RU2797889C2 - 3-carbonylamino-5-cyclopentyl-1h-pyrazole compounds with cdk2 inhibitor activity - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions includes a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1 H-pyrazol-5-yl]carbonyl}amino)-1 H-pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate, (1R,3S)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate or a pharmaceutically acceptable solvate thereof, a pharmaceutical composition and use based on these compounds, as well as a method for the treatment of cancer associated with inhibition of CDK2 activity. In formula (I), R¹ is -L¹-(5–10 membered heteroaryl containing 1–4 heteroatoms, each selected from N, O and S) or -L¹-(C₆-C₁₂ aryl), where the specified 5–10-membered heteroaryl or C₆-C₁₂ aryl is optionally substituted with one or two R⁴; R² and R³ are independently H, C₁-C₆ alkyl, C₁-C₆ fluoroalkyl, -L²-(C₃-C₇ cycloalkyl), or -L²-(4-7 membered heterocyclyl containing 1–2 heteroatoms, each selected from N or O), where each specified C₁-C₆ alkyl and C₁-C₆ fluoroalkyl is optionally substituted with one R⁵ and each specified C₃-C₇ cycloalkyl and 4–7-membered heterocyclyl optionally substituted with one or two R⁶; or R² and R³ are taken together with the N-atom to which they are attached to form a 4–6 membered heterocyclyl optionally containing an additional heteroatom that is O as a ring member, wherein the said 4–6 membered heterocyclyl optionally substituted with one to three R⁸; each L¹ and L² is independently a bond or C₁-C₂ alkylene; each R⁴ is independently F, Cl, OH, CN, C₁-C₄ alkyl, C₁-C₄ fluoroalkyl, C₁-C₄ alkoxy, C₁-C₄ fluoroalkoxy, C₃-C₈ cycloalkyl, SO₂R¹², or SO₂NR¹⁰R¹¹, where each C₁-C₄ alkyl and C₁-C₄ fluoroalkyl is optionally substituted with one R¹³; each R⁵ is independently OH, C₁-C₄ alkoxy or NR¹⁰R¹¹; each R⁶ is independently F, OH, C₁-C₄ alkyl or C₁-C₄ fluoroalkyl, where each C₁-C₄ alkyl and C₁-C₄ fluoroalkyl is optionally substituted with one R¹³; each R⁸ is independently F, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or CN; each R¹⁰ and R¹¹ independently represents H or C₁-C₄ alkyl; each R¹² is C₁-C₄ alkyl or C₃-C₆ cycloalkyl; each R¹³ is independently OH, C₁-C₄ alkoxy or NR¹⁴R¹⁵; and each R¹⁴ and R¹⁵ independently represents H or C₁-C₄ alkyl.

EFFECT: compounds of formula (I) with inhibitory activity against CDK2.

20 cl, 2 dwg, 5 tbl, 18 ex

Description

Prior Art

The field of technology to which the invention belongs

The present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts, to pharmaceutical compositions containing such compounds and salts, and to their use. The compounds, salts, and compositions of the present invention may be useful in the treatment of abnormal cell growth, such as cancer, in a subject.

Description of the Prior Art

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform important functions in the regulation of cell division and proliferation. CDKs 1-4, 6, 10, 11 are reported to play a direct role in cell cycle progression, while CDKs 3, 5 and 7-9 may play an indirect role (eg, through activation of other CDKs, regulation of transcription, or neuronal functions). CDK catalytic units are activated by binding to regulatory subunits known as cyclins, followed by phosphorylation. Cyclins can be divided into four general classes (G ₁ , G ₁ /S, S and M cyclins) whose 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 probably other heterodynes are important regulators of cell cycle development.

Overexpression of CDK2 is associated with abnormal cell cycle regulation. 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 transition. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that mediate DNA replication and E2F inactivation to complete 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).

Cyclin E, a regulatory cyclin for CDK2, is often overexpressed in cancer. Amplification or overexpression of cyclin E 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). Overexpression of cyclin E2 (CCNE2) 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 Breast Cancer, Cancer Res. (2016) 76: 2301-2313). Cyclin E amplification has also been reported to promote trastuzumab resistance in HER2+ breast cancer. (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). Cyclin E overexpression has also been reported to play a role in basal-like and triple-negative breast cancer (TNBC) as well as edematous infiltrative breast cancer. (Elsawaf & Sinn, Triple Negative Breast Cancer: Clinical and Histological Correlations, Breast Care (2011) 6:273-278; Alexander et al., Cyclin E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8: 14897-14911.)

Amplification or overexpression of cyclin E1 (CCNE1) has also been associated with poor outcomes in ovarian, gastric, endometrial, and other types of cancer. (Nakayama et al., Gene amplification of CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer (2010) 116: 2621-34; Etemadmoghadam et al., Resistance to CDK2 Inhibitors Is Associated with 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 and AKT Inhibition, Clin.Cancer Res. (2017) 23:1862-1874; Ayhan et al., CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma with a poor prognosis, Modern Pathology (2017) 30: 297-303; Ooi et al., Gene amplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, Hum Pathol (2017) 61: 58-67; Noske et al., Detection of CCNE1/URI (19q12) amplification by in situ hybridization is common in high grade and type II endometrial cancer, Oncotarget (2017) 8: 14794-14805).

A small molecule inhibitor, dinaciclib (MK-7965) inhibits CDK1, CDK2, CDK5, and CDK9 and is currently in clinical development for breast and hematologic cancers. Seliciclib (roscovitine or CYC202), which inhibits CDK2, CDK7, and CDK9, has been studied in nasopharyngeal cancer and NSCLC, and is currently being investigated in combination with sapacitabine in patients with BRCA mutations. CYC065, which inhibits CDK2 and CDK9, is in early clinical development. Despite significant efforts, there are currently no approved agents that selectively target CDK2. Cicenas et al. Highlights of the Latest Advances in Research on CDK Inhibitors. Cancers , (2014) 6:2224-2242.

There continues to be a need to discover CDK inhibitors with novel activity profiles, such as selective CDK2 inhibitors, that may be useful in the treatment of cancer or other proliferative diseases or conditions. In particular, CDK2 inhibitors may be useful in the treatment of CCNE1 or CCNE2 amplified tumors.

SUMMARY OF THE INVENTION

The present invention relates in part to compounds of formula (I) and their pharmaceutically acceptable salts. Such compounds can inhibit the activity of CDKs, including CDK2, thereby affecting biological functions. In some embodiments, the invention relates to compounds that are selective for CDK2. Also provided are pharmaceutical compositions and medicaments comprising compounds or salts of the present invention, alone or in combination with additional anti-cancer therapeutic agents.

The present invention also relates, in part, to methods for preparing the compounds, pharmaceutically acceptable salts and compositions of the invention, and to methods for using the foregoing.

In one aspect, the invention relates to a compound of formula (I):

or its pharmaceutically acceptable salt, where:

R ¹ is -L ¹ -(5-10 membered heteroaryl) or -L ¹ -(C ₆ -C ₁₂ aryl) wherein said 5-10 membered heteroaryl or C ₆ -C ₁₂ aryl is optionally substituted with one or more ^R4 ;

R ² and R ³ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -L ² -(C ₃ -C ₇ cycloalkyl) or -L ² -(4-7 membered heterocyclyl), where each specified C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one or more R ⁵ and each specified C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ ; or

R ² and R ³ are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R ⁷ ) and S(O) _q as a ring member , where the specified 4-6-membered heterocyclyl is optionally substituted by one or more R ⁸ ;

each L ¹ and L ² is independently a bond or C ₁ -C ₂ alkylene optionally substituted with one or more R ⁹ ;

each R ⁴ is independently F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C ₃ - C ₈ cycloalkyl, C(O)NR ¹⁰ R ¹¹ , SO ₂ R ¹² , SO(=NH)R ¹² or SO ₂ NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted one or more R ¹³ ;

each R ⁵ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁰ R ¹¹ ;

each R ⁶ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy or NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl optionally substituted with one or more R ¹³ ;

R ⁷ is H, C ₁ -C ₄ alkyl or C(O) -C ₁ -C ₄ alkyl;

each R ⁸ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or CN;

each R ⁹ is independently F, OH or C ₁ -C ₂ alkyl;

each R ¹⁰ and R ¹¹ independently represents H or C ₁ -C ₄ alkyl;

each R ¹² is C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl;

each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ ;

each R ¹⁴ and R ¹⁵ independently represents H or C ₁ -C ₄ alkyl; And

q is 0, 1, or 2.

In another aspect, the invention relates to a compound of formula (II):

or its pharmaceutically acceptable salt, where:

R ¹ , R ² and R ³ have the meanings defined for formula (I).

In another aspect, the invention relates to a compound of formula (III):

or its pharmaceutically acceptable salt, where:

R ¹ , R ² and R ³ have the meanings defined for formula (I).

In another aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention according to any of the formulas described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the implementation of the pharmaceutical composition includes two or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides therapeutic methods and uses, comprising administering a compound of the invention, or a pharmaceutically acceptable salt thereof, to a subject.

In one aspect, the invention relates to a method of treating abnormal cell growth, in particular cancer, 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. The compounds of the present invention may be administered as single agents, or may be administered in combination with other anti-cancer therapies, in particular with standard therapies appropriate for a particular type of cancer.

In a further aspect, the invention relates to a method of treating abnormal cell growth, in particular 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, the amounts of which are collectively effective in the treatment of said abnormal cell growth.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a subject in need of such treatment. In some embodiments, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth, in particular cancer, in a subject.

In a further aspect, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth, in particular cancer, in a subject.

In another aspect, the invention relates to a pharmaceutical composition for use in the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, the pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a drug, in particular a drug for the treatment of abnormal cell growth such as cancer.

In yet another aspect, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth, such as cancer, in a subject.

In another aspect, the invention relates to a method of treating a CDK2 mediated disorder in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to treat said disorder, particularly cancer.

Each of the embodiments of the compounds of the present invention described below may be combined with one or more other embodiments of the compounds of the present invention described herein that do not conflict with the embodiment(s) with which it is combined.

In addition, each of the embodiments described below describing the invention provides within its scope pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase "or a pharmaceutically acceptable salt thereof" is intended to be used in the description of all compounds described herein, unless expressly stated otherwise.

BRIEF DESCRIPTION OF THE FIGURES

In FIG. 1 shows the single crystal x-ray structure of (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino) -1H -pyrazole- 5-yl]cyclopentyl propan-2-ylcarbamate monohydrate (Form 1).

In FIG. 2 shows the PXRD spectrum of (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino) -1H- pyrazole-5 -yl]cyclopentyl propan-2-ylcarbamate monohydrate (Form 1).

Detailed description of the invention

The present invention can be more easily understood by referring to the following detailed description of the preferred embodiments of the invention and the examples included herein. It should be understood that the terminology used herein is only intended to describe specific embodiments and is not intended to be limiting. In addition, it should be understood that, unless specifically defined herein, the terminology used herein is to have its ordinary meaning as known in the relevant art.

As used herein, singular forms include plural forms unless otherwise noted. For example, a substituent includes one or more substituents.

The invention described herein can suitably be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms "comprising", "consisting essentially of", and "consisting of" may be replaced by any of the other two terms.

"Alkyl" refers to a saturated monovalent aliphatic hydrocarbon radical, including straight or branched chain groups having the indicated number of carbon atoms. Alkyl substituents typically contain 1-12 carbon atoms ("C ₁ -C ₁₂ alkyl"), often 1-8 carbon atoms ("C ₁ -C ₈ alkyl"), or more commonly 1-6 carbon atoms ("C ₁ -C ₆ alkyl"), 1-5 carbon atoms ("C ₁ -C ₅ alkyl"), 1-4 carbon atoms ("C ₁ -C ₄ alkyl"), or 1-2 carbon atoms ("C ₁ -C ₂ alkyl "). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like. . Preferred C ₁ -C ₄ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl. Preferred C ₁ -C ₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.

Alkyl groups described herein as optionally substituted may be substituted with one or more substituent groups, as further defined by the claims herein. Such optional substituent groups are independently selected unless otherwise indicated. The total number of substituent groups may be equal to the total number of hydrogen atoms in the alkyl fragment, to the extent that such a substitution makes chemical sense. Optionally substituted alkyl groups usually have 1 to 6 optional substituents, sometimes 1 to 5 optional substituents, 1 to 4 optional substituents, or preferably 1 to 3 optional substituents.

Examples of substituent groups on alkyl groups include halogen, -OH, C ₁ -C ₄ alkoxy, or NR ^x R ^y , where R ^x and R ^y are each independently H or C ₁ -C ₄ alkyl. It should be understood that NR ^x R ^y is used herein generically to refer to amino substituents (e.g., NR ¹⁰ R ¹¹ as part of an optional R ⁵ substituent or NR ¹⁴ R ¹⁵ as part of an optional R ¹³ substituent) as defined in the claims. In some instances, substituted alkyl groups may be specifically named with reference to a substituent group. For example, "haloalkyl" refers to an alkyl group having a certain number of carbon atoms, which is substituted with one or more halogen substituents, and usually 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. "C ₁ -C ₅ haloalkyl", C ₁ -C ₄ haloalkyl" or "C ₁ -C ₂ haloalkyl").

More specifically, fluorinated alkyl groups may specifically be referred to as "fluoroalkyl" groups (eg, C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ or C ₁ -C ₂ fluoroalkyl groups), which are usually substituted with 1, 2 or 3 fluorine atoms. For example, C ₁ -C ₄ fluoroalkyl includes trifluoromethyl (-CF ₃ ), difluoromethyl (-CF ₂ H), fluoromethyl (-CFH ₂ ), difluoroethyl (-CH ₂ CF ₂ H), and the like. Such groups may be further substituted with optional substituent groups, as further described herein. Similarly, alkyl groups substituted with -OH, C ₁ -C ₄ alkoxy or NR ^x R ^y may be referred to as "hydroxyalkyl", "alkoxyalkyl" or "aminoalkyl", in each case having the indicated number of carbon atoms.

In some embodiments of the present invention, the alkyl and fluoroalkyl groups are optionally substituted with one or more optional substituents, and preferably 1 to 4, 1 to 3, or 1 to 2 optional substituents.

"Alkylene" as used herein refers to a divalent hydrocarbyl group having a certain number of carbon atoms that can link two other groups together. Such groups may be referred to, for example, as C ₁ -C ₆ alkylene, C ₁ -C ₄ alkylene, C ₁ -C ₂ alkylene, and the like. If indicated, alkylene may also be substituted with other groups and may include one or more degrees of unsaturation (ie, an alkenylene or alkynylene moiety) or rings. The open valences of the alkylene need not be at opposite ends of the chain. Branched alkylene groups may include -CH(Me)-, -CH ₂ CH(Me)- and -C(Me) ₂ - are also included within the scope of the term alkylenes. Where an alkylene group is described as being optionally substituted, substituents include those described herein. For example, C ₁ -C ₂ alkylene may be methylene or ethylene.

"Alkoxy" refers to a monovalent -O-alkyl group in which the alkyl moiety has the indicated number of carbon atoms. Alkoxy groups typically contain 1 to 8 carbon atoms (“C ₁ -C ₈ alkoxy”), or 1 to 6 carbon atoms (“C ₁ -C ₆ alkoxy”), or 1 to 4 carbon atoms (“C ₁ - C ₄ alkoxy"). For example, C ₁ -C ₄ alkoxy includes methoxy, ethoxy, isopropoxy, t-butyloxy (ie, -OCH ₃ , -OCH ₂ CH ₃ , -OCH(CH ₃ ) ₂ , -OC(CH ₃ ) ₃ ) , etc. The alkoxy groups may optionally be substituted with one or more halogen atoms, in particular one or more fluorine atoms, up to the total number of hydrogen atoms present in the alkyl moiety. Such groups may be referred to as "haloalkoxy" (or, where fluorinated, more particularly as "fluoroalkoxy") groups having the specified number of carbon atoms and substituted with one or more halogen substituents. Usually such groups contain from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, and sometimes from 1 to 2 carbon atoms, and 1, 2 or 3 halogen atoms (for example, “C ₁ -C ₆ haloalkoxy”, “ C ₁ -C ₄ haloalkoxy" or "C ₁ -C ₂ haloalkoxy"). More specifically, fluorinated alkyl groups may specifically be referred to as "fluoroalkoxy" groups, such as C ₁ -C ₆ , C ₁ -C ₄ or C ₁ -C ₂ fluoroalkoxy groups, which are typically substituted with 1, 2 or 3 fluorine atoms. Thus, C ₁ -C ₄ fluoroalkoxy includes, but is not limited to, trifluoromethyloxy (-OCF ₃ ), difluoromethyloxy (-OCF ₂ H), fluoromethyloxy (-OCFH ₂ ), difluoroethyloxy (-OCH ₂ CF ₂ H), etc. similar.

"Cycloalkyl" refers to a non-aromatic saturated carbocyclic ring system containing a specified number of carbon atoms, which may be monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system, which is linked to the main molecule through the carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain 3 to 8 carbon atoms (“C ₃ -C ₈ cycloalkyl”), preferably 3 to 7 carbon atoms (“C ₃ -C ₇ cycloalkyl”) or 3 to 6 carbon atoms (“C ₃ -C ₆ cycloalkyl"). Representative examples of cycloalkyl rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like. Cycloalkyl groups may be optionally substituted, unsubstituted or substituted with the groups described herein.

The terms "heterocyclyl" or "heterocyclic" may be used interchangeably to refer to a non-aromatic saturated ring system containing the specified number of ring atoms, containing at least one heteroatom selected from N, O and S as ring members, where the S ring atoms are optionally substituted one or two oxo groups (i.e. S(O) _q where q is 0, 1 or 2), and where the heterocyclic ring is linked to the parent molecule via a ring atom, which may be C or N. If specifically indicated, such heterocyclic rings may be partially unsaturated. Heterocyclic rings include rings that are spirocyclic, bridged, or fused with one or more other heterocyclic or carbocyclic rings, wherein such spirocyclic, bridged, or fused rings may themselves be saturated, partially unsaturated, or aromatic to the extent that unsaturation or aromaticity is chemically meaning, provided that the point of attachment to the main molecule is an atom of the heterocyclic part of the ring system. Preferably heterocyclic rings contain 1 to 4 heteroatoms selected from N, O, and S(O) _q as ring members, and more preferably 1 to 2 ring heteroatoms, provided that such heterocyclic rings do not contain two adjacent atoms oxygen.

Heterocyclyl groups are unsubstituted or substituted with suitable substituent groups as described herein. Such substituents may be present on a heterocyclic ring attached to the parent molecule or on a spirocyclic, bridged or fused ring attached to it. In addition, the N ring atoms are optionally substituted with groups suitable for an amine, such as alkyl, acyl, carbamoyl, sulfonyl, and the like.

Heterocycles typically include 3-8 membered heterocyclyl groups and more preferably 4-7 or 4-6 membered heterocyclyl groups as defined herein.

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

In some embodiments, heterocyclic groups contain 3-8 ring members, including both carbon atoms and non-carbon heteroatoms, and often 4-7 or 4-6 ring members. In some embodiments, substituent groups containing 4-7 membered heterocycles are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, and thiomorpholinyl rings, each of which is optionally substituted like described herein if such substitution makes chemical sense.

In some embodiments of the present invention, the cycloalkyl and heterocyclyl groups are optionally substituted with one or more optional substituents as described herein.

It should be understood that no more than two N, O, or S atoms are usually connected in series, except when 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, and the like.

"Aryl" or "aromatic" refers to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having well known aromaticity characteristics, wherein at least one ring contains a fully conjugated pi electron system. Generally, aryl groups have 6 to 20 carbon atoms ("C ₆ -C ₂₀ aryl") as ring members, preferably 6 to 14 carbon atoms ("C ₆ -C ₁₄ aryl") or more preferably 6 to 12 atoms carbon ("C ₆ -C ₁₂ aryl"). Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl or heteroaryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule in such fused ring systems is atom of the aromatic part of the ring system. Non-limiting examples of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and tetrahydronaphthyl. The aryl group may be unsubstituted or substituted, as further disclosed in the present description.

Similarly, "heteroaryl" or "heteroaromatic" refers to monocyclic or fused bicyclic or polycyclic ring systems having well-known aromaticity characteristics, which contain a specified number of ring atoms, as defined above in the "aryl" section, which include at least one heteroatom, selected from N, O and S, as a ring member in an aromatic ring. The inclusion of a heteroatom allows for aromaticity in 5-membered rings as well as in 6-membered rings. Typically, heteroaryl groups contain 5 to 12 ring atoms ("5-12 membered heteroaryl"), and more preferably 5 to 10 ring atoms ("5-10 membered heteroaryl"). Heteroaryl rings are attached to the main molecule via a ring atom of the heteroaromatic ring so that aromaticity is retained. Thus, 6-membered heteroaryl rings can be attached to the host molecule via a C ring atom, while 5-membered heteroaryl rings can be attached to the host molecule via a C or N ring atom. Heteroaryl groups can also be fused to another aryl or heteroaryl ring or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule in such fused ring systems is an atom of the heteroaromatic portion of the ring system. Examples of unsubstituted heteroaryl groups include, but are not limited to, pyrazole, triazole, isoxazole, oxazole, thiazole, thiadiazole, imidazole, pyridine, pyrazine, indazole, and benzimidazole. Additional heteroaryl groups include pyrrole, furan, thiophene, oxadiazole, tetrazole, pyridazine, pyrimidine, benzofuran, benzothiophene, indole, quinoline, isoquinoline, purine, triazine, naftridine, and carbazole. In frequent embodiments, the 5- or 6-membered heteroaryl groups are pyrazole, triazole, isoxazole, oxazole, thiazole, thiadiazole, imidazole, pyridine, or pyrazine rings. The heteroaryl group may be unsubstituted or substituted, as further disclosed in the present description.

Aryl and heteroaryl moieties described herein as optionally substituted may be substituted with one or more substituent groups, which are independently selected unless otherwise indicated. The total number of substituent groups may be equal to the total number of hydrogen atoms in the aryl, heteroaryl, or heterocyclyl moiety, to the extent that such a substitution makes chemical sense and aromaticity is retained in the case of aryl and heteroaryl rings. Optionally substituted aryl or heteroaryl groups typically have 1 to 5 optional substituents, sometimes 1 to 4 optional substituents, preferably 1 to 3 optional substituents, or more preferably 1 to 2 optional substituents, as described herein.

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

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

"Hydroxy" refers to the OH group.

"Cyano" refers to the -C≡N group.

"Unsubstituted amino" refers to the group -NH ₂ . Where an amino is described as being substituted or optionally substituted, the term includes groups of the form -NR ^x R ^y , where R ^x and R ^y are each defined as further described herein. For example, "alkylamino" refers to the group -NR ^x R ^y where one of R ^x and R ^y is an alkyl group and the other is H, and "dialkylamino" refers to -NR ^x R ^y where both are from R ^x and R ^y are alkyl groups, where the alkyl groups have a specific number of carbon atoms (eg, -NH-C ₁ -C ₄ alkyl or -N(C ₁ -C ₄ alkyl) ₂ ). It should be understood that NR ^x R ^y is generally used to refer to amino substituents (e.g., NR ¹⁰ R ¹¹ as part of the optional R ⁵ substituent group or NR ¹⁴ R ¹⁵ as part of the optional R ¹³ substituent group) as defined in the claims.

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

"Optional" or "optional" means that the event or condition described later may not necessarily occur, and the description includes cases where the event or condition occurs and cases where it does not.

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). Unless 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 described group. If an optional substituent is attached via a double bond, such as an oxo (=O) substituent, then the group occupies two available valencies so that the total number of other substituents that can be included is reduced by two. Where the optional substituents are independently selected from a list of alternatives, the selected groups may be the same or different. Throughout the description it will be understood that the number and nature of optional substituent groups will be limited to the extent that such substitutions make chemical sense.

Often, a group described herein as optionally substituted with "one or more" substituent groups is optionally substituted with 1 to 4, preferably optionally substituted with 1 to 3, and more preferably optionally substituted with 1 to 2 such substituents. Reference herein that a group is "optionally substituted by one or more" from the list of optional substituents may be replaced by "optionally substituted by 1-4", "optionally substituted by 1-3", "optionally substituted by 1-2", " optionally substituted with one, two, three or four", "optionally substituted with one, two or three" or "optionally substituted with one or two" of such optional substituent groups.

In one aspect, the invention relates to a compound of formula (I):

or its pharmaceutically acceptable salt, where:

R ¹ is -L ¹ -(5-10 membered heteroaryl) or -L ¹ -(C ₆ -C ₁₂ aryl) wherein said 5-10 membered heteroaryl or C ₆ -C ₁₂ aryl is optionally substituted with one or more ^R4 ;

R ² and R ³ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -L ² -(C ₃ -C ₇ cycloalkyl) or -L ² -(4-7 membered heterocyclyl), where each specified C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one or more R ⁵ and each specified C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ ; or

R ² and R ³ are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R ⁷ ) and S(O) _q as a member rings, where the specified 4-6-membered heterocyclyl is optionally substituted with one or more R ⁸ ;

each L ¹ and L ² is independently a bond or C ₁ -C ₂ alkylene optionally substituted with one or more R ⁹ ;

each R ⁴ is independently F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C ₃ - C ₈ cycloalkyl, C(O)NR ¹⁰ R ¹¹ , SO ₂ R ¹² , SO(=NH)R ¹² or SO ₂ NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted one or more R ¹³ ;

each R ⁵ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁰ R ¹¹ ;

each R ⁶ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy or NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl optionally substituted with one or more R ¹³ ;

R ⁷ is H, C ₁ -C ₄ alkyl or C(O) -C ₁ -C ₄ alkyl;

each R ⁸ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or CN;

each R ⁹ is independently F, OH or C ₁ -C ₂ alkyl;

each R ¹⁰ and R ¹¹ independently represents H or C ₁ -C ₄ alkyl;

each R ¹² is C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl;

each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ ;

each R ¹⁴ and R ¹⁵ independently represents H or C ₁ -C ₄ alkyl; And

q is 0, 1, or 2.

The compounds of formula (I) are characterized by a syn -dependency between substituent groups at the 1- and 3-positions of the cyclopentyl ring. The compounds of formula (I) may be present as a single enantiomer having a syn -relative configuration at positions 1 and 3 (i.e. ( 1R,3S ) or ( 1S,3R )), or as a mixture of syn -enantiomeric forms, for example , a racemic mixture of ( 1R,3S ) and ( 1S,3R ).

In compounds of formula (I), R ¹ is -L ¹ -(5-10 membered heteroaryl) or -L ¹ -(C ₆ -C ₁₂ aryl) wherein said 5-10 membered heteroaryl or C ₆ -C ₁₂ aryl is optionally substituted with one or more R ⁴ .

In some embodiments, R ¹ is -L ¹ -(5-10 membered heteroaryl), wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In some such embodiments, said 5-10 membered heteroaryl is pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, indazolyl, or benzimidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In some embodiments, said 5-10 membered heteroaryl is pyrazolyl or triazolyl optionally substituted with one or more R ⁴ . In particular embodiments, said 5-10 membered heteroaryl is pyrazolyl optionally substituted with one or more R ⁴ . In other embodiments, said 5-10 membered heteroaryl is triazolyl optionally substituted with one or more R ⁴ . In other embodiments, said 5-10 membered heteroaryl is isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, indazolyl, or benzimidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In some embodiments, said 5-10 membered heteroaryl is isoxazolyl or oxazolyl optionally substituted with one or more R ⁴ . In particular embodiments, said 5-10 membered heteroaryl is isoxazolyl optionally substituted with one or more R ⁴ . In other embodiments, said 5-10 membered heteroaryl is a thiazolyl, thiadiazolyl, or imidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In yet other embodiments, said 5-10 membered heteroaryl is pyridinyl, pyrazinyl, indazolyl, or benzimidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In some embodiments of each of the above, said 5-10 membered heteroaryl is optionally substituted with one, two, three or four R ⁴ . In some embodiments of each of the above, said 5-10 membered heteroaryl is optionally substituted with one or two R ⁴ .

In other embodiments, R ¹ is -L ¹ -(C ₆ -C ₁₂ aryl), wherein said C ₆ -C ₁₂ aryl is optionally substituted with one or more R ⁴ . In some such embodiments, said C ₆ -C ₁₂ aryl is phenyl optionally substituted with one or more R ⁴ . In some embodiments of each of the above, said C ₆ -C ₁₂ aryl is optionally substituted with one, two, three, or four R ⁴ . In some embodiments of each of the above, said C ₆ -C ₁₂ aryl is optionally substituted with one or two R ⁴ .

In compounds of formula (I), L ¹ is a bond or C ₁ -C ₂ alkylene optionally substituted with one or more R ⁹ . In some such embodiments, said L ¹ is a bond or C ₁ -C ₂ alkylene optionally substituted with one, two, three, or four R ⁹ . In some such embodiments, L ¹ is a bond or C ₁ -C ₂ alkylene optionally substituted with one or two R ⁹ . In some such embodiments, L ¹ is a bond, methylene, or ethylene. In some such embodiments, L ¹ is a bond or methylene. In some embodiments of each of the above, L ¹ is a bond. In other embodiments of each of the above, L ¹ is C ₁ -C ₂ alkylene optionally substituted with one or more R ⁹ . In some such embodiments, said L ¹ is C ₁ -C ₂ alkylene optionally substituted with one, two, three, or four R ⁹ . In some such embodiments, said L ¹ is C ₁ -C ₂ alkylene optionally substituted with one or two R ⁹ . In some such embodiments, L ¹ is methylene or ethylene (ie, -CH ₂ or -CH ₂ CH ₂ -). In some embodiments, L ¹ is methylene.

In compounds of formula (I), R ² and R ³ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -L ² -(C ₃ -C ₇ cycloalkyl) or -L ² -(4 -7-membered heterocyclyl), where each specified C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one or more R ⁵ and, each specified C ₃ -C ₇ cycloalkyl and 4-7-membered heterocyclyl is optionally substituted with one or several R ⁶ ; or R ² and R ³ are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R ⁷ ) and S(O) _q as a ring member, wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ⁸ .

In some embodiments, R ² and R ³ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -L ² -(C ₃ -C ₇ cycloalkyl), or -L ² -(4-7 -membered heterocyclyl), where each specified C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one or more R ⁵ and, each specified C ₃ -C ₇ cycloalkyl and 4-7-membered heterocyclyl is optionally substituted with one or more ^R6 . In some such embodiments, said C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl are optionally substituted with one, two, three, or four R ⁵ and each said C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted one, two, three or four R ⁶ . In some such embodiments, said C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl are optionally substituted with one or two R ⁵ and each said C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or two R ⁶ .

In some embodiments, R ² and R ³ are independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ fluoroalkyl, where each of said C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one or more R ⁵ . In some such embodiments, each of said C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one, two, three, or four R ⁵ . In some such embodiments, each of said C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one or two R ⁵ . In specific embodiments, R ² and R ³ are independently H, C ₁ -C ₆ alkyl, or C ₁ -C ₆ fluoroalkyl. In specific embodiments, R ² is H and R ³ is C ₁ -C ₆ alkyl or C ₁ -C ₆ fluoroalkyl. In specific embodiments, R ² is H and R ³ is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) _{2 ,} CH ₂ CH ₂ CH ₂ CH ₃ , CH(CH ₃ )CH ₂ CH _3, CH ₂ CH(CH ₃ ) ₂ or C(CH ₃ ) ₃ .

In other embodiments, R ² and R ³ are independently H, -L ² -(C ₃ -C ₇ cycloalkyl), or -L ² -(4-7 membered heterocyclyl), where each C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ . In some such embodiments, R ² is H and R ³ is -L ² -(C ₃ -C ₇ cycloalkyl) or -L ² -(4-7 membered heterocyclyl), wherein each C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more R ⁶ . In specific embodiments, R ² is H and R ³ is -L ² -(C ₃ -C ₇ cycloalkyl), wherein said C ₃ -C ₇ cycloalkyl is optionally substituted with one or more R ⁶ . In some embodiments of each of the above, each of said C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one, two, three, or four R ⁶ . In some embodiments of each of the above, each of said C ₃ -C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or two R ⁶ . In some such embodiments, each R ⁶ is CH ₃ .

In compounds of formula (I), L ² is a bond or C ₁ -C ₂ alkylene optionally substituted with one or more R ⁹ . In some such embodiments, said L ² is a bond or C ₁ -C ₂ alkylene optionally substituted with one, two, three, or four R ⁹ . In some such embodiments, L ² is a bond or C ₁ -C ₂ alkylene optionally substituted with one or two R ⁹ . In some such embodiments, L ² is a bond, methylene, or ethylene. In some such embodiments, L ² is a bond or methylene. In some embodiments of each of the above, L ² is a bond. In other embodiments of each of the above, L ² is C ₁ -C ₂ alkylene optionally substituted with one or more R ⁹ . In some such embodiments, L ² is C ₁ -C ₂ alkylene optionally substituted with one, two, three, or four R ⁹ . In some such embodiments, L ² is C ₁ -C ₂ alkylene optionally substituted with one or two R ⁹ . In some such embodiments, L ² is methylene or ethylene (ie, -CH ₂ or -CH ₂ CH ₂ -). In some embodiments, L ² is methylene.

In some embodiments, R ² and R ³ are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R ⁷ ) and S(O) _q as a ring member, wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ⁸ , and wherein q is 0, 1, or 2. In some such embodiments, said 4-6 membered heterocyclyl is optionally substituted with one , two, three or four R ⁸ . In some such embodiments, said 4-6 membered heterocyclyl is optionally substituted with one or two R ⁸ .

In some such embodiments, R ² and R ³ are taken together with the N-atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl optionally containing an additional heteroatom selected from O, N(R ⁷ ) and S (O) _q , as a ring member, wherein said 4-6 membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl, each of which is optionally substituted with one or more R ⁸ . In some such embodiments, R ² and R ³ are taken together with the N-atom to which they are attached to form azetidinyl or pyrrolidinyl, each of which is optionally substituted with one or more R ⁸ . In specific embodiments, R ² and R ³ are taken together with the N-atom to which they are attached to form azetidinyl optionally substituted with one or more R ⁸ . In some embodiments of each of the above, said 4-6 membered heterocyclyl is optionally substituted with one, two, three, or four R ⁸ . In some embodiments of each of the above, said 4-6 membered heterocyclyl is optionally substituted with one or two R ⁸ . In some such embodiments, each R ⁸ is CH ₃ .

In compounds of formula (I), each R ⁴ is independently F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ - C ₄ fluoroalkoxy, C ₃ -C ₈ cycloalkyl, C(O)NR ¹⁰ R ¹¹ , SO ₂ R ¹² , SO(=NH)R ¹² or SO ₂ NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with one or more R ¹³ . In some embodiments, each R ⁴ is independently C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, where each C ₁ -C ₄ alkyl is optionally substituted with one or more R ¹³ . In some such embodiments, each R ¹³ is OCH ₃ . In some embodiments of each of the above, each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with one, two, three, or four R ¹³ . In some embodiments of each of the above, each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with one or two R ¹³ . In specific embodiments, each R ⁴ (or R ⁴ substituted with R ¹³ ) is independently CH _3, OCH ₃ or CH ₂ OCH _3.

In compounds of formula (I), each R ⁵ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁰ R ¹¹ . In some such embodiments, each R ⁵ is independently OH, OCH ₃ , NH ₂ , NHCH _{3 ,} or N(CH ₃ ) ₂ .

In compounds of formula (I), each R ⁶ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, or NR ¹⁰ R ¹¹ , where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with one or more R ¹³ . In some embodiments, each R ⁶ is independently C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, where each C ₁ -C ₄ alkyl is optionally substituted with one or more R ¹³ . In some embodiments of each of the above, each C ₁ -C ₄ alkyl is optionally substituted with one, two, three, or four R ¹³ . In some embodiments of each of the above, each C ₁ -C ₄ alkyl is optionally substituted with one or two R ¹³ . In some such embodiments, R ¹³ is CH ₃ or OCH ₃ . In specific embodiments, each R ⁶ is independently CH _3, OCH ₃ or CH ₂ OCH _3. In specific embodiments, each R ⁶ is independently CH ₃ .

In compounds of formula (I), R ⁷ is H, C ₁ -C ₄ alkyl or C(O) -C ₁ -C ₄ alkyl. In some embodiments, R ⁷ is H, CH ₃ or C(O)CH ₃ .

In compounds of formula (I), each R ⁸ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or CN. In specific embodiments, each R ⁸ is independently F, OH, CH ₃ , OCH _{3 ,} or CN. In specific embodiments, each R ⁸ is CH ₃ .

In the compounds of formula (I), each R ⁹ is independently F, OH or C ₁ -C ₂ alkyl. In some embodiments, R ⁹ is F, OH, or CH _3. In specific embodiments, R ⁹ is F, OH, or CH _3. In some embodiments, L ¹ and L ² are a bond or an unsubstituted C ₁ - C ₂ alkylene and R ⁹ is absent.

In the compounds of formula (I), each R ¹⁰ and R ¹¹ independently represents H or C ₁ -C ₄ alkyl. In specific embodiments, each R ¹⁰ and R ¹¹ independently represents H or CH ₃ .

In compounds of formula (I), each R ¹² is C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl. In specific embodiments, each R ¹² is CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , or cyclopropyl.

In compounds of formula (I), each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ . In specific embodiments, each R ¹³ is independently OH, OCH ₃ or NR ¹⁴ R ¹⁵ where R ¹⁴ and R ¹⁵ are independently H or CH ₃ . In specific embodiments, each R ¹³ is independently OH, OCH ₃ , NH ₂ , NHCH _{3 ,} or N(CH ₃ ) ₂ .

