a high level of anti-tumor activity, where T / C (%) = median tumor volume of treatment / median tumor volume of control x 100.

[0309] In certain embodiments, the treatment achieved by the compounds of the present invention is defined by reference to any of the following: partial response (PR), complete response (CR), overall response (OR), progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). PFS, also referred to as "time to tumor progression", indicates the length of time that cancer does not grow during and after treatment, and includes the amount of time that the patient has experienced CR or PR and the amount of time that the patient has experienced stable disease (SD). DFS represents the length of time that the patient remains disease-free during and after treatment. OS represents an extension of life expectancy compared to an original or untreated object or patient. In certain embodiments, the response to the combination of the present invention is any one of PR, CR, PFS, DFS, OR or OS, which is evaluated using the response evaluation criteria in solid tumors (Response Evaluation Criteria in Solid Tumors, RECIST) 1.1 response criteria.

[0310] The treatment regimen of the compounds of the present invention that is effective in treating cancer patients can vary according to a variety of factors, such as the disease state, age and weight of the patient, and the ability of the therapy to induce an anti-cancer response in the subject. Although an embodiment of any aspect of the present invention may not be effective in achieving a positive therapeutic effect in every subject, it should be done in a statistically significant number of subjects, as determined by any statistical test known in the art, such as Student's t-test, chi2-test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstrat-test and Wilcon on-test.

[0311] The terms "therapeutic regimen," "dosing schedule," and "dosing regimen" are used interchangeably to refer to the dosage and timing of administration of each compound of the invention, alone or in combination with another therapeutic agent.

[0312] "Improvement" refers to a reduction or improvement in one or more symptoms following treatment with a combination described herein, compared to not administering the combination. "Improvement" also includes a shortening or reduction in the duration of a symptom.

[0313] Unless otherwise indicated, "abnormal cell growth" as used herein refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Abnormal cell growth can be benign (non-cancerous) or malignant (cancerous).

[0314] Abnormal cell growth includes abnormal growth of the following: (1) tumor cells (tumors) that display increased CDK2 expression; (2) tumors that proliferate through abnormal CDK2 activation; (3) tumors characterized by amplification or overexpression of CCNE1 and / or CCNE2; and (4) tumors that are resistant to endocrine therapy, HER2 antagonists, or CDK4 / 6 inhibition.

[0315] As used herein, the term "additional anti-cancer therapeutic agent" refers to any one or more therapeutic agents other than the compounds of the present invention that are used or useful in the treatment of cancer. In certain embodiments, such additional anti-cancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, anti-angiogenic agents, topoisomerase I and II inhibitors, plant alkaloids, hormone agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as inhibitors of protein tyrosine kinases and / or serine / threonine kinases, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxins, immuno-oncology agents, and the like.

[0316] In certain embodiments, the additional anti-cancer agent is an endocrine agent, such as an aromatase inhibitor, a SERD, or a SERM.

[0317] In other embodiments, the compounds of the present invention may be administered in combination with standard of care agents. In certain embodiments, the compounds of the present invention may be administered in combination with endocrine therapy (e.g., agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole). In certain embodiments, the compounds of the present invention may be administered in combination with chemotherapeutic agents (e.g., docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine). In other embodiments, the compounds of the present invention may be administered in combination with anti-HER2 agents (e.g., trastuzumab or pertuzumab).

[0318] In certain embodiments, the additional anticancer agent is an anti-angiogenic agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (α-v / β-3), MMP-2 (matrix metalloproteinase 2) inhibitors, and MMP-9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenic agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer), and AG 13958 (Pfizer). Additional anti-angiogenic agents include varanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vantanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), neovastat™ (AE 941), tetrathiomolybdate (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY57-9352), and CP-868,596 (Pfizer). Other anti-angiogenic agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™), and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenic agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™).Still other anti-angiogenic agents include exixulin (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen (Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Toledin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Still other anti-angiogenic agents include ABT 510 (Abbott), alestat (TMI 005), AZD 8955 (AstraZeneca), incitabine (Metastat™), and PCK 3145 (Procyon). Still other anti-angiogenic agents include acitretin (Neotigason™), aplidine™, cilengtide (EMD 121974), combretastatin A4 (CA4P), and fenretinide. (4 HPR) , Halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), Remastat (BMS 275291), Catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522), and zoledronic acid (Zometa™).

[0319] In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (e.g., a method for inhibiting the basic processes of controlling cell growth, differentiation and survival by which regulatory molecules are communicated in cells). Signal transduction inhibitors include small molecules, antibodies and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (e.g., tyrosine kinase inhibitors or serine / threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal transduction inhibitors include, for example, farnesyl protein transferase inhibitors, EGF inhibitors, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitors, P70S6 kinase inhibitors, inhibitors of WNT pathways and so-called multi-target kinase inhibitors. Other examples of signal transduction inhibitors that can be used in combination with the compounds of the invention and the pharmaceutical compositions described herein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), piritrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vantanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim), and Cervene™ (TP 38).Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer), dacomitinib (Pfizer), bosutinib (Pfizer), gedatolisib (Pfizer), canerutinib (CI 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosin (Miltefosin™), BMS 599626 (Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM Biotechnology). 1), moritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD), and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE-AON (Georgetown University), and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), flavopiridol, BMS 387032 (Bristol Myers), EM 1421 (Erimos), indifsulfuron (E7070), cylicidin (CYC 200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).

[0320] In other embodiments, the additional anticancer agent is a so-called classical antineoplastic agent. Classical antineoplastic agents include, but are not limited to: hormone modulators such as hormones, anti-hormones, androgen agonists, androgen antagonists and anti-estrogen therapeutics, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activators, ribonucleases, proteosomics, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors (e.g., talazoparib, olapariv, rucaparib, niraparib, eneparib, veliparib), tubulin inhibitors, antibiotics, plant-derived spindle inhibitors, platinum-coordinated compounds, gene therapy agents, antisense oligonucleotides, vascular targeting agents (VTA) and statins. Examples of classical antineoplastic agents for use in combination therapy with the compounds of the invention, optionally with one or more other agents, include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone and progestins such as medroxyprogesterone, megestrol acetate (Megs), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; such as tamoxifen, raloxifene, lasofoxifene, afexifene, arzoxifene, bazedoxifene, femifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane and CHF 4227 (Cheisi), selective estrogen-receptor down-regulators (SERD's; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Flon), formestane; gonadotropin-releasing hormone (GnRH; also commonly called luteinizing hormone-releasing hormone [LHRH]) agonists such as buserelin (Suprefact), goserelin (Zoralide), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), ciproterone, flutamide (Eulexin), megestrol acetate, nilutamide (Nilandron), and osatetron, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprolide, triptorelin, bicalutamide; anti-androgen agents such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and combinations thereof.Other examples of classical anti-tumor agents for use in combination with the compounds of the present invention include, but are not limited to: suberolanilide hydroxamic acid (SAHA, Merck Inc. / Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, butyric acid pivaloyloxymethyl ester and PXD-101; Onconase (rannidase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diflutecan, etecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan hydrochloride (Camptosar), lortotecan, Orathecin (Rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, etecarin, topotecan, aclarubicin, doxorubicin, aminafide, amrubicin, anamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, gadolinium, hydroxyurea, nemorubicin, noxorubicin (mitoxantrone), pirarubicin, pixenolone, procarbazine, butterfly mycin, sobuzoxane, tafluposide, valrubicin, dexrazoxane (dextroxymetholone), nitrogen mustard N-oxygen compounds, cyclophosphamide, AMD-473, altretamine, AP-5280, apaziquinone, brotalicin, bendamustine, busulfan, carboquinone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, nitrogen mustard, melphalan, dibromomannitol, dibromodulcitol, mitomycin C, mitoxantrone, nimustine, ranimustine, temozolomide, thiotepa, and platinum-complexed alkylating compounds such as cisplatin, berdin (carboplatin), etaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin, and combinations thereof.

[0321] In other embodiments, the additional anticancer agent is a so-called dihydrofolate reductase inhibitor (such as methotrexate and NeuTrexin (trimetrexate glucuronide)), a purine antagonist (such as 6-mercaptopurine nucleoside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine and raltitrexed), a pyrimidine antagonist (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemcitabine™ (gemcitabine, Eli Lilly), tegafur (UFT Orzel or Uforal and TS-1 combination including tegafur, gimeracil and otostat), doxifluridine, carmofur, cytarabine (including ocfosfate, phosphate stearate, sustained release and liposomal forms), enocitabine, 5-azacitidine (Vidaza), decitabine and ethynyl cytidine) and other antimetabolites such as eflornithine, hydroxyurea, folinic acid, nolatrexed (Thymitaq), triapine, trimetrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals) and GPI 18180 (Guilford Pharm Inc) and combinations thereof.

[0322] Other examples of classical anti-tumor cytotoxic agents include, but are not limited to: Abraxane (Abraxis BioScience, Inc.), Batabulin (Amgen), EPO 906 (Novartis), Vinflunine (Bristol-Myers Squibb Company), Actinomycin D, Bleomycin, Mitomycin C, Neocarcinostatin (Zinstatin), Vinblastine, Vincristine, Vindesine, Vinorelbine (Navelbine), Docetaxel (Taxotere), Ortasai, Paclitaxel (including Taxoprexin, a DHA / paclitaxel conjugate), Cisplatin, Carboplatin, Nedaplatin, Oxaliplatin (Eloxatin), Satraplatin, Camptosar, Capecitabine (Xeloda), Oxaliplatin (Eloxatin), Taxotere, Alitretinoin, Canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargase (Oncaspar™), efamixirol (Efaproxyn™-radiation therapy), bexarotene (Targretin™), tesmilifene (DPPE-to enhance the potency of cytotoxic agents), Theratope™ (Biomira), tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafin gadolinium (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax™), and combinations thereof. Other examples of classical anti-tumor agents include, but are not limited to: Advexin (ING 201), TNFerade (GeneVec, a compound that expresses TNFα in response to radiation therapy), RB94 (Baylor College of Medicine), Genasense (Olimexan, Genta), Combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), pravastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycol, Bayer), rosuvastatin (Crestor, AstraZeneca), lovastatin, nicotinic acid (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

[0323] In other embodiments, the additional anti-cancer agent is an epigenetic modulator, such as an inhibitor of EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1 / 2 / 3, NSD1 / 2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1-9, LSD1, UTX, IDH1 / 2, or BCL6.

[0324] In other embodiments, the additional anti-cancer agent is an immunomodulator, such as an inhibitor of CTLA-4, PD-1, or PD-L1 (e.g., pembrolizumab, nivolumab, or avelumab), LAG-3, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or CAR-T-cell therapy.

[0325] "Cancer" as used herein means any malignant and / or aggressive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named after the type of cells that form them, cancers of the blood, bone marrow or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Hematological cancers include, but are not limited to leukemias, lymphomas and myelomas. Cancer also includes primary cancers originating from a specific part of the body, metastatic cancers that have spread from the place where it started to other parts of the body, recurrences from the original primary cancer after remission, and second primary cancers (this is a new primary cancer in a person with a previous cancer history that is different from the new primary cancer).

[0326] In certain embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including SCLC or NSCLC), esophageal cancer, liver cancer, pancreatic cancer or gastric cancer. In certain such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and / or CCNE2.

[0327] Dosage form and regimen

[0328] Administration of the compounds of the invention can be achieved by any method capable of delivering the compound to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

[0329] The dosage regimen can be adjusted to provide the most appropriate desired response. For example, a single bolus delivery may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is particularly advantageous to formulate parenteral compositions in dosage unit form for ease of administration and dosage consistency. The dosage unit form used herein represents a physically discrete unit suitable as a unit dose for a mammalian subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect in combination with a desired pharmaceutical carrier. The specifications of the dosage unit form of the present invention are determined by and directly depend on: (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or preventive effect to be achieved, and (b) the inherent limitations of the technology for formulating such an active compound to treat the sensitivity of an individual.

[0330] Thus, based on the disclosure provided herein, the skilled person will appreciate that dosage and quantitative administration regimens are adjusted according to methods well known in the therapeutic field. That is, the maximum tolerable dose can be easily established, and the effective amount that provides a detectable therapeutic benefit to the patient can also be determined, just as the provisional requirement for administering each medicament to provide a detectable therapeutic benefit to the patient can be determined. Therefore, although certain dosages and administration regimens are illustrated herein, these embodiments are by no means limiting the dosages and administration regimens that can be provided to patients in practicing the present invention.

[0331] It should be noted that dosage values ​​may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It should be further understood that for any particular subject, the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person managing or supervising the administration of the composition, and the dosage ranges described herein are merely exemplary and are not intended to limit the scope or practice of the claimed composition. For example, the dosage may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present invention includes intra-patient dose increases determined by a technician. Determining the appropriate dosage and regimen for the administration of a chemotherapeutic agent is well known in the relevant art, and once the teaching disclosed herein is provided, it will be understood by the technician to be included.

[0332] The amount of the compound of the present invention used will depend on the severity of the object, disorder or disease treated, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, effective dose is in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 1 to about 35 mg / kg / day, in single dose or divided dose. For 70 kg people, this is equivalent to about 0.05 to about 7 g / day, preferably about 0.1 to about 2.5 g / day. In some cases, the dosage level below the lower limit of the above range may be more than enough, and in other cases, it is possible to adopt a larger dosage without causing any harmful side effects, with the prerequisite that such a larger dosage is first divided into several small doses for use in one day.

[0333] Formulations and routes of administration

[0334] As used herein, "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0335] The pharmaceutically acceptable carrier may comprise any conventional pharmaceutical carrier or excipient. The choice of carrier and / or excipient depends largely on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

[0336] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents (such as hydrates and solvates). If necessary, the pharmaceutical composition may contain additional ingredients, such as flavoring agents, adhesives, excipients, etc. Therefore, for oral administration, tablets containing various excipients (such as citric acid) can be used with various disintegrants (such as starch, alginic acid and some composite silicates) and with adhesives (such as sucrose, gelatin and gum arabic). The example of excipients includes calcium carbonate, calcium phosphate, various sugars and various types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols without limitation. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talcum are often used for tableting purposes. Solid compositions of similar types can also be used in soft and hard filled gelatin capsules. Therefore, the non-limiting example of material includes lactose or milk sugar and high molecular weight polyethylene glycol. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, colorants or dyes and, if desired, emulsifying or suspending agents and diluents such as water, ethanol, propylene glycol, glycerol, or combinations thereof.

[0337] The pharmaceutical composition may, for example, be in a form suitable for oral administration (as tablets, capsules, pills, powders, sustained release formulations, solutions, suspensions), for parenteral injection (as sterile solutions, suspensions or emulsions), for topical administration (as ointments or creams) or for rectal administration (as suppositories).

[0338] Exemplary parenteral administration forms include solutions or suspensions of the active compound in sterile aqueous solution, for example, aqueous propylene glycol or aqueous dextrose. Such dosage forms can be suitably buffered, if necessary.

[0339] The pharmaceutical compositions may be in unit dosage form suitable for single administration of precise dosages.

[0340] Pharmaceutical compositions suitable for delivering the compounds of the present invention and methods for their preparation are readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in 'Remington's Pharmaceutical Sciences', 19th edition (Mack Publishing Company, 1995), the disclosure of which is incorporated herein by reference in its entirety.

[0341] The compounds of the invention may be administered orally. Oral administration may include swallowing, whereby the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed, whereby the compound enters the bloodstream directly from the mouth.

[0342] Formulations suitable for oral administration include solid preparations such as tablets, capsules containing microparticles, liquids or powders, lozenges (including liquid-filled lozenges), chewables, multi- and nanoparticles, gels, solid solutions, liposomes, films (including mucoadhesive films), ovules, sprays and liquid preparations.

[0343] Liquid preparations include suspensions, solutions, syrups and elixirs. Such preparations can be used as fillers in soft or hard capsules and typically include a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared by reconstitution of a solid (e.g., from a capsule).

[0344] The compounds of the invention may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 11 (6), 981-986 (2001), the disclosure of which is incorporated herein by reference in its entirety.

[0345] For tablet dosage forms, depending on the dosage, the drug can account for 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. In addition to the drug, tablets usually contain disintegrants. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, crospovidone, polyvinyl pyrrolidone, methylcellulose, microcrystalline cellulose, low alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Typically, disintegrants account for 1% to 25% by weight of the dosage form, preferably 5% to 20% by weight.

[0346] Adhesives are usually used to impart adhesiveness to tablet formulations. Suitable adhesives include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinyl pyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets can also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous lactose, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

[0347] Tablets may also optionally include surfactants, such as sodium lauryl sulfate and polysorbate 80, and glidants, such as silicon dioxide and talc. When present, the amount of surfactant is generally 0.2% to 5% by weight of the tablet, and the amount of glidant is generally 0.2% to 1% by weight of the tablet.

[0348] Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants are typically present in an amount of 0.25% to 10% by weight, preferably 0.5% to 3% by weight of the tablet.

[0349] Other conventional ingredients include antioxidants, colorants, flavorings, preservatives and taste-masking agents.

[0350] Exemplary tablets contain up to about 80% by weight of the drug, about 10% to about 90% by weight of the binder, about 0% to about 85% by weight of the diluent, about 2% to about 10% by weight of the disintegrant, and about 0.25% to about 10% by weight of the lubricant.

[0351] Tablet blends can be compressed directly or by rollers to form tablets. Alternatively, tablet blends or portions of blends can be wet, dry or melt granulated, melt solidified or extruded and then tableted. The final formulation can include one or more layers and can be coated or uncoated; or encapsulated.

[0352] The formulation of tablets is discussed in detail by H. Lieberman and L. Lachman in "Pharmaceutical Dosage Forms: Tablets, Vol. 1", Marcel Dekker, NY, NY, 1980 (ISBN 0-8247-6918-X), the disclosure of which is incorporated herein by reference in its entirety.