In the compounds of formula (I), each R ¹⁴ and R ¹⁵ independently represents H or C ₁ -C ₄ alkyl. In specific embodiments, R ¹⁴ and R ¹⁵ are independently H or CH ₃ .

In some embodiments, the compound of formula (I) has absolute stereochemistry as shown in formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² and R ³ have the meanings defined for formula (I).

In some embodiments, the compound of formula (I) has absolute stereochemistry as shown in formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R ¹ , R ² and R ³ have the meanings defined for formula (I).

The compounds of formulas (II) and (III) maintain a syn-bond between groups of substituents at the 1- and 3-positions of the cyclopentyl ring, but are present as an enantiomer, indicated essentially in enantiomerically pure form.

Each of the aspects and embodiments described herein with respect to formula (I) is also applicable to compounds of formulas (II) or (III).

In some embodiments, the invention relates to compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts, where:

R ¹ is -L ¹ -(5-10 membered heteroaryl) optionally substituted with one or two R ⁴ ;

R ² and R ³ are independently H, C ₁ -C ₆ alkyl, -L ² - ₍ C ₃ -C ₇ cycloalkyl) wherein said C ₃ -C ₇ cycloalkyl is optionally substituted with one R ⁶ ;

each L ¹ and L ² is independently a bond or methylene;

each R ⁴ is independently F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C ₃ - C ₈ cycloalkyl, C(O)NR ¹⁰ R ¹¹ , SO ₂ R ¹² , SO(=NH)R ¹² or SO ₂ NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted one R ¹³ ;

each R ⁶ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy C ₁ -C ₄ fluoroalkoxy, or NR ¹⁰ R ¹¹ where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl optionally substituted with one R ¹³ ;

each R ¹⁰ and R ¹¹ independently represents H or C ₁ -C ₄ alkyl;

each R ¹² is C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl; And

each R ¹³ is independently OH, C ₁ -C ₄ alkoxy, or NR ¹⁴ R ¹⁵ .

In other embodiments, the invention relates to compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts, where:

R ¹ is -L ¹ -(5-10 membered heteroaryl) optionally substituted with one or two R ⁴ ;

R ² and R ³ are independently H, C ₁ -C ₆ alkyl or C ₃ -C ₇ cycloalkyl optionally substituted with one C ₁ -C ₄ alkyl;

L ¹ is independently a bond or methylene; And

each R ⁴ is independently C ₁ -C ₄ alkyl optionally substituted with OH or C ₁ -C ₄ alkoxy.

In additional embodiments, the invention relates to compounds of formula (I), (II) or (III) or their pharmaceutically acceptable salts, having two or more of the following features:

R ¹ is -L ¹ -(5-10 membered heteroaryl), wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ ;

R ² and R ³ independently represent H or C ₁ -C ₆ alkyl;

L ¹ is a bond or C ₁ -C ₂ alkylene;

each R ⁴ is independently C ₁ -C ₄ alkyl, where each C ₁ -C ₄ alkyl is optionally substituted with one or more R ¹³ ;

each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ ; And

each R ¹⁴ and R ¹⁵ is independently H or C ₁ -C ₄ alkyl.

In certain such embodiments, the invention relates to compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following features:

R ¹ is -L ¹ -(5-10 membered heteroaryl) optionally substituted with one or more R ⁴ , wherein said 5-10 membered heteroaryl is pyrazolyl;

R ² is H;

R ³ is C ₁ -C ₆ alkyl, preferably C ₁ -C ₄ alkyl;

L ¹ is a bond;

each R ⁴ is independently C ₁ -C ₄ alkyl, where each C ₁ -C ₄ alkyl is optionally substituted with one or more R ¹³ ;

each R ¹³ is independently OH, OCH ₃ or NR ¹⁴ R ¹⁵ ; And

each R ¹⁴ and R ¹⁵ is independently H or CH ₃ .

In other embodiments, the invention relates to compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following features:

R ¹ is -L ¹ -(5-10 membered heteroaryl), wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ ;

R ² and R ³ are independently H or -L ² -(C ₃ -C ₇ cycloalkyl) wherein said C ₃ -C ₇ cycloalkyl is optionally substituted with one or more R ⁶ ;

L ¹ is a bond or C ₁ -C ₂ alkylene;

L ² is a bond or C ₁ -C ₂ alkylene;

each R ⁴ is independently C ₁ -C ₄ alkyl, where each C ₁ -C ₄ alkyl is optionally substituted with one or more R ¹³ ;

each R ⁶ is independently F, OH, or C ₁ -C ₄ alkyl;

each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ ; And

each R ¹⁴ and R ¹⁵ is independently H or C ₁ -C ₄ alkyl.

In yet other embodiments, the invention relates to compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following features:

R ¹ is -L ¹ -(5-10 membered heteroaryl) optionally substituted with one or more R ⁴ , wherein said 5-10 membered heteroaryl is isoxazolyl;

L ¹ is C ₁ -C ₂ alkylene;

R ² is H;

R ³ is -L ² -(C ₃ -C ₇ cycloalkyl) optionally substituted with one or more R ⁶ ;

L ² is a bond;

each R ⁴ is independently C ₁ -C ₄ alkyl, where each C ₁ -C ₄ alkyl is optionally substituted with one or more R ¹³ ;

each R ⁶ is independently F, OH, or C ₁ -C ₄ alkyl;

each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ ; And

each R ¹⁴ and R ¹⁵ is independently H or C ₁ -C ₄ alkyl.

In another aspect, the invention relates to a compound selected from the group consisting of the compounds shown in Examples 1 to 649 inclusive, or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a compound selected from the group consisting of:

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate;

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate ;

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

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate;

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl) carbamate;

(1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate;

(1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl) carbamate;

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate;

(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);

(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 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert-butyl carbamate;

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine -1-carboxylate;

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate;

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate;

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl) carbamate;

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate;

(1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl tert- butylcarbamate; And

(1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1- methylcyclobutyl) carbamate;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention relates to a compound selected from the group consisting of:

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate; And

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate;

or a pharmaceutically acceptable salt thereof.

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

In another aspect, the invention provides (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H- pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole- 5-yl]cyclopentyl propan-2-ylcarbamate in free base form.

In another aspect, the invention provides (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H- pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole- 5-yl]cyclopentyl propan-2-ylcarbamate as a pharmaceutically acceptable salt.

In some embodiments, the invention provides (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H- pyrazol-5-yl]carbonyl}amino)-1 H - pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate monohydrate (form 1). In some such embodiments, the monohydrate (Form 1) is characterized by a powder X-ray diffraction (PXRD) (2θ) pattern containing: (a) one, two, three, four, five, or more than five peaks selected from the group consisting of the peaks in Table 1 in °2θ±0.2 °2θ; (b) one, two, three, four or five peaks selected from the group consisting of 10.4, 11.7, 12.9, 18.2 and 24.2 in °2θ±0.2 °2θ; (c) any two peaks selected from the group consisting of 10.4, 11.7, 12.9, 18.2 and 24.2 in °2θ±.2 °2θ; (d) any three peaks selected from the group consisting of 10.4, 11.7, 12.9, 18.2 and 24.2 in °2θ±0.2 °2θ; (e) any four peaks selected from the group consisting of 10.4, 11.7, 12.9, 18.2 and 24.2 in °2θ±0.2 °2θ; (f) peaks at 10.4, 11.7, 12.9, 18.2 and 24.2 in °2θ±0.2 °2θ; (g) a peak at 10.4 and one, two, three or four peaks selected from the group consisting of 11.7, 12.9, 18.2 and 24.2 at °2θ±0.2 °2θ; (h) a peak at 11.7, and one, two, three or four peaks selected from the group consisting of 10.4, 12.9, 18.2 and 24.2 at °2θ±0.2 °2θ; (i) a peak at 12.9, and one, two, three or four peaks selected from the group consisting of 10.4, 11.7, 18.2 and 24.2 at °2θ±0.2 °2θ; (j) a peak at 18.2, and one, two, three or four peaks selected from the group consisting of 10.4, 11.7, 12.9 and 24.2 at °2θ±0.2 °2θ; (k) a peak at 24.2, and one, two, three, or four peaks selected from the group consisting of 10.4, 11.7, 12.9, and 18.2 at °2θ±0.2 °2θ ; or (l) the peaks at 2θ values are essentially the same as shown in FIG. 2.

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

In another embodiment, the invention provides (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl)carbamate in free base form.

In another embodiment, the invention provides (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl) cyclopentyl (1-methylcyclopropyl)carbamate in the form of a pharmaceutically acceptable salt.

In a specific embodiment, the invention relates to a compound having the structure:

,

,

or a pharmaceutically acceptable salt thereof.

In another specific embodiment, the invention relates to a compound having the structure:

,

,

or a pharmaceutically acceptable salt thereof.

In preferred embodiments, the compounds of the invention are selective CDK2 inhibitors, i. they have a lower inhibition constant (eg Ki or IC ₅₀ ) against CDK2 compared to other enzymatic targets. New data suggest that GSK3β inhibition may be related to the gastrointestinal toxicity that has been observed with some CDK inhibitors. Compounds that are selective inhibitors of CDK2 over GSK3β may provide an improved safety profile, an improved dosing schedule (eg, by reducing the need for dose reductions or dosing interruptions), and/or an increase in overall efficacy due to the possibility of higher doses. , using a continuous dosing regimen and/or increasing the total treatment time. Similarly, selective CDK2 inhibitors may have a reduced risk of certain hematological toxic effects that have been reported to be associated with CDK6 inhibition.

In some embodiments, the compounds of the invention are selective for CDK2 over CDK1. In some such embodiments, the compounds showed at least 10-fold selectivity for CDK2 over CDK1. In other embodiments, the compounds showed at least 20-fold selectivity for CDK2 over CDK1. In specific embodiments, the compounds showed at least 30-fold selectivity for CDK2 over CDK1.

In some embodiments, the compounds of the invention are selective for CDK2 over CDK4 and/or CDK6. In some such embodiments, the compounds showed at least 10-fold selectivity for CDK2 over CDK4 and/or CDK6. In other embodiments, the compounds showed at least 20-fold selectivity for CDK2 over CDK4 and/or CDK6. In specific embodiments, the compounds showed at least 30-fold selectivity for CDK2 over CDK4 and/or CDK6.

In some embodiments, the compounds of the invention are selective for CDK2 over GSK3β. In some such embodiments, the compounds showed at least 10-fold selectivity for CDK2 over GSK3β. In other embodiments, the compounds showed at least 20-fold selectivity for CDK2 over GSK3β. In specific embodiments, the compounds showed at least 30-fold selectivity for CDK2 over GSK3β.

"Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, as the active ingredient and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition includes two or more pharmaceutically acceptable carriers and/or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anti-cancer therapeutic agent.

In one aspect, the invention relates to a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition includes two or more pharmaceutically acceptable carriers and/or excipients.

In some embodiments, the pharmaceutical composition will further include at least one additional anti-cancer therapeutic agent. In some such embodiments, the combination provides an additive, more than additive, or synergistic anticancer effect.

The term "additive" is used to mean that the result of the combination of two compounds, components or target agents does not exceed the sum of each compound, component or target agent taken separately.

The term "synergism" or "synergistic effect" is used to mean that the result of the combination of two compounds, components or target agents is greater than the sum of each compound, component or target agent taken separately. 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 target agents that results in a synergistic effect, as defined herein as "synergistic".

Determination of the synergistic interaction between one or two components, the optimal range for effect, and the absolute dose ranges of each component for effect can be finally measured by administering the components in various dose ranges and/or dose ratios to patients in need of treatment. However, the observation of synergism in in vitro models or in vivo models can be a predictor of effect in humans and other species, and there are in vitro models or in vivo models as described herein to determine the synergistic effect. The results of such studies can also be used to predict effective dose ranges and plasma concentration ratios, as well as absolute doses and plasma concentrations, required in humans and other animal species, for example, by applying pharmacokinetic and/or pharmacodynamic methods.

Unless otherwise indicated, all references herein to compounds of the invention include references to their salts, solvates, hydrates, and complexes, as well as their solvates, hydrates, and salt complexes, including polymorphs, stereoisomers, and isotopically labeled versions thereof.

The compounds of the invention may exist in the form of pharmaceutically acceptable salts, such as, for example, acid addition salts and base addition salts of compounds of one of the formulas presented herein. As used herein, the term "pharmaceutically acceptable salt" refers to those salts that retain the biological efficacy and properties of the parent compound. The phrase "pharmaceutically acceptable(s) salt(s)", as used in the present description, unless otherwise indicated, includes salts of acidic or basic groups that may be present in the compounds of the formulas disclosed in this document.

For example, the compounds of the invention, which are basic in nature, are capable of forming a wide variety of salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, it is often desirable in practice to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then readily convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert this free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected inorganic or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent, the desired solid salt is obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate inorganic or organic acid to the solution.

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

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyn-1, 4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edisylate, estolate, esylate, ethyl succinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycolylarsanilate , heptanoate, hexine-1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γ-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate , methyl sulfate, monohydrogen phosphate, mucat, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phosphate / diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, triethiodide, and valerate.

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.

Compounds of the invention which include a basic group such as an amino group may form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

Alternatively, useful compounds that are acidic in nature are capable of forming base addition salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, in particular sodium and potassium salts. All these salts are obtained by traditional methods. The chemical bases that are used as reagents to prepare the pharmaceutically acceptable base addition salts of the present invention are bases that form non-toxic base salts with the acidic compounds described herein. These salts may be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide, or the like. These salts can also be obtained by treating the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together solutions of acidic compounds in lower alcohols and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness in the same manner as previously described. In any case, to ensure the completeness of the reaction and maximum yields of the target end product, stoichiometric amounts of reagents are preferably used.

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

Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed.

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

The salts of the present invention may be prepared by methods known to those skilled in the art. A pharmaceutically acceptable salt of the compounds of the invention can be readily prepared by mixing together solutions of the compound and the desired acid or desired base, as the case may be. The salt may precipitate out of solution and may be collected by filtration or may be recovered by evaporating the solvent. The degree of ionization in a salt can vary from fully ionized to almost non-ionized.

Those skilled in the art will appreciate that the compounds of the invention in free base form having a basic functional group can be converted to acid addition salts by treatment with a stoichiometric excess of the appropriate acid. The acid addition salts of the compounds of the invention can be converted to the corresponding free base by treatment 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 between about 0° and 100°C. The free base form can be isolated by conventional means such as extraction with an organic solvent. In addition, the acid addition salts of the compounds of the present invention can be interchanged by taking advantage of differences in salt solubilities, acid volatilities or acidities, or by treatment with a suitably loaded ion exchange resin. For example, reciprocation can be accomplished by reacting a salt of the compounds of the invention with a slightly stoichiometric excess of an acid at a lower pKa than the acidic component of the original salt. This transformation is usually carried out at a temperature from about 0°C to the boiling point of the solvent used as a medium for carrying out the procedure. A similar type of substitution is possible for base addition salts, usually by mediating the free base form.

The compounds of the invention may exist in both unsolvated and solvated forms. If the solvent or water is tightly bound, then the complex will have a well-defined stoichiometry, regardless of humidity. However, if the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, then 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 invention and one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term "hydrate" is used when the solvent is water. Pharmaceutically acceptable solvates of this invention include hydrates and solvates in which the crystallization solvent may be isotopically substituted, eg D ₂ O, d ₆ -acetone, d ₆ -DMSO.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes, where, unlike the aforementioned solvates, drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes comprising two or more organic and/or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the description of which is incorporated herein by reference in its entirety.

The invention also relates to prodrugs of compounds of the formulas proposed in the present invention. Thus, certain derivatives of the compounds of the invention, which themselves may have little or no pharmacological activity, may, when administered to a patient, be converted to the compounds of the invention, for example by hydrolytic cleavage. Such derivatives are called "prodrugs". Additional information regarding the use of prodrugs can be found in '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 (ed. E B Roche, American Pharmaceutical Association), the disclosures of which are incorporated herein by reference in their entirety.

The prodrugs of the invention may, for example, be prepared by replacing suitable functional groups present in the compounds of the invention with certain moieties which are known to those skilled in the art as "prodrugs" as described, for example, in "Design of Prodrugs" by H Bundgaard (Elsevier, 1985), the description of which is incorporated herein by reference in its entirety.

Some non-limiting examples of prodrugs of the invention include:

(i) where the connection contains a functional group of carboxylic acid (-COOH), its ester, for example, with the replacement of hydrogen (C ₁ -C ₈ )alkyl;

(ii) where the compound contains an alcohol functional group (-OH), its simple ether, for example, with the replacement of hydrogen (C ₁ -C ₆ )alkanoyloxymethyl or a phosphate ester group; And

(iii) if the compound contains a primary or secondary functional amino group (-NH ₂ or -NHR, R≠H), then its amide, for example, with the replacement of one or both hydrogen atoms with a suitable metabolically unstable group, such as amide, carbamate, urea, phosphonate, sulfonate, etc.

Additional examples of substituent groups in accordance with the examples above and examples of other types of prodrugs can be found in the above references. Finally, some compounds of the invention may themselves act as prodrugs of other compounds of the invention .

Also included within the scope of the invention are metabolites of compounds of the formulas described herein, ie compounds formed in vivo after drug administration.

In addition to the syn -relationship between the substituent groups at positions 1 and 3 of the cyclopentyl ring in formulas (I), (II) and (III), the compounds of the formulas presented herein may have additional asymmetric carbon atoms as part of the substituent groups, defined as R ¹ , R ² and R ³ , or optional substituents attached to these groups. At such additional asymmetric centers, a solid line is used to indicate that all possible stereoisomers at that carbon atom are included, while the use of a solid or dashed wedge-shaped line indicates that only the indicated isomer is intended to be included in that stereocenter, unless otherwise indicated. The compounds of the formulas described herein may include substituent groups containing cis and trans geometric isomers, rotational isomers, atropisomers, conformational isomers and tautomers of the compounds of the present invention, including compounds exhibiting more than one type of isomerism.

Also included are acid addition or base addition salts where the counterion is optically active, eg d-lactate or l-lysine, or racemic, eg dl-tartrate or dl-arginine.

If any racemate crystallizes, two different types of crystals are possible. The first type is the above racemic compound (true racemate) where a single homogeneous crystal form is obtained containing both enantiomers in equimolar amounts. The second type is a racemic mixture or conglomerate where two crystal forms are obtained in equimolar amounts, each containing a single enantiomer.

Compounds of the invention may exhibit tautomeric effects and have structural isomerism. For example, the compounds may exist in several tautomeric forms, including enol and imine form, and keto and enamine form, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the invention. Tautomers exist as mixtures of the tautomer group in solution. In solid form, one tautomer usually predominates. Even if one tautomer can be described, the present invention includes all tautomers of the compounds of the given formulas.

In addition, some compounds of the invention may form atropisomers (eg, substituted biaryls). Atropisomers are conformational stereoisomers that occur when rotation around a single bond in a molecule is not allowed, or is severely retarded by steric interactions with other parts of the molecule, and the substituents at either end of that single bond are unsymmetrical. The interconversion of the atropisomers is weak enough to allow separation and isolation under the given conditions. The energy barrier to thermal racemization can be determined by the steric hindrance to the free rotation of one or more bonds forming a chiral axis.

If the compound of the invention contains an alkenyl or alkenylene group, geometric cis/trans (or Z/E) isomers are possible. The cis/trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.

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

Alternatively, the racemate (or racemate precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, when the compound contains an acidic or basic group, with an acid or base, such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer(s) by methods well known to those skilled in the art.

The chiral compounds of the invention (and their chiral precursors) can be obtained in an enantiomerically enriched form using chromatography, usually HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, usually heptane or hexane, containing 0 to 50% isopropanol, usually 2 to 20%; and 0 to 5% alkylamine, typically 0.1% diethylamine. Concentration of the eluate results in an enriched mixture.

Stereoisomeric conglomerates can be separated by conventional techniques known to those skilled in the art; see, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994), the description of which is incorporated herein by reference in its entirety.

The enantiomeric purity of the compounds described herein can be described in terms of enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomer in greater amounts than the other. A racemic mixture has 0% ee, while one completely pure enantiomer has 100% ee. Similarly, diastereomeric purity can be described in terms of diastereomeric excess (de). As used herein, the terms "enantiomerically pure" or "substantially enantiomerically pure" means a compound that includes one enantiomer of the compound and is substantially free of the opposite enantiomer of the compound. A typical enantiomerically pure compound comprises 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 more 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 more 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.

The present invention also includes isotopically labeled compounds that are identical to the compounds set forth in one of the proposed formulas, except 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 normally found in nature. .

The isotopically labeled compounds of the invention can generally be prepared by conventional procedures known to those skilled in the art, or by methods analogous to those disclosed herein, using a suitable isotopically labeled reagent in place of the non-isotopically labeled reagent used elsewhere.

Examples of isotopes that may be included in the compounds of the 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 , ^18O , ^17O , ^31P , ^32P , ^35S , ^18F and ^36Cl . Certain isotopically labeled compounds of the invention, such as those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are useful in drug and/or substrate tissue distribution assays. Tritiated, ie ³ H and carbon-14, ie ¹⁴ C, isotopes are particularly preferred due to their ease of preparation and detection. In addition, substitution by heavier isotopes such as deuterium, i.e. ² H may provide some therapeutic benefits resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some instances. The isotopically labeled compounds of the invention can generally be prepared by following the procedures disclosed in the Schemes and/or in the Examples and Preparations below by replacing a non-isotopically labeled reagent with an isotopically labeled reagent.

Compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products or mixtures thereof. They can be obtained, for example, in the form of solid compacted masses, powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporation drying. Microwave or radio frequency drying can be used for this purpose.

Therapeutic Methods and Applications

The invention also provides therapeutic methods and uses comprising administering the compounds of the invention, or pharmaceutically acceptable salts thereof, alone or in combination with other therapeutics or palliatives.

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

In another aspect, the invention relates to a method of treating abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, in combination with an amount of an additional therapeutic agent (e.g., an anti-cancer therapeutic agent), where these amounts together are effective in treating said abnormal cell growth.

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of abnormal cell growth in a subject.

In a further aspect, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth in a subject.

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

In another aspect, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a drug, in particular a drug for the treatment of abnormal cell growth.

In yet another aspect, the invention relates to the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.

In frequent embodiments of the methods provided herein, the abnormal cell growth is cancer. The compounds of the present invention may be administered alone or may be administered in combination with other anti-cancer therapies, in particular standard treatments suitable for a particular type of cancer.

In some embodiments, the present methods result in one or more of the following effects: (1) inhibition of cancer cell proliferation; (2) suppression of the invasiveness of cancer cells; (3) induction of apoptosis of cancer cells; (4) inhibition of cancer cell metastasis; or (5) inhibition of angiogenesis.

In another aspect, the invention relates to a method of treating a CDK2 mediated disorder in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to treat said disorder, particularly cancer.

In certain aspects and embodiments of the compounds, compositions, methods and uses described herein, the compounds of the present invention are selective for CDK2 over other CDKs, in particular CDK1. In some embodiments, the compounds of the invention are selective for CDK2 over CDK4 and/or CDK6. In other aspects and embodiments, the compounds of the invention are selective for CDK2 over glycogen synthase kinase-3 beta (GSK3β). Compounds of the invention include compounds of any of the formulas described herein, or their pharmaceutically acceptable salts.

In another aspect, the invention relates to a method for inhibiting cancer cell proliferation in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

In another aspect, the invention relates to a method for inhibiting the invasiveness of cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the invasiveness of the cells.

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

In another aspect, the invention relates to a method for inhibiting cancer cell metastasis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

In another aspect, the invention relates to a method for inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit angiogenesis.

In frequent 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. , kidney cancer (including RCC), liver cancer (including HCC), pancreatic cancer, stomach (i.e. gastrointestinal) cancer, and 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.

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 some embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer showing primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the above, the breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

In some embodiments of the methods provided herein, the abnormal cell growth is a cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2. In some embodiments of the methods provided herein, a cancer is identified in a subject characterized by amplification or overexpression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer. In some such embodiments, the cancer is breast cancer or ovarian cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2. In some 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 some embodiments, the cancer is ovarian cancer.

In some embodiments, a compound of the invention is administered as first line therapy. In other embodiments, a compound of the invention is administered as a second (or later) line therapy. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with a hormone therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with a hormonal therapeutic agent, eg, an aromatase inhibitor, SERM, or SERD. In some embodiments, a compound of the invention is administered as second (or later) line therapy following treatment with a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as a second (or later) line therapy following treatment with one or more chemotherapeutic regimens, for example, including taxane- or platinum-based agents. In some embodiments, a compound of the invention is administered as second (or later) line therapy following treatment with HER2-targeting agents, such as trastuzumab.

As used herein, the term "effective dose" or "effective amount" of a drug, compound or pharmaceutical composition is an amount sufficient to effect any one or more beneficial or desirable, including biochemical, histological and/or behavioral symptoms, disease, complications and intermediate pathological phenotypes that occur during the development of the disease. For therapeutic use, a "therapeutically effective amount" refers to that amount of a compound administered that will alleviate to some extent one or more of the symptoms of the disease being treated. When referring to the treatment of cancer, a therapeutically effective amount refers to that amount which has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing down to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent degree (i.e. slow down to some extent, preferably stop) tumor growth or tumor invasiveness, and/or (4) attenuation to some extent (or preferably elimination) of one or more signs or symptoms associated with cancer, (5 ) reducing the dose of other drugs needed to treat the disease, and/or (6) enhancing the effect of another drug, and/or (7) delaying the progression of the disease in the patient.

An effective dose can be administered in one or more divided doses. For the purposes of the present invention, an effective dose of a drug, compound or pharmaceutical composition is an amount sufficient to effect prophylactic or therapeutic treatment directly or indirectly. As understood in the clinical context, an effective dose of a drug, compound, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition.

"Tumor" in relation to a subject diagnosed or suspected of cancer, refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or fluid. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemia (blood cancer) usually does not form solid tumors (National Cancer Institute, Dictionary of Cancer Terms).

"Tumor mass" or "tumor burden" 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(s) throughout the body, including lymph nodes and bone marrow. Tumor burden can be determined using a variety of methods known in the art, such as, for example, using a caliper, or while in the body using imaging techniques, such as ultrasound, bone scanning, computed tomography (CT) or magnetic resonance imaging (MRI).

The term "tumor size" refers to the overall size of the tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor(s) when removed from the subject, such as with a caliper, or while in the body using imaging techniques, such as scanning. bones, ultrasound, CR or MRI.

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

The term "treating" or "treatment" of cancer as used herein means administering a compound of the present invention to a subject suffering from or diagnosed with cancer in order to achieve at least one beneficial therapeutic effect, such as, for example, reducing the number of cancerous cells, reduction in tumor size, reduction in the rate of infiltration of cancer cells into peripheral organs, or reduction in the rate of tumor metastasis or tumor growth, reversal, amelioration, inhibition of progression, or prevention of the disorder or condition to which the term applies, or one or more of the symptoms of such a disorder, or states. The term "treatment" as used herein, unless otherwise indicated, refers to the act of a treatment process as a "treatment process" as defined immediately above. The term "treatment process" also includes adjuvant and neoadjuvant treatment of a subject.

For purposes of the present invention, useful or desirable clinical results include, but are not limited to, one or more of the following: reduced proliferation (or destruction) of neoplastic or cancerous cells; inhibition of metastases or neoplastic cells; reduction or slowing down of the size of the tumor; cancer remission; reduction of symptoms caused by cancer; improving the quality of life of cancer patients; reducing the dose of other drugs needed to treat cancer; delay in cancer progression; cancer treatment; overcoming one or more cancer resistance mechanisms; and/or prolonging the survival of cancer patients. A positive therapeutic effect in cancer can be measured in several ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1:1S-10S (2009). For example, with regard to tumor growth inhibition ( T/C), according to National Cancer Institute (NCI) standards, T/C less than or equal to 42% is the minimum level of antitumor activity.T/C<10% is considered high level of antitumor activity, where T/C (%) = average volume treated tumor/mean control tumor volume x 100.

In some embodiments, the treatment achieved by a compound of the 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 called Time to Tumor Progression, indicates the length of time during and after treatment that the cancer does not grow, and includes the amount of time that patients experienced CR or PR, as well as the amount of time that patients experienced stabilization of the disease (SD). DFS refers to the length of time during and after treatment during which the patient remains disease-free. OS means increased lifespan compared to naive subjects or patients, or untreated subjects or patients. In some embodiments, the response to the combination of the invention is any one of PR, CR, PFS, DFS, OR, or OS as assessed using the Solid Tumor Response Evaluation Criteria (RECIST) 1.1 response criterion.

A treatment regimen with a compound of the invention that is effective in treating a cancer patient may vary depending on such factors as the disease state, age and weight of the patient, and the ability of the therapy to elicit an anti-cancer response in the subject. Although an embodiment of any of the aspects of the invention may not be effective in achieving a beneficial therapeutic effect in every subject, it should work in relation to 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 Mann and Whitney, Kruskal-Wallis test (H-test), Jonkheer-Terpstra test and Wilcon test.

The terms "treatment regimen", "dosing protocol" and "dosing regimen" are used interchangeably to refer to the dose and timing of administration of each compound of the invention, alone or in combination with another therapeutic agent.

"Improvement" means a reduction or improvement in one or more symptoms after treatment with a combination described herein, compared with no administration of the combination. "Improvement" also includes a reduction or reduction in the duration of a symptom.

"Abnormal cell growth" as used herein, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). Abnormal cell growth can be benign (noncancerous) or malignant (cancerous).

Abnormal cell growth includes abnormal growth of: (1) tumor cells (tumors) that show increased expression of CDK2; (2) tumors that proliferate due to aberrant 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.

The term "additional anticancer therapeutic agent" in the context of the present description means any one or more therapeutic agents other than the compound of the invention, which is used or can be used in the treatment of cancer. In some embodiments, such additional antitumor therapeutics include compounds derived from the following classes: mitosis inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, angiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation, signal transduction inhibitors such as protein tyrosine kinase and/or serine/threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or oligonucleotide derivatives, cytotoxic and immuno-oncological agents, and the like.

In some embodiments, the additional anti-cancer agent is a hormonal agent, such as an aromatase inhibitor, SERD, or SERM.

In other embodiments, a compound of the invention may be administered in combination with a standard treatment. In some embodiments, a compound of the invention may be administered in combination with hormone therapy, such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole, for example. In some embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, such as docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine. In other embodiments, a compound of the invention may be administered in combination with an anti-HER2 agent, such as trastuzumab or pertuzumab.

In some embodiments, the additional anti-cancer agent is an anti-angiogenesis agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCβ inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha -v/beta-3), inhibitors of MMP-2 (matrix metalloproteinase 2), and inhibitors of MMP-9 (matrix metalloproteinase 9). Preferred angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 ( Pfizer ), and AG 13958 (Pfizer). Additional angiogenesis agents include vatalanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octasodium (Macugen™), vandetanib (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 (BAY 57- 9352) and CP-868,596 (Pfizer). Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia), and etoricoxib (Arcoxia™). Additional anti-angiogenesis agents include exisulind (Aptosyn™), salsalat (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen ( Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Additional anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Additional anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF-03446962 (Pfizer), Rebimastat ( BMS 275291) , Catumaxomab (Removab™), Lenalidomide (Revlimid™), Squalamine (EVIZON™), Thalidomide (Thalomid™), Ukrain™ (NSC 631570), Vitaxin™ (MEDI 522) , and zoledronic acid (Zometa™).

In other embodiments, the additional anti-cancer agent is a so-called signal transduction inhibitor (eg, inhibitory agents by which regulatory molecules that control fundamental processes of cell growth, differentiation, and survival are transmitted within a cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (eg 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 inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK inhibitors, c-Kit inhibitors, FLT-3 inhibitors, K-Ras inhibitors. , PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, WNT pathway inhibitors, and so-called multitarget kinase inhibitors. Additional examples of signal transduction inhibitors that can be used in combination with a compound of the invention and the pharmaceutical compositions described herein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200 ), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (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), canertinib (CI 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosine (Miltefosin™), BMS 599626 ( Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (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), alvocidib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).

In other embodiments, the additional anticancer agent is a so-called classical anticancer agent. Classical anticancer agents include, but are not limited to, hormonal modulators such as hormonal, antihormonal, androgen agonists, androgen antagonists and antiestrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing agents or gene activating agents, ribonucleases, proteosomes, topoisomerase I inhibitors, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor (such as, for example, talazoparib, olapariv, rucaparib, niraparib, iniparib, veliparib ), microtubulin inhibitors, antibiotics, plant spindle inhibitors, platinum-coordinated compounds, gene therapeutics, antisense oligonucleotides, vascular targeting agents (VTAs), and statins. Examples of classical anticancer agents used in combination therapy with a compound 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 (Megace), mifepristone (RU-486), selective estrogen receptor modulator (SERM; such as tamoxifen, raloxifene, lasofoxifene, afimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi) , selective estrogen receptor inhibitors (SERDs; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidex), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH) agonists; also commonly referred to as luteinizing hormone-releasing hormone [LHRH]), such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron), and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron), and osateron, dutasteride, epristeride, finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicalutamide; antiandrogenic agents such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and their combinations. Other examples of classical anticancer agents used in combination with a compound of the invention include, but are not limited to, hydroxamic acid suberolanilide (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MS-275, pivaloyloxymethylbutyrate and PXD-101; Onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezomib), 9-aminocamptothecin, belothecan, BN-80915 (Roche), camptothecin, diflomotecan, edotecarin, exatecan (Daiichi), hymatecan, 10-hydroxycamptothecin, irinotecan HCl (Camptosar), Lurtotecan, Oratecin (Rubitecan, Supergen), SN-38, Topotecan, Camptothecin, 10-Hydroxycamptothecin, 9-Aminocamptothecin, Irinotecan, SN-38, Edotecarin, Topotecan, Aclarubicin, Adriamycin, Amonafide, Amrubicin, Annamycin, daunorubicin, doxorubicin, elsamitrucin, epirubicin, etoposide, idarubicin, galarubicin, hydroxyurea, nemorubicin, novanthrone (mitoxantrone), pyrarubicin, pixantrone, procarbazine, rebeccamycin, sobusoxane, tafluposide, valrubicin, Zinecard (dexrazoxane), nitrogenous N-oxide mustard, cyclophosphamide , AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW-2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, mitolactol , mitomycin C, mitoxatron, nimustine, ranimustine, temozolomide, thiotepa, and platinum-coordinated alkylating compounds such as cisplatin, paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, eloxatin (oxaliplatin, Sanofi), streptozocin, satroplatin, and combinations thereof.

In still other embodiments, the additional anti-cancer agent are so-called dihydrofolate reductase inhibitors (such as methotrexate and NeuTrexin (trimetrezate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine , nelarabin, and raltitrexed), pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (pemetrexed disodium, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), tegafur ( UFT Orzel or Uforal and including TS-1 combination of tegafur, hymestat and otostat), doxyfluridine, carmofur, cytarabine (including oxphosphate, phosphate stearate, sustained release and liposomal formulations), enocytabine, 5-azacytidine (vidase), decitabine and ethinylcytidine) and other antimetabolites such as eflornithine, hydroxyurea, leucovorin, 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.

Other examples of classical antitumor 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, neocarzinostatin (zinostatin), vinblastine, vincristine, vindesine, vinorelbine (navelbin), docetaxel (taxotere), orthotaxel, paclitaxel (including taxoprexin DHA/paquiltaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (eloxatin), satraplatin, camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), taxotere alitretinoin, canfosfamide (Telcyta™), DMXAA (Antisoma), ibandronic acid, L-asparaginase, pegaspargasa (Oncaspar™), efaproxiral (Efaproxyn™ - radiation therapy), bexarotene (Targretin™) ), tesmilifen (DPPE - increases the effectiveness of cytotoxic agents), Theratope™ (Biomira), tretinoin (Vesanoid™), tirapazamine (Trizaone™), motexafine gadolinium (Xcytrin™) Cotara™ (mAb), and NBI-3001 (Protox Therapeutics) , polyglutamate-paclitaxel (Xyotax™) and combinations thereof. Additional examples of classical anticancer agents include, but are not limited to, Advexin (ING 201), TNFerade (GeneVec, a compound that expresses TNF-alpha in response to radiation therapy), RB94 (Baylor College of Medicine), Genasense (Oblimersen, Genta ), combretastatin A4P (CA4P), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), provastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc. ), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycol, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, lipitor, torcetrapib, and their combinations.

In other embodiments, the additional anticancer agent is an epigenetic modulator, e.g., an inhibitor of either 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.

In further embodiments, the additional anticancer agent is an immunomodulatory agent such as a CTLA-4, PD-1, or PD-L1 inhibitor (e.g., pembrolizumab, nivolumab, or avelumab), LAG-3, TIM-3, TIGIT, 4-1BB, OX40, GITR, CD40, or CAR-T cell therapy.

As used herein, the term "cancer" refers to any malignant and/or invasive growth or tumor caused by abnormal cell growth. Cancer includes solid tumors named for the type of cells that form them, cancers of the blood, bone marrow, or lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Blood cancers include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancer that originates at a specific site in the body, metastatic cancer that has spread from the site where it originated to other parts of the body, recurrence of the original primary cancer after remission, and second primary cancer, which is a new primary cancer in a person. with a history of previous cancer of a different type than the last.

In some 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 stomach cancer. In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

Dosage forms and administration schemes

Administration of the compounds of the invention may be by any means that allows delivery of the compounds 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.