[0353] Solid dosage forms for oral administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0354] Suitable modified release formulations are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies (e.g., high energy dispersions and permeable and coated particles) can be found in Verma et al., Pharmaceutical Technology On-line, 25(2), 1-14 (2001). The use of chewing gum to achieve controlled release is described in WO 00 / 35298. The disclosures of these references are incorporated herein by reference in their entirety.

[0355] The compounds of the present invention can also be administered directly into the bloodstream, muscle or internal organs. Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

[0356] Parenteral formulations are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably adjusted to a pH of 3-9), but, for some applications, they may be more appropriately formulated as sterile non-aqueous solutions or in dry form to be used in conjunction with a suitable vehicle (such as sterile, pyrogen-free water).

[0357] The preparation of parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art, for example, by lyophilization.

[0358] The solubility of compounds of the invention used in the preparation of parenteral solutions can be increased by the use of appropriate formulation techniques, such as the incorporation of solubilizing agents.

[0359] Preparations for parenteral administration can be formulated to release immediately and / or to regulate release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted and programmed release. Therefore, the compounds of the present invention can be formulated into solid, semisolid or thixotropic liquids for use as implanted reservoirs that provide a release of the active compound. Examples of such preparations include drug-coated stents and PGLA microspheres.

[0360] The compounds of the invention can also be applied topically to the skin or mucous membranes, that is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages, and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerol, polyethylene glycol, and propylene glycol. Penetration enhancers can be incorporated; see, for example, Finnin and Morgan, J Pharm Sci, 88 (10), 955-958 (October 1999). Other local administration methods include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needle-free (e.g., Powderject™, Bioject™, etc.) injection. The disclosures of these references are incorporated herein by reference in their entirety.

[0361] Preparations for topical administration can be formulated to be immediate and / or modified release. Modified release preparations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0362] The compounds of the invention can also be administered intranasally or by inhalation, usually in dry powder form (alone, as a mixture, for example, a dry blend with lactose, or as a mixed component granule, for example, mixed with a phospholipid such as phosphatidylcholine) from a dry powder inhaler, or as an aerosol spray from a pressurized container, pump, sprayer, nebulizer (preferably a nebulizer that produces a fine mist using electrohydrodynamics) or diffuser, with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder can include a bioadhesive, for example, chitosan or cyclodextrin.

[0363] The pressurized container, pump, spray, nebulizer or atomizer contains a solution or suspension of the compound of the invention comprising, for example, ethanol, aqueous ethanol or a suitable alternative agent (for dispersion, solubilization or prolonged release of the active), a propellant as a solvent and optionally a surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

[0364] Prior to use in dry powder or suspension formulations, the drug product is micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[0365] Capsules (e.g. made of gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated as a powder mix containing a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as l-leucine, mannitol or magnesium stearate. Lactose may be in anhydrous or lactose monohydrate form, the latter being preferred. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0366] Suitable solution formulations for atomizers that use electrohydrodynamics to generate fine mist may contain 1 μg to 20 mg of the compound of the present invention per actuation, and the actuation volume may vary between 1 μL and 100 μL. Typical formulations include a compound of the present invention, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used to replace propylene glycol include glycerol and polyethylene glycol.

[0367] Suitable flavoring agents (such as menthol and levomenthol) or sweetening agents (such as saccharin or saccharin sodium) may be added to those formulations of the invention intended for inhaled / intranasal administration.

[0368] Formulations for inhaled / intranasal administration can be formulated for immediate and / or modified release using, for example, poly(DL-lactic-co-glycolic acid) (PGLA). Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0369] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve that delivers a metered amount. The unit according to the invention is usually arranged to administer a metered dose or "puff" containing the desired amount of the compound of the invention. The total daily dose can be administered in a single dose or, more usually, in divided doses throughout the day.

[0370] The compounds of the invention may be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is the traditional suppository base but various alternatives may be used where appropriate.

[0371] Formulations for rectal / vaginal administration may be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0372] The compound of the present invention can also be directly applied to the eyes or ears, usually in the form of drops of micronized suspension or solution in isotonic, pH-adjusted sterile saline. Other preparations suitable for eye and ear administration include ointments, biodegradable (e.g., absorbable gel sponges, collagen) and non-biodegradable (e.g., silicone) implants, wafers, lenses and microparticles or cystic systems, such as lipoids or liposomes. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, fibrous polymers (e.g., hydroxypropyl methylcellulose, hydroxyethyl cellulose or methylcellulose) or heteropolysaccharide polymers (e.g., gellan gum (gelan gum)) can be incorporated with preservatives such as benzalkonium chloride. Such preparations can also be delivered by iontophoresis.

[0373] Formulations for ocular / aural administration can be formulated to be immediate and / or modified release. Modified release formulations include delayed, sustained, pulsed, controlled, targeted or programmed release.

[0374] Other technologies

[0375] The compounds of the invention may be combined with soluble macromolecular entities (such as cyclodextrins and suitable derivatives thereof or polyethylene glycol-containing polymers) in order to improve their solubility, dissolution rate, taste masking, bioavailability and / or stability for use in any of the aforementioned modes of administration.

[0376] For example, it is found that drug-cyclodextrin complexes are generally useful for most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents, or solubilizers. The most commonly used for these purposes are α-, β-, and γ-cyclodextrins, examples of which can be found in PCT Publication Nos. WO 91 / 11172, WO 94 / 02518, and WO 98 / 55148, the disclosures of which are incorporated herein by reference in their entirety.

[0377] dose

[0378] The amount of the active compound used will depend on the severity of the object, disorder or disease, the rate of administration, the disposal of the compound and the judgment of the prescribing physician. However, effective dose is usually in the range of about 0.001 to about 100 mg / kg body weight / day, preferably about 0.01 to about 35 mg / kg / day, in single dose or divided dose. For 70 kg people, this will reach about 0.07 to about 7000 mg / day, preferably about 0.7 to about 2500 mg / day. In some cases, the dosage level below the lower limit of the above range may be more than enough, and in other cases, it is possible to use a larger dosage without causing any harmful side effects, wherein such a larger dosage is usually divided into several smaller doses for use in one day.

[0379] 1) Kit consisting of components

[0380] Since it may be desirable to administer a combination of active compounds, for example, for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound according to the invention, may be conveniently combined in a kit form suitable for co-administration of the compositions. Thus, the kit of the present invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound according to the invention, and means for separately retaining the compositions, such as containers, separate bottles or separate foil packets. An example of such a kit is the familiar blister pack used for packaging tablets, capsules, etc.

[0381] The kit of the invention is particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against each other. To aid compliance, the kit typically includes instructions for administration and may be provided with a memory aid.

[0382] Combination therapy

[0383] As used herein, the term "combination therapy" means the sequential or simultaneous administration of a compound of the present invention and at least one additional drug or pharmaceutical ingredient (eg, an anticancer agent).

[0384] As noted above, the compounds of the invention may be used in combination with one or more additional anticancer agents. The efficacy of the compounds of the invention in certain tumors may be enhanced by combining with other approved or experimental cancer therapies (e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancers such as PD-1 antagonists, etc.).

[0385] When combination therapy is used, one or more additional anticancer agents may be administered sequentially or simultaneously with the compounds of the invention. In one embodiment, the additional anticancer agent is administered to the mammal (e.g., human) prior to administration of the compounds of the invention. In another embodiment, the additional anticancer agent is administered to the mammal after administration of the compounds of the invention. In another embodiment, the additional anticancer agent is administered to the mammal (e.g., human) at the same time as the compounds of the invention.

[0386] The present invention also relates to a pharmaceutical composition for treating abnormal cell growth in mammals (including humans), comprising an amount of a compound of the present invention as defined above (including hydrates, solvates and polymorphs of said compound or a pharmaceutically acceptable salt thereof) in combination with one or more (preferably one to three) additional anti-cancer therapeutic agents.

[0387] Synthesis method

[0388] The compounds of the present invention are prepared according to the exemplary procedures provided herein and modifications thereof known to those skilled in the art.

[0389] The following abbreviations are used throughout the examples: "Ac" refers to acetyl, "AcO" or "OAc" refers to acetoxy, "ACN" refers to acetonitrile, "aq" refers to aqueous, "atm" refers to atmospheric pressure, "BOC", "Boc" or "boc" refers to N-tert-butyloxycarbonyl, "Bn" refers to benzyl, "Bu" refers to butyl, "nBu" refers to n-butyl, "tBu" refers to tert-butyl, "Cbz" refers to benzyloxycarbonyl, "DCM" (CH2Cl2) refers to dichloromethane / dichloromethane, "de" refers to diastereomeric excess, "DEA" refers to diethylamine, "DIPEA" refers to diisopropylethylamine, and "DMA" refers to N,N -dimethylacetamide, "DMAP" refers to 4-dimethylaminopyridine, and "DMF" refers to N,N -dimethylformamide, "DMSO" refers to dimethyl sulfoxide, "ee" refers to enantiomeric excess, "Et" refers to ethyl, "EtOAc" refers to ethyl acetate, "EtOH" refers to ethanol, "HATU" refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, "HOAc" or "AcOH" refers to acetic acid, and "i-Pr" or " i"Pr" means isopropyl, "IPA" means isopropanol, "Me" means methyl, "MeOH" means methanol, "MS" means mass spectrometry, "MTBE" means methyl tert-butyl ether, "Ph" means phenyl, "sat." means saturated, "SFC" means supercritical fluid chromatography, "T3P" means propylphosphonic anhydride, "TFA" means trifluoroacetic acid, "THF" means tetrahydrofuran, "TLC" means thin layer chromatography, "Rf" means retention fraction, "~" means about, "rt" means retention time, "h" means hour, and "min" means minute. Example

[0390] Preparation of synthetic intermediates

[0391] Intermediate 1: {1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}benzylcarbamate ester;

[0392] Intermediate 2: {1-tert-butyl-3-[(1R,3S)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}benzylcarbamate ester.

[0393]

[0394] Two parallel reactions were each treated with trimethyl orthoformate (4.47 kg, 42.15 mol, 4.62 L) and 4-toluenesulfonic acid monohydrate (26.72 g, 140.5 mmol), each containing a solution of (±)-3-oxocyclopentanecarboxylic acid (CAS#98-78-2, 900 g, 7.02 mol) in methanol (5 L) at 13 ° C. The mixture was stirred for 25 hours at 13 ° C. Each batch was quenched with saturated NaHCO3 aqueous solution (1 L), then two batches were merged and concentrated under vacuum to remove most of methanol. The residue was diluted with ethyl acetate (4 L), and each layer was separated. The water layer was further extracted with ethyl acetate (2 x 1L). The combined organic layers were washed with saturated aqueous NaCl (3 x 1 L), dried over magnesium sulfate, filtered, and concentrated under vacuum to give (±)-methyl 3,3-dimethoxycyclopentanecarboxylate (1a, 2.5 kg, 13.28 mol, 94%) as a light yellow oil. 1 H NMR (400MHz, chloroform- d ) δ = 3.67 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 2.94-2.82 (m, 1H), 2.16-2.00 (m, 2H), 1.99-1.76 (m, 4H).

[0395] A solution of n-butyllithium (3.44 L of a 2.5 M solution in hexanes, 8.6 mol) was added to a reactor containing THF (3 L) at -65°C. Anhydrous acetonitrile (453 mL, 353 g, 8.61 mol) was added dropwise, slowly enough to maintain the internal temperature below -55°C. The mixture was stirred at -65°C for another hour. A solution of (±)-3,3-dimethoxycyclopentanecarboxylic acid methyl ester (1a, 810 g, 4.30 mol) in THF (1 L) was then added dropwise, slowly enough to maintain the internal temperature below -50°C. After stirring at -65°C for another hour, the reaction was quenched with water (4 L), neutralized to pH 7 with aqueous HCl (1 M), and extracted with ethyl acetate (3 x 3 L). The combined organic layers were washed with saturated aqueous NaCl solution (2 x 3 L), dried over magnesium sulfate, filtered, and concentrated under vacuum to give crude (±)-3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile (1b, 722 g, 3.66 mol, 85%) as a red oil which was used without further purification.

[0396] Solid sodium hydroxide (131.4 g, 3.29 mol in total) was added portionwise to a suspension of tert-butylhydrazine hydrochloride (409.4 g, 3.29 mol) in ethanol (3 L) at 16-25°C. Stirring was continued at 25°C for 1 hour. A solution of crude (±)-3-(3,3-dimethoxycyclopentyl)-3-oxopropanenitrile (1b, 540 g, 2.74 mol) in ethanol was added at 25°C, and the mixture was then heated to 75°C internally and stirred for 30 hours. The reaction was filtered, and the filtrate was concentrated under vacuum to give the crude product as a red oil. This product was combined with crude material from three additional identical preparative batches (each starting with 540 g of 1b; 4 batches totaling 2.16 kg, 10.96 mol) and purified by silica gel chromatography (eluting with 0-35% ethyl acetate in petroleum ether) to afford (±)-1-tert-butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-amine (1c, 1.60 kg, 5.98 mol, 54% yield) as a red oil. 1 H NMR (chloroform- d) δ = 5.41 (s,1H), 3.50 (br. s., 2H), 3.22 (s, 3H), 3.20 (s, 3H), 3.13 (tt, J=7.9, 9.6 Hz,1H), 2.25 (dd, J=8.0, 13.3 Hz, 1H), 2.09-2.00 (m, 1H), 1.99-1.91 (m, 1H), 1.83 (dd, J=10.8, 12.8 Hz, 2H), 1.78-1.68 (m, 1H), 1.60 (s, 9H).

[0397] Benzyl chloroformate (563.6 mL, 676.3 g, 3.96 mol) was added to a cooled (0-5°C) solution of (±)-1-tert-butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-amine (1c, 530 g, 1.98 mol) in acetonitrile (3.5 L). The mixture was stirred at 23°C for 2 hours, and then solid sodium bicarbonate (532.9 g, 6.34 mol) was added portionwise. Stirring was continued at 23°C for 26 hours. The resulting suspension was filtered, and the filtrate was concentrated under vacuum to give crude benzyl (±)-[1-tert-butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-yl]carbamate (1d, up to 980 g, 1.98 mol) as a red oil, which was used in the next step without further purification.

[0398] A solution of crude (±)-[1-tert-butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-yl]benzylcarbamate (1d, up to 980 g, 1.98 mol) in acetone (2 L) and water (2 L) at 18°C ​​was treated with 4-toluenesulfonic acid monohydrate (48.75 g, 256.3 mmol). The mixture was heated to 60°C internally for 20 hours. After concentrating under vacuum to remove most of the acetone, the aqueous residue was extracted with dichloromethane (3 x 3 L). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under vacuum to a crude red oil. The crude product is merged with the crude product from two other identical preparation batches (each derived from 1.98 mol 1c, 3 batches of 5.94 mol in total), and purified by silica gel chromatography (eluting with 0-50% ethyl acetate solution in petroleum ether) to obtain (±)-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazole-5-yl] benzyl carbamate (1e, 1.6 kg) as a yellow solid. The solid is stirred at 20 ° C for 18 hours in 10:1 petroleum ether / ethyl acetate (1.5 L). The obtained suspension is filtered, the filter cake is washed with petroleum ether (2 x 500 mL), and the solid is dried under vacuum to obtain (±)-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazole-5-yl] benzyl carbamate (1e, 1.4 kg, 3.9 mol, three batches merge 66%). 1 H NMR (DMSO- d 6) δ = 9.12 (br. s.,1H), 7.56-7.13 (m, 5H), 6.03 (s, 1H), 5.12 (s, 2H), 3.41-3.27 (m, 1H), 2.48-2.39 (m, 1H), 2.34-2.10 (m, 4H), 1.98-1.81 (m, 1H), 1.48 (s, 9H).

[0399] A solution of (±)-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]benzyl carbamate (1e, 320 g, 0.900 mol) in THF (1.5 L) was degassed under vacuum and purged with dry nitrogen (3 cycles) and then cooled to an internal temperature of -65°C. A solution of lithium triethylborohydride (1.0 M in THF, 1.80 L, 1.80 mol) was added dropwise at a rate to maintain the internal temperature below -55°C and stirring was continued at -65°C for 1.5 hours. The reaction mixture was quenched with a saturated aqueous NaHCO3 solution (1.5 L) at -40 to -30°C. Hydrogen peroxide (30% aqueous solution, 700 g) was added dropwise to the mixture while maintaining the internal temperature at -10 to 0°C. The mixture was stirred at 10°C for 1 hour and then extracted with ethyl acetate (3 x 2 L). The organic layer of merging is saturated Na2SO3 aqueous solution (2 x 1 L) and saturated NaCl aqueous solution (2 x 1L) washing.Organic matter is dried over magnesium sulfate, filtered, and condensed into a rough yellow oil under vacuum.The crude product from this batch is merged with the crude product from three other identical preparation batches (each starting from 0.900 mol 1e, 3.60 mol in total) for purification.Before chromatographic separation, the mixture merged shows~3.3:1 cis / reverse ratio by NMR.The crude product merged is purified twice by silica gel chromatography, eluted with a solution of 0-50% ethyl acetate in dichloromethane, to obtain (±)- Trans- Benzyl [1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate (1f, 960 g) was further purified by trituration as described below.

[0400] A previous batch of 1f had been obtained from a small-scale reaction, starting with a total of 120 g of 1e (0.34 mol). The column-isolated product from this batch was combined with the column-isolated product from the above batch (which had been derived from 3.60 mol of 1e, a total of 3.94 mol of 1e for all combined batches), suspended in 10:1 dichloromethane / methanol (1.5 L), and stirred at 20°C for 16 hours. The suspension was filtered, and the filter cake was washed with petroleum ether (2 x 500 mL). The solid was dried under vacuum to give clean (±)- Trans- Benzyl [1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate (1f, 840 g, 2.35 mol, 60% overall yield for all combined batches). 1 H NMR (400MHz, DMSO- d6) δ =9.07 (br. s., 1H), 7.45-7.27 (m, 5H), 5.92 (s, 1H), 5.11 (s, 2H), 4.57 (d, J=4.5 Hz, 1H), 4.21-4.07 (m, 1H), 2.88 (quin, J=8.6 Hz, 1H), 2.24-2.13 (m, 1H), 1.92-1.78 (m, 1H), 1.78-1.62 (m, 2H), 1.61-1.53 ​​(m, 1H), 1.47 (s, 9H), 1.52-1.43 (m, 1H). MS: 358 [M+H] + .