Dosing regimens can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, multiple doses may be administered separated by time, or the dose may be proportionally reduced or increased as dictated by the therapeutic situation. It is particularly useful to formulate parenteral compositions in unit dosage form for ease of administration and uniformity of dose. Unit dosage form, as used herein, refers to physically discrete units suitable as unit doses for mammals to be treated; wherein each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect together with the desired pharmaceutical carrier. The detailed definition of unit dosage forms of the invention is dictated by and depends directly on (a) the unique characteristics of the chemotherapeutic agent and the specific therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the field of drug formulation, such as the active compound for the treatment of sensitivity in individuals.

Thus, one of ordinary skill in the art will appreciate that the dosage and dosage regimen may be adjusted based on the disclosure provided, in accordance with methods well known in the art of therapy. That is, the maximum acceptable dose can be easily established, as can the effective amount that provides a detectable therapeutic benefit to the patient, as well as the time requirement for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, although examples are given for certain doses and administration schedules in the present specification, these examples do not in any way limit the dosage and administration schedule that may be offered to a patient in the practice of the present invention.

It should be noted that dosage values may vary depending on the type and severity of the condition to be alleviated and may include single or multiple doses. In addition, it should be understood that for any particular subject, specific dosing schedules should be adjusted in relation to time in accordance with individual need and professional judgment of the person administering and observing the administration of the compositions, and that the dosage ranges set forth herein are only typical. and are not intended to limit the scope or practical use of the claimed composition. For example, dosages 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 encompasses an extension of the dosage range for a patient as determined by the skilled artisan. The determination of suitable doses and regimens for the administration of chemotherapeutic agents is well known in the art, and should be understood by one of skill in the art upon receipt of the information disclosed herein.

The amount of compound of the invention administered will depend upon the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the discretion of the attending physician. However, an effective dose will typically be in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this amount would be from about 0.05 to about 7 g/day, preferably from about 0.1 to about 2.5 g/day. In some cases, dose levels below the lower end of the aforementioned range may be more than sufficient, while in other cases larger doses may be used without causing any dangerous side effect, provided such large doses are first divided into several smaller doses. doses for administration during the day.

Formulations and routes of administration

As used herein, a "pharmaceutically acceptable carrier" refers to a carrier or diluent that does not cause significant irritation to the body and does not interfere with the biological activity and properties of the administered compound.

A pharmaceutically acceptable carrier may include any conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will depend to a large extent on such factors as the particular route of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

Suitable pharmaceutical carriers include inert diluents or excipients, water, and various organic solvents (eg, hydrates and solvates). Pharmaceutical compositions may, if desired, contain additional ingredients such as flavoring agents, binders, excipients, and the like. Thus, for oral administration, tablets containing various excipients such as citric acid can be used together with various disintegrants such as starch, alginic acid and certain complex silicates, and with binders such as sucrose, gelatin and acacia. Non-limiting examples of excipients include calcium carbonate, calcium phosphate, various sugars and starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols. In addition, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type can also be used in soft and hard filled gelatin capsules. Thus, non-limiting examples of materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring agents or dyes and, if desired, emulsifiers or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin. or their combinations.

The pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulation, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment. or cream or for rectal administration as a suppository.

Typical forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions. If desired, such dosage forms may be suitably buffered.

The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise doses.

Pharmaceutical compositions suitable for the delivery of the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in 'Remington's Pharmaceutical Sciences', ^19th Edition (Mack Publishing Company, 1995), the description of which is incorporated herein by reference in its entirety.

The compounds of the invention may be administered orally. Oral administration may include swallowing such that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the blood stream directly from the mouth.

Dosage forms suitable for oral administration include solid dosage forms such as tablets, capsules containing particles, liquids or powders, lozenges (including liquid-filled), chewing gums, multi- and nanoparticles, gels, solid solution, liposome, films (including mucoadhesive), egg-shaped vaginal suppositories, sprays and liquid compositions.

Liquid compositions include suspensions, solutions, syrups and elixirs. Such compositions may be used as fillers in soft or hard capsules and typically contain 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 compositions can also be prepared by reconstitution of the moisture content of a solid, for example from a sachet.

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

For tablet dosage forms, depending on the dose, the drug can be from 1% of the mass. up to 80% wt. dosage form, more typically from 5% of the mass. up to 60% wt. dosage form. In addition to the medicine, tablets usually contain a baking powder. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium croscarmellose, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Usually the baking powder will be from 1% of the mass. up to 25% wt., preferably from 5% wt. up to 20% wt. dosage form.

Binders are typically used to impart binding properties to the tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and dibasic calcium phosphate dihydrate.

Tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80 and lubricants such as silica and talc. When they are present, surfactants are usually in amounts from 0.2% of the mass. up to 5% wt. tablets, and sliding substances are usually from 0.2% of the mass. up to 1% wt. pills.

Tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulfate. Lubricants are usually present in amounts from 0.25% of the mass. up to 10% wt., preferably from 0.5% wt. up to 3% wt. pills.

Other commonly used ingredients include antioxidants, colors, flavors, preservatives, and flavor-masking agents.

Typical tablets contain up to about 80% of the mass. medicinal product, from about 10% of the mass. up to about 90% of the mass. binder, from about 0% of the mass. up to about 85% of the mass. diluent, from about 2% of the mass. up to about 10% of the mass. baking powder and from about 0.25% of the mass. up to about 10% of the mass. lubricant.

Tablet blends may be directly compressed or compressed with a rotary cylinder to form tablets. Alternatively, tablet blends or portions of blends may be subjected to wet, dry or melt granulation, melt congealing or extrusion prior to tabletting. The final dosage form may contain one or more layers and may be coated or uncoated or encapsulated.

The preparation of tablets is described in detail in “Pharmaceutical Dosage Forms: Tablets, Vol. 1”, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the description of which is incorporated herein by reference in its entirety.

Solid dosage forms for oral administration can be made for immediate and/or modified release. Modified release dosage forms include delayed, sustained, intermittent, controlled, targeted, and programmed release.

Suitable modified release dosage forms are described in US Pat. No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic 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 descriptions of these references are incorporated herein by reference in their entirety.

The compounds of the invention can also be administered directly into the bloodstream, into a muscle, or into an internal organ. Suitable routes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injectors, needleless injection devices and infusion equipment.

Parenteral dosage forms are usually aqueous solutions which may contain excipients such as salts, carbohydrates and buffers (preferably up to a pH of 3 to 9), but in some cases they may be more suitably formulated as a sterile non-aqueous solution or in dry form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.

The preparation of parenteral dosage forms under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques well known to those skilled in the art.

The solubility of the compounds of the invention used in the preparation of parenteral solutions can be increased by suitable preparation techniques such as the incorporation of solubility improvers.

Dosage forms for parenteral administration can be prepared for immediate and/or modified release. Modified release dosage forms include delayed, sustained, intermittent, controlled, targeted, and programmed release. Thus, the compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implantable depot providing a modified release of the active compound. Examples of such dosage forms include drug-coated stents and PGLA microspheres.

The compounds of the invention can also be administered topically to the skin or mucous membrane, i. dermal or transdermal. Typical dosage forms for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, plates, implants, sponges, fibers, dressings, and microemulsions. Liposomes may also be used. Typical carriers include alcohol, water, mineral oil, liquid paraffin, medical petrolatum, glycerin, polyethylene glycol, and propylene glycol. Penetration enhancers may be included; see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Other means for topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless (eg, Powderject™, Bioject™, etc.) injection. The descriptions of these references are incorporated herein by reference in their entirety.

Dosage forms for topical administration can be made for immediate and/or modified release. Modified release dosage forms include delayed, sustained, intermittent, controlled, targeted, and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (either alone, as a mixture, for example dry mixture with lactose, or as a particulate of mixed components, for example, mixed with phospholipids such as phosphatidylcholine) from dry powder inhaler or aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) or nebulizer using a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1 ,1,1,2,3,3,3-heptafluoropropane, or without its use. For intranasal use, the powder may contain bioadhesives such as chitosan or cyclodextrin.

The pressurized container, pump, dispenser, atomizer or nebulizer contains a solution or suspension of the compound(s) of the invention containing, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilizing or extending the release of the active agent, propellant(s) into as a solvent and an optional surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

The drug product is micronized to a size suitable for inhalation delivery (typically less than 5 microns) prior to use in a dry powder or suspension formulation. This can be achieved by any suitable grinding method such as spiral jet milling, fluidized bed jet milling, supercritical fluidization to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mixture of a compound of the invention, a suitable powder base such as lactose or starch, and a performance modifier such as as l-leucine, mannitol or magnesium stearate. The lactose may be anhydrous or in the form of a monohydrate, preferably in the form of the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

Suitable solution formulations for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of a compound of the invention per inclusion, and the activation volume may vary from 1 to 100 μl. A typical composition includes a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavors such as menthol and levomenthol or sweeteners such as saccharin or sodium saccharin may be added to such inhalation/nasal compositions of the invention.

Dosage forms for inhalation/nasal administration can be made for immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid) (PGLA). Modified release dosage forms include delayed, sustained, intermittent, controlled, targeted, and programmed release.

In the case of dry powder inhalers and aerosols, the unit dose is determined by a valve that delivers a metered amount. Devices according to the invention are typically equipped to deliver a metered dose or "puff" containing the desired amount of a compound of the invention. The total daily dose may be administered in a single dose or most commonly in divided doses throughout the day.

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 base for suppositories, but various alternatives can be used if needed.

Dosage forms for rectal/vaginal administration can be made for immediate and/or modified release. Modified release dosage forms include delayed, sustained, intermittent, controlled, targeted, and programmed release.

The compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a microparticulate suspension or solution in pH-adjusted isotonic sterile saline. Other dosage forms suitable for ocular and otic administration include ointments, biodegradable (eg, hemostatic collagen sponges) and non-biodegradable (eg, silicone) implants, plates, lenses, and particulate or vesicular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulose polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer such as gelan gum may be included along with a preservative such as benzalkonium chloride. Such dosage forms can also be delivered by iontophoresis.

Ophthalmic/ear dosage forms can be formulated for immediate and/or modified release. Modified release dosage forms include delayed, sustained, intermittent, controlled, targeted, and programmed release.

Other technologies

The compounds of the invention can be combined with soluble macromolecular substances such as cyclodextrin and its suitable derivatives or polymers containing polyethylene glycol in order to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the aforementioned routes of administration.

For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and routes of administration. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, the cyclodextrin can be used as an auxiliary additive, i. as a carrier, diluent or solubilizer. Most often, alpha, beta, and gamma cyclodextrins are used for these purposes, examples of which can be found in PCT Publication Nos WO 91/11172, WO 94/02518 and WO 98/55148, the descriptions of which are incorporated herein by reference in their entirety.

Doses

The amount of active compound administered will depend upon the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the discretion of the attending physician. However, an effective dose will typically be in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 0.01 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this amount could be from about 0.07 to about 7000 mg/day, preferably from about 0.7 to about 2500 mg/day. In some cases, dose levels below the lower end of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any harmful side effect, where such large doses are usually divided into several smaller doses to be administered over a period of time. days.

Set of parts

Since it may be desirable to administer a combination of active compounds, for example for the treatment of a particular disease or condition, it is within the scope of the present invention to include two or more pharmaceutical compositions, at least one of which contains a compound of the invention, which may conveniently be combined in the form of a kit suitable for co-administration. introduction of compositions. Thus, a kit of the invention includes two or more separate pharmaceutical compositions, at least one of which comprises a compound of the invention, and means for storing said compositions separately, such as a container, sectional bottle, or sectional foil pouch. An example of such a kit is the familiar blister pack used to pack tablets, capsules and the like.

The kit of the invention is particularly suitable for administering different dosage forms, eg oral and parenteral, for administering separate compositions at different dosing intervals, or for titration of separate compositions against each other. In order to facilitate patient compliance with the regimen and treatment regimen, the kit usually contains instructions for administration and may be provided with a so-called reminder.

Combination Therapy

As used herein, the term "combination therapy" refers to administering a compound of the invention together with at least one additional pharmaceutical or medical agent (eg, an anticancer agent), either sequentially or simultaneously.

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 present invention in certain tumors can be enhanced by combination with other approved or experimental cancer treatments, e.g., radiation, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are deregulated in tumors, and others. immune enhancing agents such as PD-1 antagonists and the like.

When combination therapy is used, one or more additional anticancer agents may be administered sequentially or simultaneously with a compound of the invention. In one embodiment, an additional anti-cancer agent is administered to a mammal (eg, a human) prior to administration of a compound of the invention. In another embodiment, an additional anti-cancer agent is administered to a mammal after administration of a compound of the invention. In another embodiment, an additional anti-cancer agent is administered to a mammal (eg, a human) simultaneously with the administration of a compound of the invention.

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

Synthesis methods

Compounds of the invention are prepared in accordance with the illustrative procedures described herein and their modifications known to those skilled in the art.

The following abbreviations are used in the examples: “Ac” means acetyl, “AcO” or “OAc” means acetoxy, “ACN” means acetonitrile, “aq” means aqueous, “atm.” means atmosphere(s), “BOC”, “Boc” or “boc” means N- t- butoxycarbonyl, “Bn” means benzyl, “Bu” means butyl, “nBu” means normal butyl, “tBu” means t- butyl , “Cbz” means benzyloxycarbonyl, “DCM” (CH ₂ Cl ₂ ) means methylene chloride/dichloromethane, “de” means diastereomeric excess, “DEA” means diethylamine, “DIPEA” means diisopropylethylamine, “DMA” means N, N- dimethylacetamide, “DMAP” means 4-dimethylaminopyridine, “DMF” means N,N -dimethylformamide, “DMSO” means dimethyl sulfoxide, “ee” means enantiomeric excess, “Et” means ethyl, “EtOAc” means ethyl acetate, “EtOH” means ethanol, “HATU” means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, “HOAc” or “AcOH” means acetic acid, “i- Pr” or “ ⁱ Pr” means isopropyl, “IPA” means isopropyl alcohol, “Me” means methyl, “MeOH” means methanol, “MS” means mass spectrometry, “MTBE” means methyl tert-butyl ether, “Ph” means phenyl, "saturated." 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 retained fraction, “~” means approximately , “rt” means retention time, “h” means hours, “min” means minutes.

Examples

Preparation of synthetic intermediates

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

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

Two parallel reactions, each containing a solution of (±)-3-oxocyclopentanecarboxylic acid (CAS#98-78-2, 900 g, 7.02 mol) in methanol (5 L) at 13° C., 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). The mixture was stirred at 13°C for 25 hours. Each batch was separately quenched sat. aq. NaHCO ₃ (1 L) then the two batches were combined and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (4 L) and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2×1 L). The combined organic layers were washed with sat. aq. NaCl (3×1 L), dried over magnesium sulfate, filtered, and concentrated in vacuo to give (±)-methyl 3,3-dimethoxycyclopentanecarboxylate (1a, 2.5 kg, 13.28 mol, 94%) as light -yellow oil. ¹ H NMR (400 MHz, 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).

A solution of n -butyl lithium (3.44 L of a 2.5 M solution in hexane, 8.6 mol) was added to the reactor containing THF (3 L) at -65°C. Anhydrous acetonitrile (453 ml, 353 g, 8.61 mol) was added dropwise slowly enough to keep the internal temperature below -55°C. The mixture was stirred for an additional 1 hour at -65°C. A solution of (±)-methyl 3,3-dimethoxycyclopentanecarboxylate (1a, 810 g, 4.30 mol) in THF (1 L) was then added dropwise, slowly enough to keep the internal temperature below -50°C. After stirring for an additional hour at -65°C, the reaction was quenched with water (4 l), neutralized with water. HCl (1 M) to pH 7, and was extracted with ethyl acetate (3×3 l). The combined organic layers were washed with sat. aq. NaCl (2×3 L), dried over magnesium sulfate, filtered, and concentrated in vacuo 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.

Solid sodium hydroxide (131.4 g, total 3.29 mol) was added in portions 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, then the mixture was heated to 75°C, internal, for 30 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product as a red oil. This product was combined with crude products from three more identically prepared batches (each started with 540 g 1b; 2.16 kg, total 10.96 mol for 4 batches) and purified by silica gel chromatography (eluting 0-35% ethyl acetate in petroleum ether) to give (±)-1 -tert- butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazole-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).

Benzyl chloroformate (563.6 ml, 676.3 g, 3.96 mol) was added to a chilled (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 hydrogen carbonate (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 in vacuo to give crude (±)-benzyl [1- tert- butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-yl]carbamate (1d, 980 g, 1. 98 mol max) as a red oil, which was used in the next step without further purification.

Solution of crude (±)-benzyl [1- tert- butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol-5-yl]carbamate (1d, 980 g, 1.98 mol max) 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, internal, for 20 hours. After concentration in vacuo to remove most of the acetone, the aqueous residue was extracted with dichloromethane (3×3 L). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to a crude red oil. This crude product was combined with the crude product from two other identical batches (each prepared from 1.98 mol 1c, total 5.94 mol for 3 batches) and purified by silica gel chromatography (eluting with 0-50% ethyl acetate in petroleum ether ) to give (±)-benzyl [1- tert- butyl-3-(3-oxocyclopentyl) -1H- pyrazol-5-yl]carbamate (1e, 1.6 kg) as a yellow solid. This solid was stirred in a mixture of petroleum ether/ethyl acetate 10:1 (1.5 l) at 20°C for 18 hours. The resulting suspension was filtered, the filter cake was washed with petroleum ether (2 x 500 mL) and the solids dried under vacuum to give (±)-benzyl[1- tert- butyl-3-(3-oxocyclopentyl) -1H -pyrazole- 5-yl]carbamate (1e, 1.4 kg, 3.9 mol, 66% combined over three lots). 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).

A solution of (±)-benzyl [1- tert- butyl-3-(3-oxocyclopentyl) -1H- pyrazol-5-yl]carbamate (1e, 320 g, 0.900 mol) in THF (1.5 L) was degassed under vacuum and purged with dry nitrogen (3 cycles), then cooled to -65°C, internal. A solution of lithium triethylborohydride (1.0 M in THF, 1.80 L, 1.80 mol) was added dropwise at a rate at which the internal temperature was maintained below -55°C, then stirring was continued at -65°C for 1. 5 o'clock. The reaction mixture was quenched with sat. aq. NaHCO ₃ (1.5 L) at -40 to -30°C. Hydrogen peroxide (30% aqueous, 700 g) was added dropwise to the mixture while the internal temperature was maintained at -10 to 0°C. The mixture was stirred at 10°C for 1 hour, then was extracted with ethyl acetate (3×2 l). The combined organic layers were washed with sat. aq. Na ₂ SO ₃ (2×1 l) and sat. aq. NaCl (2×1 L). The organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to a crude yellow oil. The crude product from this lot was combined with the crude product from three other identically prepared lots (each starting at 0.900 mol 1e, 3.60 mol total) for purification. Prior to chromatography, the combined mixture showed a cis/trans ratio of ~3.3:1 by NMR. The combined crude product was purified twice by silica gel chromatography eluting with 0-50% ethyl acetate in dichloromethane) to give (±) -trans- benzyl [1- tert- butyl-3-(3-hydroxycyclopentyl) -1H -pyrazol-5-yl ]carbamate (1f, 960 g) as a light yellow solid, which was further purified by trituration as described below.

The previous batch of 1f was from smaller scale reactions starting with a total of 120 g of 1e (0.34 mol). The column product from this lot was combined with the column product from the above lot (which was prepared from 3.60 mol 1e, total 3.94 mol 1e used for all pooled lots), suspended in dichloromethane/methanol 10:1 ( 1.5 l) and stirred at 20°C for 16 hours. The suspension was filtered and the filter cake was washed with petroleum ether (2×500 ml). The solids were dried in vacuo to give pure (±) -trans- benzyl [1- tert- butyl-3-(3-hydroxycyclopentyl)-1H - pyrazol-5-yl]carbamate (1f, 840 g, 2.35 mol , 60% overall for all batches combined) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 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] ⁺ .

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

The product from the peak of the first enantiomer eluted (310 g of solid) was suspended in methanol/petroleum ether (1:10, 1 L) and stirred at 25° C. for 1 hour. The suspension was filtered, the filter pad was washed with petroleum ether (2 x 500 mL) and the solids were 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 (400 MHz, 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=4.4Hz, 1H), 4.19-4.09 (m, 1H), 2.88 (quin, J=8.6Hz, 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 ( c 1.0, MeOH). Chiral purity: >99% ee, retention time 3.371 min. Chiral SFC analysis was performed on a ChiralPak AD-3 150×4.6 mm ID, 3 µm column, heated to 40°C, eluting with CO ₂ mobile phase and a gradient of 0-40% methanol + 0.05% DEA for 5.5 min, then kept at 40% for 3 min; flowing at 2.5 ml/min.

The enantiomer peak product of the second elution (300 g solid) was suspended in methanol/petroleum ether (1:10, 1 L) and stirred at 25° C. for 1 hour. The suspension was filtered, the filter pad was washed with petroleum ether (2 x 500 ml) and the solids were dried under vacuum to give benzyl {1- tert- butyl-3-[(1 R ,3 S )-3-hydroxycyclopentyl]-1 H - pyrazol-5-yl}carbamate (intermediate 2, 255 g, 713 mmol, 36%, 94% ee) as a white solid. ¹ H NMR (400 MHz, 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-3 150×4.6 mm ID, 3 µm column, heated to 40°C, eluting with CO ₂ mobile phase and a gradient of 0-40% methanol + 0.05% DEA for 5.5 min, then kept at 40% for 3 min; flowing at 2.5 ml/min.

A sample of the second eluted enantiomer from the previous batch with [α] _D -3.1 ( c 1.1, MeOH) and 96% ee was crystallized from dichloroethane/pentane. The crystal structure was obtained by X-ray small molecule crystallography, which showed a (1 R ,3 S ) geometry. Thus, the absolute stereochemistry of intermediate 2 was determined (1R,3S) based on its comparable optical rotation and elution order in the analytical method. Intermediate 1, the enantiomer of intermediate 2, was thus assigned the stereochemistry ( 1S , 3R ).

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

A solution of prop-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 methyl 3-chloro-3-oxopropanoate (74.4 g, 545 mmol) was added dropwise over 30 minutes. The resulting solution was stirred at 15°C for 16 hours, then kept at this temperature for 2 days. The resulting suspension was filtered, the filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (eluting with 60% EtOAc/petroleum ether) to give methyl 3-oxo-3-(prop-2-yn-1-ylamino)propanoate (3a, 47 g, 67%, 90% pure by NMR) 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).

Two parallel batches were prepared according to the following procedure: A solution of methyl 3-oxo-3-(prop-2-yn-1-ylamino)propanoate (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 for 16 hours in the dark. 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 (eluting with 40% EtOAc/petroleum ether) to give methyl (5-methyl-1,3-oxazol-2-yl) acetate (3b, 26.5 g, 56.5% for 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).

A solution of methyl (5-methyl-1,3-oxazol-2-yl)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, then the residue was diluted with water (25 ml) and extracted with dichloromethane (2×30 ml). The aqueous layer was concentrated to give the crude product (~26 g) which was further purified by trituration with EtOAc/MeOH (v/v 10/1) to give lithium (5-methyl-1,3-oxazol-2-yl) acetate (intermediate compound 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).

Intermediate 4: Lithium (5-methoxypyrazin-2-yl)acetate.

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 allowed to warm to room temperature and stirred for 37 hours. The suspension was filtered, the flask and filter cake were washed with a small amount of THF and the filtrate was concentrated in vacuo to give 2-bromo-5-methoxypyrazine (4a, 23.80 g, 100%) as a solid. ¹ H NMR (400 MHz, CHLOROFORM- d ) δ=8.20 (d, J=1.2 Hz, 1H), 8.03 (d, J=1.2 Hz, 1H), 3.97 (s , 3H).

A nitrogen-flushed 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 again flushed with nitrogen, then dry dioxane (250 ml) and dimethylmalonate (22 ml, 192 mmol) were injected with a 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 solids remaining in the filter cake were suspended in water (150 ml) and the solution was slowly acidified with 4M HCl (~17 ml). This solution was extracted with ethyl acetate (2×150 ml). The ethyl acetate extracts were combined with the crude oil obtained from the filtrate and the whole was washed with sat. aq. NH ₄ Cl (50 ml), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in heptane) to give dimethyl (5-methoxypyrazin-2-yl)propanedioate (4b, 5.94 g, 67%) as an oil which solidified on 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).

A solution of dimethyl (5-methoxypyrazin-2-yl) propanedioate (4b, 7.30 g, 30.4 mmol) in DMSO (51 ml) and water (3.4 ml) was cooled to 0°C. Was added solid lithium chloride (5.15 g, 122 mmol) and the mixture was heated to 100°C for 17 hours. The dark red solution was partitioned between ethyl acetate (150 ml) and water (300 ml). The aqueous layer was further extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with half-saturated aq. NaCl and sat. aq. NaCl, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel chromatography (eluting with 0-60% ethyl acetate in heptane) to give methyl (5-methoxypyrazin-2-yl)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).

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) stirred at 25°C for 14 hours. Unreacted ester was still present according to LCMS, so more lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added and stirring was continued at 25° C. for 6 hours. The conversion was still not complete, so more lithium hydroxide monohydrate (110 mg, 2.62 mmol; total 1.049 g, 25 mmol) was added and the mixture heated to 30° C. for 2 hours. THF was removed in vacuo and the aqueous residue was lyophilized to dryness to give lithium (5-methoxypyrazin-2-yl)acetate (intermediate 4, 4.272 g, 115% of the theoretical weight 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).

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

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). The mixture was stirred at 0° C. for 45 minutes after addition was complete. The reaction mixture was washed with sat. aq. NH ₄ Cl and the organic layer was dried over sodium sulfate, filtered, and concentrated to give methyl 1-methyl-3-{[(methylsulfonyl)oxy]methyl}-1 H -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).

A solution of methyl 1-methyl-3-{[(methylsulfonyl)oxy]methyl} -1H -pyrazole-5-carboxylate (5a, 22.6 g, 91.0 mmol) in methanol (200 ml) at room temperature was treated with solid sodium methoxide (9.84 g, 182 mmol) in small portions. The reaction mixture was heated to 70°C for 30 minutes. TLC showed partial hydrolysis of the ester, so for re-esterification the cloudy mixture was acidified with 4M HCl in ethyl acetate (40 ml, 160 mmol) and continued heating at 70°C for 5 hours. The mixture was concentrated to dryness leaving a white solid. This solid was extracted with ethyl acetate/petroleum ether (1/3, 3×200 ml). The combined extracts were concentrated to dryness, then the residual solid was 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% pure by NMR) as a light yellow liquid which solidified on standing. Main component 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).

Solution of methyl 3-(methoxymethyl)-1-methyl- 1H -pyrazole-5-carboxylate (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) were stirred at room temperature for 16 hours. THF was removed in vacuo, the residue was dissolved in water (100 ml) and was extracted with dichloromethane (3×30 ml). The organic layers were discarded. The aqueous layer was concentrated and dried in vacuo to give lithium 3-(methoxymethyl)-1-methyl- 1H -pyrazole-5-carboxylate (Intermediate 5, 12.85 g, 92%) as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=6.37 (s, 1H), 4.24 (s, 2H), 4.01 (s, 3H), 3.20 (s, 3H). MS: 171 [M+H] ⁺ .

General methods and illustrative examples

Method A

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

Room temperature solution of benzyl {1- tert- butyl-3-[( 1S , 3R )-3-hydroxycyclopentyl]-1H - pyrazol-5-yl}carbamate (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 at room temperature overnight, the solution was concentrated and purified by silica gel chromatography (eluting with 0-100% ethyl acetate in n-heptane) to give ( 1R , 3S )-3-(5-{[(benzyloxy) carbonyl]amino}-1- tert- butyl- 1H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (1A, 7.30 g, 100%) as a solid foam. ¹ H NMR (400 MHz, 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] ⁺ .

Solution of (1 R ,3 S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (1A, 36 g, 69 mmol) in 2-methyltetrahydrofuran (300 ml) was cooled to 10°C. Diisopropylethylamine (26.7 g, 36 ml, 207 mmol) and propane-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 (4×200 ml) and then sat. aq. NaCl (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 -pyrazole-5 -yl)carbamate (1B, 30 g, 98%), which was used without further purification.

Suspension of room temperature (20-25°C) Pd/C (50% H ₂ O, 8 g) and crude benzyl (1- tert- butyl-3-{(1 S ,3 R )-3-[(propylcarbamoyl) hydroxy]cyclopentyl}-1 H -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), then stirred at room temperature under a hydrogen balloon for 16 hours. The suspension was filtered, the filtrate was concentrated in vacuo and the residue was crystallized from ethyl acetate (50 ml) and petroleum ether (300 ml) to give ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl propylcarbamate (1C, 17.65 g, 84%) as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=7.00 (br.t, 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 with chiral analytical SFC.

Chilled (10°C) mixture of ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H -pyrazol-3-yl)cyclopentyl propyl carbamate (1C, 8.65 g, 28.05 mmol), (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 wt.% solution in EtOAc, 53.5 g, 84.1 mmol) in dichloromethane (250 ml) was stirred for 16 hours. The reaction was quenched with sat. aq. Na ₂ CO ₃ (20 ml) and was extracted with dichloromethane (100 ml). The organic layer was washed with additional sat. aq. Na ₂ CO ₃ (2×200 ml) and sat. aq. NaCl (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. For purification, this lot was combined with two other similarly prepared lots prepared from 1.0 g and 8.0 g 1C (total SM for three lots=17.65 g, 57.23 mmol 1C). Chromatography on silica gel (eluting with 0-60% EtOAc/petroleum ether) gave ( 1R , 3S )-3-(1- tert- butyl-5-{[(2-methoxypyridin-4-yl)acetyl]amino}- 1 H -pyrazol-3-yl)cyclopentyl propyl carbamate (1D, 25 g, 95% yield for pooled lots). MS: 458 [M+H] ⁺ .

A solution of (1 R ,3 S )-3-(1- tert- butyl-5-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-3-yl)cyclopentyl propyl carbamate (1D, 20.5 g, 44.8 mmol) in formic acid (50 ml) was stirred at 75° C. for 20 hours. For purification, this lot was combined with a smaller lot (prepared from 4.50 g, 9.84 mmol 1D, for a total of 25.0 g, 54.6 mmol), concentrated to dryness, and purified by preparative HPLC [Phenomenex Gemini C18 column 250×50 mm x 10 µm; elution with a gradient of water (0.05% ammonium hydroxide v/v) in ACN for 15 minutes; flowing at 110 ml/min]. Pure ( 1R , 3S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate (Example 1, 16.61 g, 76% yield for pooled lots) as a pale yellow solid. 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 (bt, J=7.0 Hz, 3H). MS: 402 [M+H] ⁺ . Optical rotation [α] _D +17.1 ( c 1.06, MeOH). Chiral purity: 96% ee with chiral analytical SFC.

Example 2: (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propan- 2-ylcarbamate.

( 1R , 3S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate solution (1A, 2.00 g , 3.83 mmol), isopropylamine (294 mg, 4.98 mmol), and diisopropylethylamine (3.33 ml, 19.1 mmol) in THF (20 ml) 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 (4×50 ml) and sat. aq. NaCl (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).

Room temperature (10°C) suspension of crude benzyl (1- tert- butyl-3-{(1 S ,3 R )-3-[(propan-2-ylcarbamoyl)oxy]cyclopentyl}-1 H -pyrazol-5- yl)carbamate (2A, 1.8 g, 3.83 mmol) and Pd/C (wet, 200 mg) in ethyl acetate (10 ml) and THF (5 ml) were degassed and purged with hydrogen, then stirred under a hydrogen balloon at 10 °C for 16 hours. 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*10 µm column eluting with 25-45% water (0.05% ammonium hydroxide v/v) in acetonitrile. Lyophilization of product containing fractions gave ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl propan-2-ylcarbamate (2B, 1.0 g , 85%) as a yellow oil. MS: 309 [M+H] ⁺ .

Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 457 g, 0.718 mmol) was added to a cooled (0° C.) solution of (1 R ,3 S )-3-(5-amino-1- tert- butyl -1 H -pyrazol-3-yl)cyclopentyl propan-2-ylcarbamate (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 allowed to stir at room temperature (10° C.) for 16 hours, then partitioned between dichloromethane (20 ml) and sat. aq. Na ₂ CO ₃ (10 ml). The organic layer was washed with sat. aq. NaCl (10 ml), dried over sodium sulfate, filtered, and concentrated to give crude (1 R ,3 S )-3-(1- tert- butyl-5-{[(2-methyl-1,3-thiazol- 5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl propan-2-ylcarbamate (2C, 120 mg, 100% crude) as yellow gum.

Crude ( 1R , 3S )-3-(1- tert- butyl-5-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-3-yl )cyclopentyl propan-2-ylcarbamate (2C, 120 mg, 0.26 mmol) was dissolved in formic acid (5 ml) and stirred at 75° C. for 20 hours. Volatiles were removed under vacuum and the residue was purified by preparative HPLC on a 150*25 mm*5 µm Xtimate C18 column eluting with 12-52% water (0.05% ammonium hydroxide v/v) in acetonitrile. Lyophilization of fractions containing the product gave (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl )cyclopentyl propan-2-ylcarbamate (Example 2, 60.35 mg, 58%) as a white solid. ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (s, 1H), 10.58 (s, 1H), 7.41 (s, 1H), 6.95 (brd, J= 6.3 Hz, 1H), 6.29 (s, 1H), 4.98 (br s, 1H), 3.81 (s, 2H), 3.57 (br d, J=6.5 Hz, 1H), 3.03 (brs, 1H), 2.59 (s, 3H), 2.45 (brs, 1H), 2.07-1.81 (m, 2H), 1 .78-1.44 (m, 3H), 1.03 (brd, J=6.5 Hz, 6H). MS: 392 [M+H] ⁺ . Chiral purity: 99% ee with chiral analytical SFC.

Example 3: (1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ethyl carbamate

Solution of (1 R ,3 S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (1A, 2.5 g , 4.8 mmol) and ethylamine (1.08 g, 23.9 mmol) in THF (20 ml) 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 aq. NaOH until the organic layer became colorless (5×5 ml), then washed with water (5 ml) and sat. aq. 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% pure by LCMS) as a colorless oil. MS: 429 [M+H] ⁺ , 451 [M+Na] ⁺ .

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 under a hydrogen balloon at room temperature (10°C) 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 ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1 H -pyrazol-3-yl)cyclopentyl ethyl carbamate (3B, 1.15 g, 84%) as a light yellow gum which solidifies on standing to a light yellow solid. MS: 295 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM- d ) δ=5.43 (s, 1H), 5.13 (br s, 1H), 4.58 (br s, 1H), 3.50 (br s, 1H). 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 with chiral analytical SFC.

Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 0.485 ml, 0.815 mmol) was added to a room temperature (10° C.) solution of (1 R ,3 S )-3-(5-amino-1- tert- butyl- 1 H -pyrazol-3-yl) cyclopentyl ethyl carbamate (3B, 80.0 mg, 0.272 mmol), 2-(1-methyl-1 H -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). The mixture was stirred for 3 hours, then partitioned between dichloromethane (5 ml) and water (3 ml). The organic layer was washed with sat. aq. Na ₂ CO ₃ (2×3 ml), sat. aq. NH ₄ Cl (2×3 ml), water (2 ml), and sat. aq. NaCl (2 ml) then dried over sodium sulfate, filtered, and concentrated to give crude (1 R ,3 S )-3-(1 -tert- butyl-5-{[(1-methyl- 1H -indazole- 5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl ethyl carbamate (3C, 127 mg, 100% crude) as light yellow gum. MS: 489 [M+Na] ⁺ .

A solution of crude ( 1R , 3S )-3-(1- tert- butyl-5-{[(1-methyl- 1H- indazol-5-yl)acetyl]amino} -1H- pyrazol-3-yl )cyclopentyl ethyl carbamate (3C, 127 mg, 0.272 mmol) in formic acid (6 ml) was heated to 75°C for 18 hours. The reaction mixture was concentrated to dryness then purified by preparative HPLC on a DuraShell 150*25 mm*5 µm column eluting with 24-44% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization of the fractions containing the product, (1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl) cyclopentyl ethyl carbamate (example 3, 52.39 mg, 47%) was obtained as a white solid. MS: 411 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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 (bt, J=5.5Hz, 1H), 6.27(brs, 1H), 4.97(brs, 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 with chiral analytical SFC.

Example 4: (1 R .3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S )-butan-2-ylcarbamate

( 1R , 3S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate solution (1A, 22.0 g , 42.1 mmol), ( S )-(+)- 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 aq. NaOH (4×200 ml) and sat. aq. NaCl (100 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude benzyl {3-[( 1S , 3R )-3-{[( 2S )-butan-2-ylcarbamoyl]oxy}cyclopentyl]-1- tert - butyl-1 H -pyrazol-5-yl}carbamate (4A, 18 g, 94%, ~80% pure by LCMS). MS: 479 [M+Na] ⁺ .

Room temperature (10°C) solution of crude benzyl {3-[(1 S ,3 R )-3-{[(2 S )-butan-2-ylcarbamoyl]oxy}cyclopentyl]-1- tert- butyl- 1H -pyrazol-5-yl}carbamate (4A, 18 g, 39 mmol) in ethyl acetate (200 ml) and THF (100 ml) was degassed and treated with 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, the filtrate was concentrated to dryness. For purification, this batch was combined with a second batch of crude prepared in the same way from 20 g of 4A (total for both batches: 38 g, 83 mmol) and purified by preparative HPLC on a Phenomenex Gemini C18 250*50 mm*10 µm column, eluting 30-50% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate (4B, 20.1 d, 75% for united parties). MS: 323 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=6.86 (brd, 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), 1.01 (d, J=6.5 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H). Optical rotation [α] _D +4.0 ( c 1.3, MeOH). Chiral purity: 98% de with chiral analytical SFC.

Propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 592 mg, 0.93 mmol) was added to a cooled (0° C.) solution of (1 R ,3 S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate (4B, 100 mg, 0.310 mmol), 1-methyl-1H - 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 sat. aq. Na ₂ CO ₃ and sat. aq. NaCl, dried over sodium sulfate, filtered, and concentrated to give crude ( 1R , 3S )-3-(1- tert- butyl-5-{[(1-methyl-1H - 1,2,3-triazole -5-yl)carbonyl]amino} -1H -pyrazol-3-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate (4C, 130 mg, 97%) as yellow gum. MS: 432 [M+H] ⁺ ,454 [M+Na] ⁺ .

A solution of crude ( 1R , 3S )-3-(1- tert- butyl-5-{[(1-methyl-1H- 1,2,3 -triazol-5-yl)carbonyl]amino} -1H -pyrazol-3-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate (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*25 mm*5 µm column eluting with 10-51% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1 H -pyrazole-5- yl)cyclopentyl ( 2S )-butan-2-ylcarbamate (Example 4, 27.67 mg, 24%) was obtained as a pale yellow solid. MS: 376 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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 (brs, 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 (brd, J=6.5 Hz, 3H), 0.80 (brd , J=7.4 Hz, 3H). Chiral purity: >98% de using chiral analytical SFC.

Example 5: (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1 -methylcyclopropyl)carbamate

( 1R , 3S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate solution (1A, 9.50 g , 18.2 mmol), 1-methylcyclopropanamine 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 (2×300 ml), 2M aq. Na ₂ CO ₃ (300 ml), and sat. aq. 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 , 3 R )-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]-1 H -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).

A mixture of benzyl {1- tert- butyl-3-[(1 S ,3 R )-3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl] -1H- pyrazol-5-yl}carbamate (5A, 6 .28 g, 13.8 mmol) and 10% Pd/C (620 mg) in methanol (200 ml) were stirred at room temperature (20° C.) under a hydrogen balloon for 18 hours. The slurry was filtered through a Celite pad to remove the catalyst. The flask and filter pad were washed with more methanol, then the combined filtrates were concentrated to give (1 R ,3 S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl )carbamate (5B, 4.42 g, 100% crude) as a foamy solid. 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).

Solution of ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (5B, 4.00 g, 12.5 mmol ), lithium (5-methyl-1,3-oxazol-2-yl)acetate (intermediate 3, 3.52 g, 24.9 mmol), 1-[bis(dimethylamino)methylene]-1H-1,2 ,3-Triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (HATU, 14.2 g, 37.3 mmol) and triethylamine (5.30 mL 0.38.0 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 (2×200 ml) and sat. aq. NaCl (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 the crude product (5.50 g of solid). This crude material was repurified by silica gel chromatography (eluting with 100% ethyl acetate) to give pure ( 1R , 3S )-3-(1- tert- butyl-5-{[(5-methyl-1,3-oxazole -2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (5C, 4.22 g, 76%) as a solid. 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=1.1 Hz, 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).

(1 R ,3 S )-3-(1- tert- butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-3-yl solution )cyclopentyl (1-methylcyclopropyl)carbamate (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 again with 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 ethyl ether (30 ml) to give ( 1R , 3S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate (Example 5, 1.93 g, 53%) as a solid. 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 =3.4Hz, 1H), 1.93-1.81(m, 1H), 1.68(d, J=8.2Hz, 2H), 1.60-1.46(m, 1H) , 1.22 (s, 3H), 0.58 (br s, 2H), 0.49-0.42 (m, 2H).

Example 6: (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate solution (5B, 150.0 mg, 0.468 mmol), lithium (5-methoxypyrazin-2-yl) 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 sat. aq. NaHCO ₃ (8 ml) and was extracted with dichloromethane (3×8 ml). The combined organic extracts were washed with sat. aq. NaCl (15 ml) was concentrated and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give (1 R ,3 S )-3-(1- tert- butyl-5-{[(5- methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (6A, 100 mg, 45%, 81% pure by LCMS) as a light yellow gum. MS: 471 [M+H] ⁺ .

(1 R ,3 S )-3-(1- tert- Butyl-5-{[(5-methoxypyrazin-2-yl)acetyl]amino} -1H- pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl) carbamate (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 in vacuo and the residue was purified by preparative HPLC on a DuraShell 150*25 mm*5 µm column eluting with 26-46% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate (example 6, 15.55 mg, 18%) was obtained as a white solid. MS: 415 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 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 (brd, 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 with chiral analytical SFC.

Example 7: (1 R .3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate

( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate solution (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 sat. aq. NaHCO ₃ (5 ml) and sat. aq. NaCl (5 ml), dried, filtered, and concentrated to give crude (1 R ,3 S )-3-(1- tert- butyl-5-{[(5-methyl-1,2-oxazole-3- yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (7A, 95 mg, 88%) as gum. MS: 444 [M+H] ⁺ .

Crude ( 1R , 3S )-3-(1- tert- butyl-5-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino} -1H- pyrazol-3-yl )cyclopentyl (1-methylcyclopropyl)carbamate (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, the residue was dissolved in ethyl acetate (30 ml), washed with sat. aq. NaHCO ₃ (10 ml), dried, filtered, and concentrated. The crude product was purified by preparative HPLC on an Agela Durashell C18 150*25 mm 5 µ column eluting with 18-58% water (with 0.05% ammonium hydroxide) in acetonitrile to give (1 R ,3 S )-3-( 3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate (Example 7, 39.71 mg, 50 %) as a beige solid. MS: 388 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.59 (s, 1H), 7.34 (br s, 1H), 6.36-6, 03 (m, 2H), 4.97 (brs, 1H), 3.64 (s, 2H), 3.15-2.87 (m, 1H), 2.46-2.40 (m, 1H), 2.37 (s, 3H), 1.98 (brd, J=9.0 Hz, 1H), 1.90-1.81 (m, 1H), 1.77-1.59 (m, 2H), 1.54 (brd, J=8.0 Hz, 1H), 1.22 (s, 3H), 0.58 (br s, 2H), 0.49-0, 43 (m, 2H). Chiral purity: >99% ee with chiral analytical SFC.

Example 8: (1 R .3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate

Solution of ( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (5B, 5.47 g, 17.1 mmol ) and 3-(methoxymethyl)-1-methyl- 1H -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 showed that the reaction was not complete, the mixture was heated to 50°C for 3 hours, but LCMS still showed 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- 1H -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) and the reaction mixture was stirred at room temperature for 4 hours. The solution was diluted with ethyl acetate (100 ml); washed with water (200 ml), sat. aq. NaHCO ₃ (200 ml) and sat. aq. NaCl (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 ( 1R , 3S )-3-[1- tert- butyl-5-({[3-(methoxymethyl)-1 -methyl-1H - pyrazol-5-yl]carbonyl}amino) -1H -pyrazol-3-yl]cyclopentyl (1-methylcyclopropyl)carbamate (8A, 4.83 g, 60%) as a foamy solid. MS: 473 [M+H] ⁺ . ¹ H NMR (400 MHz, CHLOROFORM-d) δ=7.71 (br s, 1 H), 6.68 (br s, 1 H), 6.23 (br s, 1 H), 5 .12 (br. s, 2 H), 4.47 (s, 2 H), 4.18 (s, 3 H), 3.43 (s, 3 H), 3.03-3.16 (m , 1 H), 2.41 (brs, 1 H), 1.97-2.11 (m, 1 H), 1.87 (m, J=5.9 Hz, 4 H), 1, 63 (s, 9 H), 1.33 (s, 3 H), 0.73 (br s, 2 H), 0.52-0.61 (m, 2 H).

A solution of (1 R ,3 S )-3-[1- tert- butyl-5-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino) -1H - pyrazol-3-yl]cyclopentyl (1-methylcyclopropyl)carbamate (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 sat. aq. NaHCO ₃ (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). This solid was recrystallized from ethyl acetate/heptane to give ( 1R , 3S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino)- 1 H -pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate (Example 8, 2.90 g, 69%) as a crystalline solid. MS: 417 [M+H] ⁺ . ¹ H 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, 1H), 1.72(brs, 2H), 1.59(brs, 1H), 1.24(s, 3H) , 0.60 (br s, 2 H), 0.47 (br s, 2 H)

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

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

Solution of (1 R ,3 S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (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) were stirred at 40-50°C for 15 hours. Solvents were removed in vacuo and the residue partitioned between ethyl acetate (150 ml) and 1N aq. sodium hydroxide (2×50 m). The organic layer was washed with sat. aq. NaCl (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 ,3 R )-3-{[(4,4,4-trifluorobutan-2-yl)carbamoyl]oxy}cyclopentyl]-1 H -pyrazol-5-yl}carbamate (9A, mixture of diastereomers, 2.0 g, 82%, 79% LCMS pure), as a yellow oil. MS: 511 [M+H] ⁺ .

Benzyl {1- tert- butyl-3-[( 1S , 3R )-3-{[(4,4,4-trifluorobutan-2-yl)carbamoyl]oxy}cyclopentyl] -1H- pyrazol-5- yl}carbamate mixture (9A, 2.0 g, 3.9 mmol) was dissolved in ethyl acetate (20 ml) and THF (20 ml) and catalyst 10% Pd/C (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 filtered and concentrated to give crude (1 R ,3 S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl (4,4,4-trifluorobutan- 2-yl)carbamate (9B, mixture of diastereomers, 1.4 g, 95%, 76% pure by LCMS) as a yellow oil. MS: 377 [M+H] ⁺ .

Cooled (0°C) solution of crude (1 R ,3 S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl (4,4,4-trifluorobutan-2- yl)carbamate (9B, 225 mg, 0.598 mmol), 3-(methoxymethyl)-1-methyl- 1H -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% wt. solution in EtOAc, 1.14 g, 1.79 mmol). The mixture was heated to 20°C and stirred for 36 hours, then heated to 40°C for 90 hours. The mixture was partitioned between dichloromethane and half-saturated Na ₂ CO ₃ . The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude ( 1R , 3S )-3-[1- tert- butyl-5-({[3-(methoxymethyl)-1-methyl- 1H -pyrazole -5-yl]carbonyl}amino)-1 H -pyrazol-3-yl]cyclopentyl (4,4,4-trifluorobutan-2-yl)carbamate (9C, mixture of diastereomers, 300 mg, 95%) as yellow gum . MS: 529 [M+H] ⁺ .

A solution of crude ( 1R , 3S )-3-[1- tert- butyl-5-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino) -1H -pyrazol-3-yl]cyclopentyl (4,4,4-trifluorobutan-2-yl)carbamate (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*25 mm*5 µm column eluting with 32% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole-5- yl]cyclopentyl (4,4,4-trifluorobutan-2-yl)carbamate (9D, mixture of diastereomers, 45 mg, 17%) was obtained as a white solid. MS: 473 [M+H] ⁺ .

A mixture of diastereomers 9D was separated by chiral preparative SFC on a Phenomenex-Amylose-1 250 mm*30 mm 5 µm column eluting with 40% ethanol (+0.1%NH ₃ H ₂ O) in CO ₂ 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 4,4,4-trifluorobutan-2-yl]carbamate of each molecule was not determined.

Example 9: (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole-5- yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A. ¹ H NMR (400 MHz, 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 (brd, J=6.1 Hz, 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 (377 MHz, 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 column (150×4.6 mm ID, 3 μm) eluting with 40% ethanol (+0.05% DEA) in CO2 flowing at 2.5 ml/min, at 35°C, with pressure set to 1500 psi. Under these conditions, the retention time of this peak was 3.372 minutes.

Example 10: (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole-5- yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B. ¹ H NMR (400 MHz, DMSO-d6) δ=12.25 (br s, 1H), 10 .74 (s, 1H), 7.24 (brd, 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 (377 MHz, 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 column (150×4.6 mm ID, 3 µm), eluting with 40% ethanol (+0.05% DEA) in CO2, flowing at 2.5 ml/min, at 35°C, with pressure set to 1500 psi. Under these conditions, the retention time of this peak was 4.123 minutes.

Method B

Example eleven: (1 R .3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl tert- butyl carbamate.

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) was dissolved in DMF (200 ml) by sonication. While the solution was at room temperature, tert-butyldimethylsilyl chloride (11.0 g, 72.7 mmol) was added portionwise. After completion of the addition, the clear solution was stirred at 25° C. for 1 hour. The solvents were removed under vacuum and the residue was partitioned between ethyl acetate (500 ml) and sat. aq. NaCl (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]- 1 H -pyrazol-5-yl}carbamate (11A, 26 g, 99%) as a colorless oil. MS: 472 [M+H] ⁺ .

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

To a room temperature solution (25°C) of crude 1- tert- butyl-3-[(1 S ,3 R )-3-{[ tert- butyl(dimethyl)silyl]oxy}cyclopentyl] -1H -pyrazole-5 -amine (11B, 5.00 g, 14.8 mmol), lithium (5-methyl-1,3-oxazol-2-yl) 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 successively with water (150 ml) and sat. aq. NaCl. 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-[( 1S , 3R )-3-{[ tert- butyl(dimethyl)silyl] hydroxy}cyclopentyl]-1 H -pyrazol-5-yl}-2-(5-methyl-1,3-oxazol-2-yl)acetamide (11C, 5.5 g, 81%, 77% pure by LCMS) as a yellow oil. MS: 461 [M+H] ⁺ .

N- {1- tert- butyl-3-[(1 S ,3 R )-3-{[ tert- butyl(dimethyl)silyl]oxy}-cyclopentyl]-1 H -pyrazol-5-yl}-2 solution -(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 light yellow oily residue was dissolved in methanol (20 ml). To this was added a solution of lithium hydroxide monohydrate (2.50 g, 59.7 mmol) in water (10 ml) and the mixture was stirred for 30 minutes at 25°C. The solution was concentrated to dryness. The residue was dissolved in dichloromethane (30 ml), washed with water (10 ml) and sat. aq. NaCl (10 ml), dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting 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) as a light yellow oil. MS: 347 [M+H] ⁺ .

A suspension of 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, 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. Solvents were removed under vacuum. The residue was dissolved in ethyl acetate (200 ml), washed with sat. aq. NH ₄ Cl (100 ml) and sat. aq. NaCl, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give ( 1R , 3S )-3-(1- tert- butyl-5-{[ (5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (11E, 5.0 g, 89%, 89% pure by LCMS) as a yellow oil. MS: 512 [M+H] ⁺ .

(1 R ,3 S )-3-(1- tert- butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-3-yl solution )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, then the residue was dissolved in dichloromethane (30 ml) and washed with sat. aq. NaHCO ₃ (2×15 ml), water (15 ml), and sat. aq. 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}-1 H -pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (11F, 1.7 g, 38%) as a light yellow solid. MS: 456 [M+H] ⁺ .

A solution of (1 R ,3 S )-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) were stirred at 25° C. for 1 hour. The mixture was concentrated to dryness, the residue was dissolved in dichloromethane (80 ml), washed with 1M NaOH (2×20 ml) and sat. aq. NaCl (20 ml), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 3% methanol in dichloromethane to give crude (1 R ,3 S )-3-(3-{[(5-methyl -1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl tert- butylcarbamate (Example 11, 2.3 g, 67%, 73% HPLC purity). (1 R ,3 S )-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 h. of the product from the first batch described above (total 12.08 mmol 11F consumed in both batches) and further purified by preparative HPLC on a Phenomenex Gemimi C18 250×50 mm, 10 µm column, eluting with 3-45% water (+0. 05%NH4OH) in ACN Pure ( 1R , 3S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5- yl)cyclopentyl tert- butylcarbamate (Example 11, 2.23 g, 47% for pooled lots) was obtained as a white solid. ¹ H NMR (400 MHz, 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=1.1Hz, 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 with chiral analytical SFC.

Example 12: (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2, 2-dimethylazetidine-1-carboxylate

Propylphosphonic anhydride (T3P®, 50 wt % solution in EtOAc, 4.41 g, 6.93 mmol) was added to a chilled (0° C.) solution of 1- tert- butyl-3-[(1 S ,3 R )- 3-{[ tert- Butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H -pyrazol-5-amine (11B, 780 mg, 2.31 mmol), 3-methyl-5-isoxazoloacetic 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, then partitioned between dichloromethane and half-saturated Na ₂ CO ₃ . The organic layer was washed with sat. aq. NaCl, dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 10-50% ethyl acetate in petroleum ether) to give N- {1- tert- butyl-3-[( 1S , 3R ) -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) as a colorless oil. MS: 461 [M+H] ⁺ .

N- {1- tert- butyl-3-[(1 S ,3 R )-3-{[ tert- butyl(dimethyl)silyl]oxy}cyclopentyl]-1 H- pyrazol-5-yl}-2- solution (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, then left overnight at room temperature. The mixture was concentrated to dryness, the residue was dissolved in methanol (30 ml) and aqueous NH ₄ OH (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-[( 1S , 3R )-3-hydroxycyclopentyl] -1H -pyrazole- 5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide (12B, 1.0 g) as light yellow oil. MS: 347 [M+H] ⁺ .

N- {1- tert- Butyl-3-[(1 S ,3 R )-3-hydroxycyclopentyl]-1 H -pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5) solution -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 hours. The solvents were removed under vacuum, the residue was dissolved in dichloromethane (30 ml) and the solution was washed successively with sat. aq. NH ₄ Cl (15 ml) and sat. aq. NaCl (15 ml). The organic layer was dried, concentrated, and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give ( 1R , 3S )-3-(1- tert- butyl-5-{[(3-methyl- 1,2-oxazol-5-yl)acetyl]amino} -1H -pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (12C, 1.3 g). MS: 512 [M+H] ⁺ .

A solution of (1 R ,3 S )-3-(1- tert- butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-3-yl )cyclopentyl 4-nitrophenyl carbonate (12C, 1.3 g) in formic acid (20 ml) was heated to 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 sat. aq. NaHCO ₃ (2×15 ml), water (15 ml), and sat. aq. 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-{[(3-methyl-1 ,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate (12D, 850 mg, 81% over 5 steps based on 11B) as a white solid. MS: 456 [M+H] ⁺ .

A solution of (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl 4-nitrophenyl carbonate ( 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) were stirred at 15°C for 1 hour, then concentrated and the residue was purified by preparative HPLC (on a 150*30 mm*10 µm Xbridge column, eluting with 17-57% water (0.05 % ammonium hydroxide v/v) in acetonitrile). After lyophilization, (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl 2, 2-Dimethylazetidine-1-carboxylate (Example 12, 28.21 mg, 53%) was obtained as a white solid. MS: 402 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ=12.13 (brd, 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 (brt, 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 with chiral analytical SFC.

Example 13: (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole-5- yl]cyclopentyl propan-2-ylcarbamate

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

Crude N- {1- tert- butyl-3-[( 1S , 3R )-3-{[ tert- butyl(dimethyl)silyl]oxy}cyclopentyl] -1H- 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 give N- {1- tert- butyl-3-[( 1S , 3R )-3-hydroxycyclopentyl]- 1H -pyrazol-5-yl}-3-(methoxymethyl)-1-methyl- 1H -pyrazole-5-carboxamide (13B, 8.0 g, 78%) as yellow gum. MS: 376 [M+H] ⁺ .

N- {1- tert -Butyl-3-[( 1S , 3R )-3-hydroxycyclopentyl] -1H- pyrazol-5-yl}-3-(methoxymethyl)-1-methyl- 1H -pyrazole solution -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 0-45% ethyl acetate in petroleum ether) to give ( 1R , 3S )-3-[1- tert- butyl-5-({[3-(methoxymethyl )-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-3-yl]cyclopentyl 4-nitrophenyl carbonate (13C, 10.6 g, 92%) as light brown gum. MS: 541 [M+H] ⁺ .

Solution 1 R ,3 S )-3-[1- tert- butyl-5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole -3-yl]cyclopentyl 4-nitrophenyl carbonate (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 sat. aq. _NaHC03 . The organic layer was washed with water (30 ml) and sat. water. NaCl (30 ml), dried over sodium carbonate, filtered, and concentrated to give crude ( 1R , 3S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazole-5 -yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl 4-nitrophenyl carbonate (13D, 8.5 g, 90%, 86% pure by LCMS) as light yellow glass. MS: 485 [M+H] ⁺ .

Room temperature (27°C) solution of crude (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl 4-nitrophenyl carbonate (13D, 1.7 g, 3.5 mmol) and 2-propylamine (1.04 g, 17.5 mmol) in THF (30 mL) was stirred for 6 hours. The solution was concentrated to dryness and the residue was combined with the residue from a second batch prepared from 1.7 g, 3.5 mmol 13D (total 6.27 mmol 13D used for two combined batches) to give 3.2 g of crude product. The product was purified by preparative HPLC on a Phenomenex Gemini C18 250*50mm*10 µm column eluting with 15-45% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole-5- yl]cyclopentyl propan-2-ylcarbamate (Example 13, 2.06 g, 78%) was obtained as a white crystalline solid which was found to be a monohydrate based on elemental analysis (Form 1). MS: 405 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ=12.23 (br s, 1H), 10.73 (br s, 1H), 7.11 (s, 1H), 6.96 (br s, 1H). 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 (qvd, 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 (brd, J=6.8 Hz, 1H), 1.95-1.83 (m, 1H), 1.73 (brd, J=8, 5 Hz, 2H), 1.61 (br s, 1H), 1.03 (br d, J=6.3 Hz, 6H). Optical rotation [α] _D +4.8 ( c 1.0, MeOH). Chiral purity: >99% ee with chiral analytical SFC. Anal. Calculated for C ₁₉ H ₂₈ N ₆ O ₄ -H ₂ O: C, 54.02; H, 7.16; N, 19.89. Found: C, 53.94; H, 7.22; N, 19.81. The white crystalline solid above (500 mg) was recrystallized from 9:1 H ₂ O/CH ₃ CN (2 ml) by heating until dissolved and then allowing the resulting solution to stand at room temperature for 18 hours. For 18 hours larger monohydrate crystals were formed (Form 1). X-ray diffraction on a single crystal of a selected crystal of this material gave the structure shown in FIG. 1.

The crystalline solid obtained above as the monohydrate (form 1) was further characterized by powder x-ray diffraction (PXRD).

Instrumental powder x-ray diffraction:

Powder X-ray diffraction analysis was performed on a Bruker AXS D8 Advance diffractometer with a Cu radiation source. Diffracted radiation was recorded with a LYNXEYE_EX detector with motorized slits. Both primary and secondary are equipped with 2.5-soller slots. The voltage and current of the X-ray tube were set to 40 kV and 40 mA, respectively. Data was collected on a Theta-Theta goniometer by scanning the blocked pair at Cu K-alpha wavelength from 3.0 to 40.0 degrees 2-theta in 0.01 degree steps using a scan rate of 1.0 seconds per step. Samples were obtained by placing in a silicon low background sample. Data were collected and analyzed using Bruker DIFFRAC Plus software. The PXRD data file was not processed prior to the peak search. The peak search algorithm in the EVA software was applied to pre-assign the peaks using a threshold of 1. Adjustments were made manually to ensure validity; the results of the automatic assignments were visually checked and the peak positions were adjusted to the maximum peak. Typically, peaks with a relative intensity of ≥3% were chosen. Peaks that were not resolved or matched with noise were not selected. Typical error associated with USP PXRD peak position is up to +/- 0.2° 2-theta (USP-941).

PXRD diagram of the monohydrate form 1 of example 13 is shown in Fig.2. A list of PXRD peaks and relative intensity data for the compound of Example 13, Monohydrate Form 1 (2-theta°) are shown in Table 1 below:

Table 1 Angle (2-theta °)±0.2 °2θ Relative intensity (%) Angle (2 theta °)±0.2 °2θ Relative intensity
(%) 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%

Example 14: (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazole-5- yl]cyclopentyl (2 S )-butan-2-ylcarbamate

A solution of crude ( 1R , 3S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H- pyrazol-5-yl]carbonyl}amino) -1H- pyrazol-5-yl ]cyclopentyl 4-nitrophenyl carbonate (13D, 5.5 g, 11 mmol), ( S )-(+)- 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*50 mm*10 µm column eluting with 25-45% water (0.05% ammonium hydroxide v/v) in acetonitrile to give (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2-ylcarbamate (Example 14, 3.50 g, 74%) as a light yellow solid. MS: 419 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ=12.23 (br s, 1H), 10.72 (s, 1H), 7.11 (s, 1H), 6.90 (br d, J=8.2Hz, 1H), 6.42(brs, 1H), 5.00(brs, 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 with chiral analytical SFC.

Example 15: (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1 -methylcyclopropyl)carbamate

A solution of (1 R ,3 S )-3-(1- tert- butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-3-yl )cyclopentyl 4-nitrophenyl carbonate (12C, 1.64 g, 3.2 mmol) in DMF (10.7 mL) was treated with 1-methylcyclopropan-1-amine hydrochloride (516 mg, 4.8 mmol) and diisopropylethylamine (1.7 ml, 9.6 mmol). The mixture was stirred under nitrogen for 2 hours at 60° C., then at room temperature overnight. After dilution with ethyl acetate (150 ml), the solution was washed with deionized water (20 ml), 2 M aq. Na ₂ CO ₃ (20 ml), and sat. aq. NaCl (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 ( 1R , 3S )-3-(1- tert- butyl-5-{ [(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-3-yl)cyclopentyl (1-methylcyclopropyl)carbamate (15A, 1.58 g, 82%) as oils.

Solution 1 R ,3 S )-3-(1- tert- butyl-5-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-3-yl) cyclopentyl (1-methylcyclopropyl)carbamate (15A, 1.50 g, 3.4 mmol) in formic acid (10 ml) was heated in an oil bath at 100°C for 1 hour. Most of the formic acid was removed under vacuum. The residue was treated with sat. aq. NaHCO3 (30 ml) 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 (eluting with 0-40% isopropanol in heptane) to give a white solid (960 mg). This 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 an oil bath at 60°C for 1 hour, and allowed to cool to room temperature with stirring for another 3 hours. The solid was collected by filtration and dried (50°C, 10 mmHg) to give ( 1R , 3S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate (example 15 565 mg, 41%) as a white solid. MS: 388 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.61 (s, 1H), 7.34 (br s, 1H), 6.28 (br s, 1H). 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).

Method C

Example 16: (1 R .3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl (2 S )-butan-2-ylcarbamate

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., 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 the unreacted starting alcohol was still present, so additional N,N'-disuccinimidyl carbonate (2.36 g; 10.92 g total, 42.63 mmol) and triethylamine ((2.8 ml; 7. 5 ml, 54 mmol), and continued stirring at room temperature for another 5 hours. The solvents were removed under vacuum, and the residue was diluted with ethyl acetate (150 ml) and deionized water (100 ml). The resulting emulsion was filtered under vacuum to remove a white solid The filtrate layers were separated The filter cake was washed with ethyl acetate (2 x 100 ml) and those that were washed were used to further extract the aqueous layer The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated The residue was purified by silica gel chromatography (eluting with 20-70% ethyl acetate in heptane) to give benzyl {1- tert- butyl-3-[( 1S , 3R )-3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl }oxy)cyclopentyl]-1 H -pyrazol-5-yl}carbamate (16A, 4.5 g, 54%) as a solid. ¹ H NMR (400 MHz, 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] ⁺ .

A solution of benzyl {1- tert- butyl-3-[(1 S ,3 R )-3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1 H -pyrazol- 5-yl}carbamate (16A, 3.5 g, 7.0 mmol) and 10% Pd/C (1.2 g) in ethyl acetate (150 ml) were stirred under hydrogen balloon at room temperature (23°C) for night. The mixture was filtered through a Celite pad, the filter pad was washed 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 directly in the next step. MS: 365 [M+H] ⁺ .

Crude 1-[({[( 1R , 3S )-3-(5-amino-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl]oxy}carbonyl)oxy]pyrrolidine-2,5 -dione (16B, 7.0 mmol max) was dissolved in DMF (20 ml), 1,2-oxazol-5-ylacetic acid (CAS# 4992-21-6, 1.4 g, 11 mmol) and propylphosphonic anhydride were added (T3P®, 11 ml 50 wt% solution in EtOAc, 14 mmol) 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 sat. aq. NaHCO ₃ and extracted with ethyl acetate (3x). The combined organic layers were washed with sat. aq. NaHCO ₃ (2x) and sat. aq. NaCl (1x), dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 30-100% ethyl acetate in heptane to give 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%) as white foam ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ=8.35 (d, J=1.7 Hz, 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] ⁺ .

N- (1- tert- butyl-3-{(1 S ,3 R )-3-[(2,5-dioxopyrrolidin-1-yl)oxy]cyclopentyl}-1 H -pyrazol-5-yl)- solution 2-(1,2-oxazol-5-yl)acetamide (16C, 158 mg, 0.334 mmol), diisopropylethylamine (0.15 mL, 0.91 mmol), and ( S )-(+)- sec- butylamine ( 50 μl, 0.50 mmol) in dichloromethane (3.5 ml) was stirred at 20°C for 3 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed with sat. aq. NaHCO ₃ (2×3 ml), deionized water (3 ml), sat. aq. NH ₄ Cl (3 ml) and sat. aq. NaCl (3 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated to dryness to give crude ( 1R , 3S )-3-{1- tert- butyl-5-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-3-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate (16D, 115.0 mg, 80%) as a yellow gel. ¹ H NMR (400 MHz, DMSO- d ₆ ) 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] ⁺ .

Crude ( 1R , 3S )-3-{1- tert- Butyl-5-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-3-yl}cyclopentyl ( 2S )- Butan-2-ylcarbamate (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 obtained two-phase mixture were separated. The top layer of triethylsilane was discarded. The lower acid layer was concentrated to dryness, dissolved in acetonitrile and again concentrated to dryness. The residue was further dried in vacuo to give the crude product as a brown waxy solid (109.9 mg). Acetonitrile (5 ml) was added and the suspension was stirred at room temperature for 1 hour. The resulting precipitate was collected by vacuum filtration and air dried to give ( 1R , 3S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate (Example 16, 42.1 mg, 42%) as an off-white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) 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] ⁺ .

Method D

Example 17: (1 R .3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl tert- butyl carbamate

( 1R , 3S )-3-(5-{[(benzyloxy)carbonyl]amino}-1- tert- butyl- 1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate solution (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 ( 1R , 3S )-3-(5-{[(benzyloxy)carbonyl]amino} -1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (17A, 3.6 g, 81%, 82% pure by LCMS) as a light yellow solid. MS: 467 [M+H] ⁺ .

( 1R , 3S )-3-(5-{[(benzyloxy)carbonyl]amino} -1H- pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate mixture (17A, 2.2 g, 4.7 mmol) and t- butylamine (1.38 g, 18.9 mmol) in THF (40 ml) was stirred at room temperature (29° C.) for 18 hours. The solvents were removed in vacuo 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 }-1 H -pyrazol-5-yl)carbamate (17B, 1.5 g, 79%) as light yellow glass. MS: 401 [M+H] ⁺ .

Ethyl chloroformate (970 mg, 8.94 mmol) was added in portions 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), then the mixture was stirred at room temperature for 18 hours . The solution was washed with sat. aq. NH ₄ Cl (3×5 ml) and sat. aq. NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated to give crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3-{( 1S , 3R )-3-[( tert- butylcarbamoyl) hydroxy]cyclopentyl}-1 H -pyrazole-1-carboxylate (17C, 2.0 g, >99%) as light yellow gum, which was used without further purification. MS: 473 [M+H] ⁺ .

Crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3-{( 1S , 3R )-3-[( tert- butylcarbamoyl)oxy]cyclopentyl} -1H- pyrazole-1-carboxylate (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 under a hydrogen balloon at room temperature (29° C.) for 1.5 hours. 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-{(1 S ,3 R )-3-[( tert- butylcarbamoyl)oxy]cyclopentyl}-1 H -pyrazole-1-carboxylate (17D, 900 mg, 63%, 56% from 17A) as light yellow gum. MS: 339 [M+H] ⁺ .

A 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) at room temperature (29° C.) was treated propylphosphonic anhydride (T3P®, 50% wt. solution in EtOAc, 1.41 g, 2.22 mmol), then stirred at room temperature for 6 hours. The solution was diluted with dichloromethane (10 ml), then washed with water (5 ml), sat. aq. NaHCO ₃ (2×5 ml), sat. aq. NH ₄ Cl (5 ml) and sat. aq. NaCl (5 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude ethyl 3-{( 1S , 3R )-3-[( tert- butylcarbamoyl)oxy]cyclopentyl}-5-[(1,2-oxazole-3 -ylacetyl)amino]-1 H -pyrazole-1-carboxylate (17E, 331 mg, 100%) as brown gum. MS: 448 [M+H] ⁺ .

This 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) within 1 hour. The mixture was allowed to stand overnight, 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 5 µ column, eluting with 20-50% water (0.05% ammonium hydroxide v/v) in acetonitrile . After lyophilization of fractions containing the product, (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl tert-butyl carbamate (example 17, 74.84 mg, 27%, 99% ee with chiral analytical SFC) was obtained as a white solid. ¹ H NMR (500 MHz, 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] ⁺ .

Method E

Example 18: (1 R .3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclobutyl)carbamate

A solution of benzyl {1- tert- butyl-3-[(1 S ,3 R )-3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1 H -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 in vacuo and the residue was dissolved in dichloromethane (25 ml). The solution was washed with water (2×5 ml), sat. aq. NH ₄ Cl (5 ml) and sat. aq. NaCl (5 ml). The organic layer was dried over sodium sulfate, filtered, 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]-1 H -pyrazol-5-yl}carbamate (18A, 920 mg, 82%) as light yellow gum. MS: 469 [M+H] ⁺ .

Benzyl {1- tert- butyl-3-[( 1S , 3R )-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl] -1H- pyrazol-5-yl}carbamate (18A, 920 mg , 1.96 mmol) was stirred in formic acid (10 ml) at 75°C for 18 hours. The volatiles were removed under vacuum and the residue was partitioned between dichloromethane (20 ml) and sat. aq. _NaHC03 . The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-80% ethyl acetate in petroleum ether) to give benzyl {3-[( 1S , 3R )-3-{[(1 -methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1 H -pyrazol-5-yl}carbamate (18B, 500 mg, 62%) as light yellow gum. MS: 435 [M+Na] ⁺ .

Ethyl chloroformate (197 mg, 1.82 mmol) was added in portions to a solution of the resulting benzyl {3-[(1 S ,3 R )-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl] -1H -pyrazole- 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, then washed with sat. aq. NH ₄ Cl (2×5 ml) and sat. aq. NaCl (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% NMR purity) as light yellow glass. ¹ H NMR (400 MHz, CHLOROFORM-d) δ=9.50 (s, 1H), 7.44-7.32 (m, 5H), 7.33-7.32 (m, 1H), 6, 62(brs, 1H), 5.22(s, 2H), 5.17(brs, 1H), 4.51(q, J=7.0Hz, 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] ⁺ .

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

Crude ethyl 5-amino-3-[( 1S , 3R )-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl] -1H- pyrazole-1-carboxylate (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), sat. aq. NH ₄ Cl (2×3 ml) and sat. water. NaCl (3 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated to give crude ethyl 3-[(1 S ,3 R )-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-5-{[(5-methyl -1,3,4-thiadiazol-2-yl)acetyl]amino}-1 H -pyrazole-1-carboxylate (18E, 140 mg, 100% crude) as light yellow gum. MS: 513 [M+Na] ⁺ .

A mixture of crude ethyl 3-[(1 S ,3 R )-3-{[(1-methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-5-{[(5-methyl-1,3,4-thiadiazol-2-yl )acetyl]amino}-1 H -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) were stirred at room temperature (35°C) for 30 minutes, then left to stand overnight. The suspension was concentrated to ~3 ml, solids were removed by filtration, and the filtrate was purified by preparative HPLC on a DuraShell 150*25 mm*5 µm column, eluting with 27-47% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization of fractions containing the product, (1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1 H -pyrazole-5 -yl)cyclopentyl (1-methylcyclobutyl)carbamate (Example 18, 30.89 mg, 26%, >99% ee with chiral analytical SFC) was obtained as a white solid. ¹ H NMR (500 MHz, DMSO-d6) δ=12.14 (br s, 1H), 10.78 (s, 1H), 7.18 (br s, 1H), 6.30 (br s, 1H). 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(brs, 2H), 1.99(brd, J=8.9Hz, 1H), 1.92-1.83(m, 1H ), 1.82-1.75(m, 2H), 1.74-1.63(m, 4H), 1.57(brs, 1H), 1.34-1.23(m, 3H ). MS: 419 [M+H] ⁺ .

Additional compounds according to the invention were obtained using modifications of the methods given in this document as examples. When chiral starting materials were available, the compounds were prepared and isolated as individual stereoisomers having a known absolute configuration as indicated by the (R) and (S) marks on their structures. When racemic starting materials were used, the compounds were synthesized as a mixture of diastereomers and then separated into individual stereoisomers by an appropriate chiral preparative HPLC or SFC method before characterization and testing. In these cases, known stereocenters are drawn with wedge bonds and labeled with (R) and (S) labels; unknown stereocenters are depicted as planar bonds marked with an asterisk and their explanation is included in Table 2. Where relative but not absolute stereochemistry is known, structures are drawn with wedge-shaped bonds marked with an asterisk, without labels (R) and/or ( S), and an explanation is included in Table 2.