[0401] Separation by chiral SFC (±)- Trans- Enantiomers of benzyl [1-tert-butyl-3-(3-hydroxycyclopentyl)-1H-pyrazol-5-yl]carbamate (1f, 700 g, 1.96 mol).

[0402] The product from the first eluting enantiomer peak (310 g solid) was suspended in methanol / petroleum ether (1:10, 1 L) and stirred for 1 hour at 25° C. The suspension was filtered, the filter pad was washed with petroleum ether (2 x 500 mL), and the solid was dried under vacuum to give benzyl {1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (Intermediate 1, 255 g, 713 mmol, 36%, >99% ee) as a white solid. 1 H NMR (400MHz, DMSO- d 6) δ = 9.08 (br. s., 1H), 7.58-7.20 (m, 5H), 5.92 (s, 1H), 5.11 (s, 2H), 4.57 (d, J=4.4 Hz, 1H), 4.19-4.09 (m, 1H), 2.88 (quin, J=8.6 Hz, 1H), 2.24-2.13 (m, 1H), 1.91-1.79 (m, 1H), 1.79-1.61 (m, 2H), 1.61-1.53 ​​(m, 1H), 1.47 (s, 9H), 1.52-1.44 (m, 1H). MS: 358 [M+H] + . Optical rotation [α] D +3.76 ( c1.0, MeOH). Chiral purity: >99%ee, retention time 3.371 min. Chiral SFC analysis was performed on a ChiralPak AD-3 150 x 4.6 mm ID, 3µm column heated to 40°C, eluting with CO2 mobile phase and a gradient of 0-40% methanol + 0.05% DEA over 5.5 min, then holding at 40% for 3 min; flow rate 2.5 mL / min.

[0403] The product from the second eluting enantiomeric peak (300 g solid) was suspended in methanol / petroleum ether (1:10, 1 L) and stirred for 1 hour at 25° C. The suspension was filtered, the filter pad was washed with petroleum ether (2 x 500 mL), and the solid was dried under vacuum to give benzyl {1-tert-butyl-3-[(1R,3S)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (Intermediate 2, 255 g, 713 mmol, 36%, 94% ee) as a white solid. 1 H NMR (400MHz, DMSO- d 6)δ = 9.08 (br. s., 1H), 7.55-7.19 (m, 5H), 5.92 (s, 1H), 5.11 (s, 2H), 4.57(d, J=4.4 Hz, 1H), 4.23-4.07 (m, 1H), 2.88 (quin, J=8.7 Hz, 1H), 2.23-2.14(m, 1H), 1.90-1.79 (m, 1H), 1.77-1.61 (m, 2H), 1.61-1.53 ​​(m, 1H), 1.47 (s,9H), 1.52-1.44 (m, 1H). MS: 358 [M+H] + . Optical rotation [α] D -2.43 ( c 1.0, MeOH). Chiral purity: 94%ee, retention time 3.608 min. Chiral SFC analysis was performed on a ChiralPak AD-3 150 x 4.6 mm ID, 3µm column heated to 40°C, eluting with CO2 mobile phase and a gradient of 0-40% methanol + 0.05% DEA over 5.5 min, then holding at 40% for 3 min; flow rate 2.5 mL / min.

[0404] will have [α] D -3.1 ( cA sample of the second eluting enantiomer from the previous batch was crystallized from dichloroethane / pentane at 1.1, MeOH) and 96% ee. The crystal structure was obtained by small molecule X-ray crystallography and showed (1 R ,3 S ) geometry. Based on its comparable optical rotation and elution order in the analytical method, the absolute stereochemistry of intermediate 2 was assigned as (1 R ,3 S ). Intermediate 1, the enantiomer of intermediate 2, is thus designated as (1 S ,3 R ) Stereochemistry.

[0405] Intermediate 3: (5-methyl-1,3-oxazol-2-yl)acetic acid

[0406]

[0407] The solution of the propan-2-yl-1-amine (25.0 g, 450 mmol) in dichloromethane (500 mL) at 15 ° C was treated with triethylamine (138 g, 1360 mmol) and DMAP (5.55 g, 45.4 mmol). The mixture was cooled to 0 ° C and lasted for 30 minutes and added dropwise 3-chloro-3-oxopropanoic acid methyl esters (74.4 g, 545 mmol). The solution obtained was stirred at 15 ° C for 16 hours, then left standstill at this temperature for 2 days. The suspension obtained was filtered, the filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (eluted with 60% EtOAc / petroleum ether) to obtain 3-oxo-3-(propan-2-alkynes-1-ylamino) methyl propionate (3a, 47 g, 67%, by NMR90% purity) as a light yellow oil. 1 H NMR (400 MHz, chloroform- d ) δ =7.43 (br s, 1H), 4.09 (dd, J=2.6, 5.3 Hz, 2H), 3.76 (s, 3H), 3.36 (s, 2H), 2.25 (s, 1H).

[0408] Two parallel batches were carried out according to the following procedure: a solution of 3-oxo-3-(prop-2-yn-1-ylamino)propionic acid methyl ester (3a, 23.5 g, 151 mmol) in acetonitrile (300 mL) was treated with gold trichloride (2.50 g, 8.24 mmol) at room temperature (20 ° C). The resulting mixture was heated to 70 ° C in the dark for 16 hours. The two batches were then combined, filtered to remove the catalyst, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (eluted with 40% EtOAc / petroleum ether) to obtain (5-methyl-1,3-oxazol-2-yl) acetate methyl ester (3b, 26.5 g, 56.5% for the combined batches) as a light yellow oil. 1 H NMR (400 MHz, chloroform- d ) δ = 6.68 (d, J=1.0 Hz, 1H), 3.80 (s, 2H), 3.75 (s, 3H), 2.30 (d, J=1.3 Hz, 3H).

[0409] A solution of (5-methyl-1,3-oxazol-2-yl)methyl acetate (3b, 26.5 g, 170.8 mmol) in THF (80 mL) and water (20 mL) was treated with lithium hydroxide monohydrate (7.17 g, 171 mmol) and stirred at room temperature (25 ° C) for 2 hours. The mixture was concentrated to remove most of the THF, and the residue was then diluted with water (25 mL) and extracted with dichloromethane (2x 30 mL). The aqueous layer was concentrated to give a crude product (~26 g), which was further purified by grinding with EtOAc / MeOH (v / v 10 / 1) to give (5-methyl-1,3-oxazol-2-yl)lithium acetate (intermediate 3, 21.7 g, 90%) as a light yellow solid. 1 H NMR (400 MHz, deuterium oxide) δ = 6.63 (d, J=1.0 Hz, 1H), 3.59 (s,2H), 2.22 (d, J=1.0 Hz, 3H).

[0410] Intermediate 4: (5-methoxypyrazin-2-yl)lithium acetate.

[0411]

[0412] A solution of 2,5-dibromopyrazine (30.0 g, 126 mmol) in THF (252 mL) was cooled to 0 °C. Sodium methoxide (25 wt % solution in methanol, 29.0 mL, 27.3 g, 126 mmol) was added dropwise over 18 minutes. The solution was warmed to room temperature and stirred for 37 hours. The suspension was filtered, the flask and filter cake were rinsed with a small amount of THF, and the filtrate was concentrated under vacuum to give 2-bromo-5-methoxypyrazine (4a, 23.80 g, 100%) as a solid. 1 H NMR (400MHz, chloroform- d ) δ = 8.20 (d, J=1.2 Hz, 1H), 8.03 (d, J=1.2 Hz, 1H), 3.97 (s, 3H).

[0413] A nitrogen purged flask was charged with copper (I) iodide (2.82 g, 14.8 mmol), 2-picolinic acid (3.65 g, 29.6 mmol), cesium carbonate (36.2 g, 111 mmol), and 2-bromo-5-methoxypyrazine (4a, 7.00 g, 37.03 mmol). The flask was purged with nitrogen again, and then dry dioxane (250 mL) and dimethyl malonate (22 mL, 192 mmol) were introduced via syringe. Nitrogen was bubbled through the solution for 10 minutes. The mixture was heated at 100 °C for 36 hours. After cooling to room temperature, the suspension was filtered and the filtrate was concentrated to an oil. The solid remaining in the filter cake was suspended in water (150 mL), and the solution was slowly acidified with 4M HCl (~17 mL). The solution was extracted with ethyl acetate (2 x 150 mL). The ethyl acetate extract was merged with the crude oil obtained from the filtrate, and all were washed with saturated NH4Cl aqueous solution (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a solution of 0-50% ethyl acetate in heptane) to obtain dimethyl (5-methoxypyrazine-2-yl) propanediol (4b, 5.94 g, 67%) as an oil, which solidified after standing. 1 H NMR (400 MHz, chloroform- d ) δ = 8.23 ​​(d, J=1.3 Hz, 1H), 8.18 (d, J=1.3 Hz, 1H), 4.90 (s, 1H), 3.97 (s, 3H), 3.79 (s, 6H).

[0414] A solution of dimethyl (5-methoxypyrazine-2-yl)propanediate (4b, 7.30 g, 30.4 mmol) in DMSO (51 mL) and water (3.4 mL) was cooled to 0 °C. Solid lithium chloride (5.15 g, 122 mmol) was added and the mixture was heated to 100 °C for 17 hours. The dark red solution was distributed between ethyl acetate (150 mL) and water (300 mL). The aqueous layer was further extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with a half-saturated aqueous solution of NaCl and a saturated aqueous solution of NaCl, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluted with a solution of 0-60% ethyl acetate in heptane) to give (5-methoxypyrazine-2-yl) methyl acetate (4c, 3.86 g, 70%) as an oil. 1 H NMR (400 MHz, chloroform- d ) δ = 8.18 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 3.96 (s, 3H), 3.79 (s, 2H), 3.73 (s, 3H).

[0415] A suspension of methyl (5-methoxypyrazin-2-yl)acetate (4c, 3.86 g, 21.2 mmol) and lithium hydroxide monohydrate (889 mg, 21.2 mmol) in THF (42 mL) and water (42 mL) was stirred at 25 °C for 14 h. Unreacted ester was still present as determined by LCMS, so additional lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added and stirring continued at 25 °C for 6 h. Conversion was still not complete, so even more lithium hydroxide monohydrate (110 mg, 2.62 mmol; total 1.049 g, 25 mmol) was added and the mixture was heated to 30 °C for 2 h. THF was removed under vacuum and the aqueous residue was lyophilized to dryness, leaving lithium (5-methoxypyrazin-2-yl)acetate (intermediate 4, 4.272 g, 115% of the theoretical mass of 3.71 g) as a mixture with lithium hydroxide. 1 H NMR (400 MHz, deuterium oxide) δ = 8.14 (d, J = 1.3 Hz, 1H), 8.01 (d, J = 1.2 Hz, 1H), 3.93 (s, 3H), 3.64 (s, 2H).

[0416] Intermediate 5: Lithium 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylate.

[0417]

[0418] A solution of methanesulfonyl chloride (11.32 g, 98.8 mmol) in dichloromethane (50 mL) was added dropwise to a cooled (0°C) mixture of methyl 3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (CAS# 1208081-25-7, 15.0 g, 88.1 mmol) and diisopropylethylamine (14.8 g, 115 mmol) in dichloromethane (250 mL). After the addition was complete, the mixture was stirred at 0°C for 45 minutes. The reaction mixture was washed with saturated aqueous NH4Cl solution, and the organic layer was dried over sodium sulfate, filtered, and concentrated to give methyl 1-methyl-3-{[(methylsulfonyl)oxy]methyl}-1H-pyrazole-5-carboxylate (5a, 22.6 g, >99%) as a yellow oil, which was used without further purification. 1 H NMR (400 MHz, chloroform- d ) δ = 6.98 (s, 1H), 5.26 (s, 2H), 4.20 (s, 3H), 3.91 (s, 3H), 3.03 (s, 3H).

[0419] A room temperature solution of methyl 1-methyl-3-{[(methylsulfonyl)oxy]methyl}-1H-pyrazole-5-carboxylate (5a, 22.6 g, 91.0 mmol) in methanol (200 mL) was treated with small portions of solid sodium methoxide (9.84 g, 182 mmol). The reaction was heated to 70 °C for 30 minutes. TLC indicated partial hydrolysis of the ester, so to re-esterify, the cloudy mixture was acidified with 4M HCl in ethyl acetate (40 mL, 160 mmol) and heated at 70 °C for an additional 5 hours. The mixture was concentrated to dryness to leave a white solid. The solid was extracted with ethyl acetate / petroleum ether (1 / 3, 3 x 200 mL). The combined extracts were concentrated to dryness and the residual solid was then re-extracted with ethyl acetate / petroleum ether (1 / 3, 100 mL), dried over sodium sulfate, filtered, and concentrated to give methyl 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylate (5b, 14.5 g, 86%, 80% purity by NMR) as a pale yellow liquid which solidified upon standing. Major components only: 1 H NMR (400 MHz, chloroform- d ) δ = 6.83 (s, 1H), 4.45 (s, 2H), 4.16 (s, 3H), 3.88 (s, 3H), 3.39 (s, 3H).

[0420] A solution of 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-formic acid methyl ester (5b, 14.5 g, 78.7 mmol) and lithium hydroxide monohydrate (3.47 g, 82.7 mmol) in THF (150 mL) and water (50 mL) was stirred at room temperature for 16 hours. THF was removed under vacuum, and the residue was dissolved in water (100 mL) and extracted with dichloromethane (3 x 30 mL). The organic layer was abandoned. The water layer was concentrated and dried under vacuum to obtain 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-formic acid lithium (intermediate 5, 12.85 g, 92%) as a yellow solid. 1 H NMR (400MHz, DMSO- d 6) δ = 6.37 (s, 1H), 4.24 (s, 2H), 4.01 (s, 3H), 3.20 (s, 3H). MS: 171 [M+H] + .

[0421] General Methods and Representative Examples

[0422] Method A

[0423] Example 1: Propylcarbamic acid (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}- 1 H -pyrazol-5-yl)cyclopentyl ester

[0424]

[0425] A room temperature solution of {1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}benzylcarbamate (Intermediate 1, 5.00 g, 14.0 mmol) and 4-nitrophenyl chloroformate (4.23 g, 21.0 mmol) in anhydrous dichloromethane (50 mL) was treated with pyridine (3.40 mL, 42.0 mmol) and 4-(dimethylamino)pyridine (170 mg, 1.4 mmol). After stirring overnight at room temperature, the solution was concentrated and purified by silica gel chromatography (eluting with 0-100% ethyl acetate in n-heptane) to give carbonic acid (1 40 mg, 1 40 mmol) as a solid foam. R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (1A, 7.30 g, 100%). 1 H NMR (400MHz, chloroform- d) δ = 8.24-8.14 (m, 2H), 7.36-7.22 (m, 7H), 6.21 (br. s., 1H), 6.06 (br. s., 1H), 5.25 - 5.15 (m, 1H), 5.12 (s, 2H), 3.15-2.97 (m, 1H), 2.58-2.47 (m, 1H), 2.09-1.78 (m, 5H), 1.51 (s, 9H). MS: 523 [M+H] + .

[0426] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H A solution of 1-(2-pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (1A, 36 g, 69 mmol) in 2-methyltetrahydrofuran (300 mL) was cooled to 10°C. Diisopropylethylamine (26.7 g, 36 mL, 207 mmol) and propan-1-amine (6.11 g, 8.52 mL, 103 mmol) were added, and the solution was stirred at 10°C for 16 hours. After concentration to dryness, the residue was diluted with ethyl acetate (600 mL), washed with 1M NaOH (4 x 200 mL), and then washed with saturated aqueous NaCl solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude benzyl (1-tert-butyl-3-{(1S,3R)-3-[(propylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (1B, 30 g, 98%) which was used without further purification.

[0427] A room temperature (20-25° C.) suspension of Pd / C (50% H2O, 8 g) and crude benzyl (1-tert-butyl-3-{(1S,3R)-3-[(propylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (1B, 30 g, 68 mmol) in ethyl acetate (300 mL) and THF (150 mL) was degassed and purged with hydrogen (3 cycles) and then stirred at room temperature under a hydrogen balloon for 16 hours. The suspension was filtered, the filtrate was concentrated under vacuum, and the residue was crystallized from ethyl acetate (50 mL) and petroleum ether (300 mL) to give propylcarbamic acid (1B) as a white solid. R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (1C, 17.65 g, 84%). 1H NMR (400MHz, DMSO- d 6) δ = 7.00 (brt, J=5.6 Hz, 1H), 5.23 (s, 1H), 4.95 (br s, 1H), 4.82-4.58 (m, 2H), 2.91 (q,J=6.6 Hz, 2H), 2.85-2.73 (m, 1H), 2.37-2.21 (m, 1H), 1.92-1.76 (m, 2H), 1.72-1.52 (m, 3H), 1.48 (s, 9H), 1.44-1.32 (m, 2H), 0.82 (t, J=7.4 Hz, 3H). MS: 309[M+H] + . ] + . Optical rotation [α] D -4.04 ( c 0.89, MeOH). Chiral purity: 98%ee by chiral analysis SFC.

[0428] The cooled (10°C) propylcarbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H A mixture of 1-(2-methoxypyridin-4-yl)-1-(2-(2-(2-methoxypyridin-3-yl)-cyclopentyl)-1-(2-(2-methoxypyridin-4-yl)-acetic acid (CAS# 464152-38-3, 5.86 g, 33.7 mmol), diisopropylethylamine (14.7 mL, 84.1 mmol) and propylphosphonic anhydride (T3P®, 50% by weight solution in EtOAc, 53.5 g, 84.1 mmol) in dichloromethane (250 mL) was stirred for 16 hours. The reaction was quenched with saturated Na2CO3 aqueous solution (20 mL) and extracted with dichloromethane (100 mL). The organic layer was washed with more saturated Na2CO3 aqueous solution (2 x 200 mL) and saturated NaCl aqueous solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. For purification, this batch was combined with two other similarly prepared batches derived from 1.0 g and 8.0 g of 1C (total SM for three batches = 17.65 g, 57.23 mmol 1C). Silica gel chromatography (eluting with 0-60% EtOAc / petroleum ether) yielded propylcarbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H-pyrazol-3-yl)cyclopentyl ester (1D, 25 g, 95% yield for combined batches). MS: 458 [M+H] + .

[0429] Propyl carbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H A solution of 1-pyrazol-3-yl)cyclopentyl ester (1D, 20.5 g, 44.8 mmol) in formic acid (50 mL) was stirred at 75 °C for 20 hours. For purification, this batch was combined with a smaller batch (from 4.50 g, 9.84 mmol 1D, total 25.0 g, 54.6 mmol), concentrated to dryness, and purified by preparative HPLC [Phenomenex Gemini C18 250 x 50mm x 10µm column; eluted with a gradient of water (0.05% ammonium hydroxide v / v) in ACN over 15 minutes; flow at 110 mL / min]. Pure propylcarbamic acid (1D) was obtained as a light yellow solid. R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 1, 16.61 g, 76% yield for combined batches). 1 H NMR (400 MHz, chloroform- d ) δ = 11.62-9.81 (m, 1H), 9.06 (br s, 1H), 8.06 (d, J=5.3 Hz, 1H), 6.79(d, J=5.3 Hz, 1H), 6.66 (s, 1H), 6.50 (s, 1H), 5.24-4.94 (m, 2H), 3.88 (s,3H), 3.58 (s, 2H), 3.19-2.83 (m, 3H), 2.54-2.28 (m, 1H), 2.04 (br s, 1H),1.97-1.70 (m, 4H), 1.54-1.34 (m, 2H), 0.85 (br t, J=7.0 Hz, 3H). MS: 402 [M+H] + . Optical rotation [α] D +17.1 ( c 1.06, MeOH). Chiral purity: 96%ee by chiral analysis SFC.

[0430] Example 2: Propane-2-ylcarbamic acid (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl1-amino- H -pyrazol-5-yl)cyclopentyl ester .

[0431]

[0432] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H A solution of (1-tert-butyl-3-{(1S,3R)-3-[(propan-2-ylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamic acid benzyl ester (2A, 1.8 g, 100% crude) was stirred at 10 °C for 4 hours. After concentration to dryness, the residue was diluted with ethyl acetate (100 mL), and the solution was washed with 1M sodium hydroxide (4 x 50 mL) and saturated aqueous NaCl solution (30 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude benzyl (1-tert-butyl-3-{(1S,3R)-3-[(propan-2-ylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (2A, 1.8 g, 100% crude).

[0433] A room temperature (10°C) suspension of crude (1-tert-butyl-3-{(1S,3R)-3-[(propan-2-ylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)benzylcarbamate (2A, 1.8 g, 3.83 mmol) and Pd / C (wet, 200 mg) in ethyl acetate (10 mL) and THF (5 mL) was degassed and purged with hydrogen, then stirred at 10°C for 16 hours under a hydrogen balloon. The catalyst was removed by filtration, and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC on a Phenomenex Gemini C18 250*50mm*10µm column, eluting with a solution of 25-45% water (0.05% ammonium hydroxide v / v) in acetonitrile. The fractions containing the product were lyophilized to give propan-2-ylcarbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (2B, 1.0 g, 85%). MS: 309 [M+H] + .

[0434] Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 457, g. 0.718 mmol) was added to a cooled (0° C.) propan-2-ylcarbamic acid (1 R ,3 S)-3-(5-amino-1-tert-butyl-1 H 3-pyrazol-3-yl)cyclopentyl ester (2B, 80 mg, 0.26 mmol), diisopropylethylamine (92.7 mg, 0.718 mmol) and (2-methyl-1,3-thiazol-5-yl)acetic acid (CAS# 52454-65-6, 45.1 mg, 0.287 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature (10 ° C) for 16 hours and then partitioned between dichloromethane (20 mL) and saturated aqueous Na2CO3 solution (10 mL). The organic layer was washed with saturated aqueous NaCl solution (10 mL), dried over sodium sulfate, filtered, and concentrated to give crude propan-2-ylcarbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (2C, 120 mg, 100% crude).

[0435] The crude propan-2-ylcarbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (2C, 120 mg, 0.26 mmol) was dissolved in formic acid (5 mL) and stirred at 75°C for 20 hours. The volatiles were removed under vacuum and the residue was purified by preparative HPLC on an Xtimate C18 150*25mm*5µm column, eluting with 12-52% water (0.05% ammonium hydroxide v / v) in acetonitrile. The fractions containing the product were lyophilized to give propan-2-ylcarbamic acid (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 2, 60.35 mg, 58%). 1H NMR(400MHz, DMSO-d6) δ = 12.10 (s, 1H), 10.58 (s, 1H), 7.41 (s, 1H), 6.95 (br d,J=6.3 Hz, 1H), 6.29 (s, 1H), 4.98 (br s, 1H), 3.81 (s, 2H), 3.57 (br d, J=6.5Hz, 1H), 3.03 (br s, 1H), 2.59 (s, 3H), 2.45 (br s, 1H), 2.07-1.81 (m, 2H),1.78-1.44 (m, 3H), 1.03 (br d, J=6.5 Hz, 6H). MS: 392 [M+H] + . Chiral purity: 99%ee by chiral analysis SFC.

[0436] Example 3: Ethylcarbamic acid (1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}- 1 H -pyrazol-5-yl)cyclopentyl ester

[0437]

[0438] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H A solution of (1-tert-butyl-3-{(1S,3R)-3-[(ethylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamic acid benzyl ester (3A, 2.0 g, 97%, >80% purity by LCMS) was stirred at 30 °C for 3 hours, concentrated to dryness, and the residue was dissolved in dichloromethane (30 mL). The solution was washed with aqueous NaOH until the organic layer was colorless (5 x 5 mL), then washed with water (5 mL) and saturated aqueous NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated to give crude benzyl (1-tert-butyl-3-{(1S,3R)-3-[(ethylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (3A, 2.0 g, 97%, >80% purity by LCMS) as a colorless oil. MS: 429 [M+H] + , 451 [M+Na] + .

[0439] Crude benzyl (1-tert-butyl-3-{(1S,3R)-3-[(ethylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (3A, 2.0 g, 4.7 mmol) was dissolved in ethyl acetate (30 mL) and THF (10 mL), the solution was degassed, and 10% Pd / C catalyst (wet, 200 mg) was added. The suspension was stirred at room temperature (10°C) under a hydrogen balloon for 2 hours. The catalyst was removed by filtration, the filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (eluting with 0-60% ethyl acetate in petroleum ether) to give ethylcarbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (3B, 1.15 g, 84%), which solidified to a light yellow solid after standing. MS: 295 [M+H] + . 1 H NMR (400MHz, chloroform- d ) δ = 5.43 (s, 1H), 5.13 (br s, 1H),4.58 (br s, 1H), 3.50 (br s, 2H), 3.31-3.13 (m, 2H), 2.99 (quin, J=8.5 Hz,1H), 2.53-2.39 (m, 1H), 2.04-1.96 (m, 1H), 1.95-1.87 (m, 1H), 1.87-1.68 (m,3H), 1.62 (s, 9H), 1.14 (t, J=7.2 Hz, 3H). Chiral purity: >98%ee by chiral analysis SFC.

[0440] Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 0.485 mL, 0.815 mmol) was added to ethylcarbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (3B, 80.0 mg, 0.272 mmol), 2-(1-methyl-1 H1-Indazol-5-yl)acetic acid (CAS# 1176749-66-8, 59.1 mg, 0.311 mmol) and diisopropylethylamine (0.142 mL, 0.815 mmol) in dichloromethane (5 mL) at room temperature (10 ° C). The mixture was stirred for 3 hours and then partitioned between dichloromethane (5 mL) and water (3 mL). The organic layer was washed with saturated aqueous Na2CO3 (2 x 3 mL), saturated aqueous NH4Cl (2 x 3 mL), water (2 mL), and saturated aqueous NaCl (2 mL), then dried over sodium sulfate, filtered, and concentrated to give crude ethylcarbamic acid (1 ) as a light yellow gum. R ,3 S )-3-(1-tert-butyl-5-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (3C, 127 mg, 100% crude). MS: 489 [M+Na] + .

[0441] The crude ethylcarbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H A solution of 2-(4-pyrazol-3-yl)cyclopentyl ester (3C, 127 mg, 0.272 mmol) in formic acid (6 mL) was heated at 75°C for 18 hours. The reaction mixture was concentrated to dryness and then purified by preparative HPLC on a DuraShell 150*25mm*5µm column, eluting with 24-44% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization of the product-containing fractions, ethylcarbamic acid (1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 3, 52.39 mg, 47%). MS: 411 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ = 12.05 (br s, 1H), 10.51 (s, 1H), 8.06-7.95 (m, 1H), 7.64 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.35 (dd, J=1.4, 8.7 Hz, 1H), 7.02 (brt, J=5.5 Hz, 1H), 6.27 (br s, 1H), 4.97 (br s, 1H), 4.04-3.95 (m, 3H), 3.66 (s, 2H), 3.10-2.85 (m, 3H), 2.43 (td, J=6.9, 14.0 Hz, 1H), 2.04-1.92 (m, 1H), 1.91-1.80 (m, 1H), 1.74-1.49 (m, 3H), 0.97 (t, J=7.2 Hz, 3H). Chiral purity: 99%ee by chiral analysis SFC.

[0442] Embodiment 4: (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazole-5- yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester

[0443]

[0444] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (1A, 22.0 g, 42.1 mmol), ( S A solution of )-(+)-sec-butylamine (4.00 g, 54.7 mmol) and diisopropylethylamine (36.7 mL, 211 mmol) in THF (300 mL) was stirred at 10 °C for 16 hours. The mixture was concentrated to dryness, and the residue was diluted with ethyl acetate (500 mL). The solution was washed with 1M aqueous NaOH (4 x 200 mL) and saturated aqueous NaCl (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude benzyl {3-[(1S,3R)-3-{[(2S)-butyl-2-carbamoyl]oxy}cyclopentyl]-1-tert-butyl-1H-pyrazol-5-yl}carbamate (4A, 18 g, 94%, ~80% purity by LCMS). MS: 479 [M+Na] + .

[0445] A room temperature (10°C) solution of crude {3-[(1S,3R)-3-{[(2S)-butyl-2-carbamoyl]oxy}cyclopentyl]-1-tert-butyl-1H-pyrazol-5-yl}benzylcarbamate (4A, 18 g, 39 mmol) in ethyl acetate (200 mL) and THF (100 mL) was degassed and treated with a Pd / C catalyst (wet, 5 g). The suspension was stirred under a hydrogen balloon for 16 hours. The mixture was filtered to remove the catalyst and the filtrate was concentrated to dryness. For purification, this batch was combined with a second batch of crude material derived from 20 g of 4A by the same method (total of two batches: 38 g, 83 mmol) and purified by preparative HPLC on a Phenomenex Gemini C18 250*50mm*10µm column, eluting with 30-50% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization, (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (4B, 20.1 g, combined batch 75%). MS: 323 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ = 6.86 (br d, J=8.3 Hz, 1H), 5.22 (s, 1H), 4.94 (br s, 1H), 4.82-4.49 (m, 2H), 3.46-3.36 (m, 1H), 2.90-2.71 (m, 1H), 2.38-2.24 (m, 1H), 1.91-1.75 (m, 2H), 1.74-1.53 ​​(m, 3H), 1.52-1.46 (m, 9H), 1.43-1.27 (m, 2H), 0.81 (t, J=7.4 Hz, 3H). Optical rotation [α] D +4.0 ( c 1.3, MeOH). Chiral purity: 98%de by chiral analysis SFC.

[0446] Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 592 mg, 0.93 mmol) was added to a cooled (0°C) (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S)-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (4B, 100 mg, 0.310 mmol), 1-methyl-1 H -1,2,3-triazole-5-carboxylic acid (CAS# 716361-91-0, 59.1 mg, 0.465 mmol) and diisopropylethylamine (120 mg, 0.93 mmol) in dichloromethane (5 mL). The mixture was stirred at 10 °C for 18 hours, then washed with saturated aqueous Na2CO3 and saturated aqueous NaCl, dried over sodium sulfate, filtered, and concentrated to give crude (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (4C, 130 mg, 97%). MS: 432 [M+H] + ,454 [M+Na] + .

[0447] The crude (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1 H A solution of 4-pyrazol-3-yl)cyclopentyl ester (4C, 130 mg, 0.301 mmol) in formic acid (3 mL) was stirred at 75°C for 6 days. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC on a DuraShell 150*25mm*5µm column, eluting with 10-51% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization, (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 4, 27.67 mg, 24%). MS: 376 [M+H] + . 1 HNMR (400MHz, DMSO- d6) δ = 12.32 (br s, 1H), 11.14 (s, 1H), 8.46 (s, 1H), 6.90 (br d, J=8.0 Hz, 1H), 6.45 (br s, 1H), 5.00 (br d, J=3.8 Hz, 1H), 4.25 (s,3H), 3.36 (br s, 2H), 3.29-2.99 (m, 1H), 2.09-2.01 (m, 1H), 1.95-1.84 (m,1H), 1.81-1.56 (m, 3H), 1.44-1.27 (m, 2H), 1.01 (br d, J=6.5 Hz, 3H), 0.80(br t, J = 7.4 Hz, 3H). Chiral purity: > 98% de by chiral analysis SFC.

[0448] Example 5: (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl) Acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester

[0449]

[0450] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H A solution of 1-(2-(4-pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (1A, 9.50 g, 18.2 mmol), 1-methylcyclopropylamine hydrochloride (2.93 g, 27.2 mmol) and diisopropylethylamine (10.0 mL, 58.2 mmol) in DMF (80 mL) was stirred at 60° C. for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (300 mL) and water (300 mL). The organic layer was washed with water (2 x 300 mL), 2M aqueous Na2CO3 (300 mL), and saturated aqueous NaCl (300 mL), then dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-100% ethyl acetate in heptane) to give benzyl {1-tert-butyl-3-[(1S,3R)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}carbamate (5A, 6.28 g, 76%) as a solid. MS: 455 [M+H] + . 1 H NMR (400 MHz, chloroform- d) δ =7.45-7.30 (m, 5H), 6.30 (br. s., 1H), 6.10 (br. s., 1H), 5.20 (s, 2H), 5.15(br. s., 1H), 5.06 (br. s., 1H), 3.08 (quin, J=8.3 Hz, 1H), 2.44 (br. s.,1H), 2.12-1.97 (m, 1H), 1.96-1.75 (m, 4H), 1.58 (s, 9H), 1.35 (br. s., 3H), 0.74 (br. s., 2H), 0.58 (br. s., 2H).

[0451] A mixture of {1-tert-butyl-3-[(1S,3R)-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}benzylcarbamate (5A, 6.28 g, 13.8 mmol) and 10% Pd / C (620 mg) in methanol (200 mL) was stirred at room temperature (20° C.) for 18 hours under a hydrogen balloon. The suspension was filtered through a celite pad to remove the catalyst. The flask and filter pad were rinsed with additional methanol, and the combined filtrate was then concentrated to give (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (5B, 4.42 g, 100% crude). MS: 321 [M+H] + . 1 H NMR (400 MHz, methanol- d 4) δ = 5.06 (br. s., 1H),3.14-2.97 (m, 1H), 2.58-2.37 (m, 1H), 2.14-2.00 (m, 1H), 2.00-1.69 (m, 4H),1.69-1.54 (m, 10H), 1.31 (s, 3H), 0.74-0.66 (m, 2H), 0.60-0.53 (m, 2H).

[0452] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 HA solution of (5-methyl-1,3-oxazol-2-yl)cyclopentyl ester (5B, 4.00 g, 12.5 mmol), (5-methyl-1,3-oxazol-2-yl) lithium acetate (Intermediate 3, 3.52 g, 24.9 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 14.2 g, 37.3 mmol) and triethylamine (5.30 mL0, 38.0 mmol) in DMF (100 mL) was stirred at 60 °C for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was further washed with water (2 x 200 mL) and saturated aqueous NaCl solution (200 mL). The combined aqueous layers were extracted with ethyl acetate (200 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (eluting with 10-100% ethyl acetate in heptane) to give impure product (5.50 g solid). The impure material was re-purified by silica gel chromatography (eluting with 100% ethyl acetate) to give pure (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (5C, 4.22 g, 76%). MS: 444 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ = 9.78(s, 1H), 7.32 (br. s., 1H), 6.78 (d, J=1.1 Hz, 1H), 5.93 (s, 1H), 4.97 (br.s., 1H), 3.83 (s, 2H), 3.03-2.88 (m, 1H), 2.42-2.30 (m, 1H), 2.27 (d, J=1.1Hz, 3H), 1.98-1.88 (m, 1H), 1.87-1.77 (m, 1H), 1.73-1.58 (m, 3H), 1.49 (s,9H), 1.23 (s, 3H), 0.63-0.56 (m, 2H), 0.50-0.44 (m, 2H).