The selected compounds and their respective characterization data are presented in Table 2 below.

table 2 Example No.
(Way) Structure; IUPAC name; stereochemistry, notes LCMS [M+H] ^{+ 1} H NMR (ppm); ¹⁹ F NMR (ppm); Optical rotation; Chiral HPLC/SFC Conditions 19
(A)

(1S,3R)-3-(3-{[(2-метоксипиридин-4-ил)ацетил]амино}-1H-пиразол-5-ил)циклопентил пропилкарбамат
Все стереоцентры известны

(1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propylcarbamate
All stereocenters are known 402.3 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=11.32-10.73 (m, 1H), 9.43 (br s, 1H), 8.03 (d, J=5.3 Hz, 1H), 6.77 (d, J=4.8 Hz, 1H), 6.65 (s, 1H), 6.47 (br s, 1H), 5.17 (br t, J=5 .8 Hz, 1H), 5.09 (br s, 1H), 3.86 (s, 3H), 3.57 (s, 2H), 3.11-2.97 (m, 3H), 2 .45-2.31 (m, 1H), 2.00 (brd, J=4.8 Hz, 1H), 1.91-1.68 (m, 4H), 1.50-1.36 (m, 2H), 0.84 (bt, J=7.3 Hz, 3H) 20
(A)

(1 S ,3 R )-3-{3-[(1,3-thiazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propyl carbamate
All stereocenters are known 378.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (s, 1H), 10.62 (s, 1H), 8.97 (s, 1H), 7.73 (s, 1H), 7 .04 (bt, J=5.3 Hz, 1H), 6.30 (s, 1H), 5.03-4.95 (m, 1H), 3.92 (s, 2H), 3, 11-2.98(m, 1H), 2.91(q, J=6.4Hz, 2H), 2.47-2.40(m, 1H), 2.08-1.95(m, 1H), 1.94-1.82(m, 1H), 1.77-1.53(m, 3H), 1.44-1.31(m, 2H), 0.81(t, J= 7.4Hz, 3H) 21
(A)

(1 S ,3 R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate
All stereocenters are known 402.3 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=9.93 (s, 1H), 8.21-8.12 (m, 1H), 8.09 (d, J=2.3 Hz, 1H) , 7.56 (dd, J=2.5, 8.5 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.62-6.49 (m, 1H), 5.21-5.14 (m, 1H), 4.90-4.82 (m, 1H), 3.93 (s, 3H), 3.62 (s, 2H), 3.20-3, 01 (m, 3H), 2.46 (ddd, J=6.8, 8.7, 14.9 Hz, 1H), 2.15-2.06(m, 1H), 1.98-1, 76 (m, 4H), 1.56-1.42 (m, 2H), 0.93-0.85 (m, 3H) 22
(A)

(1 S ,3 R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate
All stereocenters are known 392.3 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=10.24 (br s, 1H), 8.55 (s, 1H), 7.49 (s, 1H), 6.64-6.50 ( m, 1H), 5.22-5.13 (m, 1H), 4.98-4.87 (m, 1H), 3.88 (s, 2H), 3.21-3.00 (m, 3H), 2.68 (s, 3H), 2.57-2.43 (m, 1H), 2.17-2.04 (m, 1H), 1.99-1.77 (m, 4H) , 1.57-1.41 (m, 2H), 0.90 (t, J=7.4 Hz, 3H) 23
(A)

(1 S ,3 R )-3-(3-{[(2-methyl- 1H -benzimidazol-5-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propylcarbamate
All stereocenters are known 425.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.34-11.82 (m, 2H), 10.46 (br s, 1H), 7.62-7.27 (m, 2H), 7.20-6.92 (m, 2H), 6.41-6.13 (m, 1H), 5.16-4.78 (m, 1H), 3.63 (s, 2H), 3. 11-2.96(m, 1H), 2.90(q, J=6.5Hz, 2H), 2.49-2.36(m, 4H), 2.05-1.81(m, 2H), 1.76-1.50 (m, 3H), 1.44-1.27 (m, 2H), 0.90-0.69 (m, 3H) 24
(A)

(1 S ,3 R )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylcarbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl propylcarbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (br s, 1H), 10.81 (s, 1H), 7.30 (d, J=7.3 Hz, 1H), 7 .14 (t, J=7.7 Hz, 1H), 7.02 (bt, J=5.6 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 6 .78 (d, J=8.0 Hz, 1H), 6.28 (s, 1H), 4.98 (br.s, 1H), 4.78 (dd, J=6.3, 8.8 Hz, 1H), 4.64 (t, J=9.2 Hz, 1H), 4.45 (dd, J=6.4, 9.2 Hz, 1H), 3.12-2.96 (m , 1H), 2.89 (q, J=6.7 Hz, 2H), 2.47-2.37 (m, 1H), 2.06-1.94 (m, 1H), 1.93- 1.79 (m, 1H), 1.77-1.62 (m, 2H), 1.60-1.48 (m, 1H), 1.44-1.27 (m, 2H), 0, 79(t, J=7.4Hz, 3H)
[α] _D ²⁵ -42.0 ( c 0.1, MeOH)
Peak 1 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 40% IPA (0.1% NH3.H2O) in CO ₂ ; Flow rate: 6.5 ml/min Column temperature 40°C 25
(A)

(1 S ,3 R )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylcarbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl propylcarbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 ¹ H NMR (400 MHz, DMSO-d6) ä=12.12 (br s, 1H), 10.80 (s, 1H), 7.30 (d, J=7.5 Hz, 1H), 7 .14 (t, J=7.7 Hz, 1H), 7.03 (bt, J=5.4 Hz, 1H), 6.83 (t, J=7.2 Hz, 1H), 6 .78 (d, J=8.0 Hz, 1H), 6.28 (br.s, 1H), 4.98 (br.s, 1H), 4.78 (dd, J=6.3, 8 .8 Hz, 1H), 4.64 (t, J=9.2 Hz, 1H), 4.45 (dd, J=6.3, 9.3 Hz, 1H), 3.11-2.97 (m, 1H), 2.89 (q, J=6.6 Hz, 2H), 2.48-2.37 (m, 1H), 2.04-1.93 (m, 1H), 1, 92-1.79 (m, 1H), 1.76-1.62 (m, 2H), 1.61-1.51 (m, 1H), 1.44-1.29 (m, 2H), 0.80 (t, J=7.4Hz, 3H)
[α] _D ²⁵ +39.3 ( c 0.1, MeOH)
Peak 2 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 40% IPA (0.1% NH3.H2O) in CO ₂ ; Flow rate: 6.5 ml/min Column temperature 40°C 26
(A)

(1 S ,3 R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate
All stereocenters are known 392.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 6.95 (brd, J= 7.8 Hz, 1H), 6.28 (s, 1H), 4.98 (br s, 1H), 3.81 (s, 2H), 3.65-3.48 (m, 1H), 3.16-2.93 (m, 1H), 2.58 (s, 3H), 2.47-2.37 (m, 1H), 2.05-1.94 (m, 1H), 1, 91-1.78 (m, 1H), 1.77-1.63 (m, 2H), 1.55 (b.t., J=13.7 Hz, 1H), 1.02 (b.d., J=6.3Hz, 6H) 27
(B)

( 1S , 3R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( cis -4-hydroxycyclohexyl)carbamate
All stereocenters are known; the cyclohexyl ring is meso- N, O-cis . 463.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.57 (s, 1H), 7.15-7.08 (m, 1H), 7.02 ( brd, J=6.3 Hz, 2H), 6.97 (brd, J=7.3 Hz, 1H), 6.27 (brd s, 1H), 4.96 (brd , J=1.8 Hz, 1H), 4.31 (br s, 1H), 3.63 (s, 3H), 3.30-3.19 (m, 1H), 3.07-2, 96 (m, 1H), 2.46-2.38 (m, 1H), 1.98 (brd, J=8.5 Hz, 1H), 1.91-1.81 (m, 1H) , 1.74-1.63 (m, 2H), 1.61-1.48 (m, 5H), 1.41 (brd, J=10.3 Hz, 4H) 28
(B)

( 1S , 3R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate
All stereocenters are known; the cyclohexyl ring is meso- N, O-trans . 463.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.56 (s, 1H), 7.16-7.07 (m, 1H), 7.06-6, 98 (m, 2H), 6.92 (brd, J=7.5 Hz, 1H), 6.27 (s, 1H), 5.01-4.91 (m, 1H), 4.53 (d, J=4.3 Hz, 1H), 3.63 (s, 2H), 3.22-3.13 (m, 1H), 3.04-2.95 (m, 1H), 2, 43-2.37 (m, 1H), 2.01-1.93 (m, 1H), 1.86 (ddd, J=2.8, 6.7, 9.9 Hz, 1H), 1, 81-1.61 (m, 7H), 1.59-1.50 (m, 1H), 1.20-1.07 (m, 4H) 29
(C)

(1 S ,3 R )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2R )-butan-2-ylcarbamate
All stereocenters are known 376.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (s, 1H), 10.66 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 6.88 (br.d, J=8.0 Hz, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 4.99 (br.s, 1H), 3.92 (s, 2H), 3.39-3.36(m, 1H), 3.12-2.94(m, 1H), 2.49-2.40(m, 1H), 2.05-1.95( m, 1H), 1.94-1.82 (m, 1H), 1.79-1.50 (m, 3H), 1.46-1.27 (m, 2H), 1.00 (d, J=6.8Hz, 3H), 0.80 (WT, J=7.4Hz, 3H)
[α] _D ²⁵ +3.6( c 0.11, MeOH) thirty
(C)

(1 S ,3 R )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 376.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (s, 1H), 10.66 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 6.88 (brd, J=8.0 Hz, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 4.99 (br.s, 1H), 3.92 (s, 2H), 3.36 (d, J=2.8 Hz, 1H), 3.12-2.98 (m, 1H), 2.49-2.41 (m, 1H), 2.05-1 .95 (m, 1H), 1.94-1.79 (m, 1H), 1.77-1.51 (m, 3H), 1.41-1.29 (m, 2H), 1.00 (d, J=6.5Hz, 3H), 0.79 (t, J=7.4Hz, 3H)
[α] _D ²⁵ -15.0 ( c 0.11, MeOH) 31
(A)

(1 S ,3 R )-3-(3-{[(1-methyl- 1H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 376.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.33 (br s, 1H), 11.15 (br s, 1H), 8.46 (s, 1H), 6.91 (br s, 1H). d, J=8.3 Hz, 1H), 6.44 (s, 1H), 5.00 (br s, 1H), 4.24 (s, 3H), 3.43-3.37 (m , 1H), 3.13-3.01 (m, 1H), 2.49-2.40 (m, 1H), 2.08-1.98 (m, 1H), 1.96-1.83 (m, 1H), 1.79-1.68 (m, 2H), 1.67-1.56 (m, 1H), 1.40-1.28 (m, 2H), 1.00 (d , J=6.5Hz, 3H), 0.81 (t, J=7.3Hz, 3H) 32
(A)

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate
All stereocenters are known 390.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (s, 1H), 10.64 (s, 1H), 6.89 (brd, J=8.3 Hz, 1H), 6 .30 (brs, 1H), 6.22 (s, 1H), 4.99 (brs, 1H), 3.83 (s, 2H), 3.35-3.30 (m, 1H ), 3.10-2.99 (m, 1H), 2.48-2.40 (m, 1H), 2.20 (s, 3H), 2.06-1.82 (m, 2H), 1.77-1.51 (m, 3H), 1.41-1.27 (m, 2H), 1.00 (d, J=6.5 Hz, 3H), 0.80 (t, J= 7.4Hz, 3H) 33
(A)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate
All stereocenters are known 406.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (s, 1H), 10.56 (s, 1H), 7.41 (s, 1H), 6.86 (brd, J= 8.0Hz, 1H), 6.29(brs, 1H), 4.99(brs, 1H), 3.82(s, 2H), 3.34(brs, 1H), 3.12-2.97 (m, 1H), 2.59 (s, 3H), 2.48-2.39 (m, 1H), 2.05-1.95 (m, 1H), 1, 94-1.82 (m, 1H), 1.77-1.65 (m, 2H), 1.63-1.52 (m, 1H), 1.43-1.27 (m, 2H), 1.00 (d, J=6.5Hz, 3H), 0.80 (t, J=7.4Hz, 3H) 34
(A)

(1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 401.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.60 (s, 1H), 8.47 (d, J=13.6 Hz, 2H), 6 .88 (brd, J=8.3 Hz, 1H), 6.28 (s, 1H), 4.99 (br.s, 1H), 3.83 (s, 2H), 3.42- 3.37 (m, 1H), 3.11-2.97 (m, 1H), 2.47 (s, 3H), 2.45 (brd, J=6.0 Hz, 1H), 2 .07-1.80 (m, 2H), 1.78-1.49 (m, 3H), 1.40-1.26 (m, 2H), 0.99 (d, J=6.5 Hz , 3H), 0.78 (t, J=7.3 Hz, 3H) 35
(A)

(1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 400.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (s, 1H), 10.54 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.58 (dd, J=2.3, 8.0Hz, 1H), 7.18 (d, J=8.0Hz, 1H), 6.86 (br.d, J=8.0Hz, 1H), 6.27 (s, 1H), 4.97 (br s, 1H), 3.56 (s, 2H), 3.34-3.31 (m, 1H), 3.10-2.93 ( m, 1H), 2.47-2.39 (m, 4H), 2.03-1.93 (m, 1H), 1.91-1.80 (m, 1H), 1.75-1, 61 (m, 2H), 1.60-1.50 (m, 1H), 1.32 (td, J=7.1, 11.1 Hz, 2H), 0.99 (d, J=6, 5Hz, 3H), 0.78(t, J=7.4Hz, 3H) 36
(A)

(1 R ,3 S )-3-{3-[(1,3-thiazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 392.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.63 (s, 1H), 8.97 (s, 1H), 7.73 (s, 1H) , 6.88 (brd, J=8.3 Hz, 1H), 6.30 (br.s, 1H), 4.99 (br.s, 1H), 4.05-3.79 (m , 2H), 3.36-3.31 (m, 1H), 3.12-2.98 (m, 1H), 2.49-2.41 (m, 1H), 2.07-1.81 (m, 2H), 1.77-1.52 (m, 3H), 1.42-1.26 (m, 2H), 1.00 (d, J=6.5 Hz, 3H), 0, 79 (t, J=7.4Hz, 3H) 37
(A)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 416.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.58 (s, 1H), 8.08 (d, J=5.3 Hz, 1H), 6.98 -6.81(m, 2H), 6.74(s, 1H), 6.28(brs, 1H), 4.98(brs, 1H), 3.83(s, 3H), 3.59 (s, 2H), 3.35 (br s, 1H), 3.10-2.96 (m, 1H), 2.49-2.40 (m, 1H), 2.04- 1.81 (m, 2H), 1.78-1.52 (m, 3H), 1.42-1.25 (m, 2H), 1.00 (d, J=6.5 Hz, 3H) , 0.79 (t, J=7.4 Hz, 3H) 38
(A)

(1 R ,3 S )-3-{3-[(phenylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 385.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (s, 1H), 10.51 (br s, 1H), 7.34-7.27 (m, 4H), 7.27- 7.20(m, 1H), 6.87(brd, J=8.3Hz, 1H), 6.29(brs, 1H), 4.98(brs, 1H), 3 .58 (s, 2H), 3.36-3.30 (m, 1H), 3.09-2.96 (m, 1H), 2.45 (td, J=7.2, 14.0 Hz , 1H), 2.05-1.80 (m, 2H), 1.77-1.50 (m, 3H), 1.40-1.26 (m, 2H), 1.00 (d, J =6.5Hz, 3H), 0.79 (t, J=7.4Hz, 3H) 39
(A)

(1 R ,3 S )-3-{3-[([1,2,4]triazolo[1,5- a ]pyrimidin-6-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2 S )-butan-2-ylcarbamate
All stereocenters are known 427.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.66 (s, 1H), 9.33 (d, J=2.0 Hz, 1H), 8 .84 (d, J=2.3 Hz, 1H), 8.71-8.56 (m, 1H), 6.94-6.72 (m, 1H), 6.28 (br s, 1H ), 4.98 (br. s, 1H), 3.86 (s, 2H), 3.42 (br. d, J=4.8 Hz, 1H), 3.15-2.91 (m, 1H), 2.48-2.39 (m, 1H), 2.07-1.80 (m, 2H), 1.78-1.50 (m, 3H), 1.45-1.22 ( m, 2H), 1.06-0.89 (m, 3H), 0.85-0.68 (m, 3H) 40
(A)

(1 R ,3 S )-3-[3-({[2-(ethylsulfonyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 477.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.59 (s, 1H), 8.04-7.85 (m, 1H), 7.70 ( dt, J=1.1, 7.5 Hz, 1H), 7.59-7.48 (m, 2H), 6.87 (brd, J=8.3 Hz, 1H), 6.26 (br.s, 1H), 4.98 (br.s, 1H), 4.17 (s, 2H), 3.37-3.29 (m, 3H), 3.10-2.96 (m , 1H), 2.49-2.39 (m, 1H), 2.07-1.79 (m, 2H), 1.77-1.48 (m, 3H), 1.42-1.24 (m, 2H), 1.12 (t, J=7.4 Hz, 3H), 0.99 (bd, J=6.5 Hz, 3H), 0.78 (t, J=7, 4Hz, 3H) 41(A)

(1 R ,3 S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl (2 S )-butan-2-ylcarbamate
All stereocenters are known 405.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.24 (s, 1H), 10.66 (s, 1H), 6.89 (brd, J=8.3 Hz, 1H), 6 .59 (s, 1H), 6.42 (br. s, 1H), 5.00 (br. d, J=4.1 Hz, 1H), 3.94 (s, 3H), 3.78 ( s, 3H), 3.43-3.36 (m, 1H), 3.13-3.02 (m, 1H), 2.56-2.52 (m, 1H), 2.09-1, 99 (m, 1H), 1.97-1.86 (m, 1H), 1.80-1.69 (m, 2H), 1.67-1.57 (m, 1H), 1.43- 1.31(m, 2H), 1.01(d, J=6.6Hz, 3H), 0.81(t, J=7.4Hz, 3H) 42
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate
All stereocenters are known 375.3 ¹ H NMR (400 MHz, DMSO-d6) δ=11.39 (s, 1H), 9.88 (s, 1H), 6.64 (d, J=1.9 Hz, 1H), 6.31 (s, 1H), 6.05 (brd, J=8.3 Hz, 1H), 5.59 (br.s, 1H), 4.16 (br.s, 1H), 3.24 ( s, 3H), 2.61-2.54 (m, 1H), 2.32-2.18 (m, 1H), 1.72-1.68 (m, 1H), 1.27-1, 14 (m, 1H), 1.12-1.00 (m, 1H), 0.97-0.84 (m, 2H), 0.82-0.72 (m, 1H), 0.58- 0.44(m, 2H), 0.16(d, J=6.6Hz, 3H), -0.04(t, J=7.4Hz, 3H) 43(A)

(1 R ,3 S )-3-{3-[([1,3]thiazolo[4,5- b ]pyridin-7-ylcarbonyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 429.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.40 (s, 1H), 11.49 (br s, 1H), 9.81 (s, 1H), 8.93 (d, J= 5.0 Hz, 1H), 8.37 (d, J=5.0 Hz, 1H), 6.92 (brd, J=8.3 Hz, 1H), 6.56 (br s, 1H), 5.03 (brs, 1H), 3.34-3.31 (m, 1H), 3.20-3.08 (m, 1H), 2.48 (brs, 1H) , 2.12-2.03 (m, 1H), 1.97-1.85 (m, 1H), 1.77 (brd, J=9.8 Hz, 2H), 1.66 (br .t, J=14.1 Hz, 1H), 1.44-1.30 (m, 2H), 1.02 (d, J=6.8 Hz, 3H), 0.81 (t, J= 7.4Hz, 3H) 44
(A)

(1 R ,3 S )-3-[3-({[4-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butane-2 -ylcarbamate
All stereocenters are known 493.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (br s, 1H), 10.53 (br s, 1H), 7.45-7.38 (m, 2H), 7, 25 (dd, J=2.6, 8.4 Hz, 1H), 6.86 (brd, J=8.0 Hz, 1H), 6.25 (br s, 1H), 4.97 (br s, 1H), 4.08 (s, 2H), 3.83 (s, 3H), 3.37 (br s, 1H), 3.28 (s, 3H), 3.08- 2.95 (m, 1H), 2.45-2.37 (m, 1H), 2.03-1.93 (m, 1H), 1.91-1.80 (m, 1H), 1, 76-1.62 (m, 2H), 1.59-1.48 (m, 1H), 1.38-1.26 (m, 2H), 0.98 (brd, J=6.5 Hz, 3H), 0.77 (WT, J=7.3 Hz, 3H) 45
(A)

(1 R ,3 S )-3-[3-({[4-methyl-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butane-2 -ylcarbamate
All stereocenters are known 477.1 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (s, 1H), 10.56 (s, 1H), 7.77 (s, 1H), 7.49 (d, J=6, 5 Hz, 1H), 7.38 (d, J=7.8 Hz, 1H), 6.88 (brd, J=8.5 Hz, 1H), 6.26(s, 1H), 4 .98 (br s, 1H), 4.13 (s, 2H), 3.31-3.23 (m, 4H), 3.11-2.96 (m, 1H), 2.48-2 .44 (m, 1H), 2.39 (s, 3H), 1.99 (brd, J=8.3 Hz, 1H), 1.93-1.83 (m, 1H), 1, 76-1.63 (m, 2H), 1.62-1.50 (m, 1H), 1.33 (br.dd, J=6.9, 11.2 Hz, 2H), 0.99 ( d, J=6.5Hz, 3H), 0.78 (t, J=7.3Hz, 3H) 46
(A)

(1 R ,3 S )-3-(3-{[(3-methylimidazo[1,2- b ]pyridazin-6-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (2 S )-butan-2-ylcarbamate
All stereocenters are known 440.4 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=10.72 (br s, 1H), 10.11 (br s, 1H), 7.84 (d, J=9.3 Hz, 1H) , 7.56 (d, J=0.7 Hz, 1H), 7.07 (d, J=9.3 Hz, 1H), 6.62 (br. s, 1H), 5.17 (br. s, 1H), 4.66 (brd, J=7.9 Hz, 1H), 3.91 (s, 2H), 3.65-3.53 (m, 1H), 3.19 (quin , J=8.2 Hz, 1H), 2.56-2.43 (m, 4H), 2.18-2.06 (m, 1H), 1.98-1.84 (m, 4H), 1.47-1.34 (m, 2H), 1.15-1.01 (m, 3H), 0.85 (t, J=7.4 Hz, 3H) 47
(A)

(1 R ,3 S )-3-(3-{[(2-methylimidazo[1,2- b ]pyridazin-6-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (2 S )-butan-2-ylcarbamate
All stereocenters are known 440.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.69 (s, 1H), 7.99 (s, 1H), 7.93 (d, J= 9.3 Hz, 1H), 7.15 (d, J=9.3 Hz, 1H), 6.87 (brd, J=8.3 Hz, 1H), 6.29 (br s, 1H), 4.98 (brs, 1H), 3.87 (s, 2H), 3.38 (brs, 1H), 3.10-2.97 (m, 1H), 2.48 -2.40(m, 1H), 2.38(s, 3H), 2.06-1.80(m, 2H), 1.78-1.49(m, 3H), 1.42-1 .24 (m, 2H), 0.99 (brd, J=6.5Hz, 3H), 0.78 (brd, J=7.3Hz, 3H) 48
(A)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate
All stereocenters are known 439.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.05 (br s, 1H), 10.51 (br s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7.56 (brd, J=8.5 Hz, 1H), 7.35 (brd, J=8.5 Hz, 1H), 6.86 (brd, J=8 .0 Hz, 1H), 6.28 (br.s, 1H), 4.97 (br.s, 1H), 4.01 (s, 3H), 3.67 (s, 2H), 3.30 (brs, 1H), 3.11-2.92 (m, 1H), 2.46-2.37 (m, 1H), 2.04-1.91 (m, 1H), 1.85 (brd, J=5.8 Hz, 1H), 1.76-1.61 (m, 2H), 1.54 (br.s, 1H), 1.43-1.15 (m, 2H ), 0.98 (brd, J=6.5 Hz, 3H), 0.77 (brd, J=7.2 Hz, 3H) 49
(A)

(1 R ,3 S )-3-(3-{[(2-sulfamoylphenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate
All stereocenters are known 463.8 ¹ H NMR (400 MHz, DMSO-d6) δ=12.25-11.99 (m, 1H), 10.67-10.42 (m, 1H), 7.91 (brd, J=6 .6 Hz, 1H), 7.56 (brd, J=6.0 Hz, 1H), 7.46 (br s, 4H), 6.88 (br d, J=6.1 Hz , 1H), 6.28 (br.s, 1H), 4.98 (br.s, 1H), 4.12 (br.s, 2H), 3.47-3.42 (m, 1H), 3.03 (brs, 1H), 2.46-2.39 (m, 1H), 1.98 (brs, 1H), 1.87 (brs, 1H), 1.69 ( brs, 2H), 1.56 (brs, 1H), 1.34 (brs, 2H), 0.99 (brs, 3H), 0.79 (brs, 3H) 50
(A)

(1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2 -ylcarbamate
All stereocenters are known 492.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (s, 1H), 10.56 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.17 -6.99(m, 2H), 6.87(brd, J=7.8Hz, 1H), 6.27(s, 1H), 4.97(brs, 1H), 4, 13 (s, 2H), 3.84 (s, 3H), 3.39 (br s, 1H), 3.22 (s, 2H), 3.27-3.15 (m, 1H), 3 .08-2.99 (m, 1H), 2.44 (brd, J=6.5 Hz, 1H), 2.08-1.79 (m, 2H), 1.78-1.47 (m, 3H), 1.42-1.24 (m, 2H), 0.99 (brd, J=6.5 Hz, 3H), 0.82-0.73 (m, 1H), 0.78 (WT, J=7.4Hz, 2H) 51
(A)

(1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2-ylcarbamate
All stereocenters are known 419.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.24 (br s, 1H), 10.74 (br s, 1H), 7.52 (s, 1H), 7.12 (br s, 1H). s, 1H), 6.90 (brd, J=8.0 Hz, 1H), 6.42 (br.s, 1H), 5.00 (br.s, 1H), 4.69 (br.s, 1H) .t, J=5.6 Hz, 2H), 3.66 (br. t, J=5.6 Hz, 2H), 3.46 (br. s, 1H), 3.18 (s, 3H) , 3.12-3.00 (m, 1H), 2.46-2.36 (m, 1H), 2.03 (brd, J=7.0 Hz, 1H), 1.94-1 .82 (m, 1H), 1.79-1.68 (m, 2H), 1.65-1.55 (m, 1H), 1.44-1.22 (m, 2H), 1.00 (bd, J=6.5 Hz, 3H), 0.80 (t, J=7.3 Hz, 3H) 52
(A)

(1 R ,3 S )-3-[3-({[2-hydroxy-5-(methylsulfonyl)pyridin-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S ) -butan-2-ylcarbamate
All stereocenters are known 479.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.52-11.80 (m, 2H), 10.60 (s, 1H), 7.94 (s, 1H), 6.89 (br. d, J=8.3 Hz, 1H), 6.37 (s, 1H), 6.27 (br.s, 1H), 4.98 (br.s, 1H), 3.89 (s, 2H ), 3.39 (br s, 1H), 3.25 (s, 3H), 3.09-2.98 (m, 1H), 2.49-2.41 (m, 1H), 2, 09-1.95 (m, 1H), 1.87 (brd, J=8.3 Hz, 1H), 1.78-1.64 (m, 2H), 1.63-1.50 ( m, 1H), 1.34 (br.dd, J=6.9, 11.4 Hz, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.79 (t, J =7.4Hz, 3H) 53
(A)

(1 R ,3 S )-3-[3-({[1-(2-hydroxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2-ylcarbamate
All stereocenters are known 405.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.25 (s, 1H), 10.76 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 7.11 (d, J=1.8 Hz, 1H), 6.92 (brd, J=8.0 Hz, 1H), 6.44 (s, 1H), 5.01 (br s, 1H) , 4.87 (t, J=5.5 Hz, 1H), 4.58 (t, J=6.3 Hz, 2H), 3.70 (kv, J=5.9 Hz, 2H), 3 .44-3.37 (m, 1H), 3.13-3.02 (m, 1H), 2.50-2.44 (m, 1H), 2.07-1.99 (m, 1H) , 1.96-1.85 (m, 1H), 1.80-1.70 (m, 2H), 1.67-1.56 (m, 1H), 1.41-1.30 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H) 54
(A)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -indazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propyl carbamate
All stereocenters are known 425.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.05 (br s, 1H), 10.51 (br s, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.03 (br s, 1H), 6.27 ( brs, 1H), 4.97 (brs, 1H), 4.01 (s, 3H), 3.66 (s, 2H), 3.09-2.95 (m, 1H), 2 .88 (q, J=6.6 Hz, 2H), 2.44-2.35 (m, 1H), 1.97 (brd, J=8.0 Hz, 1H), 1.91- 1.78(m, 1H), 1.74-1.61(m, 2H), 1.54(brs, 1H), 1.42-1.29(m, 2H), 0.79( t, J=7.4Hz, 3H) 55
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -indazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate
All stereocenters are known 425.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (br s, 1H), 10.53 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H) , 7.56 (d, J=8.5 Hz, 1H), 7.37 (dd, J=1.4, 8.7 Hz, 1H), 6.93 (brd, J=7.8 Hz, 1H), 6.28 (s, 1H), 4.98 (br s, 1H), 4.06-3.99 (m, 3H), 3.68 (s, 2H), 3.61 -3.54 (m, 1H), 3.09-2.97 (m, 1H), 2.44 (td, J=7.2, 13.9 Hz, 1H), 2.05-1.93 (m, 1H), 1.91-1.81 (m, 1H), 1.75-1.63 (m, 2H), 1.61-1.50 (m, 1H), 1.08-0 .96 (m, 6H) 56
(A)

(1 R ,3 S )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylcarbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propan-2- ylcarbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (br s, 1H), 10.81 (s, 1H), 7.30 (d, J=7.5 Hz, 1H), 7 .14 (t, J=7.5 Hz, 1H), 6.93 (brd, J=7.5 Hz, 1H), 6.87-6.74 (m, 2H), 6.29 ( brs, 1H), 4.98 (brs, 1H), 4.79 (dd, J=6.1, 8.7 Hz, 1H), 4.65 (t, J=9.2 Hz , 1H), 4.46 (dd, J=6.1, 9.4 Hz, 1H), 3.56 (br.dd, J=6.8, 13.3 Hz, 1H), 3.04 ( latitude, J=7.5 Hz, 1H), 2.48-2.38 (m, 1H), 2.07-1.79 (m, 2H), 1.77-1.49 (m, 3H), 1.02 (broad, J=5.8 Hz, 6H)
[α] _D ²⁵ -50 ( c 0.12, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5 ml/min; Column temperature 35°C 57
(A)

(1 R ,3 S )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylcarbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propan-2- ilcarbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (br s, 1H), 10.81 (s, 1H), 7.30 (d, J=7.3 Hz, 1H), 7 .14 (t, J=7.8 Hz, 1H), 6.93 (brd, J=8.3 Hz, 1H), 6.87-6.74 (m, 2H), 6.29 ( brs, 1H), 4.98 (brs, 1H), 4.79 (dd, J=6.0, 8.8 Hz, 1H), 4.65 (t, J=9.0 Hz , 1H), 4.46 (dd, J=6.4, 9.4 Hz, 1H), 3.65-3.47 (m, 1H), 3.04 (brd, J=8.0 Hz , 1H), 2.44 (brd, J=7.0 Hz, 1H), 2.08-1.80 (m, 2H), 1.79-1.47 (m, 3H), 1, 11-0.88 (m, 6H)
[α] _D ²⁵ +47 ( c 0.4, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5 ml/min; Column temperature 35°C 58
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methyl(propan-2-yl)carbamate
All stereocenters are known 416.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.56 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6 .91 (dd, J=1.3, 5.3 Hz, 1H), 6.74 (s, 1H), 6.29 (br.s, 1H), 5.01 (br.s, 1H), 4.37-4.01 (m, 1H), 3.89-3.79 (m, 3H), 3.58 (s, 2H), 3.16-2.98 (m, 1H), 2, 61 (brs, 3H), 2.46-2.26 (m, 1H), 2.05-1.94 (m, 1H), 1.93-1.81 (m, 1H), 1, 79-1.60 (m, 3H), 0.99 (bd, J=6.5 Hz, 6H) 59
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methyl(propan-2-yl)carbamate
All stereocenters are known 416.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (br s, 1H), 10.52 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 7 .63 (dd, J=2.5, 8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.28 (br.s, 1H), 5.01 ( brs, 1H), 4.31-4.00 (m, 1H), 3.85-3.77 (m, 3H), 3.53 (s, 2H), 3.08 (quin, J= 7.9 Hz, 1H), 2.61 (brs, 3H), 2.44-2.33 (m, 1H), 2.05-1.96 (m, 1H), 1.93-1 .81 (m, 1H), 1.79-1.61 (m, 3H), 0.99 (brd, J=6.6 Hz, 6H) 60
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate
All stereocenters are known 375.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.04 (br s, 1H), 10.35 (br s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.95 (brd, J=7.6 Hz, 1H), 6.29 (br s, 1H), 4.98 (br s, 1H), 3.78 (s, 3H ), 3.57 (br.dd, J=6.7, 13.4 Hz, 1H), 3.39 (s, 2H), 3.11-2.97 (m, 1H), 2.48- 2.38 (m, 1H), 2.09-1.79 (m, 2H), 1.78-1.50 (m, 3H), 1.02 (brd, J=6.5 Hz, 6H) 61
(B)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2-methylbutan-2 -yl)carbamate
All stereocenters are known [M+Na]+ 424.8 ¹ H NMR (400 MHz, DMSO-d6) δ=12.03 (br s, 1H), 10.34 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H) , 6.62 (br.s, 1H), 6.27 (br.s, 1H), 4.95 (br.s, 1H), 3.77 (s, 3H), 3.38 (br.s , 2H), 3.10-2.91 (m, 1H), 2.47-2.37 (m, 1H), 2.04-1.93 (m, 1H), 1.91-1.78 (m, 1H), 1.76-1.62 (m, 2H), 1.56 (brd, J=7.5 Hz, 3H), 1.13 (s, 6H), 0.74 ( t, J=7.4Hz, 3H) 62
(B)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2-methylbutan- 2-yl)carbamate
All stereocenters are known 404.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.62 (s, 1H), 6.74 (d, J=1.1 Hz, 1H), 6 .62 (br s, 1H), 6.28 (s, 1H), 4.95 (br s, 1H), 3.79 (s, 2H), 3.03 (quin, J=8.6 Hz, 1H), 2.47-2.40 (m, 1H), 2.25 (d, J=0.9 Hz, 3H), 2.04-1.94 (m, 1H), 1.92 -1.82(m, 1H), 1.74-1.64(m, 2H), 1.56(q, J=7.2Hz, 3H), 1.13(s, 6H), 0, 73 (t, J=7.5Hz, 3H) 63
(A)

( 1R , 3S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [(2ξ)-4,4,4-trifluorobutane -2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 430.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (s, 1H), 10.65 (br s, 1H), 8.83 (s, 1H), 7.19 (br d, J=8.3Hz, 1H), 6.53(s, 1H), 6.29(brs, 1H), 4.99(brd, J=2.5Hz, 1H), 3, 89-3.78 (m, 1H), 3.75 (s, 2H), 3.09-2.97 (m, 1H), 2.45-2.29 (m, 3H), 2.04- 1.95 (m, 1H), 1.92-1.84 (m, 1H), 1.77-1.63 (m, 2H), 1.61-1.52 (m, 1H), 1. 10 (wd, J=6.5Hz, 3H)
[α] _D ²⁰ -2.85 ( c 0.117, MeOH)
Peak 1 of 2: Column: Xtimate C18 150*25mm*5µm; Mobile phase: 22-52% CH3CN in water (0.05% v/v ammonium hydroxide); Flow Rate: 25ml/min 64
(A)