[0453] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S)-3-(1-tert-butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H A solution of (1-methylcyclopropyl)carbamic acid (5C, 4.20 g, 9.47 mmol) in formic acid (50 mL) was stirred at 100 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated to remove most of the formic acid. The residue was partitioned between ethyl acetate (200 mL) and sodium bicarbonate (200 mL). The aqueous layer was extracted with more ethyl acetate (200 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated to dryness. The solid residue was triturated twice with diethyl ether (30 mL) to give (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 5, 1.93 g, 53%). MS: 388 [M+H] + . 1 H NMR (400 MHz, DMSO- d 6) δ = 12.08 (br. s., 1H), 10.59 (br. s., 1H), 7.32(br. s., 1H), 6.74 (d, J=1.0 Hz, 1H), 6.27 (br. s., 1H), 4.97 (br. s., 1H),3.79 (s, 2H), 3.14-2.93 (m, 1H), 2.44 (dd, J=14.1, 7.0 Hz, 1H), 2.26 (d, J=0.7 Hz, 3H), 1.99 (t, J=3.4 Hz, 1H), 1.93-1.81 (m, 1H), 1.68 (d, J=8.2 Hz,2H), 1.60-1.46 (m, 1H), 1.22 (s, 3H), 0.58 (br. s., 2H), 0.49- 0.42 (m, 2H).

[0454] Example 6: (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl 1-amino-1 H -pyrazol-5-yl)cyclopentyl ester

[0455]

[0456] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 HA solution of (1-methylcyclopropyl)carbamic acid (1-methylcyclopropyl)carbamic acid (5B, 150.0 mg, 0.468 mmol), (5-methoxypyrazine-2-yl) lithium acetate (intermediate 4, 118 mg, 0.702 mmol), diisopropylethylamine (182 mg, 1.40 mmol) and propylphosphonic anhydride (T3P®, 50 wt % solution in EtOAc, 447 mg, 0.702 mmol) in dichloromethane (10.0 mL) was stirred at 40 ° C for 30 hours. The reaction was quenched with saturated aqueous NaHCO3 solution (8 mL) and extracted with dichloromethane (3 x 8 mL). The combined organic extracts were washed with saturated aqueous NaCl solution (15 mL), concentrated, and purified by silica gel chromatography (eluted with 50% ethyl acetate in petroleum ether) to give (1-methylcyclopropyl)carbamic acid ... R ,3 S )-3-(1-tert-butyl-5-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (6A, 100 mg, 45%, 81% purity by LCMS). MS: 471 [M+H] + .

[0457] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (6A, 100 mg, 0.213 mmol) was dissolved in formic acid (5 mL) and stirred at 75°C for 16 hours. The solution was concentrated under vacuum, and the residue was purified by preparative HPLC on a DuraShell 150*25mm*5µm column, eluting with 26-46% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization, (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 6, 15.55 mg, 18%). MS: 415 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ = 12.07 (br s, 1H), 10.54 (s, 1H), 8.23 ​​(d, J=1.3 Hz,1H), 8.16 (s, 1H), 7.35 (br s, 1H), 6.26 (br s, 1H), 4.96 (br s, 1H), 3.89(s, 3H), 3.77 (s, 2H), 3.02 (br d, J=8.5 Hz, 1H), 2.47-2.39 (m, 1H), 1.97 (brd, J=9.3 Hz, 1H), 1.90-1.80 (m, 1H), 1.72-1.59 (m, 2H), 1.58-1.45 (m, 1H), 1.21 (s, 3H), 0.57 (br s, 2H), 0.48-0.40 (m, 2H). Chiral purity: 99%ee by chiral analysis SFC.

[0458] Example 7: (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl) Acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester

[0459]

[0460] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H A solution of (5-methyl-1,2-oxazol-3-yl)cyclopentyl ester (5B, 78 mg, 0.24 mmol), (5-methyl-1,2-oxazol-3-yl)acetic acid (CAS#57612-87-0, 51.5 mg, 0.365 mmol), diisopropylethylamine (0.130 mL, 0.730 mmol) and propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 0.435 mL, 0.730 mmol) in dichloromethane (5.0 mL) was stirred at 30-35° C. for 18 hours. The solution was washed with saturated aqueous NaHCO3 (5 mL) and saturated aqueous NaCl (5 mL), dried, filtered, and concentrated to give crude (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (7A, 95 mg, 88%). MS: 444[M+H] + .

[0461] The crude (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H 1-Pyrazol-3-yl)cyclopentyl ester (7A, 95 mg, 0.21 mmol) was dissolved in formic acid (5.0 mL) and heated to 75 °C for 15 hours. The sample was concentrated to dryness, and the residue was dissolved in ethyl acetate (30 mL), washed with saturated aqueous NaHCO3 (10 mL), dried, filtered, and concentrated. The crude product was purified by preparative HPLC on an Agela DuraShell C18 150*25mm 5µ column eluted with 18-58% water (containing 0.05% ammonium hydroxide) in acetonitrile to give (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 7, 39.71 mg, 50%). MS: 388[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.59 (s, 1H), 7.34 (brs, 1H), 6.36-6.03 (m, 2H), 4.97 (br s, 1H), 3.64 (s, 2H), 3.15-2.87 (m, 1H),2.46-2.40 (m, 1H), 2.37 (s, 3H), 1.98 (br d, J=9.0 Hz, 1H), 1.90-1.81 (m,1H), 1.77-1.59 (m, 2H), 1.54 (br d, J=8.0 Hz, 1H), 1.22 (s, 3H), 0.58 (br s,2H), 0.49-0.43 (m, 2H). Chiral purity: chiral analysis SFC>99%ee.

[0462] Example 8: (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester

[0463]

[0464] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1H -pyrazol-3-yl)cyclopentyl ester (5B, 5.47 g, 17.1 mmol) and 3-(methoxymethyl)-1-methyl-1 H A solution of 5-pyrazole-5-carboxylic acid (Intermediate 5, 4.36 g, 25.6 mmol) in ethyl acetate (80 mL) was treated with diisopropylethylamine (9.00 mL, 52.4 mmol) and propylphosphonic anhydride (T3P®, 50 wt % solution in EtOAc, 10.9 g, 10.0 mL, 31.4 mmol) and stirred at room temperature overnight. Since LCMS indicated that the reaction was not complete, the mixture was heated to 50 °C for 3 hours, but LCMS still indicated incomplete conversion. After cooling to room temperature, the solution was partitioned between ethyl acetate (100 mL) and deionized water (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was dissolved in ethyl acetate (80 mL). Additional 3-(methoxymethyl)-1-methyl-1- H -pyrazole-5-carboxylic acid (Intermediate 5, 2.90 g, 17.1 mmol), diisopropylethylamine (9.00 mL, 52.4 mmol) and T3P (10.0 mL, 33.6 mmol) were added and the reaction was stirred at room temperature for 4 hours. The solution was diluted with ethyl acetate (100 mL); washed with water (200 mL), saturated aqueous NaHCO3 solution (200 mL), and saturated aqueous NaCl solution (200 mL); dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with a gradient of 0-100% ethyl acetate in heptane) to give (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-3-yl]cyclopentyl ester (8A, 4.83 g, 60%). MS: 473 [M+H] + . 1H NMR(400 MHz, chloroform-d) δ = 7.71 (br. s., 1 H), 6.68 (br. s., 1 H), 6.23 (br. s., 1H), 5.12 (br. s., 2 H), 4.47 (s, 2 H), 4.18 (s, 3 H), 0.73 (br. s., 2 H), 0.52-0.61 (m, 2 H).

[0465] (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H A solution of [1-methylcyclopropyl]carbamic acid (8A, 4.77 g, 10.1 mmol) in formic acid (50 mL) was stirred at 100 °C for 2 hours. After cooling to room temperature, most of the formic acid was removed under vacuum and the residue was partitioned between ethyl acetate (200 mL) and saturated aqueous NaHCO3 (200 mL). The aqueous layer was extracted with ethyl acetate (200 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-10% methanol in ethyl acetate) to give a white solid (3.15 g). The solid was recrystallized from ethyl acetate / heptane to give (1-methylcyclopropyl)carbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester (Example 8, 2.90 g, 69%). MS: 417 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ = 12.20 (br. s., 1 H), 10.69 (s, 1 H), 7.33 (br. s., 1 H), 7.11 (s, 1 H), 6.41 (br. s., 1 H), 4.99 (br.s., 1 H), 4.33 (s, 2 H), 4.05 (s, 3 H), 3.27 (s, 3 H), 3.00-3.13 (m, 1 H), 2.41-2.49 (m, 1 H), 1.97-2.10 (m, 1 H), 1.83-1.95 (m, 1 H), 1.72 (br. s., 2H), 1.59 (br. s., 1H), 1.24 (s, 3 H), 0.60 (br. s., 2 H), 0.47 (br. s., 2H).

[0466] Example 9: [(2ξ)-4,4,4-trifluorobutyl-2-yl]carbamic acid (1R,3S)-3-[3-({[3-(methoxymethyl [1-Methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester - Isomer A

[0467] Example 10: [(2ξ)-4,4,4-trifluorobutyl-2-yl]carbamic acid (1R,3S)-3-[3-({[3-(methoxymethyl [1-Methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl ester - Isomer B

[0468]

[0469] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 HA solution of 1-(2-pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (1A, 2.5 g, 4.8 mmol), 4,4,4-trifluorobutan-2-amine (CAS# 37143-52-5, 900 mg, 5.5 mmol) and diisopropylethylamine (4.17 mL, 23.9 mmol) in 2-methyltetrahydrofuran (40 mL) and dichloromethane (20 mL) was stirred at 40-50° C. for 15 hours. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (150 mL) and 1N aqueous sodium hydroxide solution (2 x 50 m). The organic layer was washed with saturated aqueous NaCl solution (60 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 15-30% ethyl acetate in petroleum ether) to give benzyl {1-tert-butyl-3-[(1S,3R)-3-{[(4,4,4-trifluorobutan-2-yl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}carbamate (9A, mixture of diastereomers, 2.0 g, 82%, 79% pure by LCMS) as a yellow oil. MS: 511 [M+H] + .

[0470] {1-tert-butyl-3-[(1S, 3R)-3-{[(4,4,4-trifluorobutyl-2-yl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-5-yl}benzyl carbamate mixture (9A, 2.0 g, 3.9 mmol) was dissolved in ethyl acetate (20 mL) and THF (20 mL), and 10% Pd / C catalyst (50% wet, 650 mg) was added. The suspension was degassed, filled with hydrogen from a balloon, and stirred at 20-25° C. under a hydrogen balloon for 16 hours. The catalyst was removed by filtration, and the filtrate was concentrated to obtain crude (4,4,4-trifluorobutyl-2-yl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (9B, mixture of diastereomers, 1.4 g, 95%, 76% purity by LCMS). MS: 377 [M+H] + .

[0471] The cooled (0°C) crude (4,4,4-trifluorobutan-2-yl)carbamic acid (1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl ester (9B, 225 mg, 0.598 mmol), 3-(methoxymethyl)-1-methyl-1 HA solution of -pyrazole-5-carboxylate (intermediate 5, 173 mg, 0.897 mmol) and diisopropylethylamine (232 mg, 1.79 mmol) in dichloromethane (10 mL) was treated with propylphosphonic anhydride (T3P®, 50% by weight solution in EtOAc, 1.14 g, 1.79 mmol). The mixture was warmed to 20° C. and stirred for 36 hours, then warmed to 40° C. for 90 hours. The mixture was distributed between dichloromethane and half-saturated Na2CO3. The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude (4,4,4-trifluorobutan-2-yl)carbamic acid (1 R ,3 S )-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-3-yl]cyclopentyl ester (9C, mixture of diastereomers, 300 mg, 95%). MS: 529 [M+H] + .

[0472] The crude (4,4,4-trifluorobutan-2-yl)carbamic acid (1 R ,3 S )-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H A solution of [-pyrazol-3-yl] cyclopentyl ester (9C, 300 mg, 0.57 mmol) in formic acid (10 mL) was stirred at 80°C for 2 hours. The mixture was concentrated to dryness and the residue was purified by preparative HPLC on a DuraShell 150*25mm*5µm column, eluting with 32% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization, (4,4,4-trifluorobutan-2-yl)carbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester (9D, mixture of diastereomers, 45 mg, 17%). MS: 473 [M+H] + .

[0473] The diastereomeric mixture 9D was separated by chiral preparative SFC on a Phenomenex-Amylose-1 250mm*30mm 5µm column eluted with 40% ethanol (+0.1% NH3H2O) in CO2 to give Example 9 (peak 1, 12.26 mg, 27%, 99%de) and Example 10 (peak 2, 11.53 mg, 26%, 98%de) as white solids. The absolute stereochemistry of the chiral center in the 4,4,4-trifluorobutan-2-yl]carbamate was not determined for each molecule.

[0474] Example 9: (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A. 1 H NMR(400MHz, DMSO-d6) δ = 12.25 (br s, 1H), 10.74 (s, 1H), 7.22 (br d, J=8.4 Hz,1H ), 7.12 (s, 1H), 6.43 (br s, 1H), 5.10-4.96 (m, 1H), 4.34 (s, 2H), 4.05 (s,3H), 3.92-3.79 (m, 1H), 3.27 (s, 3H), 3.17-3.03 (m, 1H), 2.46 (br d, J=6.1Hz, 1H), 2.43-2.31 (m, 2H), 2.12-1.85 (m, 2H), 1.80-1.57 (m, 3H), 1.13 (d, J=6.7 Hz, 3H). 19 F NMR (377MHz, DMSO-d6) δ = -62.57 (s, 3F). MS: 473 [M+H] + . Optical rotation: [α] D -2 ( c 0.1, MeOH). Chiral purity: 99% de. Chiral SFC / MS analysis was performed on a Chiralpak AD-3 (150×4.6mm ID, 3µm) column, eluting with 40% ethanol (+0.05% DEA) in CO2 at 2.5 mL / min, at 35°C, with the pressure set at 1500 psi. Under these conditions, the peak had a retention time of 3.372 minutes.

[0475] Example 10: (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B. 1 H NMR(400MHz, DMSO-d6) δ = 12.25 (br s, 1H), 10.74 (s, 1H), 7.24 (br d, J=8.3 Hz,1H), 7.12 (s, 1H), 6.42 (br s, 1H), 5.16-4.91 (m, 1H), 4.34 (s, 2H), 4.05 (s,3H), 3.84 (td, J=7.0, 13.8 Hz, 1H), 3.27 (s, 3H), 3.16-3.01 (m, 1H), 2.50-2.46 (m, 1H), 2.45-2.29 (m, 2H), 2.12-1.99 (m, 1H), 1.95-1.85 (m, 1H), 1.80-1.53 ​​(m, 3H), 1.13 (d, J=6.7 Hz, 3H). 19 F NMR (377MHz, DMSO-d6) δ = -62.56 (s,3F). MS: 473 [M+H] + . Optical rotation: [α] D +10 ( c 0.1, MeOH). Chiral purity: 98% de. Chiral SFC / MS analysis was performed on a Chiralpak AD-3 (150×4.6 mm ID, 3µm) column, eluting with 40% ethanol (+0.05% DEA) in CO2, flowing at 2.5 mL / min, at 35°C, and setting the pressure at 1500 psi. Under these conditions, the peak had a retention time of 4.123 minutes.

[0476] Method B

[0477] Example 11: tert-Butylcarbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl] Amino}-1 H -pyrazol-5-yl) cyclopentyl ester.

[0478]

[0479] Benzyl {1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (Intermediate 1, 20 g, 56 mmol) and imidazole (5.71 g, 83.9 mmol) were dissolved in DMF (200 mL) under sonication. When the solution was at room temperature, tert-butyldimethylsilyl chloride (11.0 g, 72.7 mmol) was added in portions. After the addition was complete, the clear solution was stirred at 25 °C for 1 hour. The solvent was removed under vacuum and the residue was partitioned between ethyl acetate (500 mL) and saturated aqueous NaCl solution (200 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude benzyl {1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}carbamate (11A, 26 g, 99%) as a colorless oil. MS: 472 [M+H] + .

[0480] Crude {1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}benzylcarbamate (11A, 26 g, 55 mmol) was dissolved in ethyl acetate (100 mL) and THF (100 mL). Pd / C (50% wet, 4 g) was added, the solution was degassed, and stirred at 25 °C for 2 hours under a hydrogen balloon. The mixture was then filtered, and the filtrate was concentrated under vacuum to give crude 1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}carbamate as a light yellow oil. S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -Pyrazole-5-amine (11B, 19 g, >99%). MS: 338[M+H] + .

[0481] To the crude 1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 HTo a room temperature (25°C) solution of -pyrazol-5-amine (11B, 5.00 g, 14.8 mmol), (5-methyl-1,3-oxazol-2-yl) lithium acetate (Intermediate 3, 3.14 g, 21.3 mmol), and diisopropylethylamine (5.74 g, 44.4 mmol) in DMF (150 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 8.45 g, 22.2 mmol). The mixture was heated to 40°C for 1 hour, then diluted with ethyl acetate (300 mL) and washed sequentially with water (150 mL) and saturated aqueous NaCl solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 30% ethyl acetate in petroleum ether) to give N -{1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazol-5-yl}-2-(5-methyl-1,3-oxazol-2-yl)acetamide (11C, 5.5 g, 81%, 77% pure by LCMS). MS: 461 [M+H] + .

[0482] Will N -{1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl]-1 H A solution of 1-pyrazol-5-yl}-2-(5-methyl-1,3-oxazol-2-yl)acetamide (11C, 5.5 g, 11.9 mmol) in formic acid (50 mL) was stirred at 25°C for 14 hours. The solution was concentrated to dryness and the pale yellow oily residue was dissolved in methanol (20 mL). A solution of lithium hydroxide monohydrate (2.50 g, 59.7 mmol) in water (10 mL) was added thereto, and the mixture was stirred at 25°C for 30 minutes. The solution was concentrated to dryness. The residue was dissolved in dichloromethane (30 mL), washed with water (10 mL) and saturated aqueous NaCl solution (10 mL), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 3% methanol in dichloromethane) to give N -{1-tert-butyl-3-[(1 S ,3 R )-3-Hydroxycyclopentyl]-1 H-pyrazol-5-yl}-2-(5-methyl-1,3-oxazol-2-yl)acetamide (11D, 3.8 g, 92%, 79% pure by LCMS). MS: 347 [M+H] + .

[0483] Will N -{1-tert-butyl-3-[(1 S ,3 R )-3-Hydroxycyclopentyl]-1 H A suspension of 1-(5-methyl-1,3-oxazol-2-yl)-2-(11D, 3.8 g, 11 mmol), DMAP (134 mg, 1.10 mmol), pyridine (2.60 g, 32.9 mmol) and 4-nitrophenyl chloroformate (4.42 g, 21.9 mmol) in dichloromethane (40 mL) and THF (40 mL) was stirred at 25 °C for 2 hours. The solvent was removed under vacuum. The residue was dissolved in ethyl acetate (200 mL), washed with saturated aqueous NH4Cl solution (100 mL) and saturated aqueous NaCl solution, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give carbonic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (11E, 5.0 g, 89%, 89% purity by LCMS). MS: 512 [M+H] + .

[0484] Carbonic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 HA solution of (1R,3S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (11E, 5.0 g, 9.8 mmol) in formic acid (30 mL) was stirred at 75 °C for 16 hours. The mixture was concentrated to remove most of the formic acid, and the residue was then dissolved in dichloromethane (30 mL) and washed with saturated aqueous NaHCO3 (2 x 15 mL), water (15 mL), and saturated aqueous NaCl (15 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 80% ethyl acetate in petroleum ether) to give (1R,3S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (11F, 1.7 g, 38%) as a light yellow solid. MS: 456 [M+H] + .

[0485] A solution of (1R,3S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (11F, 4.00 g, 8.78 mmol) and tert-butylamine (6.42 g, 87.8 mmol) in THF (30 mL) was stirred at 25 °C for 1 hour. The mixture was concentrated to dryness and the residue was dissolved in dichloromethane (80 mL), washed with 1M NaOH (2 x 20 mL) and saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 3% methanol in dichloromethane) to give impure tert-butylcarbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H1H-pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (Example 11, 2.3 g, 67%, 73% pure by HPLC). A second batch of (1R,3S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (11F, 1.50 g, 3.29 mmol) was dissolved in tert-butylamine (10 mL) and stirred at 40°C for 1 hour. The reaction mixture was concentrated to dryness and the crude product thus obtained was combined with 2.3 g of impure product from the first batch above (a total of 12.08 mmol 11F was consumed in two batches) and further purified by preparative HPLC on a Phenomenex Gemimi C18 250x50 mm, 10µm column eluting with 3-45% water (+0.05% NH4OH) in ACN. Pure tert-butylcarbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 11, 2.23 g, combined batch 47%). 1 H NMR (400MHz, DMSO- d 6) δ = 12.10 (s, 1H), 10.62 (s, 1H), 6.87-6.63 (m, 2H), 6.29 (d, J=1.8 Hz, 1H), 4.96 (br s, 1H), 3.79 (s,2H), 3.03 (quin, J=8.6 Hz, 1H), 2.48-2.40 (m, 1H), 2.25 (d, J=1.1 Hz, 3H), 2.04-1.94 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.63 (m, 2H), 1.55 (br s, 1H), 1.19 (s, 9H). MS: 390 [M+H] + . Optical rotation [α] D +3.5 ( c 0.8, MeOH). Chiral purity: 98%ee by chiral analysis SFC.

[0486] Example 12: 2,2-Dimethylazetidine-1-carboxylic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol- 5-amino)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester

[0487]

[0488] Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 4.41 g, 6.93 mmol) was added to a cooled (0°C) 1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazole-5-amine (11B, 780 mg, 2.31 mmol), 3-methyl-5-isoxazoleacetic acid (CAS# 19668-85-0, 489 mg, 3.47 mmol) and diisopropylethylamine (1.23 mL, 6.93 mmol) in dichloromethane (10 mL). The mixture was stirred at 30 ° C for 1 hour and then partitioned between dichloromethane and half-saturated Na2CO3. The organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 10-50% ethyl acetate in petroleum ether) to give N -{1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide (12A, 1.1 g). MS: 461 [M+H] + .

[0489] Will N -{1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H A solution of 1-pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide (12A, 1.1 g) in formic acid (15 mL) was stirred at 45°C for 1 hour and then allowed to stand at room temperature overnight. The mixture was concentrated to dryness, the residue was dissolved in methanol (30 mL) and aqueous NH4OH (10 mL), and the solution was stirred at 20°C for 1 hour. The mixture was concentrated and purified by silica gel chromatography (eluting with 1 / 10 methanol / dichloromethane) to give N -{1-tert-butyl-3-[(1 S ,3 R )-3-Hydroxycyclopentyl]-1 H -pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide (12B, 1.0 g). MS: 347 [M+H] + .

[0490] Will N -{1-tert-butyl-3-[(1 S ,3 R )-3-Hydroxycyclopentyl]-1 H A solution of 1-pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide (12B, 1.0 g) in dichloromethane (30 mL) and THF (30 mL) was treated with DMAP (70.5 mg, 0.577 mmol), pyridine (1.14 g, 14.4 mmol) and 4-nitrophenyl chloroformate (1.16 g, 5.77 mmol). The resulting suspension was stirred at 20 °C for 12 h. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (30 mL), and the solution was washed sequentially with saturated aqueous NH4Cl solution (15 mL) and saturated aqueous NaCl solution (15 mL). The organic layer was dried, concentrated, and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give carbonic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (12C, 1.3 g). MS: 512 [M+H] + .

[0491] Carbonic acid (1 R ,3 S )-3-(1-tert-butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H A solution of 4-nitrophenyl 4-pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (12C, 1.3 g) in formic acid (20 mL) was heated at 75 °C for 16 hours. Most of the formic acid was removed under vacuum, the residue was dissolved in dichloromethane (30 mL), and the solution was washed successively with saturated aqueous NaHCO3 (2 x 15 mL), water (15 mL), and saturated aqueous NaCl (15 mL). The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 80% ethyl acetate in petroleum ether) to give carbonic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 4-nitrophenyl ester (12D, 850 mg, 81% based on 11B over 5 steps). MS: 456 [M+H] + .

[0492] Carbonic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H A solution of 2-(4-(2-pyrazol-5-yl)cyclopentyl 4-nitrophenyl ester (12D, 60 mg, 0.13 mmol), 2,2-dimethylazetidine (CAS#1086266-55-8, 13.5 mg, 0.158 mmol) and diisopropylethylamine (102 mg, 0.79 mmol) in dichloromethane (1 mL) and 2-methyltetrahydrofuran (1 mL) was stirred at 15°C for 1 hour, then concentrated and the residue was purified by preparative HPLC (on an Xbridge 150*30mm*10µm column) eluted with 17-57% water (0.05% ammonium hydroxide v / v) in acetonitrile). After lyophilization, 2,2-dimethylazetidine-1-carboxylic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 12, 28.21 mg, 53%). MS: 402 [M+H] + . 1 H NMR (400MHz, DMSO- d 6) δ = 12.13 (br d, J=8.2 Hz,1H), 10.62 (br s, 1H), 6.29 (s, 1H), 6.21 (s, 1H), 5.03-4.91 (m, 1H), 3.82(s, 2H), 3.71 (br t, J=8.4 Hz, 1H), 3.64 (t, J=7.5 Hz, 1H), 3.12-3.01 (m,1H), 2.41 (dt, J=6.7, 15.5 Hz, 1H), 2.19 (s, 3H), 2.04-1.97 (m, 1H), 1.96-1.89 (m, 2H), 1.87-1.79 (m, 1H), 1.77-1.57 (m, 3H), 1.37-1.27 (m, 6H). Chiral purity: 99%ee by chiral analysis SFC.

[0493] Example 13: Propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H - Pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester

[0494]

[0495] Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 50.3 g, 79.1 mmol) was added to 1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazole-5-amine (11B, 8.90 g, 26.4 mmol), 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid lithium (Intermediate 5, 5.83 g, 34.3 mmol) and diisopropylethylamine (10.2 g, 79.1 mmol) in 2-methyltetrahydrofuran (100.0 mL) at room temperature (26 ° C). The resulting mixture was stirred at this temperature for 18 hours. After the mixture was concentrated to dryness, the residue was dissolved in dichloromethane (150 mL), and the solution was washed with water (2 x 30 mL), saturated aqueous NaHCO3 solution (2 x 30 mL) and saturated aqueous NaCl solution (30 mL) in sequence. The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude product as an oil. N -{1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazol-5-yl}-3-(methoxymethyl)-1-methyl-1 H -Pyrazole-5-carboxamide (13A, 12.9 g, 100%). MS: 490[M+H] + .

[0496] The rough N -{1-tert-butyl-3-[(1 S ,3 R )-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazol-5-yl}-3-(methoxymethyl)-1-methyl-1 H -pyrazole-5-carboxamide (13A, 12.9 g, 26.3 mmol) was dissolved in formic acid (80 mL) and stirred at room temperature (27°C) for 30 minutes. The mixture was concentrated to dryness, and the residue was dissolved in methanol (80 mL). A solution of lithium hydroxide monohydrate (3.43 g, 81.8 mmol) in water (15 mL) was added, and the mixture was stirred at room temperature (27°C) for 1 hour. The mixture was concentrated to dryness, and the residue was purified by silica gel chromatography (eluting with 0-80% ethyl acetate in petroleum ether) to giveN -{1-tert-butyl-3-[(1 S ,3 R )-3-Hydroxycyclopentyl]-1 H -pyrazol-5-yl}-3-(methoxymethyl)-1-methyl-1 H -Pyrazole-5-carboxamide (13B, 8.0 g, 78%). MS: 376 [M+H] + .

[0497] Will N -{1-tert-butyl-3-[(1 S ,3 R )-3-Hydroxycyclopentyl]-1 H -pyrazol-5-yl}-3-(methoxymethyl)-1-methyl-1 H A solution of 1-pyrazole-5-carboxamide (13B, 8.0 g, 21 mmol) in dichloromethane (80 mL) and THF (80 mL) was treated with DMAP (260 mg, 2.13 mmol), pyridine (5.06 g, 63.9 mmol) and 4-nitrophenyl chloroformate (8.59 g, 42.6 mmol). The resulting yellow suspension was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness and purified by silica gel chromatography (eluting with a solution of 0-45% ethyl acetate in petroleum ether) to obtain carbonic acid (1 R ,3 S )-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-3-yl]cyclopentyl 4-nitrophenyl ester (13C, 10.6 g, 92%). MS: 541 [M+H] + .

[0498] Carbonate 1 R ,3 S )-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 HA solution of 1-pyrazol-3-yl]cyclopentyl 4-nitrophenyl ester (13C, 10.6 g, 19.6 mmol) in formic acid (80 mL) was stirred at 70°C for 18 hours. The solution was concentrated to dryness. The residue was dissolved in dichloromethane (150 mL), and the solution was neutralized with saturated aqueous NaHCO3 solution. The organic layer was washed with water (30 mL) and saturated aqueous NaCl solution (30 mL), dried over sodium carbonate, filtered, and concentrated to give crude carbonic acid (13C) as a light yellow glass. R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl 4-nitrophenyl ester (13D, 8.5 g, 90%, 86% purity by LCMS). MS: 485 [M+H] + .

[0499] The crude carbonic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H A solution of 1-pyrazol-5-yl]cyclopentyl 4-nitrophenyl ester (13D, 1.7 g, 3.5 mmol) and 2-propylamine (1.04 g, 17.5 mmol) in THF (30 mL) was stirred at room temperature (27°C) for 6 hours. The solution was concentrated to dryness, and the residue was combined with the residue from the second batch (which had been derived from 1.7 g, 3.5 mmol 13D) (the combined two batches consumed a total of 6.27 mmol 13D) to give 3.2 g of crude product. The product was purified by preparative HPLC on a Phenomenex Gemini C18 250*50mm*10µm column, eluting with 15-45% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization, propan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester (Example 13, 2.06 g, 78%), found to be a monohydrate (Form 1) based on elemental analysis. MS: 405 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ =12.23 (br s, 1H), 10.73 (br s, 1H), 7.11 (s, 1H), 6.96 (br d, J=7.0 Hz, 1H), 6.41 (br s, 1H), 5.00 (br s, 1H), 4.33 (s, 2H), 4.04 (s, 3H), 3.57 (qd, J=6.6, 13.4 Hz, 1H), 3.26 (s, 3H), 3.17-2.96 (m, 1H), 2.48-2.39 (m, 1H), 2.03(br d, J=6.8 Hz, 1H), 1.95-1.83 (m, 1H), 1.73 (br d, J=8.5 Hz, 2H), 1.61 (brs, 1H), 1.03 (br d, J=6.3 Hz, 6H). Optical rotation [α] D +4.8 ( c 1.0, MeOH). Chiral purity: >99%ee by chiral analysis SFC. 19 H 28 Calculated analysis for N6O4-H2O: C, 54.02; H, 7.16; N, 19.89. Found: C, 53.94; H, 7.22; N, 19.81. The white crystalline solid from above (500 mg) was recrystallized from 9: 1 H2O / CH3CN (2 mL) as follows: heating until dissolved, and then standing the resulting solution at room temperature for 18 h. Over the 18 h period, larger crystals of the monohydrate (Form 1) formed. Figure 1 Single crystal X-ray diffraction from selected crystals of this substance is provided in the structure of .

[0500] The crystalline solid prepared above as a monohydrate (Form 1) was further characterized by powder X-ray diffraction (PXRD).

[0501] Instrumental Powder X-ray Diffraction:

[0502] Powder X-ray diffraction analysis was performed using a Bruker AXS D8 Advance diffractometer equipped with a Cu radiation source. The diffracted radiation was detected with a LYNXEYE_EX detector with a motorized slit. Both the primary and secondary were equipped with 2.5 Soller slits. The X-ray tube voltage and amperage were set at 40 kV and 40 mA, respectively. Data were collected in a locked-coupled scan at Cu K-α wavelength from 3.0 to 40.0 degrees 2-θ in a θ-θ goniometer with an increment of 0.01 degree, using a scan speed of 1.0 seconds per step. The samples were prepared by placing in a silicon low-background sample. Data were collected and analyzed using Bruker DIFFRAC Plus software. The PXRD data files were not processed before peak searching. The peak search algorithm in the EVA software was used for preliminary peak assignments using a threshold of 1. Manual adjustments were made to ensure validity; the output of the automatic assignments was visually inspected and the peak positions were adjusted to the peak maximum. Peaks with a relative intensity of ≥3% were generally selected. Peaks that were unresolved or consistent with noise were not selected. Typical errors associated with PXRD peak positions as specified in the United States Pharmacopeia are up to ±0.2° 2-θ (USP-941).

[0503] The PXRD pattern of the monohydrate of Form 1 of Example 13 is as follows: Figure 2 The following Table 1 provides a list of PXRD peaks and relative intensity data (2-θ°) for the monohydrate of Compound Form 1 of Example 13:

[0504] Table 1

[0505] Angle (2-θ°) ±0.2°2θ Relative strength (%) Angle (2θ°) ±0.2°2θ Relative strength (%) 3.9 19.5% 25.0 25.9% 9.1 18.3% 25.7 8.3% 10.4 96.5% 26.0 10.1% 11.7 64.3% 26.3 15.1% 12.9 41.4% 26.6 8.4% 16.0 15.5% 27.0 5.0% 18.2 100.0% 27.6 21.3% 18.6 14.4% 28.2 31.7% 19.4 38.1% 28.9 5.2% 19.6 20.3% 30.4 6.8% 20.0 10.5% 31.1 7.8% 20.3 20.6% 31.5 9.9% 20.6 43.0% 33.9 11.6% 20.8 26.1% 35.1 3.3% 21.0 23.7% 35.8 3.0% 22.2 20.6% 36.6 7.1% 22.7 3.4% 37.6 3.9% 23.5 22.9% 38.3 5.2% 24.2 64.0%

[0506] Example 14: (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester

[0507]

[0508] The crude carbonic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl 4-nitrophenyl ester (13D, 5.5 g, 11 mmol), ( SA solution of )-(+)-sec-butylamine (1.49 g, 13.6 mmol) and diisopropylethylamine (4.40 g, 34.1 mmol) in THF (100 mL) was stirred at room temperature (30°C) for 18 hours. The reaction mixture was concentrated to dryness, and the residue was purified by preparative HPLC on a Phenomenex Gemini C18 250*50mm*10µm column, eluting with 25-45% water (0.05% ammonium hydroxide v / v) in acetonitrile to give (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ester (Example 14, 3.50 g, 74%). MS: 419 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.23 (br s, 1H), 10.72 (s, 1H), 7.11 (s, 1H), 6.90 (br d, J=8.2 Hz, 1H), 6.42 (br s, 1H), 5.00(br s, 1H), 4.33 (s, 2H), 4.04 (s, 3H), 3.43-3.37 (m, 1H), 3.26 (s, 3H), 3.14-2.98 (m, 1H), 2.45 (br s, 1H), 2.08-1.97 (m, 1H), 1.95-1.82 (m, 1H),1.80-1.68 (m, 2H), 1.67-1.52 (m, 1H), 1.42-1.26 (m, 2H), 1.00 (d, J=6.5 Hz,3H), 0.80 (t, J=7.4 Hz, 3H). Optical rotation [α] D +16.6 ( c 2.05, MeOH). Chiral purity: >99%ee by chiral analysis SFC.