( 1R , 3S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [(2ξ)-4,4,4-trifluorobutane -2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 430.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (s, 1H), 10.63 (s, 1H), 8.83 (d, J=1.0 Hz, 1H), 7.20 (bd, J=8.0 Hz, 1H), 6.53 (s, 1H), 6.29 (s, 1H), 5.04-4.95 (m, 1H), 3.84- 3.77 (m, 1H), 3.75 (s, 2H), 3.07-2.98 (m, 1H), 2.46-2.32 (m, 3H), 2.04-1, 95 (m, 1H), 1.94-1.84 (m, 1H), 1.77-1.64 (m, 2H), 1.61-1.50 (m, 1H), 1.11 ( br.d, J=6.8 Hz, 3H)
[α] _D ²⁵ +8.12 ( c 0.197, MeOH)
Peak 2 of 2: Column: Xtimate C18 150*25 mm*5 µm; Mobile phase: from 22-52% CH3CN in water (0.05% ammonium hydroxide v/v); Flow Rate: 25ml/min 65
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2ξ)-4 ,4,4-trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 443.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.04 (s, 1H), 10.35 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.19 (brd, J=8.3 Hz, 1H), 6.29 (s, 1H), 6.10 (d, J=2.3 Hz, 1H), 4.99 (brd, J= 2.0Hz, 1H), 3.88-3.79(m, 1H), 3.76(s, 3H), 3.52(s, 2H), 3.07-2.98(m, 1H ), 2.48-2.30 (m, 3H), 2.05-1.95 (m, 1H), 1.92-1.83 (m, 1H), 1.77-1.63 (m , 2H), 1.61-1.52 (m, 1H), 1.10 (d, J=6.5 Hz, 3H)
[α] _D ²⁵ -3.56 ( c 0.15, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150×4.6 mm×3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO2; Flow rate: 2.5ml/min 66
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2ξ)-4 ,4,4-trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 443.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.04 (br.dd, J=5.9, 9.4 Hz, 1H), 10.36 (br.s, 1H), 7.55 ( d, J=2.0 Hz, 1H), 7.24-7.16 (m, 1H), 6.31-6.22 (m, 1H), 6.10 (d, J=2.0 Hz , 1H), 5.04-4.94 (m, 1H), 3.86-3.78 (m, 1H), 3.76 (s, 3H), 3.52 (s, 2H), 3, 08-2.97 (m, 1H), 2.47-2.29 (m, 3H), 2.05-1.94 (m, 1H), 1.93-1.83 (m, 1H), 1.77-1.62 (m, 2H), 1.60-1.49 (m, 1H), 1.11 (d, J=6.5 Hz, 3H)
[α] _D ²⁵ +2.73 ( c 0.22, MeOH);
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm x3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO2; Flow rate: 2.5ml/min 67
(A)

(1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 471.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (s, 1H), 10.54 (s, 1H), 8.23 (d, J=1.3 Hz, 1H), 8.16 (s, 1H), 7.17 (brd, J=8.3 Hz, 1H), 6.27 (s, 1H), 5.02-4.95 (m, 1H), 3.89 ( s, 3H), 3.85-3.79 (m, 1H), 3.77 (s, 2H), 3.07-2.99 (m, 1H), 2.47-2.29 (m, 3H), 2.03-1.94(m, 1H), 1.91-1.83(m, 1H), 1.73-1.62(m, 2H), 1.60-1.52( m, 1H), 1.12-1.07 (m, 3H)
[α] _D ²⁵ -1.67 ( c 0.12, MeOH);
Peak 1 of 2: Column: Chiralpak AD-3 150×4.6 mm×3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ , Flow rate: 2.5 ml/min 68
(A)

(1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 471.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (s, 1H), 10.54 (s, 1H), 8.22 (d, J=1.0 Hz, 1H), 8.16 (s, 1H), 7.19 (brd, J=8.5 Hz, 1H), 6.27 (s, 1H), 5.05-4.94 (m, 1H), 3.89 ( s, 3H), 3.85-3.78 (m, 1H), 3.77 (s, 2H), 3.02 (dt, J=1.3, 8.3 Hz, 1H), 2.47 -2.30(m, 3H), 2.04-1.93(m, 1H), 1.91-1.83(m, 1H), 1.73-1.62(m, 2H), 1 .58-1.48 (m, 1H), 1.14-1.07 (m, 3H)
[α] _D ²⁵ +6.67 (c 0.11, MeOH);
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm x3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ , Flow rate: 2.5 ml/min 69
(A)

(1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 440.3 ¹ H NMR (400 MHz, DMSO-d6) ä=12.23 (s, 1H), 10.87 (s, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.20 (dd, J=2.3, 8.0Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.22 (brd, J=8.3Hz, 1H), 6.46 (s, 1H), 5.02 (brd, J=5.5 Hz, 1H), 3.90-3.77 (m, 1H), 3.14-3.01 (m, 1H), 2.53 (s, 3H), 2.49-2.44 (m, 1H), 2.43-2.31 (m, 2H), 2.08-1.99 (m, 1H) , 1.96-1.84 (m, 1H), 1.78-1.69 (m, 2H), 1.67-1.57 (m, 1H), 1.12 (d, J=6, 5Hz, 3H)
[α] _D ²⁵ -2 ( c 0.1, MeOH)
Peak 1 of 2: Column: ChiralPak AD-3 150×4.6 mm×3 µm; Gradient: 40% IPA (0.1% Ethanolamine) in CO ₂ ; Flow rate: 2.5ml/min Column temperature 40°C 70
(A)

(1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 440.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.23 (s, 1H), 10.87 (s, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.20 (dd, J=2.3, 8.0Hz, 1H), 7.36 (d, J=8.3Hz, 1H), 7.23 (brd, J=8.5Hz, 1H), 6.46 (s, 1H), 5.02 (brd, J=5.0 Hz, 1H), 3.83 (td, J=7.0, 14.2 Hz, 1H), 3.15 -3.01(m, 1H), 2.53(s, 3H), 2.47(br s, 1H), 2.45-2.29(m, 2H), 2.04(br d , J=7.8 Hz, 1H), 1.96-1.85 (m, 1H), 1.80-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.13 (d, J=6.5 Hz, 3H)
[α] _D ²⁵ +8 ( c 0.1, MeOH)
Peak 2 of 2: Column: ChiralPak AD-3 150 x 4.6 mm x 3 µm; Gradient: 40% IPA (0.1% Ethanolamine) in CO ₂ ; Flow rate: 2.5ml/min Column temperature 40°C 71
(B)

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 444.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.14 (s, 1H), 10.64 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.29 (brs, 1H), 6.22 (s, 1H), 5.06-4.93 (m, 1H), 3.94-3.69 (m, 3H), 3.14-2.93 (m, 1H), 2.48-2.29 (m, 3H), 2.20 (s, 3H), 2.07-1.80 (m, 2H), 1.77-1.52 (m , 3H), 1.12 (d, J=6.8 Hz, 3H)
[α] _D ²⁵ -1.0 ( c 0.2, MeOH)
Peak 1 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% IPA (0.1% NH3.H2O) in CO ₂ ; Flow rate: 7ml/min Column temperature 40°C 72
(B)

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 444.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (br s, 1H), 10.64 (s, 1H), 7.20 (d, J=8.5 Hz, 1H), 6 .28 (s, 1H), 6.22 (s, 1H), 5.07-4.90 (m, 1H), 3.89-3.77 (m, 3H), 3.13-2.98 (m, 1H), 2.48-2.26 (m, 3H), 2.20 (s, 3H), 2.06-1.83 (m, 2H), 1.79-1.51 (m , 3H), 1.12 (d, J=6.5 Hz, 3H)
[α] _D ²⁵ +1.0 ( c 0.2, MeOH)
Peak 2 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% IPA (0.1% NH3.H2O) in CO ₂ ; Flow rate: 7ml/min Column temperature 40°C 73
(B)

(1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 455.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.64-10.53 (m, 1H), 8.50-8.42 (m, 2H), 7.18 (d, J=8.3 Hz, 1H), 6.27 (br.s, 1H), 5.02-4.94 (m, 1H), 3.85-3.78 (m, 3H), 3.07-2.96(m, 1H), 2.46(s, 3H), 2.44-2.26(m, 3H), 2.03-1.95(m, 1H) , 1.91-1.82 (m, 1H), 1.72-1.62 (m, 2H), 1.57 (dt, J=5.0, 9.0 Hz, 1H), 1.09 (d, J=6.8Hz, 3H)
[α] _D ²⁵ -1.82° ( c 0.11, MeOH)
Pick 1 out of 2; Column: Chiralpak AD-3 50 x 3 mm x 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 74
(B)

(1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 455.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.60 (s, 1H), 8.46 (d, J=13.6 Hz, 2H), 7.20 (bd, J=8.3 Hz, 1H), 6.27 (s, 1H), 5.02-4.94 (m, 1H), 3.84-3.76 (m, 3H), 3.02 (quin, J=8.4 Hz, 1H), 2.46 (s, 3H), 2.45-2.25 (m, 3H), 2.03-1.94 (m, 1H) , 1.92-1.83 (m, 1H), 1.75-1.63 (m, 2H), 1.60-1.49 (m, 1H), 1.10 (d, J=6, 8Hz, 3H)
[α] _D ²⁵ +6.67 ( c 0.12, MeOH)
Pick 2 out of 2; Column: Chiralpak AD-3 50×3 mm×3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 75
(B)

(1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 454.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.17-11.90 (m, 1H), 10.62-10.49 (m, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.58 (dd, J=2.1, 7.9 Hz, 1H), 7.22-7.13 (m, 2H), 6.25 (s, 1H), 5.02 -4.94(m, 1H), 3.87-3.76(m, 1H), 3.57(s, 2H), 3.08-2.96(m, 1H), 2.46-2 .28 (m, 6H), 2.03-1.93 (m, 1H), 1.92-1.81 (m, 1H), 1.76-1.61 (m, 2H), 1.55 (dt, J=4.8, 9.3Hz, 1H), 1.10 (d, J=6.8Hz, 3H)
[α] _D ²⁵ +4.44 ( c 0.120, MeOH)
Peak 1 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; Flow rate: 7ml/min; Column temperature 40°C 76
(B)

(1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 454.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.25-11.76 (m, 1H), 10.73-10.48 (m, 1H), 8.35 (s, 1H), 7, 62-7.54 (m, 1H), 7.18 (brd, J=8.0 Hz, 2H), 6.29-6.21 (m, 1H), 5.05-4.91 ( m, 1H), 3.88-3.75 (m, 1H), 3.57 (s, 2H), 3.08-2.94 (m, 1H), 2.45-2.25 (m, 6H), 2.06-1.93(m, 1H), 1.91-1.83(m, 1H), 1.76-1.61(m, 2H), 1.59-1.48( m, 1H), 1.15-1.06 (m, 3H)
[α] _D ²⁵ +5.56 ( c 0.108, MeOH)
Peak 2 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; Flow rate: 7ml/min; Column temperature 40°C 77
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 470.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.59 (s, 1H), 8.08 (d, J=5.3 Hz, 1H), 7 .17 (brd, J=8.5 Hz, 1H), 6.92 (dd, J=1.3, 5.3 Hz, 1H), 6.74 (s, 1H), 6.27 ( s, 1H), 5.07-4.92 (m, 1H), 3.90-3.76 (m, 4H), 3.59 (s, 2H), 3.11-2.97 (m, 1H), 2.48-2.27 (m, 3H), 2.05-1.94 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.52 ( m, 3H), 1.11 (d, J=6.8 Hz, 3H)
[α] _D ²⁵ +2.98 ( c 0.134, MeOH)
Peak 1 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% IPA (0.1% NH3.H2O) in CO ₂ ; Flow rate: 6.5ml/min; Column temperature 40°C 78
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 470.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.59 (s, 1H), 8.08 (d, J=5.0 Hz, 1H), 7 .19 (brd, J=8.5 Hz, 1H), 6.98-6.88 (m, 1H), 6.74 (s, 1H), 6.27 (s, 1H), 5, 00 (brs, 1H), 3.91-3.75 (m, 4H), 3.59 (s, 2H), 3.12-2.97 (m, 1H), 2.49-2, 27 (m, 3H), 2.07-1.80 (m, 2H), 1.77-1.62 (m, 2H), 1.61-1.49 (m, 1H), 1.12 ( d, J=6.8Hz, 3H)
[α] _D ²⁵ +8.0 ( c 0.1, MeOH)
Peak 2 of 2: Column: SS WHELK-O1 (250mm*50mm,10µm); Mobile phase: 35% IPA (0.1% NH3.H2O) in CO ₂ ; Flow rate: 6.5ml/min; Column temperature 40°C 79
(B)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 460.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 7.18 (br d, J=8.5Hz, 1H), 6.27(brs, 1H), 4.99(brs, 1H), 3.86-3.73(m, 3H), 3.10-2 .95 (m, 1H), 2.58 (s, 3H), 2.47-2.28 (m, 3H), 2.04-1.95 (m, 1H), 1.92-1.81 (m, 1H), 1.75-1.63 (m, 2H), 1.61-1.52 (m, 1H), 1.11 (d, J=6.8 Hz, 3H)
¹⁹ F NMR (376 MHz, DMSO-d6) δ=-62.57 (br s, 3F);
[α] _D ²⁵ +3 ( c 0.2, MeOH)
Peak 1 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; Flow rate: 7ml/min; Column temperature 40 C 80
(B)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 460.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 7.19 (d, J= 8.3Hz, 1H), 6.27(s, 1H), 4.99(brs, 1H), 3.87-3.79(m, 3H), 3.08-2.97(m , 1H), 2.58 (s, 3H), 2.47-2.28 (m, 3H), 2.04-1.95 (m, 1H), 1.93-1.82 (m, 1H ), 1.76-1.62 (m, 2H), 1.60-1.49 (m, 1H), 1.12 (d, J=6.8 Hz, 3H)
¹⁹ F NMR (376 MHz, DMSO-d6) δ=-62.55 (br s, 3F);
[α] _D ²⁵ +12 ( c 0.2, MeOH)
Peak 2 of 2: Column: SS WHELK-O1 (250 mm*50 mm, 10 µm); Mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; Flow rate: 7ml/min; Column temperature 40°C 81
(A)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 444.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (s, 1H), 10.62 (br s, 1H), 7.18 (br d, J=8.6 Hz, 1H) , 6.74 (s, 1H), 6.28 (br.s, 1H), 4.99 (br.d, J=2.0 Hz, 1H), 3.83 (br.d, J=6 .2 Hz, 1H), 3.79 (s, 2H), 3.08-2.98 (m, 1H), 2.46-2.32 (m, 3H), 2.25 (s, 3H) , 2.04-1.95 (m, 1H), 1.93-1.83 (m, 1H), 1.74-1.54 (m, 3H), 1.10 (brd, J= 6.6Hz, 3H)
[α] _D ²⁵ -1.91 ( c 0.115, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 82
(A)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 444.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (s, 1H), 10.62 (br s, 1H), 7.20 (br d, J=8.3 Hz, 1H) , 6.74 (d, J=1.1 Hz, 1H), 6.28 (br.s, 1H), 5.05-4.94 (m, 1H), 3.88-3.80 (m , 1H), 3.79 (s, 2H), 3.09-2.99 (m, 1H), 2.47-2.31 (m, 3H), 2.25 (d, J=1.0 Hz, 3H), 2.06-1.95 (m, 1H), 1.95-1.85 (m, 1H), 1.75-1.64 (m, 2H), 1.61-1, 51 (m, 1H), 1.11 (d, J=6.7 Hz, 3H)
[α] _D ²⁵ +1.74 ( c 0.115, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 83
(A)

( 1R , 3S )-3-{3-[(1,3-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [(2ξ)-4,4,4-trifluorobutane -2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 430.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.17 (brd, J= 8.2Hz, 1H), 7.00(s, 1H), 6.28(s, 1H), 5.05-4.94(m, 1H), 3.89-3.80(m, 1H ), 3.78 (s, 2H), 3.09-3.00 (m, 1H), 2.46-2.34 (m, 3H), 2.00 (brd, J=9.3 Hz, 1H), 1.88 (dt, J=2.9, 6.5 Hz, 1H), 1.75-1.64 (m, 2H), 1.62-1.53 (m, 1H) , 1.11 (d, J=6.7 Hz, 3H)
[α] _D ²⁵ -1.82 ( c 0.11, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150×4.6 mm×3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 84
(A)

( 1R , 3S )-3-{3-[(1,3-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [(2ξ)-4,4,4-trifluorobutane -2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 430.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.18 (br d, J=8.8Hz, 1H), 7.00(s, 1H), 6.28(brs, 1H), 5.00(brd, J=2.0Hz, 1H), 3, 87-3.79 (m, 1H), 3.78 (s, 2H), 3.03 (bt, J=8.7 Hz, 1H), 2.47-2.34 (m, 3H) , 2.05-1.96 (m, 1H), 1.89 (ddd, J=2.9, 6.6, 9.7 Hz, 1H), 1.75-1.64 (m, 2H) , 1.61-1.50 (m, 1H), 1.12 (brd, J=6.6 Hz, 3H)
[α] _D ²⁵ +8.60 ( c 0.31, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 150×4.6 mm×3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 85
(A)

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl [(2ξ)-4,4,4-trifluorobutane -2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 430.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.14 (s, 1H), 10.68 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.00 (br s, 1H), 3.91 (s, 2H) , 3.82 (td, J=7.1, 13.7 Hz, 1H), 3.10-2.98 (m, 1H), 2.48-2.28 (m, 3H), 2.06 -1.95(m, 1H), 1.95-1.83(m, 1H), 1.77-1.52(m, 3H), 1.10(d, J=6.8Hz, 3H )
[α] _D ²⁵ -4 ( c 0.1, MeOH)
Pick 1 out of 2; Column: Chiralpak AD-3 150×4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 86
(A)

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl [(2ξ)-4,4,4-trifluorobutane -2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 430.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.14 (s, 1H), 10.67 (s, 1H), 8.49 (d, J=1.5 Hz, 1H), 7.21 (brd, J=8.5 Hz, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.00 (br.s, 1H), 3.91 (s, 2H), 3.87-3.77 (m, 1H), 3.08-2.98 (m, 1H), 2.47-2.27 (m, 3H), 2.00 (brd, J=8.3 Hz, 1H), 1.94-1.83 (m, 1H), 1.75-1.63 (m, 2H), 1.60-1.48 (m, 1H), 1 .11 (d, J=6.5 Hz, 3H)
[α] _D ²⁵ +12 ( c 0.1, MeOH)
Pick 2 out of 2; Column: Chiralpak AD-3 150×4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 87
(A)

(1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [( 2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 473.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.26 (d, J=1.5 Hz, 1H), 10.75 (s, 1H), 7.51 (d, J=1.8 Hz , 1H), 7.22 (brd, J=8.5 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 6.42 (s, 1H), 5.06 -4.97 (m, 1H), 4.69 (t, J=5.6 Hz, 2H), 3.84 (quind, J=6.7, 13.7 Hz, 1H), 3.66 ( t, J=5.6 Hz, 2H), 3.18 (s, 3H), 3.13-3.02 (m, 1H), 2.47-2.30 (m, 3H), 2.08 -1.99 (m, 1H), 1.96-1.84 (m, 1H), 1.78-1.69 (m, 2H), 1.63 (ddd, J=4.5, 9, 3, 13.8 Hz, 1H), 1.12 (d, J=6.8 Hz, 3H)
[α] _D ²⁵ -7.27 ( c 0.11, MeOH)
Peak 1 of 2: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.1% Ethanolamine) in CO ₂ ; Flow rate: 2.5ml/min Column temperature 40°C 88
(A)

(1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [( 2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 473.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.26 (s, 1H), 10.75 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.23 (brd, J=8.3 Hz, 1H), 7.13 (d, J=1.8 Hz, 1H), 6.42 (s, 1H), 5.01 (brd, J= 4.5 Hz, 1H), 4.69 (t, J=5.6 Hz, 2H), 3.83 (td, J=7.1, 13.6 Hz, 1H), 3.66 (t, J=5.6Hz, 2H), 3.18(s, 3H), 3.14-3.00(m, 1H), 2.49-2.25(m, 3H), 2.09-1 .98 (m, 1H), 1.98-1.83 (m, 1H), 1.81-1.67 (m, 2H), 1.65-1.53 (m, 1H), 1.12 (d, J=6.5Hz, 3H)
[α] _D ²⁵ +7.22 ( c 0.12, MeOH);
Peak 2 of 2: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.1% Ethanolamine) in CO ₂ ; Flow rate: 2.5ml/min Column temperature 40°C 89
(A)

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl methyl[(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 444.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (br s, 1H), 10.65 (s, 1H), 8.48 (d, J=1.5 Hz, 1H), 6 .36 (s, 1H), 6.30 (s, 1H), 5.00 (br s, 1H), 4.52-4.31 (m, 1H), 3.90 (s, 2H), 3.13-3.01 (m, 1H), 2.68-2.56 (m, 4H), 2.45-2.30 (m, 2H), 2.01 (brd, J=7 .8 Hz, 1H), 1.88 (bd, J=5.8 Hz, 1H), 1.79-1.62 (m, 3H), 1.10 (d, J=7.0 Hz, 3H)
[α] _D ²⁵ -10 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 90
(A)

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl methyl[(2ξ)-4,4,4- trifluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate has not been determined 444.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (br s, 1H), 10.65 (s, 1H), 8.48 (d, J=1.5 Hz, 1H), 6 .36 (s, 1H), 6.30 (s, 1H), 5.04 (brd, J=9.8 Hz, 1H), 4.42 (br s, 1H), 3.90 ( s, 2H), 3.08 (bt, J=7.9 Hz, 1H), 2.65 (s, 3H), 2.62-2.53 (m, 1H), 2.45-2 .38 (m, 1H), 2.38-2.24 (m, 1H), 2.01 (brd, J=7.5 Hz, 1H), 1.86 (brd, J=4 .8 Hz, 1H), 1.78-1.57 (m, 3H), 1.10 (br.dd, J=6.9, 15.2 Hz, 3H)
[α] _D ²⁵ -4 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 91
(B)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2 S )-4,4,4-trifluorobutan-2-yl]carbamate
All stereocenters are known 430.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.31 (br s, 1H), 11.12 (s, 1H), 8.46 (s, 1H), 7.21 (d, J= 8.4Hz, 1H), 6.44(brs, 1H), 5.02(brs, 1H), 4.24(s,3H), 3.92-3.75(m, 1H ), 3.15-3.00 (m, 1H), 2.47-2.24 (m, 3H), 2.04 (d, J=7.8 Hz, 1H), 1.89 (d, J=5.4Hz, 1H), 1.73(t, J=8.1Hz, 2H), 1.60(brs, 1H), 1.13(d, J=6.6Hz, 3H)
¹⁹ F NMR (376 MHz, DMSO-d6) δ=-62.58 (s, 3F) 92
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2S )- 4,4,4-trifluorobutan-2-yl]carbamate
All stereocenters are known 443.4 ¹ H NMR (400 MHz, METHANOL-d4) d 7.54 (s, 1H), 7.42 (s, 1H), 6.35 (br. s, 1H), 5.09 (br. s, 1H ), 3.89-4.02 (m, 1H), 3.86 (s, 3H), 3.53 (s, 2H), 3.07-3.22 (m, 1H), 2.45- 2.54 (m, 1H), 2.17-2.44 (m, 2H), 2.10 (d, J=6.97 Hz, 1H), 1.72-2.01 (m, 4H) , 1.21 (d, J=6.60 Hz, 3H)
[α] _D ²² +10.0 ( c 0.3, MeOH) 93
(A)

( 1R , 3S )-3-(3-{[(4-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [( 2S ) -4,4,4-trifluorobutan-2-yl]carbamate
All stereocenters are known 444.1 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (s, 1H), 10.63 (s, 1H), 7.71 (s, 1H), 7.21 (brd, J= 8.3 Hz, 1H), 6.28 (s, 1H), 4.99 (br s, 1H), 3.86-3.81 (m, 1H), 3.80 (s, 2H), 3.08-2.99 (m, 1H), 2.47-2.34 (m, 3H), 2.05 (d, J=1.0 Hz, 3H), 2.00 (brd, J=8.3 Hz, 1H), 1.88 (br.s, 1H), 1.69 (br.dd, J=10.8, 15.6 Hz, 2H), 1.55 (br.s , 1H), 1.11 (d, J=6.8 Hz, 3H)
[α] _D ²⁵ +12.41 ( c 0.145, MeOH); 94
(A)

( 1R , 3S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2 S )-4,4,4-trifluorobutan-2-yl]carbamate
All stereocenters are known 459.3 ¹ H NMR (500 MHz, DMSO-d6) δ=12.25 (s, 1H), 10.66 (s, 1H), 7.22 (brd, J=8.4 Hz, 1H), 6, 58 (s, 1H), 6.41 (s, 1H), 5.01 (br s, 1H), 3.93 (s, 3H), 3.83 (td, J=6.9, 13, 9 Hz, 1H), 3.77 (s, 3H), 3.12-3.03 (m, 1H), 2.54-2.51 (m, 1H), 2.44-2.29 (m , 2H), 2.08-1.99 (m, 1H), 1.94-1.84 (m, 1H), 1.79-1.66 (m, 2H), 1.64-1.54 (m, 1H), 1.12 (d, J=6.7 Hz, 3H) 95
(B)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (4,4, 4-trifluoro-2-methylbutan-2-yl)carbamate
All stereocenters are known 458.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (s, 1H), 10.62 (s, 1H), 7.12 (br s, 1H), 6.74 (d, J= 1.3 Hz, 1H), 6.29 (d, J=2.0 Hz, 1H), 4.98 (br s, 1H), 3.79 (s, 2H), 3.11-2, 95 (m, 1H), 2.79-2.61 (m, 2H), 2.48-2.41 (m, 1H), 2.25 (d, J=1.0 Hz, 3H), 2 .04-1.95(m, 1H), 1.92-1.82(m, 1H), 1.75-1.62(m, 2H), 1.55(brs, 1H), 1 .27 (s, 6H) 96
(B)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4-difluorobutan-2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4-difluorobutan-2-yl]carbamate has not been determined 426.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (s, 1H), 10.61 (s, 1H), 7.12 (brd, J=8.3 Hz, 1H), 6 .74 (d, J=1.0 Hz, 1H), 6.29 (s, 1H), 6.18-5.84 (m, 1H), 4.99 (br s, 1H), 3, 79 (s, 2H), 3.73-3.60 (m, 1H), 3.10-2.98 (m, 1H), 2.48-2.39 (m, 1H), 2.25 ( d, J=1.0 Hz, 3H), 2.06-1.82 (m, 4H), 1.78-1.51 (m, 3H), 1.07 (d, J=6.8 Hz , 3H)
[α] _D ²⁵ -4 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 50×3 mm x3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 97
(B)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 4,4-difluorobutan-2-yl]carbamate - Isomer B
Single stereoisomer, absolute configuration of chiral center in 4,4-difluorobutan-2-yl]carbamate not determined 426.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (s, 1H), 10.61 (s, 1H), 7.13 (brd, J=8.3 Hz, 1H), 6 .74 (d, J=1.0 Hz, 1H), 6.29 (d, J=1.5 Hz, 1H), 6.18-5.83 (m, 1H), 4.99 (br. s, 1H), 3.79 (s, 2H), 3.72-3.59 (m, 1H), 3.11-2.97 (m, 1H), 2.48-2.39 (m, 1H), 2.25 (d, J=1.3 Hz, 3H), 2.06-1.81 (m, 4H), 1.78-1.52 (m, 3H), 1.08 (br .d, J=6.8 Hz, 3H)
[α] _D ²⁵ +18 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 50×3 mm×3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 98
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4-difluorobutan- 2-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 4,4-difluorobutan-2-yl]carbamate has not been determined 452.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.11 (bd, J=8.0 Hz, 1H), 6.91 (dd, J=1.1, 5.1 Hz, 1H), 6.73 (s, 1H), 6.27 (s, 1H), 6.18-5.83 (m, 1H), 4.98 (br s, 1H), 3.82 (s, 3H), 3.74-3.63 (m, 1H), 3 .58 (s, 2H), 3.08-2.96 (m, 1H), 2.48-2.39 (m, 1H), 2.04-1.80 (m, 4H), 1.77 -1.49 (m, 3H), 1.07 (bd, J=6.8 Hz, 3H)
[α] _D ²⁵ -4° ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 99
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-4,4-difluorobutan- 2-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 4,4-difluorobutan-2-yl]carbamate has not been determined 452.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 7.12 (bd, J=8.0 Hz, 1H), 6.91 (dd, J=1.1, 5.1 Hz, 1H), 6.73 (s, 1H), 6.28 (s, 1H), 6.17-5.84 (m, 1H), 4.99 (br s, 1H), 3.82 (s, 3H), 3.67 (td, J=6.8, 13, 4 Hz, 1H), 3.58 (s, 2H), 3.09-2.96 (m, 1H), 2.47-2.38 (m, 1H), 2.05-1.80 (m , 4H), 1.76-1.51 (m, 3H), 1.07 (brd, J=6.8 Hz, 3H)
[α] _D ²⁵ +18 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 100
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S )-1-fluoropropan-2 -yl]carbamate
All stereocenters are known 420.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.5 Hz, 1H), 7 .15 (brd, J=7.9 Hz, 1H), 6.91 (dd, J=1.3, 5.3 Hz, 1H), 6.73 (s, 1H), 6.27 ( br s, 1H), 4.99 (br s, 1H), 4.30 (br d, J=5.5 Hz, 1H), 4.18 (br d, J=5.5 Hz , 1H), 3.83 (s, 3H), 3.80-3.67 (m, 1H), 3.58 (s, 2H), 3.09-2.96 (m, 1H), 2, 48-2.39 (m, 1H), 2.03-1.94 (m, 1H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 2H), 1.62-1.52 (m, 1H), 1.02 (brd, J=6.7 Hz, 3H) 101
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S ,3 R )-3- fluorobutan-2-yl]carbamate
All stereocenters are known 434.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.58 (s, 1H), 8.08 (d, J=5.3 Hz, 1H), 7.17 (bd, J=8.6 Hz, 1H), 6.92 (dd, J=1.2, 5.2 Hz, 1H), 6.74 (s, 1H), 6.28 (d, J=1.5 Hz, 1H), 4.99 (brd, J=1.8 Hz, 1H), 4.66-4.30 (m, 1H), 3.83 (s, 3H), 3.66-3.48 (m, 3H), 3.16-2.93 (m, 1H), 2.48-2.42 (m, 1H), 2.08-1.81 (m, 2H ), 1.78-1.48 (m, 3H), 1.31-1.09 (m, 3H), 1.04 (brd, J=6.6 Hz, 3H) 102
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3,3,3-trifluoropropyl)carbamate
All stereocenters are known 456.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (s, 1H), 10.59 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.28 (t, J=5.8 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 6.73 (s, 1H), 6.27 (s, 1H), 4.99 (brs, 1H), 3.82 (s, 3H), 3.58 (s, 2H), 3.23-3.15 (m, 2H), 3.08-2.97 (m, 1H ), 2.47-2.34 (m, 3H), 2.03-1.94 (m, 1H), 1.91-1.82 (m, 1H), 1.75-1.63 (m , 2H), 1.61-1.51 (m, 1H) 103
(B)

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl (3,3,3-trifluoropropyl)carbamate
All stereocenters are known 459.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.25 (d, J=1.3 Hz, 1H), 10.74 (s, 1H), 7.31 (brt, J=5, 5 Hz, 1H), 7.13 (s, 1H), 6.43 (s, 1H), 5.15-4.92 (m, 1H), 4.34 (s, 2H), 4.05 ( s, 3H), 3.27 (s, 3H), 3.25-3.17 (m, 2H), 3.15-3.03 (m, 1H), 2.49-2.32 (m, 3H), 2.13-1.84 (m, 2H), 1.82-1.57 (m, 3H) 104
(B)

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl [(1 S )-1-cyclopropylethyl]carbamate
All stereocenters are known 431.4 ¹ H NMR (500 MHz, DMSO-d6) δ=12.23 (s, 1H), 10.73 (s, 1H), 7.12 (s, 1H), 7.02 (brd, J=8 .1 Hz, 1H), 6.43 (s, 1H), 4.99 (br.s, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.26 (s , 3H), 3.13-3.02 (m, 1H), 3.02-2.93 (m, 1H), 2.52 (brd, J=1.7 Hz, 1H), 2, 10-1.99(m, 1H), 1.95-1.84(m, 1H), 1.73(brd, J=7.6Hz, 2H), 1.61(brs, 1H), 1.08 (d, J=6.7 Hz, 3H), 0.81 (brd, J=7.8 Hz, 1H), 0.40-0.28 (m, 2H), 0.24 (br.dd, J=4.2, 8.8Hz, 1H), 0.09 (qvd, J=4.8, 9.3Hz, 1H) 105
(B)

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl [(1 R )-1-cyclopropylethyl]carbamate
All stereocenters are known 431.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.23 (s, 1H), 10.85-10.66 (m, 1H), 7.12 (s, 1H), 7.02 (br. d, J=8.1Hz, 1H), 6.42(brs, 1H), 5.00(brs, 1H), 4.33(s, 2H), 4.05(s, 3H ), 3.26 (s, 3H), 3.14-2.88 (m, 2H), 2.48-2.38 (m, 1H), 2.02 (td, J=7.3, 15 .1 Hz, 1H), 1.95-1.84 (m, 1H), 1.82-1.69 (m, 2H), 1.61 (br.s, 1H), 1.12-1, 03 (m, 3H), 0.89-0.72 (m, 1H), 0.42-0.19 (m, 3H), 0.14-0.00 (m, 1H) 106
(B)

(1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 S )-1-cyclopropylethyl]carbamate
All stereocenters are known 429.3 ¹ H NMR (500MHz, DMSO-d6) δ=12.07 (br s, 1H), 10.54 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.00 (brd, J=8.4 Hz, 1H), 6.28 (s, 1H), 4.96 (brd, 1H), 3.89 (s, 3H), 3.77 (s, 2H), 3.08-2.92 (m, 2H), 2.47-2.39 (m, 1H), 1.98 (brd, J=8.7 Hz, 1H), 1.93-1.82(m, 1H), 1.75-1.62(m, 2H), 1.55(brs, 1H), 1.07(brd, J=6.4 Hz, 3H), 0.77 (brs, 1H), 0.34 (brd, J=4.0 Hz, 1H), 0.31-0.25 (m, 1H), 0.22 (wd, J=4.6 Hz, 1H), 0.11-0.00 (m, 1H) 107
(D)

( 1R , 3S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert-butyl carbamate
All stereocenters are known 389.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (br s, 1H), 10.68-10.62 (m, 1H), 6.78 (br s, 1H), 6, 29 (br s, 1H), 6.22 (s, 1H), 4.96 (br d, J=2.3 Hz, 1H), 3.82 (s, 2H), 3.11-2 .95 (m, 1H), 2.47-2.41 (m, 1H), 2.20 (s, 3H), 2.04-1.95 (m, 1H), 1.92-1.83 (m, 1H), 1.68 (bt, J=8.1 Hz, 2H), 1.60-1.50 (m, 1H), 1.19 (s, 9H) 108
(D)

( 1R , 3S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl tert- butylcarbamate
All stereocenters are known 376.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.12 (br s, 1H), 10.67 (s, 1H), 8.49 (s, 1H), 6.77 (br s, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 4.96 (br s, 1H), 3.91 (s, 2H), 3.03 (quin, J=8 .5 Hz, 1H), 2.47-2.42 (m, 1H), 2.03-1.94 (m, 1H), 1.93-1.80 (m, 1H), 1.74- 1.60 (m, 2H), 1.55 (brs, 1H), 1.19 (s, 9H)
[α] _D ²⁵ +8.20 ( c 0.13, MeOH); 109
(D)

( 1R , 3S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate
All stereocenters are known M + Na ⁺ 438.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (br s, 1H), 10.56 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H) , 6.76 (br s, 1H), 6.26 (br s, 1H), 4.95 (br s, 1H), 3.89 (s, 3H), 3.77 (s, 2H ), 3.01 (bt, J=8.2 Hz, 1H), 2.47-2.40 (m, 1H), 2.01-1.83 (m, 2H), 1.74- 1.62 (m, 2H), 1.54 (brs, 1H), 1.18 (s, 9H) 110
(D)

(1 R ,3 S )-3-(3-{[(2-methyl-2 H -1,2,3-triazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butyl carbamate
All stereocenters are known 390.4 ¹ H NMR (500MHz, DMSO-d6) δ=12.07 (br.s, 1H), 10.53 (br.s, 1H), 7.59 (s, 1H), 6.77 (br.s , 1H), 6.28 (br s, 1H), 4.95 (br s, 1H), 4.08 (s, 3H), 3.68 (s, 2H), 3.07-2, 96 (m, 1H), 2.47-2.42 (m, 1H), 2.02-1.94 (m, 1H), 1.91-1.81 (m, 1H), 1.75- 1.61 (m, 2H), 1.54 (brs, 1H), 1.19 (s, 9H) 111
(B)

(1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl tert- butyl carbamate
All stereocenters are known 419.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.23 (s, 1H), 10.74 (s, 1H), 7.12 (s, 1H), 6.79 (br s, 1H) , 6.42 (d, J=1.5 Hz, 1H), 4.98 (br s, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.26 ( s, 3H), 3.11-3.00 (m, 1H), 2.49-2.41 (m, 1H), 2.06-1.97 (m, 1H), 1.94-1, 82 (m, 1H), 1.77-1.67 (m, 2H), 1.60 (br s, 1H), 1.21 (s, 9H) 112
(B)

( 1R , 3S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate
All stereocenters are known M + Na ⁺ 410.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.03 (br s, 1H), 10.35 (br s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 6.77 (br s, 1H), 6.28 (br s, 1H), 4.95 (br s, 1H), 3.77 (s, 3H), 3.38 (s , 2H), 3.08-2.93(m, 1H), 2.44(brs, 1H), 2.05-1.93(m, 1H), 1.86(brs, 1H ), 1.75-1.61 (m, 2H), 1.54 (br s, 1H), 1.19 (s, 9H) 113
(B)

( 1R , 3S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate
All stereocenters are known 406.4 ¹ H NMR (400 MHz, DMSO-d6) ä=12.09 (s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 6.77 (br s, 1H) , 6.28 (s, 1H), 4.95 (brd, J=2.5 Hz, 1H), 3.81 (s, 2H), 3.07-2.97 (m, 1H), 2.58 (s, 3H), 2.47-2.40 (m, 1H), 2.01-1.93 (m, 1H), 1.91-1.82 (m, 1H), 1, 73-1.63 (m, 2H), 1.55 (bt, J=13.2 Hz, 1H), 1.19 (s, 9H) 114
(B)

( 1R , 3S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate
All stereocenters are known 416.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (s, 1H), 10.53 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.62 (dd, J=2.3, 8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.27 (d, J=1.5 Hz, 1H), 4 .99-4.90(m, 1H), 3.81(s, 3H), 3.52(s, 2H), 3.05-2.96(m, 1H), 2.44(td, J =7.3, 14.1 Hz, 1H), 2.01-1.91(m, 1H), 1.89-1.80(m, 1H), 1.73-1.61(m, 2H ), 1.58-1.48 (m, 1H), 1.18 (s, 9H) 115
(D)

( 1R , 3S )-3-(3-{[(4-chloropyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butylcarbamate
All stereocenters are known 420.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.04 (br s, 1H), 10.67-10.48 (m, 1H), 8.46 (d, J=5.3 Hz, 1H), 7.58-7.48 (m, 1H), 7.42 (dd, J=2.0, 5.3 Hz, 1H), 6.73 (brs, 1H), 6.34 -6.22(m, 1H), 4.96(brs, 1H), 3.83(s, 2H), 3.11-2.95(m, 1H), 2.48-2.38 (m, 1H), 2.04-1.94 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.62 (m, 2H), 1.55 (br .s, 1H), 1.19 (s, 9H) 116
(B)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopentyl) -carbamate
All stereocenters are known 432.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.56 (s, 1H), 7.40 (s, 1H), 6.82 (br s, 1H), 6.28 (brs, 1H), 4.95 (brs, 1H), 3.80 (s, 2H), 3.10-2.94 (m, 1H), 2.58 (s, 3H), 2.47-2.38 (m, 1H), 2.04-1.79 (m, 4H), 1.68 (bt, J=7.7 Hz, 2H), 1.63-1.48 (m, 5H), 1.42 (br.dd, J=6.3, 11.8 Hz, 2H), 1.24 (s, 3H) 117
(B)

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl (1-methylcyclopentyl)carbamate
All stereocenters are known 402.1 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.65 (br s, 1H), 8.48 (s, 1H), 6.83 (br s, 1H). s, 1H), 6.37 (s, 1H), 6.29 (br s, 1H), 4.96 (br s, 1H), 3.91 (s, 2H), 3.10-2 .96(m, 1H), 2.46-2.40(m, 1H), 2.06-1.80(m, 4H), 1.69(brs, 2H), 1.55(br .d, J=14.7 Hz, 5H), 1.41 (br s, 2H), 1.25 (s, 3H) 118
(B)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (1-methylcyclobutyl) carbamate
All stereocenters are known 402.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.62 (s, 1H), 7.16 (br s, 1H), 6.74 (d, J=1.1Hz, 1H), 6.29(s, 1H), 4.97(brs, 1H), 3.79(s, 2H), 3.11-2.97(m, 1H ), 2.45-2.41 (m, 1H), 2.25 (d, J=1.0 Hz, 5H), 2.03-1.95 (m, 1H), 1.92-1, 84 (m, 1H), 1.83-1.76 (m, 2H), 1.74-1.63 (m, 4H), 1.56 (br s, 1H), 1.30 (s, 3H) 119
(B)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclobutyl)carbamate
All stereocenters are known M + Na ⁺ 422.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.03 (br s, 1H), 10.35 (br s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 7.17 (br s, 1H), 6.29 (br s, 1H), 4.97 (br s, 1H), 3.77 (s, 3H), 3.38 (br .s, 2H), 3.09-2.95 (m, 1H), 2.43 (br.s, 1H), 2.20 (br.s, 2H), 1.98 (br.d, J =6.5 Hz, 1H), 1.92-1.75 (m, 3H), 1.70 (brd, J=8.3 Hz, 4H), 1.56 (br s, 1H) , 1.30 (s, 3H) 120
(B)

(1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl] carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined M + Na ⁺ 470.9 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.23 (br.s, 1H), 6.87 (br.d, J=5.9 Hz, 2H), 6.75 (dt, J= 2.2, 8.9Hz, 1H), 6.52(brs, 1H), 5.28(brs, 1H), 5.16(brs, 1H), 4.02-3 .85 (m, 3H), 3.67 (s, 2H), 3.57 (d, J=9.0 Hz, 1H), 3.17 (quin, J=8.0 Hz, 1H), 2 .42 (brs, 1H), 2.32-2.19 (m, 1H), 2.16-2.02 (m, 1H), 1.98-1.79 (m, 5H), 1 .47 (s, 3H)
[α] _D ²⁵ +16.67 ( c 0.2, MeOH)
Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 121
(B)

(1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl] carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined M + Na ⁺ 470.9 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.16 (br s, 1H), 6.87 (br d, J=6.0 Hz, 2H), 6.50 (br s, 1H), 5.17 (br s, 1H), 5.29-5.10 (m, 1H), 4.00-3.84 (m, 3H), 3.67 (s, 2H), 3 .57 (d, J=9.0 Hz, 1H), 3.62-3.52 (m, 1H), 3.17 (quin, J=7.9 Hz, 1H), 2.43 (br. s, 1H), 2.24 (brd, J=6.6 Hz, 1H), 2.16-2.04 (m, 1H), 1.98-1.78 (m, 5H), 1 .48 (s, 3H)
[α] _D ²⁰ +12 ( c 0.2, MeOH)
Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 122
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3- yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 444.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (br s, 1H), 10.53 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7 .63 (dd, J=2.4, 8.5 Hz, 1H), 7.22 (br.s, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.27 ( brs, 1H), 4.97 (brs, 1H), 3.87-3.78 (m, 4H), 3.72 (t, J=7.1 Hz, 2H), 3.53 (s, 2H), 3.42 (d, J=8.6 Hz, 1H), 3.02 (bt, J=8.1 Hz, 1H), 2.48-2.39 (m, 1H), 2.19-2.08 (m, 1H), 2.04-1.93 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.62 ( m, 3H), 1.56 (br s, 1H), 1.30 (s, 3H)
[α] _D ²⁰ +17 ( c 0.2, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C, 123
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3- yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 444.4 ¹ H NMR (400 MHz, CHLOROFORM-d) δ=8.16 (br s, 1H), 8.09 (s, 1H), 7.62-7.50 (m, 1H), 6.75 ( d, J=8.6 Hz, 1H), 6.49 (s, 1H), 5.16 (br s, 2H), 4.04-3.83 (m, 6H), 3.62 (s , 2H), 3.57 (d, J=9.0 Hz, 1H), 3.23-3.09 (m, 1H), 2.44 (brd, J=7.1 Hz, 1H) , 2.24 (brd, J=5.4 Hz, 1H), 2.12 (br.s, 1H), 1.95-1.80 (m, 5H), 1.47 (s, 3H )
[α] _D ²⁰ +11 ( c 0.2, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C, 124
(A)

(1 R ,3 S )-3-{3-[(phenylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 413.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (s, 1H), 10.52 (s, 1H), 7.30 (d, J=4.3 Hz, 4H), 7.23 (qvd, J=4.2, 8.3 Hz, 2H), 6.28 (s, 1H), 4.97 (br.s, 1H), 3.81 (br.d, J=8.5 Hz, 1H), 3.75-3.68 (m, 2H), 3.57 (s, 2H), 3.41 (d, J=8.5 Hz, 1H), 3.07-2.95 (m, 1H), 2.48-2.40 (m, 1H), 2.18-2.09 (m, 1H), 2.03-1.93 (m, 1H), 1.92-1 .81 (m, 1H), 1.77-1.62 (m, 3H), 1.61-1.49 (m, 1H), 1.30 (s, 3H)
Peak 1 of 2: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 µm; Gradient: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min Column temperature 40°C 125
(A)

( 1R , 3S )-3-{3-[(phenylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 413.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (br s, 1H), 10.52 (s, 1H), 7.38-7.13 (m, 6H), 6.28 ( brs, 1H), 4.97 (brs, 1H), 3.80 (brd, J=8.3Hz, 1H), 3.71 (brd, J=7.0Hz , 2H), 3.57 (s, 2H), 3.42 (d, J=8.5 Hz, 1H), 3.07-2.95 (m, 1H), 2.48-2.40 ( m, 1H), 2.14 (brd, J=6.5 Hz, 1H), 1.98 (brd, J=8.3 Hz, 1H), 1.91-1.81 (m , 1H), 1.77-1.62 (m, 3H), 1.55 (br s, 1H), 1.30 (s, 3H)
Peak 2 of 2: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 µm; Gradient: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min Column temperature 40°C 126
(D)

(1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 450.3 ¹ H NMR (500 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.58 (s, 1H), 7.24 (br s, 1H), 6.96 (s, 1H ), 6.30 (br.s, 1H), 4.98 (br.s, 1H), 3.96 (s, 3H), 3.81 (br.d, J=7.6Hz, 1H), 3.76-3.68 (m, 4H), 3.42 (d, J=8.5 Hz, 1H), 3.08-2.97 (m, 1H), 2.48-2.42 ( m, 1H), 2.19-2.10 (m, 1H), 1.99 (brd, J=9.5 Hz, 1H), 1.87 (brd, J=6.4, 10.1Hz, 1H), 1.77-1.64(m, 3H), 1.57(brs, 1H), 1.31(s, 3H)
[α] _D ²⁵ +4 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 127
(D)

(1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 450.3 ¹ H NMR (500 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.58 (s, 1H), 7.24 (br s, 1H), 6.96 (s, 1H ), 6.30 (s, 1H), 4.98 (br.s, 1H), 3.96 (s, 3H), 3.80 (br.d, J=7.6Hz, 1H), 3, 75-3.67 (m, 4H), 3.42 (d, J=8.5 Hz, 1H), 3.08-2.98 (m, 1H), 2.48-2.42 (m, 1H), 2.20-2.12 (m, 1H), 1.99 (brd, J=9.3 Hz, 1H), 1.91-1.83 (m, 1H), 1.78 -1.64(m, 3H), 1.56(brs, 1H), 1.31(s, 3H)
[α] _D ²⁵ +6 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 128
(A)

(1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl (1-methylcyclopropyl)carbamate
All stereocenters are known 374.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.65 (s, 1H), 8.48 (s, 1H), 7.34 (br s, 1H), 6.37 (s, 1H), 6.28 (br s, 1H), 4.97 (br s, 1H), 3.91 (s, 2H), 3.14-2.96 (m, 1H), 2.46-2.41 (m, 1H), 1.98 (brd, J=8.8 Hz, 1H), 1.92-1.79 (m, 1H), 1.72-1.59 (m, 2H), 1.53 (br s, 1H), 1.22 (s, 3H), 0.58 (br s, 2H), 0.50-0, 41 (m, 2H) 129
(A)

(1 R ,3 S )-3-(3-{[(4-chloropyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate
All stereocenters are known 418.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (br s, 1H), 10.56 (br s, 1H), 8.46 (d, J=5.4 Hz, 1H) , 7.52 (d, J=1.8 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.33 (br.s, 1H), 6.27 (br. s, 1H), 4.96 (br s, 1H), 3.83 (s, 2H), 3.02 (br d, J=8.4 Hz, 1H), 2.48-2.39 (m, 1H), 1.97 (brd, J=8.1 Hz, 1H), 1.91-1.80 (m, 1H), 1.74-1.57 (m, 2H), 1.57-1.47(m, 1H), 1.22(s, 3H), 0.57(brs, 2H), 0.50-0.43(m, 2H) 130
(A)

(1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate
All stereocenters are known 453.3 ¹ H NMR (500 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.72 (s, 1H), 9.12 (s, 1H), 8.86 (s, 1H), 7.34 (s, 1H), 6.40-6.15 (m, 1H), 5.10-4.85 (m, 1H), 4.06 (s, 2H), 3.07-2, 97 (m, 1H), 2.48-2.40 (m, 1H), 1.97 (brd, J=8.1 Hz, 1H), 1.91-1.81 (m, 1H) , 1.72-1.57 (m, 2H), 1.52 (br s, 1H), 1.21 (s, 3H), 0.56 (br s, 2H), 0.47-0 .41 (m, 2H) 131
(A)

(1 R ,3 S )-3-(3-{[(4-chloro-5-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate
All stereocenters are known 432.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.05 (br s, 1H), 10.52 (s, 1H), 8.41 (s, 1H), 7.47 (s, 1H) , 7.33 (br.s, 1H), 6.26 (br.s, 1H), 4.96 (br.s, 1H), 3.77 (s, 2H), 3.02 (br.d , J=8.0 Hz, 1H), 2.46-2.37 (m, 1H), 2.32-2.25 (m, 3H), 1.97 (brd, J=8.8 Hz, 1H), 1.90-1.77 (m, 1H), 1.77-1.58 (m, 2H), 1.57-1.44 (m, 1H), 1.21 (s, 3H), 0.57 (brs, 2H), 0.48-0.40 (m, 2H) 132
(A)

(1 R ,3 S )-3-{3-[(1,5-naphthyridin-2-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl (1-methylcyclopropyl)carbamate
All stereocenters are known 435.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.69 (s, 1H), 8.97 (d, J=4.5 Hz, 1H), 8 .37 (dd, J=5.4, 8.4 Hz, 2H), 7.81-7.74 (m, 2H), 7.33 (br.s, 1H), 6.28 (br.s , 1H), 4.95 (brs, 1H), 4.07 (s, 2H), 3.01 (brs, 1H), 2.43-2.37 (m, 1H), 1, 97 (brd, J=7.5 Hz, 1H), 1.92-1.80 (m, 1H), 1.65 (br.s, 2H), 1.52 (br.s, 1H) , 1.21 (s, 3H), 0.56 (br.s, 2H), 0.43 (br.s, 2H) 133
(A)

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl 2,2-dimethylpiperidine -1-carboxylate
All stereocenters are known 430.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (br s, 1H), 10.62 (s, 1H), 6.29 (br s, 1H), 6.21 (s, 1H), 5.02-4.95 (m, 1H), 3.82 (s, 2H), 3.30 (brd, J=3.8 Hz, 2H), 3.07 (quin, J = 8.2 Hz, 1H), 2.44-2.37 (m, 1H), 2.19 (s, 3H), 2.05-1.97 (m, 1H), 1.90-1, 82 (m, 1H), 1.78-1.68 (m, 2H), 1.64 (dt, J=4.3, 8.9 Hz, 1H), 1.47 (s, 6H), 1 .31 (s, 6H) 134
(B)

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylpyrrolidine -1-carboxylate
All stereocenters are known 416.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.24-12.02 (m, 1H), 10.62 (s, 1H), 6.30 (br s, 1H), 6.22 ( s, 1H), 5.09-4.94 (m, 1H), 3.83 (s, 2H), 3.35-3.26 (m, 2H), 3.09 (brd, J= 8.0 Hz, 1H), 2.48-2.33 (m, 1H), 2.20 (s, 3H), 2.08-1.97 (m, 1H), 1.94-1.81 (m, 1H), 1.80-1.61 (m, 7H), 1.33-1.22 (m, 6H) 135
(A)

(1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl 2,2-dimethylpyrrolidin-1-carboxylate
All stereocenters are known 402.2 ¹ H NMR (400 MHz, DMSO-d6, T=80C) δ=11.90 (br s, 1H), 10.30 (br s, 1H), 8.76 (d, J=1.8 Hz, 1H), 6.51 (d, J=1.5 Hz, 1H), 6.28 (br s, 1H), 5.04 (br s, 1H), 3.77 (s, 2H ), 3.34 (b.t, J=6.5 Hz, 2H), 3.14 (b.d, J=3.3 Hz, 1H), 2.46 (b.s, 1H), 2 .11-1.98 (m, 1H), 1.96-1.86 (m, 1H), 1.84-1.62 (m, 7H), 1.31 (s, 6H) 136
(A)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylpyrrolidin- 1-carboxylate
All stereocenters are known 415.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.22-11.91 (m, 1H), 10.35 (br s, 1H), 7.54 (s, 1H), 7.29 ( s, 1H), 6.30 (br s, 1H), 5.15-4.85 (m, 1H), 3.78 (s, 3H), 3.33-3.21 (m, 3H) , 3.06 (brd, J=6.5 Hz, 1H), 2.44-2.32 (m, 1H), 2.00 (brd, J=6.8 Hz, 1H), 1.94-1.58 (m, 9H), 1.37-1.21 (m, 6H) 137
(A)

(1 R ,3 S )-3-{3-[([1,2,4]triazolo[1,5- a ]pyrimidin-6-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl 2 ,2-dimethylpyrrolidine-1-carboxylate
All stereocenters are known 453.2 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.66 (s, 1H), 9.33 (d, J=2.0 Hz, 1H), 8 .84 (d, J=2.3 Hz, 1H), 8.66 (s, 1H), 6.29 (br s, 1H), 5.13-4.89(m, 1H), 3, 85 (s, 2H), 3.33-3.29 (m, 1H), 3.26 (bt, J=6.1 Hz, 1H), 3.13-3.02 (m, 1H) , 2.44-2.32 (m, 1H), 2.06-1.96 (m, 1H), 1.93-1.82 (m, 1H), 1.80-1.57 (m, 7H), 1.35-1.19 (m, 6H) 138
(A)

(1 R ,3 S )-3-{3-[(1,3-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl 2,2-dimethylpyrrolidin-1-carboxylate
All stereocenters are known 402.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.23-12.01 (m, 1H), 10.57 (s, 1H), 8.26 (s, 1H), 6.99 (s, 1H), 6.29 (br s, 1H), 5.12-4.87 (m, 1H), 3.77 (s, 2H), 3.32-3.25 (m, 2H), 3 .06 (brd, J=7.0 Hz, 1H), 2.45-2.35 (m, 1H), 2.01 (br.s, 1H), 1.85 (br.s, 1H ), 1.81-1.58 (m, 7H), 1.34-1.21 (m, 6H) 139
(A)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpyrrolidine-1-carboxylate
All stereocenters are known 418.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.58 (s, 1H), 7.41 (s, 1H), 6.30 (s, 1H) , 5.02 (brs, 1H), 3.81 (s, 3H), 3.24 (brs, 2H), 3.13-3.02 (m, 1H), 2.59 (s , 3H), 2.45-2.36 (m, 1H), 2.06-1.97 (m, 1H), 1.95-1.59 (m, 7H), 1.48 (br.s , 1H), 1.14-0.98 (m, 3H) 140
(A)

(1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-2 -methylpyrrolidine-1-carboxylate
All stereocenters are known 401.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.05 (br s, 1H), 10.35 (br s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.29 (br s, 1H), 5.01 (br s, 1H), 3.78 (s, 4H), 3.38-3.34 (m, 2H), 3.24 (br.s, 2H), 3.07 (quin, J=8.2 Hz, 1H), 2.42 (br.d, J=8.3 Hz, 1H), 2.12-1.58 ( m, 8H), 1.49 (brs, 1H), 1.13-0.98 (m, 3H) 141
(A)

(1 R ,3 S )-3-{3-[([1,2,4]triazolo[1,5- a ]pyrimidin-6-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2 S )-2-methylpyrrolidine-1-carboxylate
All stereocenters are known 438.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (br s, 1H), 10.65 (s, 1H), 9.33 (s, 1H), 8.84 (d, J= 2.0Hz, 1H), 8.66(s, 1H), 6.30(s, 1H), 5.01(brs, 1H), 3.90-3.68(m, 3H), 3.29-3.15 (m, 2H), 3.14-3.02 (m, 1H), 2.44-2.36 (m, 1H), 2.01 (brd, J=9 .0 Hz, 1H), 1.95-1.58 (m, 7H), 1.45 (brs, 1H), 1.13-0.94 (m, 3H) 142
(B)

(1 R ,3 S )-3-[3-({[2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl 2,2-dimethylazetidine-1-carboxylate
All stereocenters are known 475.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (brd, J=7.0 Hz, 1H), 10.59 (brd s, 1H), 7.96 (dd, J= 1.3, 8.0 Hz, 1H), 7.72-7.64 (m, 1H), 7.58-7.52 (m, 1H), 7.50 (d, J=7.5 Hz , 1H), 6.27 (s, 1H), 5.04-4.91 (m, 1H), 4.18 (s, 2H), 3.69 (bt, J=8.3 Hz, 1H), 3.63 (t, J=7.7 Hz, 1H), 3.28 (s, 3H), 3.06 (brd, J=8.5 Hz, 1H), 2.48- 2.34 (m, 1H), 2.04-1.96 (m, 1H), 1.96-1.79 (m, 3H), 1.77-1.56 (m, 3H), 1, 37-1.25 (m, 6H) 143
(B)

(1 S ,3 R )-3-[3-({[2-(methylsulfonyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl 2,2-dimethylazetidine-1-carboxylate
All stereocenters are known 475.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (brd, J=8.0 Hz, 1H), 10.58 (brd s, 1H), 7.96 (dd, J= 1.1, 7.9 Hz, 1H), 7.71-7.64 (m, 1H), 7.57-7.52 (m, 1H), 7.50 (d, J=7.8 Hz , 1H), 6.27 (s, 1H), 5.02-4.90 (m, 1H), 4.18 (s, 2H), 3.69 (bt, J=7.8 Hz, 1H), 3.63 (t, J=7.7 Hz, 1H), 3.28 (s, 3H), 3.11-3.00 (m, 1H), 2.46-2.32 (m , 1H), 2.04-1.96 (m, 1H), 1.94-1.88 (m, 2H), 1.87-1.79 (m, 1H), 1.76-1.65 (m, 2H), 1.64-1.55 (m, 1H), 1.34 (d, J=5.8Hz, 3H), 1.28 (d, J=9.5Hz, 3H) 144
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine-1-carboxylate
All stereocenters are known 428.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (br s, 1H), 10.51 (br s, 1H), 8.06 (br s, 1H), 7.62 ( dd, J=2.4, 8.4 Hz, 1H), 6.76 (brd, J=8.5 Hz, 1H), 6.27 (br s, 1H), 5.07-4 .85(m, 1H), 3.87-3.77(m, 3H), 3.73-3.59(m, 2H), 3.52(brs, 2H), 3.04(br .s, 1H), 2.46-2.32 (m, 1H), 1.99 (br.s, 1H), 1.96-1.88 (m, 2H), 1.84 (br.s , 1H), 1.76-1.54 (m, 3H), 1.37-1.25 (m, 6H) 145
(B)

(1 S ,3 R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine-1-carboxylate
All stereocenters are known 428.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.07 (brd, J=7.0 Hz, 1H), 10.51 (brd s, 1H), 8.06 (d, J= 2.0 Hz, 1H), 7.62 (dd, J=2.5, 8.5 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.28 (br. s, 1H), 5.06-4.90 (m, 1H), 3.81 (s, 3H), 3.72-3.66 (m, 1H), 3.63 (t, J=7, 7 Hz, 1H), 3.52 (s, 2H), 3.10-2.99 (m, 1H), 2.45-2.32 (m, 1H), 2.05-1.96 (m , 1H), 1.95-1.89 (m, 2H), 1.87-1.77 (m, 1H), 1.76-1.65 (m, 2H), 1.62 (br.dd , J=4.9, 9.2 Hz, 1H), 1.34 (d, J=5.8 Hz, 3H), 1.28 (d, J=8.3 Hz, 3H) 146
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine-1-carboxylate
All stereocenters are known 428.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (brd, J=7.3 Hz, 1H), 10.57 (brd s, 1H), 8.07 (d, J= 5.3 Hz, 1H), 6.91 (d, J=4.3 Hz, 1H), 6.73 (s, 1H), 6.28 (br s, 1H), 5.08-4, 86 (m, 1H), 3.82 (s, 3H), 3.74-3.54 (m, 4H), 3.06 (brd, J=7.3 Hz, 1H), 2.46 -2.34(m, 1H), 2.05-1.78(m, 4H), 1.77-1.55(m, 3H), 1.41-1.21(m, 6H) 147
(B)

(1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine -1-carboxylate
All stereocenters are known 402.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (br s, 1H), 10.61 (br s, 1H), 6.74 (s, 1H), 6.28 (br s, 1H), 6.28 (br s, 1H). s, 1H), 4.98 (brd, J=19.1Hz, 1H), 3.79 (s, 2H), 3.70 (brd, J=6.8Hz, 1H), 3 .64 (b.t, J=7.4 Hz, 1H), 3.07 (b.d, J=6.8 Hz, 1H), 2.42 (b.s, 1H), 2.25 ( s, 3H), 2.12-1.81 (m, 4H), 1.79-1.52 (m, 3H), 1.45-1.22 (m, 6H) 148
(B)

(1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine- 1-carboxylate
All stereocenters are known 401.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.02 (brd, J=2.2 Hz, 1H), 10.34 (s, 1H), 7.53 (s, 1H), 7 .28 (s, 1H), 6.27 (s, 1H), 5.04-4.90 (m, 1H), 3.77 (s, 3H), 3.72 (dt, J=3.2 , 7.5 Hz, 1H), 3.64 (t, J=7.5 Hz, 1H), 3.38 (s, 2H), 3.10-2.98 (m, 1H), 2.42 (dt, J=8.0, 15.1 Hz, 1H), 2.04-1.97 (m, 1H), 1.96-1.90 (m, 2H), 1.89-1.79 (m, 1H), 1.77-1.66 (m, 2H), 1.65-1.56 (m, 1H), 1.38-1.28 (m, 6H) 149
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,4 S )-2,4 -dimethylazetidine-1-carboxylate
All stereocenters are known 428.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.3, 5.3 Hz, 1H), 6.73 (s, 1H), 6.27 (s, 1H), 4.99-4.91 (m, 1H), 4, 22-4.11(m, 2H), 3.82(s, 3H), 3.58(s, 2H), 3.08-2.98(m, 1H), 2.45-2.37( m, 1H), 1.99 (brd, J=8.5 Hz, 1H), 1.85 (t, J=6.7 Hz, 3H), 1.76-1.64 (m, 2H ), 1.59 (dt, J=4.4, 9.0 Hz, 1H), 1.28 (d, J=6.0 Hz, 3H), 1.20 (d, J=6.3 Hz , 3H) 150
(B)

(1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,4 S )-2,4-dimethylazetidine-1-carboxylate
All stereocenters are known 401.9 ¹ H NMR (400 MHz, DMSO-d6) δ=12.13 (s, 1H), 10.62 (s, 1H), 6.29 (d, J=1.8 Hz, 1H), 6.21 (s, 1H), 5.02-4.95 (m, 1H), 4.25-4.15 (m, 2H), 3.82 (s, 2H), 3.06 (br s, 1H ), 2.41 (brd, J=7.8 Hz, 1H), 2.19 (s, 3H), 2.00 (brd, J=8.5 Hz, 1H), 1.87 (t, J=6.7 Hz, 3H), 1.76-1.65 (m, 2H), 1.59 (brs, 1H), 1.30-1.21 (m, 6H) 151
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2-methylazetidine-1-carboxylate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 2-methylazetidine has not been determined 414.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.54 (br s, 1H), 8.06 (d, J=2.0 Hz, 1H) , 7.63 (dd, J=2.4, 8.4 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.28 (br s, 1H), 5, 06-4.88(m, 1H), 4.30-4.14(m, 1H), 3.82(s, 3H), 3.72(bt, J=7.3Hz, 2H) , 3.53(s, 2H), 3.06(quin, J=8.2Hz, 1H), 2.43-2.34(m, 1H), 2.29-2.18(m, 1H ), 2.04-1.94(m, 1H), 1.92-1.80(m, 1H), 1.78-1.58(m, 4H), 1.24(brs, 3H )
[α] _D ²⁵ +15.0 ( c 0.12, MeOH)
Peak 1 of 2 Column: Chiralpak AD-3 50×3 mm×3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 152
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2-methylazetidine-1-carboxylate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 2-methylazetidine has not been determined 414.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (br s, 1H), 10.54 (br s, 1H), 8.07 (d, J=1.8 Hz, 1H) , 7.63 (dd, J=2.3, 8.5 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.28 (br s, 1H), 4, 98 (br s, 1H), 4.20 (br d, J=7.0 Hz, 1H), 3.82 (s, 3H), 3.72 (br s, 2H), 3.53 (s, 2H), 3.06 (brt, J=8.3 Hz, 1H), 2.39 (brd, J=6.8, 14.1 Hz, 1H), 2.22 ( latitude, J=7.8 Hz, 1H), 2.06-1.94 (m, 1H), 1.91-1.80 (m, 1H), 1.75-1.57 (m, 4H), 1.24 (brs, 3H)
[α] _D ²⁵ -21.15° ( c 0.104, MeOH)
Peak 2 of 2 Column: Chiralpak AD-3 50×3 mm x3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 153
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2-methylazetidine-1-carboxylate - Isomer A
Single stereoisomer; the absolute configuration of the chiral center in 2-methylazetidine has not been determined 414.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.58 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6 .91 (dd, J=1.0, 5.3 Hz, 1H), 6.74 (s, 1H), 6.28 (br.s, 1H), 5.06-4.89 (m, 1H ), 4.30-4.15 (m, 1H), 3.83 (s, 3H), 3.71 (bt, J=7.5 Hz, 2H), 3.58 (s, 2H) , 3.06 (quin, J=8.3 Hz, 1H), 2.44-2.35 (m, 1H), 2.28-2.16 (m, 1H), 2.05-1.95 (m, 1H), 1.91-1.80 (m, 1H), 1.78-1.56 (m, 4H), 1.24 (brs, 3H)
[α] _D ²⁵ +17.40 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 50 x 3 mm x 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 154
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (2ξ)-2-methylazetidine-1-carboxylate - Isomer B
Single stereoisomer; the absolute configuration of the chiral center in 2-methylazetidine has not been determined 414.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.59 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6 .91 (dd, J=1.0, 5.3 Hz, 1H), 6.74 (s, 1H), 6.28 (br.s, 1H), 4.98 (br.s, 1H), 4.26-4.12 (m, 1H), 3.83 (s, 3H), 3.72 (br s, 2H), 3.58 (s, 2H), 3.07 (quin, J= 8.1 Hz, 1H), 2.43-2.33 (m, 1H), 2.29-2.16 (m, 1H), 2.05-1.94 (m, 1H), 1.92 -1.78(m, 1H), 1.76-1.57(m, 4H), 1.24(bd, J=4.3Hz, 3H)
[α] _D ²⁵ -33.15 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 50 x 3 mm x 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min Column temperature 40°C 155
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R* ,3 S* )-3 -cyano-2-methylazetidine-1-carboxylate - Isomer A
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 439.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.09 (s, 1H), 10.58 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.3, 5.3 Hz, 1H), 6.74 (s, 1H), 6.29 (s, 1H), 5.04-4.95 (m, 1H), 4, 41 (quin, J=6.3 Hz, 1H), 4.02-3.88 (m, 2H), 3.82 (s, 3H), 3.58 (s, 2H), 3.39-3 .34 (m, 1H), 3.07 (bt, J=8.0 Hz, 1H), 2.39 (td, J=7.3, 14.4 Hz, 1H), 1.99 ( br.d, J=7.8 Hz, 1H), 1.93-1.83 (m, 1H), 1.80-1.59 (m, 3H), 1.33 (br.d, J= 4.0Hz, 3H)
[[α] _D ²⁵ -10 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 50×3 mm ID, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min; Column temperature 40°C 156
(B)

(1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R* ,3 S* )-3 -cyano-2-methylazetidine-1-carboxylate - Isomer B
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 439.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.59 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6 .92 (dd, J=1.3, 5.3 Hz, 1H), 6.74 (s, 1H), 6.29 (br.s, 1H), 5.01 (br.s, 1H), 4.40 (quin, J=6.3 Hz, 1H), 4.05-3.90 (m, 2H), 3.82 (s, 3H), 3.58 (s, 2H), 3.33 -3.26(m, 1H), 3.07(brt, J=8.2Hz, 1H), 2.43-2.31(m, 1H), 2.00(q, J=7 .7 Hz, 1H), 1.91-1.81 (m, 1H), 1.80-1.62 (m, 3H), 1.33 (brd, J=6.0 Hz, 3H)
[α] _D ²⁵ -8 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 50x3mm I, D, 3 µm; Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 2ml/min; Column temperature 40°C 157
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S* ,3 R* )-3 -cyano-2-methylazetidine-1-carboxylate - Isomer A
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 439.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (s, 1H), 10.54 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.63 (dd, J=2.4, 8.4 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.28 (br. s, 1H), 5.01 (br. s, 1H), 4.40 (quin, J=6.3 Hz, 1H), 4.04-3.88 (m, 2H), 3.81 (s, 3H), 3.53 (s, 2H ), 3.34-3.28 (m, 1H), 3.07 (quin, J=8.2 Hz, 1H), 2.42-2.32 (m, 1H), 2.04-1, 95 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.60 (m, 3H), 1.32 (brd, J=5.8 Hz, 3H)
[α] _D ²⁵ -8 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 158
(B)

(1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S* ,3 R* )-3 -cyano-2-methylazetidine-1-carboxylate - Isomer B
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 439.4 ¹ H NMR (400 MHz, DMSO-d6) δ=12.08 (s, 1H), 10.53 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.63 (dd, J=2.4, 8.4 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.28 (s, 1H), 5.04-4.94 ( m, 1H), 4.41 (quin, J=6.3 Hz, 1H), 4.02-3.87 (m, 2H), 3.81 (s, 3H), 3.52 (s, 2H ), 3.39-3.35 (m, 1H), 3.06 (quin, J=8.0 Hz, 1H), 2.44-2.34 (m, 1H), 1.99 (br. d, J=7.5 Hz, 1H), 1.90-1.81 (m, 1H), 1.80-1.56 (m, 3H), 1.32 (br s, 3H)
[α] _D ²⁵ -10 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 159
(B)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S* , 3 R* )-3-cyano-2-methylazetidine-1-carboxylate - Isomer A
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 429.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (s, 1H), 10.60 (s, 1H), 7.40 (s, 1H), 6.31 (s, 1H), 5 .02 (brs, 1H), 4.41 (quin, J=6.2 Hz, 1H), 4.09-3.87 (m, 2H), 3.81 (s, 2H), 3, 39-3.35 (m, 1H), 3.08 (quin, J=8.3 Hz, 1H), 2.58 (s, 3H), 2.43-2.31 (m, 1H), 2 .04-1.96 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.61 (m, 3H), 1.34 (brd, J=6, 0Hz, 3H)
[α] _D ²⁵ -6 ( c 0.1, MeOH)
Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 160
(B)

(1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S* , 3 R* )-3-cyano-2-methylazetidine-1-carboxylate - Isomer B
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 429.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.11 (s, 1H), 10.59 (s, 1H), 7.40 (s, 1H), 6.30 (br s, 1H) , 5.06-4.95 (m, 1H), 4.42 (quin, J=6.3 Hz, 1H), 4.04-3.89 (m, 2H), 3.80 (s, 2H ), 3.40-3.35 (m, 1H), 3.08 (quin, J=8.3 Hz, 1H), 2.58 (s, 3H), 2.40 (td, J=7, 3, 14.4 Hz, 1H), 2.00 (brd, J=7.8 Hz, 1H), 1.91-1.82 (m, 1H), 1.81-1.60 (m , 3H), 1.40-1.39 (m, 1H), 1.34 (brd, J=5.3 Hz, 2H)
[α] _D ²⁵ -10 ( c 0.1, MeOH)
Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm ID, 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; Flow rate: 2.5ml/min; Column temperature 35°C 161
(B)

(1 R ,3 S )-3-{3-[(phenylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl (2 S* ,3 R* )-3-cyano-2-methylazetidine-1- carboxylate - Isomer A
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 408.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (s, 1H), 10.50 (s, 1H), 7.34-7.21 (m, 5H), 6.29 (s, 1H), 4.99 (brd, J=2.8 Hz, 1H), 4.41 (quin, J=6.2 Hz, 1H), 4.02-3.88 (m, 2H), 3.57 (s, 2H), 3.40-3.35 (m, 1H), 3.06 (quin, J=8.2 Hz, 1H), 2.47-2.32 (m, 1H) , 1.99 (brd, J=7.0 Hz, 1H), 1.89-1.80 (m, 1H), 1.79-1.59 (m, 3H), 1.32 (br .s, 3H)
[α] _D ²⁵ -16.3 ( c 0.11, MeOH)
Peak 1 of 2: Column: Chiralpak AD-3 50*4.6 mm ID, 3 µm: Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 4ml/min; Column temperature 40°C 162
(B)

(1 R ,3 S )-3-{3-[(phenylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl (2 S* ,3 R* )-3-cyano-2-methylazetidine-1- carboxylate - Isomer B
Single stereoisomer; the methyl and cyano groups on the azetidine ring are trans, but the absolute stereochemistry of these groups has not been determined 408.3 ¹ H NMR (400 MHz, DMSO-d6) δ=12.06 (s, 1H), 10.51 (s, 1H), 7.33-7.21 (m, 5H), 6.29 (s, 1H), 5.01 (br s, 1H), 4.40 (quin, J=6.3 Hz, 1H), 4.03-3.88 (m, 2H), 3.57 (s, 2H ), 3.32-3.24 (m, 1H), 3.07 (quin, J=8.3 Hz, 1H), 2.47-2.33 (m, 1H), 1.99 (br. d, J=7.5 Hz, 1H), 1.93-1.79 (m, 1H), 1.79-1.60 (m, 3H), 1.32 (brd, J=5, 8Hz, 3H)
[α] _D ²⁵ -7.27 ( c 0.12, MeOH)
Peak 2 of 2: Column: Chiralpak AD-3 50*4.6 mm ID, 3 µm: Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; Flow rate: 4ml/min; Column temperature 40°C

Additional compounds of the invention were prepared by modifications of the methods exemplified herein and are shown in Table 3.