[0509] Example 15: (1-Methylcyclopropyl)carbamic acid (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl) Acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester

[0510]

[0511] Carbonic acid (1 R ,3 S)-3-(1-tert-butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H A solution of (1-methylcyclopropyl)carbamic acid (12C, 1.64 g, 3.2 mmol) in DMF (10.7 mL) was treated with 1-methylcyclopropane-1-amine hydrochloride (516 mg, 4.8 mmol) and diisopropylethylamine (1.7 mL, 9.6 mmol). The mixture was stirred at 60 °C for 2 hours under nitrogen and then stirred at room temperature overnight. After dilution with ethyl acetate (150 mL), the solution was washed with deionized water (20 mL), 2 M aqueous Na2CO3 solution (20 mL) and saturated aqueous NaCl solution (20 mL). The combined aqueous layers were back-extracted with ethyl acetate (30 mL). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 0-100% ethyl acetate in heptane) to give (1-methylcyclopropyl)carbamic acid (12C) as an oil. R ,3 S )-3-(1-tert-butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ester (15A, 1.58 g, 82%).

[0512] (1-Methylcyclopropyl)carbamic acid 1 R ,3 S )-3-(1-tert-butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H A solution of 1-pyrazol-3-yl)cyclopentyl ester (15A, 1.50 g, 3.4 mmol) in formic acid (10 mL) was heated in a 100°C oil bath for 1 hour. Most of the formic acid was removed under vacuum. The residue was treated with saturated NaHCO3 aqueous solution (30 mL) and then extracted with ethyl acetate (150 mL, then 50 mL). The combined organic layers were dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-40% isopropanol in heptane) to give a white solid (960 mg). The solid was dissolved in acetonitrile (20 mL) and water (10 mL), and the solution was lyophilized overnight to give a white solid (796 mg). The lyophilized material was suspended in ethyl acetate (28 mL), stirred in a 60°C oil bath for 1 hour, and cooled to room temperature with stirring for another 3 hours. The solid was collected by filtration and dried (50° C., 10 mmHg) to give (1-methylcyclopropyl)carbamic acid (1 R ,3 S)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester (Example 15 565 mg, 41%). MS: 388 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.61 (s, 1H), 7.34 (br s, 1H), 6.28 (br s,1H), 6.21 (s, 1H), 4.97 (br s, 1H), 3.82 (s, 2H), 3.14-2.94 (m, 1H), 2.48-2.39 (m, 1H), 2.20 (s, 3H), 1.99 (s, 1H), 1.93-1.80 (m, 1H), 1.78-1.60 (m,2H), 1.54 (br s, 1H), 1.22 (s, 3H), 0.58 (br s, 2H), 0.49-0.42 (m, 2H). Optical rotation [α] D +10.0°( c 0.2, MeOH).

[0513] Method C

[0514] Example 16: (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino Base]-1 H -pyrazol-5-yl}cyclopentyl ester

[0515]

[0516] Triethylamine (4.7 mL, 33.4 mmol) was added to a suspension of benzyl {1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (Intermediate 1, 5.97 g, 16.7 mmol) in anhydrous acetonitrile (50 mL). The solution was cooled to 0°C and then N,N'-disuccinimidyl carbonate (8.56 g, 33.4 mmol) was added. After stirring at 0°C for 10 minutes, the cooling bath was removed and the mixture was stirred at room temperature (23°C) for 24 hours. LCMS indicated that unreacted starting alcohol was still present, so additional N,N'-disuccinimidyl carbonate (2.36 g; total 10.92 g, 42.63 mmol) and triethylamine ((2.8 mL; total 7.5 mL, 54 mmol)) were added and stirring continued at room temperature for an additional 5 hours. The solvent was removed under vacuum and the residue was diluted with ethyl acetate (150 mL) and deionized water (100 mL). The resulting emulsion was suction filtered to remove white solids. The layers of the filtrate were separated. The filter cake was washed with ethyl acetate (2 x 100 mL) and 4% ethanol. 5-dioxopyrrolidine-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1H-pyrazoles-5-yl}benzylcarbamate (16A, 4.5 g, 54%) was obtained as solid. 1 H NMR (400MHz, chloroform- d ) δ = 7.42-7.34 (m, 5H), 6.24 (br. s., 1H), 6.13 (br. s., 1H), 5.30-5.22 (m, 1H), 5.20 (s, 2H), 3.21-3.12 (m, 1H), 2.82 (s, 4H), 2.57 (ddd, J=6.7, 8.4, 14.8 Hz, 1H), 2.15-2.05(m, 2H), 2.04-1.87 (m, 3H), 1.59 (s, 9H). MS: 499 [M+H] + .

[0517] A solution of benzyl {1-tert-butyl-3-[(1S,3R)-3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1H-pyrazol-5-yl}carbamate (16A, 3.5 g, 7.0 mmol) and 10% Pd / C (1.2 g) in ethyl acetate (150 mL) was stirred under a hydrogen balloon at room temperature (23° C.) overnight. The mixture was filtered through a pad of celite, the filter pad was rinsed with ethyl acetate (3 x 30 mL), and the combined filtrates were concentrated to give crude 1-[({[(1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H -pyrazol-3-yl)cyclopentyl]oxy}carbonyl)oxy]pyrrolidine-2,5-dione (16B), which was used immediately in the next step. MS: 365 [M+H] + .

[0518] The crude 1-[({[(1 R ,3 S )-3-(5-amino-1-tert-butyl-1 H

[0063] 1,2-oxazol-3-yl)cyclopentyl]oxy}carbonyl)oxy]pyrrolidine-2,5-dione (16B, up to 7.0 mmol) was dissolved in DMF (20 mL), 1,2-oxazol-5-yl acetic acid (CAS# 4992-21-6, 1.4 g, 11 mmol) and propylphosphonic anhydride (T3P®, 11 mL of a 50 wt % solution in EtOAc, 14 mmol) were added, and the solution was cooled to 0° C. under nitrogen. Triethylamine (3.5 ml, 25 mmol) was added dropwise over 10 minutes, slowly enough to keep the internal temperature below 20° C. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The reaction was quenched with saturated NaHCO3 aqueous solution and extracted with ethyl acetate (3x). The combined organic layers were washed with saturated aqueous NaHCO3 (2x) and saturated aqueous NaCl (1x), dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 30-100% ethyl acetate in heptane) to give 4-(2-nitropropene) as a white foam. N -(1-tert-butyl-3-{(1 S ,3 R )-3-[(2,5-dioxopyrrolidin-1-yl)oxy]cyclopentyl}-1 H -pyrazol-5-yl)-2-(1,2-oxazol-5-yl)acetamide (16C, 2.46 g, 74%). 1 H NMR (400MHz, methanol- d4) δ = 8.35 (d, J=1.7Hz, 1H), 6.42-6.37 (m, 1H), 6.05 (s, 1H), 5.33-5.23 (m, 1H), 3.98 (s, 2H), 3.16 (td, J=8.8, 17.2 Hz, 1H), 2.82 (s, 4H), 2.63-2.51 (m, 1H), 2.16-2.02 (m,3H), 2.00-1.80 (m, 3H), 1.56 (s, 9H). MS: 474 [M+H] + .

[0519] Will N -(1-tert-butyl-3-{(1 S ,3 R )-3-[(2,5-dioxopyrrolidin-1-yl)oxy]cyclopentyl}-1 H -pyrazol-5-yl)-2-(1,2-oxazol-5-yl)acetamide (16C, 158 mg, 0.334 mmol), diisopropylethylamine (0.15 mL, 0.91 mmol) and ( S A solution of )-(+)-sec-butylamine (50 µL, 0.50 mmol) in dichloromethane (3.5 mL) was stirred at 20 °C for 3 h. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous NaHCO3 (2 x 3 mL), deionized water (3 mL), saturated aqueous NH4Cl (3 mL), and saturated aqueous NaCl (3 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness to leave crude (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-{1-tert-butyl-5-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-3-yl}cyclopentyl ester (16D, 115.0 mg, 80%). 1 H NMR (400MHz, DMSO- d6) δ = 9.79 (s, 1H), 8.50 (d, J=1.7 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.40 (d, J=1.6 Hz, 1H), 5.93 (s, 1H), 4.97 (br. s.,1H), 3.95 (s, 2H), 3.43-3.33 (m, 1H), 2.95 (quin, J=8.5 Hz, 1H), 2.40-2.31(m, 1H), 1.99-1.77 (m, 2H), 1.76-1.57 (m, 3H), 1.47 (s, 9H), 1.39-1.30 (m,2H), 1.00 (d, J=6.6 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H). MS: 432 [M+H] + .

[0520] The crude (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-{1-tert-butyl-5-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-3-yl}cyclopentyl ester (16D, 115.0 mg, 0.2665 mmol) was dissolved in formic acid (6.0 mL) and triethylsilane (1.5 mL) and stirred at 70°C for 18 hours. The layers of the resulting two-phase mixture were separated. The upper triethylsilane layer was discarded. The lower acid layer was concentrated to dryness, dissolved in acetonitrile, and concentrated to dryness again. The residue was further dried under vacuum to give the crude product (109.9 mg) as a waxy brown solid. Acetonitrile (5 mL) was added, and the suspension was stirred at room temperature for 1 hour. The resulting precipitate was collected by suction filtration and air-dried to give (2 S )-Butan-2-ylcarbamic acid (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl ester (Example 16, 42.1 mg, 42%). 1 H NMR (400MHz, DMSO- d6) δ = 12.11 (br.s., 1H), 10.65 (s, 1H), 8.48 (d, J=1.7 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.37(d, J=1.5 Hz, 1H), 6.29 (br. s., 1H), 4.98 (br. s., 1H), 3.91 (s, 2H), 3.43-3.33 (m, 1H), 3.11-2.97 (m, 1H), 2.48-2.38 (m, 1H), 2.05-1.94 (m, 1H), 1.94-1.81 (m, 1H), 1.78-1.62 (m, 2H), 1.61-1.50 (m, 1H), 1.41-1.27 (m, 2H), 0.99 (d, J=6.6 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H). MS: 376 [M+H] + .

[0521] Method D

[0522] Example 17: tert-Butylcarbamic acid (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1 H - Pyrazol-5-yl}cyclopentyl ester

[0523]

[0524] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1-tert-butyl-1 H A solution of 1-pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (1A, 5.00 g, 9.57 mmol) in formic acid (30 mL) was stirred at 75 °C for 20 hours. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography (eluting with 50-70% ethyl acetate in petroleum ether) to give carbonic acid (1A) as a light yellow solid. R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1 H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl ester (17A, 3.6 g, 81%, 82% purity by LCMS). MS: 467 [M+H] + .

[0525] Carbonic acid (1 R ,3 S )-3-(5-{[(Benzyloxy)carbonyl]amino}-1 HA mixture of (1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamic acid benzyl ester (17B, 1.5 g, 79%) was prepared by stirring at room temperature (29°C) for 18 hours. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (eluting with 0-90% ethyl acetate in petroleum ether) to give benzyl (3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (17B, 1.5 g, 79%) as a light yellow glass. MS: 401 [M+H] + .

[0526] Ethyl chloroformate (970 mg, 8.94 mmol) was added portionwise to a room temperature (29°C) solution of benzyl (3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (17B, 1.50 g, 3.75 mmol) and diisopropylethylamine (1.45 g, 11.2 mmol) in dichloromethane (30 mL), and the mixture was stirred at room temperature for 18 hours. The solution was washed with saturated aqueous NH4Cl (3 x 5 mL) and saturated aqueous NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated to give crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazole-1-carboxylate (17C, 2.0 g, >99%) as a light yellow gum, which was used without further purification. MS: 473 [M+H] + .

[0527] Crude 5-{[(benzyloxy)carbonyl]amino}-3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazole-1-carboxylic acid ethyl ester (17C, 2.0 g, 4.2 mmol (if pure)) was dissolved in ethyl acetate (15 mL) and THF (15 mL). 10% Pd / C catalyst (200 mg) was added, degassed, and stirred at room temperature (29° C.) for 1.5 hours under a hydrogen balloon. The suspension was filtered to remove the catalyst, the filtrate was concentrated to dryness, and the residue was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in petroleum ether, then 0-30% ethyl acetate in dichloromethane) to give ethyl 5-amino-3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazole-1-carboxylate (17D, 900 mg, 63%, 56% from 17A) as a light yellow gum. MS: 339 [M+H] + .

[0528] A room temperature (29° C.) solution of ethyl 5-amino-3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazole-1-carboxylate (17D, 250 mg, 0.739 mmol), diisopropylethylamine (286 mg, 2.22 mmol) and 1,2-oxazol-3-ylacetic acid (CAS# 57612-86-9, 113 mg, 0.887 mmol) in dichloromethane (10 mL) was treated with propylphosphonic anhydride (T3P®, 50 wt % solution in EtOAc, 1.41 g, 2.22 mmol) and then stirred at room temperature for 6 hours. The solution was diluted with dichloromethane (10 mL), then washed with water (5 mL), saturated NaHCO3 aqueous solution (2 x5 mL), saturated NH4Cl aqueous solution (5 mL), and saturated NaCl aqueous solution (5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude 3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-5-[(1,2-oxazol-3-ylacetyl)amino]-1H-pyrazole-1-carboxylic acid ethyl ester (17E, 331 mg, 100%) as a brown gum. MS: 448 [M+H] + .

[0529] The crude ethyl 3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-5-[(1,2-oxazol-3-ylacetyl)amino]-1H-pyrazole-1-carboxylate (17E, 331 mg, 0.739 mmol) was dissolved in methanol (5 mL), a solution of lithium hydroxide monohydrate (93.1 mg, 2.22 mmol) in water (1 mL) was added, and the mixture was stirred at room temperature (30°C) for 1 hour. The mixture was allowed to stand overnight and then concentrated to dryness. The residue was dissolved in methanol (3 mL), filtered, and the filtrate was purified by preparative HPLC on a YMC-Actus Triart C18 150*30 5µ column, eluting with 20-50% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization of the product-containing fractions, tert-butylcarbamic acid (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl ester (Example 17, 74.84 mg, 27%, 99%ee by chiral analysis SFC). 1 H NMR (500MHz, DMSO-d6) δ = 12.09 (br s, 1H), 10.63 (s, 1H), 8.83 (s, 1H), 6.76 (br s, 1H), 6.53(s, 1H), 6.29 (s, 1H), 4.96 (br s, 1H), 3.75 (s, 2H), 3.02 (quin, J=8.7 Hz,1H), 2.47-2.41 (m, 1H), 2.04-1.93 (m, 1H), 1.92-1.79 (m, 1H), 1.78-1.61 (m,2H), 1.55 (br s, 1H), 1.19 (s, 9H). MS: 376 [M+H] + .

[0530] Method E

[0531] Example 18: (1-Methylcyclobutyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazole- 2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ester

[0532]

[0533] A solution of benzyl {1-tert-butyl-3-[(1S,3R)-3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1H-pyrazol-5-yl}carbamate (16A, 1.20 g, 2.41 mmol), 1-methylcyclobutylamine hydrochloride (CAS# 174886-05-6, 439 mg, 3.61 mmol) and diisopropylethylamine (1.56 g, 12.0 mmol) in THF (15 mL) was stirred at room temperature (32°C) for 18 hours. The mixture was concentrated under vacuum and the residue was dissolved in dichloromethane (25 mL). The solution was washed with water (2 x 5 mL), saturated aqueous NH4Cl solution (5 mL) and saturated aqueous NaCl solution (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (eluting with 0-30% ethyl acetate in petroleum ether) to give benzyl {1-tert-butyl-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}carbamate (18A, 920 mg, 82%) as a light yellow gum. MS: 469 [M+H] + .

[0534] {1-tert-butyl-3-[(1S, 3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-5-yl}benzylcarbamate (18A, 920 mg, 1.96 mmol) was stirred in formic acid (10 mL) at 75 ° C for 18 hours. Volatiles were removed under vacuum, and the residue was distributed between dichloromethane (20 mL) and saturated NaHCO3 aqueous solution. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-80% ethyl acetate in petroleum ether) to obtain {3-[(1S, 3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-5-yl}benzylcarbamate (18B, 500 mg, 62%) as a light yellow gum. MS: 435 [M+Na] + .

[0535] Ethyl chloroformate (197 mg, 1.82 mmol) was added portionwise to a solution of the given benzyl {3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}carbamate (18B, 500 mg, 1.21 mmol) and diisopropylethylamine (470 mg, 3.64 mmol) in dichloromethane (15 mL). The mixture was stirred at room temperature (35° C.) for 4 hours and then washed with saturated aqueous NH4Cl solution (2 x 5 mL) and saturated aqueous NaCl solution (5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-1-carboxylate (18C, 560 mg, 95%, 80% pure by NMR) as a light yellow glass. 1 H NMR (400MHz, chloroform-d) δ = 9.50 (s,1H), 7.44-7.32 (m, 5H), 7.33-7.32 (m, 1H), 6.62 (br. s., 1H), 5.22 (s, 2H),5.17 (br. s., 1H), 4.51 (q, J=7.0 Hz, 2H), 3.25-3.13 (m, 1H), 2.51-2.30 (m,2H), 2.14-2.03 (m, 1H), 2.00-1.73 (m, 8H), 1.47 (t, J=7.2 Hz, 4H), 1.44 (s,3H). MS: 485 [M+H] + ; 507 [M+Na] + .

[0536] A suspension of crude 5-{[(benzyloxy)carbonyl]amino}-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-1-carboxylic acid ethyl ester (18C, 560 mg, 1.16 mmol) and Pd / C catalyst (wet, 50% by weight, 150 mg) in ethyl acetate (10 mL) and THF (10 mL) was degassed, backfilled with hydrogen, and then stirred at room temperature for 1 hour under a hydrogen balloon. The catalyst was removed by filtration, and the filtrate was concentrated to give crude 5-amino-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-1-carboxylic acid ethyl ester (18D, 430 mg, 100% crude) as a light yellow gum. MS: 351 [M+H] +; 373 [M+Na] + .

[0537] Crude 5-amino-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-1-carboxylic acid ethyl ester (18D, 100.0 mg, 0.285 mmol) and sodium 2-(5-methyl-1,3,4-thiadiazol-2-yl)acetate (CAS# 1909316-87-5, 77.6 mg, 0.428 mmol) were suspended in dichloromethane (10 mL) at room temperature (35° C.). Diisopropylethylamine (184 mg, 1.43 mmol) and propylphosphonic anhydride (T3P®, 50 wt % solution in EtOAc, 545 mg, 0.856 mmol) were added and the resulting solution was stirred at 35° C. for 3 hours. The reaction mixture was washed with water (3 mL), saturated NH4Cl aqueous solution (2 x 3 mL) and saturated NaCl aqueous solution (3 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude 3-[(1S, 3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-5-{[(5-methyl-1,3,4-thiadiazole-2-yl)acetyl]amino}-1H-pyrazole-1-carboxylic acid ethyl ester (18E, 140 mg, 100% crude) as a light yellow gum. MS: 513 [M+Na] + .

[0538] A mixture of crude ethyl 3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-5-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1H-pyrazole-1-carboxylate (18E, 140 mg, 0.285 mmol) and lithium hydroxide monohydrate (35.9 mg, 0.856 mmol) in methanol (5 mL) and water (1 mL) was stirred at room temperature (35°C) for 30 minutes and then allowed to stand overnight. The suspension was concentrated to ~3 mL, the solids were removed by filtration, and the filtrate was purified by preparative HPLC on a DuraShell 150*25mm*5µm column, eluting with 27-47% water (0.05% ammonium hydroxide v / v) in acetonitrile. After lyophilization of the product-containing fractions, (1-methylcyclobutyl)carbamic acid (1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1 H-pyrazol-5-yl)cyclopentyl ester (Example 18, 30.89 mg, 26%, >99% ee by chiral analysis SFC). 1 H NMR (500MHz, DMSO-d6)δ = 12.14 (br s, 1H), 10.78 (s, 1H), 7.18 (br s, 1H), 6.30 (br s, 1H), 4.97(br s, 1H), 4.19 (s, 2H), 3.13-2.95 (m, 1H), 2.69 (s, 3H), 2.48-2.40 (m, 1H), 2.21 (br s, 2H), 1.99 (br d, J=8.9 Hz, 1H), 1.92-1.83 (m, 1H), 1.82-1.75 (m,2H), 1.74-1.63 (m, 4H), 1.57 (br s, 1H), 1.34-1.23 (m, 3H). MS: 419 [M+H] + .

[0539] Additional compounds of the invention are prepared by modification of the methods exemplified herein. When chiral starting reactants are available, the compounds are prepared and isolated as having structures such as ( R )and( S ) marks the single stereoisomers of known absolute configuration as shown. When racemic starting reactants were used, the compounds were synthesized as mixtures of diastereomers and then separated into the single stereoisomers by appropriate chiral preparative HPLC or SFC methods prior to characterization and testing. In these cases, known stereocenters were drawn with wedge bonds and with ( R )and( S ) marks; unknown stereocenters are drawn as planar bonds with asterisks and explanations are included in Table 2. In cases where relative but not absolute stereochemistry is known, the structure is drawn with asterisked wedges and no ( R ) and / or ( S ) and an explanation is included in Table 2.

[0540] Selected compounds and their corresponding characterization data are listed in Table 2 below.

[0541] Table 2

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548]

[0549]

[0550]

[0551]

[0552]

[0553]

[0554]

[0555]

[0556]

[0557]

[0558]

[0559]

[0560]

[0561]

[0562]

[0563]

[0564]

[0565]

[0566]

[0567]

[0568]

[0569]

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577]

[0578]

[0579]

[0580]

[0581]

[0582]

[0583]

[0584]

[0585]

[0586]

[0587]

[0588]

[0589]

[0590]

[0591]

[0592]

[0593]

[0594]

[0595]

[0596]

[0597]

[0598]

[0599]

[0600] Additional compounds of the invention were prepared by modification of the methods exemplified herein and are shown in Table 3.

[0601] Table 3

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613]

[0614]

[0615]

[0616]

[0617]

[0618]

[0619]

[0620]

[0621]

[0622]

[0623]

[0624]

[0625]

[0626]

[0627]

[0628]

[0629]

[0630]

[0631]

[0632]

[0633]

[0634]

[0635]

[0636]

[0637]

[0638]

[0639]

[0640]

[0641]

[0642]

[0643]

[0644]

[0645]

[0646]

[0647]

[0648]

[0649]

[0650]

[0651]

[0652]

[0653]

[0654]

[0655]

[0656]

[0657]

[0658]

[0659]

[0660]

[0661]

[0662]

[0663]

[0664] Biochemical assays

[0665] CDK2 / Cyclin E1 full-length mobility shift assay

[0666] The purpose of the CDK2 / Cyclin E1 assay is to evaluate the inhibition (% inhibition, K) of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. iapp and K i=Values). CDK2 / cyclin E1 full length catalyzes the generation of ADP from ATP with transfer of a phosphoryl group to the substrate peptide FL-peptide-18 (5-FAM-QSPKKG-CONH2, CPC Scientific, Sunnyvale, CA) (SEQ ID NO: 1). Mobility shift assays separate fluorescently labeled peptides (substrate and phosphorylated product) electrophoretically after the kinase reaction. Substrate and product are measured by LabChip EZ Reader and the ratio of these values ​​is used to generate the % conversion of substrate to product. Wild-type CDK2 / wild-type full-length cyclin E1 enzyme complexes were produced in-house (baculovirus expression, LJIC-2080 / LJIC-2103) and phosphorylated by CDK7 / cyclin H1 / Mat1 enzyme complexes at a CDK2:CDK7 ratio of 50:1 (concentration mg / mL) in the presence of 10 mM MgCl2 and 5 mM ATP at room temperature for 1 hour. A typical reaction solution (50 μL final reaction volume) contained 2% DMSO (± inhibitor), 4 mM MgCl2, 1 mM DTT, 150 μM ATP (ATP K m = 67.4 μM), 0.005% Tween-20, 3 μM FL-peptide-18 and 0.36 nM (catalytically active active site) phosphorylated wild-type full-length CDK2 / cyclin E1 enzyme complex. The assay was started by adding ATP after 15 min of preincubation with enzyme and inhibitor in the reaction mixture at room temperature. The reaction was terminated after 45 min at room temperature by adding 50 μL 80 mM EDTA. The data were fitted to the Morrison tight binding competitive inhibition equation with enzyme concentration as a variable. 1, 2 To determine K i value.

[0667] GSK3β (GSK3β) mobility shift assay

[0668] The purpose of the GSK3β assay is to evaluate the inhibition (% inhibition, K) of small molecule inhibitors by using a fluorescence-based microfluidic mobility shift assay. iapp and K ivalues). GSK3β catalyzes the generation of ADP from ATP with the transfer of a phosphoryl group to the substrate peptide FL-peptide-15 (5-FAM-KRREILSRRPpSYR-COOH, CPC Scientific, Sunnyvale, CA) (SEQ ID NO:2). Mobility shift assays separate fluorescently labeled peptides (substrate and phosphorylated product) electrophoretically following the kinase reaction. Substrate and product are measured by LabChip EZ Reader and the ratio of these values ​​is used to generate the % conversion of substrate to product. Active GSK3β (H350L) was purchased from Upstate / Millipore. A typical reaction solution (50 μL final reaction volume) contained 2% DMSO (± inhibitor), 4 mM MgCl2, 1 mM DTT, 40 μM ATP (ATP K m = 9.43 μM), 0.005% Tween-20, 2 μM FL-peptide-15, and 0.6 nM GSK3β. After preincubation of the reaction mixture with enzyme and inhibitor for 15 min at room temperature, the assay was started by adding ATP. The reaction was terminated after 30 min at room temperature by adding 50 μL 80 mM EDTA. K was determined by fitting the data to the Morrison tight binding competitive inhibition equation with enzyme concentration as a variable. i value. See Morrison, JF (1969) Kinetics of the reversibleinhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimica et biophysica acta 185 , 269-286; Murphy, DJ (2004)Determination of accurate KI values ​​for tight-binding enzyme inhibitors: anin silico study of experimental error and assay design, Analytical Biochemistry 327 , 61-67.

[0669] CDK4 / Cyclin D1 mobility shift assay

[0670] The purpose of the CDK4 / cyclin D1 assay was to evaluate inhibition (% inhibition, K) in the presence of small molecule inhibitors using a fluorescence-based microfluidic mobility shift assay. iapp and Ki Values). CDK4 / Cyclin D3 catalyzes the generation of ADP from ATP with transfer of a phosphoryl group to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:3). Mobility shift assays separate fluorescently labeled peptides (substrate and phosphorylated product) electrophoretically after the kinase reaction. Substrate and product are measured by LabChip EZ Reader and the ratio of these values ​​is used to generate the % conversion of substrate to product. A typical reaction solution contains 2% DMSO (± inhibitor), 10 mM MgCl2, 1 mM DTT, 3.5 mM ATP, 0.005% TW-20, 3 μM 5-FAM-Dyrktide, 3 nM (active site) activated CDK4 / Cyclin D1 in 40 mM HEPES buffer (pH 7.5).

[0671] After preincubation of the enzyme and inhibitor in the reaction mixture at 22°C for 18 min, the inhibitor K of activated CDK4 / cyclin D1 (2007 E1 / 2008 +PO4) was initiated by adding ATP (50 μL final reaction volume). i The reaction was stopped after 195 min by adding 50 μL 30 mM EDTA. K was determined by plotting the fractional velocity as a function of inhibitor concentration fitted to the Morrison equation with enzyme concentration as a variable. i Sure.

[0672] CDK6 / Cyclin D3 mobility shift assay

[0673] The purpose of the CDK6 / cyclin D3 assay is to evaluate inhibition (% inhibition, K iapp and K iValues). CDK6 / cyclin D3 catalyzes the generation of ADP from ATP with transfer of a phosphoryl group to the substrate peptide 5-FAM-Dyrktide (5-FAM-RRRFRPASPLRGPPK) (SEQ ID NO:3). Mobility shift assays separate fluorescently labeled peptides (substrate and phosphorylated product) electrophoretically after the kinase reaction. Substrate and product are measured by LabChip EZ Reader and the ratio of these values ​​is used to generate the % conversion of substrate to product. A typical reaction solution contains 2% DMSO (± inhibitor), 2% glycerol, 10 mM MgCl2, 1 mM DTT, 3.5 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide, 4 nM (active site) activated CDK6 / cyclin D3 in 40 mM HEPES buffer (pH 7.5).

[0674] After preincubation of the enzyme and inhibitor in the reaction mixture at 22°C for 18 min, the inhibitor K of activated CDK6 / cyclin D3 (LJIC-2009G1 / 2010 +PO4) was initiated by adding ATP (50 μL final reaction volume). i The reaction was stopped after 95 min by adding 50 μL 30 mM EDTA. K was determined by plotting the fractional velocity as a function of inhibitor concentration fitted to the Morrison equation with enzyme concentration as a variable. i Sure.

[0675] For fitting the tight-binding inhibitor data generated by CDK4 and CDK6 mobility shift assays, the equations and principles were adapted from Morrison, JF (1969) Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimica and biophysica ACTA 185 , 269-286; and Murphy, DJ (2004) and Determination of accurate K i values ​​for tight-binding enzyme inhibitors: an in silico study of experimental error and assay design, Analytical biochemistry 327 , 61-67.

[0676] Biological activity data

[0677] Biological activity data for representative compounds of the invention are provided in Table 4 below.

[0678] Table 4

[0679]

[0680]

[0681]

[0682]

[0683]

[0684]

[0685]

[0686]

[0687]

[0688]

[0689]

[0690]

[0691]

[0692]

[0693]

[0694]

[0695]

[0696]

[0697]

[0698]

[0699]

[0700]

[0701]

[0702]

[0703]

[0704]

[0705]

[0706]

[0707]

[0708] Additional biological activity data for selected compounds are provided in Table 5 below.

[0709] Table 5

[0710]

[0711] All publications and patent applications cited in the specification are hereby incorporated by reference in their entirety. It will be apparent to one skilled in the art that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. Sequence Listing <110> Pfizer Inc. Behenna, Douglas C Freeman-Cook, Kevin D Hoffman, Robert L Nagata, Asako Ninkovic, Sacha Sutton, Scott C <120> CDK2 inhibitors <130> PC72484A <160> 3 <170> PatentIn Version 3.5 <210> 1 <211> 6 <212> PRT <213> Artificial <220> <223> Synthetic constructs <220> <221> MISC_FEATURE <222> (1) <223> 5-FAM labeled glutamine <220> <221> MISC_FEATURE <222> (6) <223> Glycine carboxamide <400> 1 Gln Ser Pro Lys Lys Gly 1 5 <210> 2 <211> 10 <212> PRT <213> Artificial <220> <223> Synthetic constructs <220> <221> MISC_FEATURE <222> (1) <223> 5-FAM labeled lysine <220> <221> MISC_FEATURE <222> (11)..(11) <223> Phosphorylation on serine <400> 2 Lys Arg Arg Glu Ile Leu Ser Arg Arg Pro 1 5 10 <210> 3 <211> 15 <212> PRT <213> Artificial <220> <223> Synthetic constructs <220> <221> MISC_FEATURE <222> (1) <223> 5-FAM labeled arginine <400> 3 Arg Arg Arg Phe Arg Pro Ala Ser Pro Leu Arg Gly Pro Pro Lys 1 5 10 15

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 Yes-L 1 -(5-10 membered heteroaryl) or -L 1 -(C6-C 12 aryl), wherein the 5-10 membered heteroaryl or C6-C 12 The aryl group is optionally substituted with one or more R 4 replace; R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by one or more R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by one or more R 6 substituted; and wherein the 4-7 membered heterocyclyl is a non-aromatic saturated ring system containing at least one heteroatom selected from N, O and S as a ring member; or R 2 and R 3 Together with the N-atom to which they are attached, they form a 4-6 membered heterocyclic group, the heterocyclic group optionally containing a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclic group is optionally replaced by one or more R 8 replace; Each L 1 and L 2 is independently a bond or optionally substituted by one or more R 9 Substituted C1-C2 alkylene; Each R 4 are independently F, Cl, OH, CN, NR 10 R 11 , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O)NR 10 R 11 、SO2R 12 、SO(=NH)R 12 or SO2NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 replace; Each R 5 are independently OH or C1-C4 alkoxy; Each R 6 is independently OH, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by one or more R 13 replace; R 7 is H, C1-C4 alkyl or C(O)-C1-C4 alkyl; Each R 8 are independently OH, C1-C4 alkyl, C1-C4 alkoxy or CN; Each R 9 are independently C1-C2 alkyl; Each R 10 and R 11 are independently H or C1-C4 alkyl; Each R 12 is C1-C4 alkyl or C3-C6 cycloalkyl; Each R 13 are independently OH or C1-C4 alkoxy; and q is 0, 1, or 2.

2. The compound according to claim 1 having the formula (II): or a pharmaceutically acceptable salt thereof.

3. Compounds of formula (III): or a pharmaceutically acceptable salt thereof, wherein: R 1 Yes-L 1 -(5-10 membered heteroaryl) or -L 1 -(C6-C 12 aryl), wherein the 5-10 membered heteroaryl or C6-C 12 The aryl group is optionally substituted with one or more R 4 replace; R 2 and R 3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L 2 -(C3-C7 cycloalkyl) or -L 2 -(4-7 membered heterocyclyl), wherein each of the C1-C6 alkyl and C1-C6 fluoroalkyl groups is optionally substituted by one or more R 5 and each of the C3-C7 cycloalkyl and 4-7 membered heterocyclic groups is optionally substituted by one or more R 6 substituted; and wherein the 4-7 membered heterocyclyl is a non-aromatic saturated ring system containing at least one heteroatom selected from N, O and S as a ring member; or R 2 and R 3 Together with the N-atom to which they are attached, they form a 4-6 membered heterocyclic group, the heterocyclic group optionally containing a radical selected from O, N(R 7 ) and S(O) q as ring members, wherein the 4-6 membered heterocyclic group is optionally replaced by one or more R 8 replace; Each L 1 and L 2 is independently a bond or optionally substituted by one or more R 9 Substituted C1-C2 alkylene; Each R 4 are independently F, Cl, OH, CN, NR 10 R 11 , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O)NR 10 R 11 、SO2R 12 、SO(=NH)R 12 or SO2NR 10 R 11 , wherein each C1-C4 alkyl group and C1-C4 fluoroalkyl group is optionally substituted by one or more R 13 replace; Each R 5 are independently OH or C1-C4 alkoxy; Each R 6 is independently OH, C1-C4 alkyl or C1-C4 fluoroalkyl, wherein each C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by one or more R 13 replace; R 7 is H, C1-C4 alkyl or C(O)-C1-C4 alkyl; Each R 8 are independently OH, C1-C4 alkyl, C1-C4 alkoxy or CN; Each R 9 are independently C1-C2 alkyl; Each R 10 and R 11 are independently H or C1-C4 alkyl; Each R 12 is C1-C4 alkyl or C3-C6 cycloalkyl; Each R 13 are independently OH or C1-C4 alkoxy; and q is 0, 1, or 2.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 Yes-L 1 -(5-10 membered heteroaryl), wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered heteroaryl is pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridyl, pyrazinyl, indazolyl or benzimidazolyl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 replace.

6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 Substituted pyrazolyl.

7. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the 5-10 membered heteroaryl is optionally substituted by one or more R 4 Substituted isoxazolyl.

8. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein L 1 is a bond or a methylene group.

9. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein each R 4 is independently C1-C4 alkyl or C1-C4 alkoxy, wherein each C1-C4 alkyl is optionally substituted by one or more R 13 replace.

10. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is H and R 3 It is a C1-C6 alkyl group.

11. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 2 is H and R 3 Yes-L 2 -(C3-C7 cycloalkyl), wherein the C3-C7 cycloalkyl is optionally substituted by one or more R 6 replace.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein L 2 is a bond or a methylene group.

13. A compound selected from the group consisting of: (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate; and (1R,3S)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate.

14. A compound, wherein the compound is Monohydrate.

15. A pharmaceutical composition comprising the compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

16. Use of a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating cancer in a subject in need thereof.

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