Table 3 Example No Structure LCMS [M+H] ⁺ IUPAC name 163

361.3 (1 S ,3 R )-3-(3-{[(1-methyl- 1H -pyrazol-5-yl)carbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl propylcarbamate 164

361.4 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-5-yl)carbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 165

361.2 ( 1S , 3R )-3-{3-[(1H - imidazol-4-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propyl carbamate 166

362.3 ( 1S , 3R )-3-{3-[(1,3-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl propyl carbamate 167

362.1 ( 1R , 3S )-3-{3-[(1,3-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl propyl carbamate 168

362.3 (1 S ,3 R )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propyl carbamate 169

362.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propyl carbamate 170

372.3 (1 S ,3 R )-3-(3-{[(2-methylpyridin-4-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate 171

372.3 ( 1S , 3R )-3-{3-[(pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propyl carbamate 172

375.3 (1 S ,3 R )-3-(3-{[(1,3-dimethyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propylcarbamate 173

375.3 (1 R ,3 S )-3-(3-{[(1,3-dimethyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate 174

375.3 (1 S ,3 R )-3-(3-{[(1,3-dimethyl- 1H -pyrazol-4-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate 175

376.4 (1 S ,3 R )-3-(3-{[(2-methyl-1,3-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 176

376.0 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 177

376.4 (1 S ,3 R )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 178

376.0 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 179

378.09 (1 R ,3 S )-3-{3-[(1,3-thiazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propyl carbamate 180

386.3 (1 S ,3 R )-3-(3-{[(2,6-dimethylpyridin-3-yl)carbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 181

386.4 (1 R ,3 S )-3-(3-{[(2,6-dimethylpyridin-3-yl)carbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 182

388.4 (1 S ,3 R )-3-(3-{[(6-methoxypyridin-3-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate 183

388.4 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate 184

388.2 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propyl carbamate 185

392.1 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 186

402.3 (1 S ,3 R )-3-(3-{[(5-methoxypyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propylcarbamate 187

402.3 (1 R ,3 S )-3-(3-{[(5-methoxypyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propylcarbamate 188

402.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propylcarbamate 189

408.1 (1 S ,3 R )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 190

408.1 (1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 191

411.3 (1 S ,3 R )-3-{3-[(imidazo[1,2-a]pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propylcarbamate 192

413.3 ( 1S , 3R )-3-(3-{[( 5S )-5-(dimethylamino)-6,7-dihydro- 5H- cyclopenta[b]pyridin-2-yl]amino} -1H -pyrazol-5-yl)cyclopentyl propyl carbamate 193

418.2 (1 S ,3 R )-3-(3-{[(5-hydroxy-2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 194

418.2 (1 S ,3 R )-3-(3-{[(3-hydroxy-2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propyl carbamate 195

418.4 (1 R ,3 S )-3-{3-[({1-[2-(dimethylamino)ethyl] -1H -pyrazol-5-yl}carbonyl)amino] -1H -pyrazol-5-yl} cyclopentyl propyl carbamate 196

428.1 ( 1R , 3S )-3-{3-[(1,3-Benzothiazol-7-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl propyl carbamate 197

430.4 (1 S ,3 R )-3-[3-({[2-(2-aminoethoxy)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl propyl carbamate 198

[M+Na] ⁺
452.2 (1 S ,3 R )-3-[3-({[4-(2-aminoethoxy)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl propyl carbamate 199

431.3 (1 S ,3 R )-3-(3-{[(3-methylimidazo[2,1- b ][1,3]thiazol-6-yl)acetyl]amino}-1 H- pyrazol-5-yl )cyclopentyl propyl carbamate 200

445.2 (1 S ,3 R )-3-(3-{[(2,3-dimethylimidazo[2,1- b ][1,3]thiazol-6-yl)acetyl]amino}-1 H- pyrazole-5 -yl) cyclopentyl propyl carbamate 201

448.2 (1 R ,3 S )-3-[3-({[2-(ξ-methylsulfonimidoyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propylcarbamate - Isomer A 202

448.2 (1 R ,3 S )-3-[3-({[2-(ξ-methylsulfonimidoyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propylcarbamate - Isomer B 203

449.3 (1 S ,3 R )-3-[3-({[2-(methylsulfonyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl propyl carbamate 204

449.9 (1 R ,3 S )-3-(3-{[(2-sulfamoylphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propylcarbamate 205

463.4 (1 R ,3 S )-3-[3-({[2-(ethylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propyl carbamate 206

463.4 (1 R ,3 S )-3-[3-({[5-methyl-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propyl carbamate 207

463.4 (1 R ,3 S )-3-[3-({[4-methyl-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propyl carbamate 208

464.3 (1 R ,3 S )-3-[3-({[2-methyl-5-(methylsulfonyl)pyridin-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propyl carbamate 209

463.8 (1 R ,3 S )-3-[3-({[2-(methylsulfamoyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl propyl carbamate 210

475.4 (1 R ,3 S )-3-[3-({[2-(cyclopropylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propyl carbamate 211

477.3 (1 R ,3 S )-3-[3-({[2-(propan-2-ylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propylcarbamate 212

479.3 (1 R ,3 S )-3-[3-({[4-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propylcarbamate 213

479.1 (1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propyl carbamate 214

480.3 (1 R ,3 S )-3-[3-({[2-methoxy-5-(methylsulfonyl)pyridin-4-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl propyl carbamate 215

493.3 (1 R ,3 S )-3-[5-({[4-(methoxymethyl)-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-3-yl]cyclopentyl propyl carbamate 216

429.3 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (3,3,3 -trifluoropropyl)carbamate 217

430.4 (1 R ,3 S )-3-(3-{[(2-methyl-2 H -1,2,3-triazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (3,3,3-trifluoropropyl)carbamate 218

430.4 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (3,3, 3-trifluoropropyl)carbamate 219

432.3 (1 R ,3 S )-3-{3-[(1,3-thiazol-2-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl (3,3,3-trifluoropropyl)carbamate 220

441.3 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3,3,3-trifluoropropyl)carbamate 221

446.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-thiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (3,3, 3-trifluoropropyl)carbamate 222

457.4 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3,3,3-trifluoropropyl)carbamate 223

462.1 (1 R ,3 S )-3-(3-{[(5-methoxy-1,3-thiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3,3, 3-trifluoropropyl)carbamate 224

533.3 (1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (3,3,3-trifluoropropyl ) carbamate 225

403.9 ( 1R , 3S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl dipropyl carbamate 226

347.9 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ethyl carbamate 227

372.3 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ethyl carbamate 228

375.1 (1 R ,3 S )-3-(3-{[(4-fluorophenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ethylcarbamate 229

378.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ethyl carbamate 230

387.3 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ethylcarbamate 231

388.2 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ethyl carbamate 232

388.2 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ethyl carbamate 233

393.1 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ethylcarbamate 234

414.3 (1 R ,3 S )-3-{3-[(1,3-Benzothiazol-4-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ethyl carbamate 235

413.8 ( 1R , 3S )-3-{3-[(1,3-Benzothiazol-7-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ethyl carbamate 236

361.9 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl ethyl(methyl)carbamate 237

386.3 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 238

389.3 (1 R ,3 S )-3-(3-{[(4-fluorophenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 239

392.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 240

401.3 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 241

402.3 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 242

402.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 243

402.3 (1 S ,3 R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 244

402.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 245

407.3 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ethyl(methyl)carbamate 246

384.0 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl (2,2-difluoroethyl)carbamate 247

408.3 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2-difluoroethyl)carbamate 248

411.1 (1 R ,3 S )-3-(3-{[(4-fluorophenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (2,2-difluoroethyl)carbamate 249

414.1 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2- difluoroethyl) carbamate 250

423.2 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (2,2-difluoroethyl)carbamate 251

424.2 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2-difluoroethyl)carbamate 252

424.2 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2-difluoroethyl)carbamate 253

429.1 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2-difluoroethyl)carbamate 254

432.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2, 2-trifluoroethyl)carbamate 255

442.2 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2,2,2-trifluoroethyl)carbamate 256

374.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methylcarbamate 257

360.2 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl carbamate 258

376.2 ( 1S , 3R )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl butylcarbamate 259

376.1 ( 1R , 3S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl butylcarbamate 260

361.4 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -imidazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 261

362.4 (1 S ,3 R )-3-(3-{[(1-methyl- 1H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 262

362.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 263

362.3 ( 1S , 3R )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl propan-2-ylcarbamate 264

372.3 ( 1S , 3R )-3-{3-[(pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propan-2-ylcarbamate 265

372.2 ( 1R , 3S )-3-{3-[(pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl propan-2-ylcarbamate 266

375.3 (1 S ,3 R )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 267

375.3 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 268

376.4 (1 S ,3 R )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 269

376.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 270

376.4 (1 S ,3 R )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 271

376.4 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 272

376.4 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 273

392.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-thiazol-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 274

392.3 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-thiazol-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 275

401.3 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 276

402.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 277

403.4 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 278

405.3 (1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propan- 2-ylcarbamate 279

407.4 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 280

408.3 (1 R ,3 S )-3-(3-{[(5-methoxy-1,3-thiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 281

408.3 (1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 282

419.9 (1 R ,3 S )-3-(3-{[(5-chloro-6-methylpyridin-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 283

428.4 ( 1R , 3S )-3-{3-[(1,3-Benzothiazol-4-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl propan-2-ylcarbamate 284

427.8 ( 1R , 3S )-3-{3-[(1,3-Benzothiazol-7-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl propan-2-ylcarbamate 285

432.5 (1 R ,3 S )-3-(3-{[(2,5-dimethoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl propan-2-ylcarbamate 286

440.3 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyridin-2-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate 287

441.1 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate 288

479.3 (1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate 289

390.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methyl(propan-2 -yl)carbamate 290

390.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methyl(propan-2 -yl)carbamate 291

533.3 (1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [(2ξ)-1,1 ,1-trifluoropropan-2-yl]carbamate - Isomer A 292

533.3 (1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [(2ξ)-1,1 ,1-trifluoropropan-2-yl]carbamate - Isomer B 293

376.2 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butyl carbamate 294

386.4 ( 1R , 3S )-3-{3-[(pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl tert- butylcarbamate 295

390.4 ( 1R , 3S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert-butyl carbamate 296

390.4 ( 1R , 3S )-3-(3-{[(4-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert-butyl carbamate 297

390.1 (1 R ,3 S )-3-(3-{[(4-methyl-1 H -1,2,3-triazol-1-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl tert- butyl carbamate 298

391.4 ( 1R , 3S )-3-(3-{[(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 299

401.4 ( 1R , 3S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butylcarbamate 300

404.3 ( 1R , 3S )-3-(3-{[(5-fluoropyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butylcarbamate 301

404.4 ( 1R , 3S )-3-(3-{[(3-fluoropyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butylcarbamate 302

405.3 (1 R ,3 S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butyl carbamate 303

406.2 ( 1R , 3S )-3-(3-{[(5-methyl-1,3-thiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 304

406.0 ( 1R , 3S )-3-(3-{[(2-methyl-1,3-thiazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 305

407.4 ( 1R , 3S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butylcarbamate 306

416.4 ( 1R , 3S )-3-(3-{[(2-cyclopropyl-1,3-oxazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert-butyl carbamate 307

416.3 ( 1R , 3S )-3-(3-{[(2-methoxypyridin-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 308

419.4 (1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl tert- butyl carbamate 309

419.4 (1 R ,3 S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butyl carbamate 310

420.3 ( 1R , 3S )-3-(3-{[(5-chloropyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tert- butylcarbamate 311

422.3 ( 1R , 3S )-3-(3-{[(5-Methoxy-1,3-thiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 312

433.9 ( 1R , 3S )-3-(3-{[(5-Chloro-6-methylpyridin-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 313

433.9 ( 1R , 3S )-3-(3-{[(3-Chloro-4-methylpyridin-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert- butylcarbamate 314

436.4 (1 R ,3 S )-3-[3-({[4-(difluoromethyl)pyridin-2-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl tert- butylcarbamate 315

446.4 ( 1R , 3S )-3-(3-{[(2,5-dimethoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tert-butyl carbamate 316

454.4 (1 R ,3 S )-3-[3-({[4-(trifluoromethyl)pyridin-2-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl tert- butylcarbamate 317

455.4 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl tert- butylcarbamate 318

458.1 (1 R ,3 S )-3-[3-({[2-(2,2,2-trifluoroethyl)-2 H -1,2,3-triazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl tert- butyl carbamate 319

493.4 (1 R ,3 S )-3-[3-({[5-Methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl tert-butyl carbamate 320

375.3 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate 321

375.3 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -imidazol-5-yl)carbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate 322

376.2 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl (2 R )-butan-2-ylcarbamate 323

376.2 (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate 324

386.3 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 325

387.3 (1 R ,3 S )-3-{3-[(pyrazin-2-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( 2S )-butan-2-ylcarbamate 326

389.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate 327

389.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate 328

389.4 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate 329

389.4 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -imidazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butane -2-ylcarbamate 330

390.3 (1 R ,3 S )-3-(3-{[(2-methyl-2 H -1,2,3-triazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 331

390.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 332

390.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate 333

390.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate 334

391.4 (1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 335

400.4 (1 R ,3 S )-3-(3-{[(2-methylpyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 336

401.2 (1 R ,3 S )-3-(3-{[(6-methylpyrazin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 337

403.4 (1 R ,3 S )-3-(3-{[(1,5-dimethyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S ) -butan-2-ylcarbamate 338

403.4 (1 R ,3 S )-3-(3-{[(1,3-dimethyl- 1H -pyrazol-5-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S ) -butan-2-ylcarbamate 339

404.1 (1 R ,3 S )-3-(3-{[(2-ethyl-2 H -1,2,3-triazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 340

404.4 (1 R ,3 S )-3-(3-{[(3,5-dimethyl-1,2-oxazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 341

406.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-thiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate 342

406.2 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate 343

406.2 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-thiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- butan-2-ylcarbamate 344

407.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 345

416.4 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 346

416.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 347

417.1 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 348

417.3 (1 R ,3 S )-3-(3-{[(6-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 349

417.3 (1 R ,3 S )-3-[3-({[1-(propan-2-yl)-1 H -pyrazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate 350

418.2 (1 R ,3 S )-3-[3-({[1-(propan-2-yl)-1 H -1,2,3-triazol-4-yl]acetyl}amino)-1 H -pyrazole -5-yl]cyclopentyl (2 S )-butan-2-ylcarbamate 351

419.4 (1 R ,3 S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (2 S )-butan-2-ylcarbamate 352

420.3 (1 R ,3 S )-3-(3-{[(2,4-dimethyl-1,3-thiazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 353

422.4 (1 R ,3 S )-3-(3-{[(5-methoxy-1,3-thiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S )- butan-2-ylcarbamate 354

426.3 (1 R ,3 S )-3-{3-[(imidazo[1,2- a ]pyrimidin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2S )-butan-2 -ylcarbamate 355

431.3 (1 R ,3 S )-3-{3-[(imidazo[2,1- b ][1,3]thiazol-6-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl (2 S )-butan-2-ylcarbamate 356

432.2 (1 R ,3 S )-3-{5-[({1-[2-(dimethylamino)ethyl] -1H -pyrazol-5-yl}carbonyl)amino] -1H- pyrazol-3-yl} cyclopentyl ( 2S )-butan-2-ylcarbamate 357

440.4 (1 R ,3 S )-3-(3-{[(7-methylimidazo[1,2- a ]pyrimidin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (2 S )-butan-2-ylcarbamate 358

446.4 (1 R ,3 S )-3-(3-{[(2,5-dimethoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S )-butan-2- ilcarbamate 359

446.3 (1 R ,3 S )-3-(3-{[(2-methylimidazo[2,1- b ][1,3,4]thiadiazol-6-yl)acetyl]amino}-1 H -pyrazole-5 -yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 360

454.4 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyridin-2-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2 -ylcarbamate 361

454.4 (1 R ,3 S )-3-(3-{[(2-methyl-1-oxo-2,3-dihydro-1H - isoindol-4-yl)acetyl]amino} -1H- pyrazole-5 -yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 362

455.1 (1 R ,3 S )-3-[3-({[6-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (2 S )-butan-2 -ylcarbamate 363

455.3 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (2 S )-butan-2 -ylcarbamate 364

456.3 (1 R ,3 S )-3-[3-({[4-(dimethylcarbamoyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate 365

457.4 (1 R ,3 S )-3-[3-({[1-methyl-5-(trifluoromethyl)-1 H -pyrazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate 366

458.1 (1 R ,3 S )-3-[3-({[1-(2,2,2-trifluoroethyl)-1 H -1,2,3-triazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2-ylcarbamate 367

460.4 (1 R ,3 S )-3-(3-{[(2-ethylimidazo[2,1- b ][1,3,4]thiadiazol-6-yl)acetyl]amino} -1H- pyrazole-5 -yl)cyclopentyl ( 2S )-butan-2-ylcarbamate 368

462.3 (1 R ,3 S )-3-[3-({[2-(ξ-methylsulfonimidoyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate - Isomer A 369

462.3 (1 R ,3 S )-3-[3-({[2-(ξ-methylsulfonimidoyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate - Isomer B 370

463.4 (1 R ,3 S )-3-[3-({[2-(methylsulfonyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate 371

477.3 (1 R ,3 S )-3-[3-({[5-methyl-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2 -ylcarbamate 372

477.3 (1 R ,3 S )-3-[3-({[3-methyl-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-butan-2 -ylcarbamate 373

478.4 (1 R ,3 S )-3-[3-({[2-methyl-5-(methylsulfonyl)pyridin-4-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl ( 2S ) -butan-2-ylcarbamate 374

477.9 (1 R ,3 S )-3-[3-({[2-(methylsulfamoyl)phenyl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate 375

494.4 (1 R ,3 S )-3-[3-({[2-methoxy-5-(methylsulfonyl)pyridin-4-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (2 S ) -butan-2-ylcarbamate 376

507.3 (1 R ,3 S )-3-[5-({[4-(methoxymethyl)-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-3-yl]cyclopentyl (2 S )-butane -2-ylcarbamate 377

516.3 (1 R ,3 S )-3-[3-({[1-methyl-3-(methylsulfonyl)-1 H -indol-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl ( 2S )-butan-2-ylcarbamate 378

393.3 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2S )- 1-fluoropropan-2-yl]carbamate 379

394.4 ( 1R , 3S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [( 2S ) -1-fluoropropan-2-yl]carbamate 380

407.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S ,3 R )-3-fluorobutan-2-yl]carbamate 381

407.3 ( 1R , 3S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2S *, 3 S *)-3-fluorobutan-2-yl]carbamate - Isomer A 382

407.4 ( 1R , 3S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2S *, 3 S *)-3-fluorobutan-2-yl]carbamate - Isomer B 383

408.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S , 3 R )-3-fluorobutan-2-yl]carbamate 384

434.4 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S *,3 S *)- 3-fluorobutan-2-yl]carbamate - Isomer A 385

434.4 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S *,3 S *)- 3-fluorobutan-2-yl]carbamate - Isomer B 386

425.4 ( 1R , 3S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2ξ)-4 ,4-Difluorobutan-2-yl]carbamate - Isomer A 387

425.4 ( 1R , 3S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2ξ)-4 ,4-Difluorobutan-2-yl]carbamate - Isomer B 388

436.4 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-3,3-difluorobutan- 2-yl]carbamate - Isomer A 389

436.4 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-3,3-difluorobutan- 2-yl]carbamate - Isomer B 390

442.4 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 3,3-difluorobutan-2-yl]carbamate - Isomer A 391

442.2 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 3,3-difluorobutan-2-yl]carbamate - Isomer B 392

452.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-3,3-difluorobutan- 2-yl]carbamate - Isomer A 393

452.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-3,3-difluorobutan- 2-yl]carbamate - Isomer B 394

443.4 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 R )- 4,4,4-trifluorobutan-2-yl]carbamate 395

444.3 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 R ) -4,4,4-trifluorobutan-2-yl]carbamate 396

444.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 1,1,1-trifluorobutan-2-yl]carbamate - Isomer A 397

444.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(2ξ)- 1,1,1-trifluorobutan-2-yl]carbamate - Isomer B 398

454.4 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-1,1,1- trifluorobutan-2-yl]carbamate - Isomer A 399

454.4 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-1,1,1- trifluorobutan-2-yl]carbamate - Isomer B 400

457.4 (1 R ,3 S )-3-(3-{[(1,5-dimethyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2ξ) -4,4,4-trifluorobutan-2-yl]carbamate - Isomer A 401

457.4 (1 R ,3 S )-3-(3-{[(1,5-dimethyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [(2ξ) -4,4,4-trifluorobutan-2-yl]carbamate - Isomer B 402

459.3 ( 1R , 3S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2 R )-4,4,4-trifluorobutan-2-yl]carbamate 403

460.4 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 1,1,1-trifluorobutan-2-yl]carbamate - Isomer A 404

460.4 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 1,1,1-trifluorobutan-2-yl]carbamate - Isomer B 405

470.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-1,1,1- trifluorobutan-2-yl]carbamate - Isomer A 406

470.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-1,1,1- trifluorobutan-2-yl]carbamate - Isomer B 407

471.3 (1 R ,3 S )-3-[3-({[1-(propan-2-yl)-1 H -pyrazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A 408

471.3 (1 R ,3 S )-3-[3-({[1-(propan-2-yl)-1 H -pyrazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B 409

486.5 (1 R ,3 S )-3-{5-[({1-[2-(dimethylamino)ethyl] -1H -pyrazol-5-yl}carbonyl)amino] -1H- pyrazol-3-yl} cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A 410

486.5 (1 R ,3 S )-3-{5-[({1-[2-(dimethylamino)ethyl] -1H -pyrazol-5-yl}carbonyl)amino] -1H -pyrazol-3-yl} cyclopentyl [(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B 411

444.2 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl methyl[(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A 412

444.2 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl methyl[(2ξ)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B 413

457.4 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methyl[(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer A 414

457.4 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl methyl[(2ξ)- 4,4,4-trifluorobutan-2-yl]carbamate - Isomer B 415

390.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1H-pyrazol-5-yl}cyclopentyl [( 2S )-2-methylbutyl]carbamate 416

404.3 ( 1R , 3S )-3-(3-{[(2-methyl-1,3-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [( 2S ) -2-methylbutyl]carbamate 417

420.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl [( 2S )- 2-methylbutyl]carbamate 418

390.0 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl (2,2-dimethylpropyl)carbamate 419

374.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl (1-methylcyclopropyl)carbamate 420

384.3 (1 R ,3 S )-3-{3-[(pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl (1-methylcyclopropyl)carbamate 421

387.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 422

388.4 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl) carbamate 423

390.3 (1 R ,3 S )-3-{3-[(1,3-thiazol-4-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl (1-methylcyclopropyl)carbamate 424

398.3 (1 R ,3 S )-3-(3-{[(5-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 425

398.4 (1 R ,3 S )-3-(3-{[(4-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 426

398.4 (1 R ,3 S )-3-(3-{[(6-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 427

398.4 (1 R ,3 S )-3-(3-{[(3-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 428

399.4 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 429

402.3 (1 R ,3 S )-3-(3-{[(3-fluoropyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 430

402.3 (1 R ,3 S )-3-(3-{[(5-fluoropyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 431

404.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl) carbamate 432

414.3 (1 R ,3 S )-3-(3-{[(2-cyclopropyl-1,3-oxazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl) carbamate 433

414.3 (1 R ,3 S )-3-(3-{[(5-methoxypyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 434

414.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 435

416.4 (1 R ,3 S )-3-(3-{[(3-fluoro-6-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 436

416.1 (1 R ,3 S )-3-[3-({[1-(propan-2-yl)-1 H -1,2,3-triazol-4-yl]acetyl}amino)-1 H -pyrazole -5-yl]cyclopentyl (1-methylcyclopropyl)carbamate 437

418.4 (1 R ,3 S )-3-(3-{[(5-chloropyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 438

432.3 (1 R ,3 S )-3-(3-{[(3-chloro-5-methylpyridin-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 439

432.3 (1 R ,3 S )-3-(3-{[(5-chloro-3-methylpyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 440

432.3 (1 R ,3 S )-3-(3-{[(5-chloro-4-methylpyridin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 441

432.3 (1 R ,3 S )-3-(3-{[(3-chloro-4-methylpyridin-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 442

432.3 (1 R ,3 S )-3-(3-{[(5-chloro-6-methylpyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (1-methylcyclopropyl)carbamate 443

434.4 (1 R ,3 S )-3-[3-({[4-(difluoromethyl)pyridin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate 444

452.4 (1 R ,3 S )-3-[3-({[4-(trifluoromethyl)pyridin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate 445

452.4 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyridin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate 446

456.0 (1 R ,3 S )-3-[3-({[1-(2,2,2-trifluoroethyl)-1 H -1,2,3-triazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate 447

491.4 (1 R ,3 S )-3-[3-({[5-methoxy-2-(methylsulfonyl)phenyl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (1-methylcyclopropyl)carbamate 448

402.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (1-ethylcyclopropyl) carbamate 449

413.4 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-ethylcyclopropyl)carbamate 450

429.3 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1-ethylcyclopropyl)carbamate 451

442.4 (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl [1-(2,2,2-trifluoroethyl) cyclopropyl]carbamate 452

452.1 (1 R ,3 S )-3-(3-{[(6-methylpyridin-3-yl)carbonyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [1-(2,2,2-trifluoroethyl )cyclopropyl]carbamate 453

456.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [1-(2 ,2,2-trifluoroethyl)cyclopropyl]carbamate 454

456.1 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl [1-(2 ,2,2-trifluoroethyl)cyclopropyl]carbamate 455

467.3 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [1-(2,2,2-trifluoroethyl )cyclopropyl]carbamate 456

483.3 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [1-(2,2,2-trifluoroethyl )cyclopropyl]carbamate 457

485.4 (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl [1-(2,2,2-trifluoroethyl)cyclopropyl]carbamate 458

374.3 ( 1R , 3S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl cyclobutylcarbamate 459

403.4 (1 R ,3 S )-3-(3-{[(5-methyl-1,3,4-oxadiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (1- methylcyclobutyl)carbamate 460

387.9 ( 1R , 3S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H -pyrazol-5-yl}cyclopentyl cyclopentylcarbamate 461

402.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl [(1 R ,2 S )-2-methylcyclopentyl ]carbamate 462

416.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-oxazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(1 R , 2 S )-2-methylcyclopentyl]carbamate 463

432.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 R , 2 S )-2-methylcyclopentyl]carbamate 464

432.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 S , 2 R )-2-methylcyclopentyl]carbamate 465

374.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl (cyclopropylmethyl)carbamate 466

388.4 (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl [(1 S )-1-cyclopropylethyl]carbamate 467

388.2 (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1 H -pyrazol-5-yl}cyclopentyl [(1 R )-1-cyclopropylethyl]carbamate 468

402.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 S ) -1-cyclopropylethyl]carbamate 469

402.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 R ) -1-cyclopropylethyl]carbamate 470

413.4 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 S )-1-cyclopropylethyl]carbamate 471

413.4 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1 R )-1-cyclopropylethyl]carbamate 472

429.3 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(1 R )-1-cyclopropylethyl]carbamate 473

404.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl ]carbamate - Isomer A 474

404.3 (1 R ,3 S )-3-{3-[(1,2-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl ]carbamate - Isomer B 475

418.4 (1 S ,3 R )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 476

418.4 (1 S ,3 R )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 477

418.4 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 478

418.4 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 479

433.4 ( 1R , 3S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 480

433.4 ( 1R , 3S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 481

434.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 482

434.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)- 3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 483

442.9 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 484

442.9 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 485

445.4 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3- yl]carbamate - Isomer A 486

445.4 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3- yl]carbamate - Isomer B 487

447.5 (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 488

447.5 (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 489

455.4 (1 R ,3 S )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylacetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ) -3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 490

455.4 (1 R ,3 S )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylacetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ) -3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 491

455.4 (1 R ,3 S )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylacetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ) -3-methyltetrahydrofuran-3-yl]carbamate - Isomer C 492

455.4 (1 R ,3 S )-3-(3-{[(3ξ)-2,3-dihydro-1-benzofuran-3-ylacetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(3ξ) -3-methyltetrahydrofuran-3-yl]carbamate - Isomer D 493

483.3 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl [(3ξ)-3-methyltetrahydrofuran -3-yl]carbamate - Isomer A 494

483.3 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl [(3ξ)-3-methyltetrahydrofuran -3-yl]carbamate - Isomer B 495

485.4 (1 R ,3 S )-3-[3-({[1-methyl-5-(trifluoromethyl)-1 H -pyrazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer A 496

485.4 (1 R ,3 S )-3-[3-({[1-methyl-5-(trifluoromethyl)-1 H -pyrazol-4-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl [(3ξ)-3-methyltetrahydrofuran-3-yl]carbamate - Isomer B 497

444.2 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [( 2S )-tetrahydrofuran-2-ylmethyl ]carbamate 498

449.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [( 2R )-tetrahydrofuran-2-ylmethyl]carbamate 499

449.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [( 2S )-tetrahydrofuran-2-ylmethyl]carbamate 500

434.3 (1 S ,3 R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tetrahydro- 2H - pyran-4-ylcarbamate 501

443.3 (1 S ,3 R )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tetrahydro- 2H- pyran-4-ylcarbamate 502

443.3 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl tetrahydro- 2H- pyran-4-ylcarbamate 503

444.3 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tetrahydro- 2H- pyran-4-ylcarbamate 504

444.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl tetrahydro- 2H- pyran-4-ylcarbamate 505

449.4 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl tetrahydro- 2H- pyran-4-ylcarbamate 506

431.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (4-methyltetrahydro-2 H -pyran-4-yl) carbamate 507

431.4 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (4-methyltetrahydro-2 H -pyran-4-yl) carbamate 508

432.3 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (4-methyltetrahydro- 2 H -pyran-4-yl) carbamate 509

[M + Na] ⁺ 486.0 (1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (4-methyltetrahydro- 2 H -pyran-4-yl) carbamate 510

448.2 ( 1S , 3R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [( 3S * ,4 R *)-3-methyltetrahydro-2 H -pyran-4-yl]carbamate - Isomer A 511

448.2 ( 1S , 3R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [( 3S * ,4 R *)-3-methyltetrahydro-2 H -pyran-4-yl]carbamate - Isomer B 512

458.3 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl (tetrahydro- 2H- pyran-4-ylmethyl ) carbamate 513

463.4 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl (tetrahydro- 2H- pyran-4-ylmethyl)carbamate 514

496.4 (1 S ,3 R )-3-[3-({[6-(trifluoromethyl)pyridin-3-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl (tetrahydro- 2H- pyran- 4-ylmethyl)carbamate 515

463.4 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(3ξ)-tetrahydro- 2H- pyran-3 -ylmethyl]carbamate - Isomer A 516

463.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(3ξ)-tetrahydro- 2H- pyran-3 -ylmethyl]carbamate - Isomer B 517

401.4 (1 R ,3 S )-3-{5-[(phenylacetyl)amino]-1H - pyrazol-3-yl}cyclopentyl [( 2S )-1-methoxypropan-2-yl]carbamate 518

421.4 ( 1R , 3S )-3-(3-{[(3-methoxy-1-methyl- 1H -pyrazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl [( 2 S )-1-methoxypropan-2-yl]carbamate 519

432.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2 S )-1-methoxypropan-2 -yl]carbamate 520

433.4 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [( 2S )-1-methoxypropan-2 -yl]carbamate 521

435.4 (1 R ,3 S )-3-[5-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-3-yl]cyclopentyl [(2 S )-1-methoxypropan-2-yl]carbamate 522

438.3 ( 1R , 3S )-3-(3-{[(5-methoxy-1,3-thiazol-2-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [( 2S ) -1-methoxypropan-2-yl]carbamate 523

471.3 (1 R ,3 S )-3-[3-({[5-(trifluoromethyl)pyrazin-2-yl]acetyl}amino)-1 H- pyrazol-5-yl]cyclopentyl [(2 S )-1- methoxypropan-2-yl]carbamate 524

420.0 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(2ξ)- 2-(hydroxymethyl)butyl]carbamate - Isomer A 525

420.1 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl [(2ξ)- 2-(hydroxymethyl)butyl]carbamate - Isomer B 526

420.1 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 2-(hydroxymethyl)butyl]carbamate - Isomer A 527

420.0 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 2-(hydroxymethyl)butyl]carbamate - Isomer B 528

436.1 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 2-(hydroxymethyl)butyl]carbamate - Isomer A 529

436.1 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)- 2-(hydroxymethyl)butyl]carbamate - Isomer B 530

445.4 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl]carbamate - Isomer A 531

445.4 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl]carbamate - Isomer B 532

446.2 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl ]carbamate - Isomer A 533

446.2 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl ]carbamate - Isomer B 534

446.2 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl ]carbamate - Isomer A 535

446.2 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl ]carbamate - Isomer B 536

451.2 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl]carbamate - Isomer A 537

451.2 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-(hydroxymethyl)butyl]carbamate - Isomer B 538

437.3 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(2ξ)-3-hydroxy-2-methylpropyl] carbamate - Isomer A 539

437.3 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(2ξ)-3-hydroxy-2-methylpropyl] carbamate - Isomer B 540

431.3 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-hydroxybutyl]carbamate - Isomer A 541

431.3 (1 R ,3 S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl [(2ξ)-2-hydroxybutyl]carbamate - Isomer B 542

437.3 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-hydroxybutyl]carbamate - Isomer A 543

437.3 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(2ξ)-2-hydroxybutyl]carbamate - Isomer B 544

442.4 ( 1S , 3R )-3-(3-{[(2-methylpyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxycyclohexyl)carbamate 545

442.4 ( 1S , 3R )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxycyclohexyl)carbamate 546

442.4 ( 1S , 3R )-3-(3-{[(5-methylpyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxycyclohexyl)carbamate 547

442.4 ( 1S , 3R )-3-(3-{[(2-methylpyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate 548

442.4 ( 1S , 3R )-3-(3-{[(6-methylpyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate 549

442.4 ( 1S , 3R )-3-(3-{[(5-methylpyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate 550

448.4 ( 1S , 3R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis -4- hydroxycyclohexyl)carbamate 551

448.4 ( 1S , 3R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( trans -4- hydroxycyclohexyl)carbamate 552

458.3 ( 1S , 3R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxycyclohexyl)carbamate 553

458.4 ( 1S , 3R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxycyclohexyl)carbamate 554

458.4 ( 1S , 3R )-3-(3-{[(5-methoxypyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxycyclohexyl)carbamate 555

458.3 ( 1S , 3R )-3-(3-{[(2-Methoxypyridin-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate 556

458.3 ( 1S , 3R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate 557

458.3 ( 1S , 3R )-3-(3-{[(5-methoxypyridin-2-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( trans -4-hydroxycyclohexyl)carbamate 558

441.3 ( 1S , 3R )-3-{3-[(phenylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( cis- 4-hydroxy-4-methylcyclohexyl)carbamate 559

441.3 ( 1S , 3R )-3-{3-[(phenylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( trans -4-hydroxy-4-methylcyclohexyl)carbamate 560

459.3 ( 1S , 3R )-3-(3-{[(4-fluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxy-4-methylcyclohexyl)carbamate 561

459.3 ( 1S , 3R )-3-(3-{[(4-fluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( trans- 4-hydroxy-4-methylcyclohexyl)carbamate 562

462.3 ( 1S , 3R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( cis -4- hydroxy-4-methylcyclohexyl)carbamate 563

462.3 ( 1S , 3R )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( trans -4- hydroxy-4-methylcyclohexyl)carbamate 564

471.3 ( 1S , 3R )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxy-4-methylcyclohexyl)carbamate 565

471.3 ( 1S , 3R )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( trans -4-hydroxy-4-methylcyclohexyl)carbamate 566

471.3 ( 1R , 3S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxy-4-methylcyclohexyl)carbamate 567

471.3 ( 1R , 3S )-3-(3-{[(4-methoxyphenyl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( trans -4-hydroxy-4-methylcyclohexyl)carbamate 568

472.4 ( 1S , 3R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( cis -4-hydroxy-4-methylcyclohexyl) carbamate 569

472.4 ( 1S , 3R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( trans -4-hydroxy-4-methylcyclohexyl) carbamate 570

472.4 ( 1S , 3R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( cis -4-hydroxy-4-methylcyclohexyl) carbamate 571

472.4 ( 1S , 3R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( trans -4-hydroxy-4-methylcyclohexyl) carbamate 572

477.3 ( 1R , 3S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( cis- 4-hydroxy-4-methylcyclohexyl)carbamate 573

477.3 ( 1R , 3S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( trans -4-hydroxy-4-methylcyclohexyl)carbamate 574

437.3 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl (2-hydroxy-2-methylpropyl)carbamate 575

449.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [( cis- 3-hydroxycyclobutyl)methyl]carbamate 576

449.4 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [( trans -3-hydroxycyclobutyl)methyl]carbamate 577

482.3 (1 S ,3 R )-3-[3-({[6-(trifluoromethyl)pyridin-3-yl]acetyl}amino)-1H - pyrazol-5-yl]cyclopentyl [( trans -3-hydroxycyclobutyl) methyl]carbamate 578

449.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl {[(1 R ,2 R )-2-( hydroxymethyl)cyclopropyl]methyl}carbamate 579

449.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl {[(1 S ,2 S )-2-( hydroxymethyl)cyclopropyl]methyl}carbamate 580

482.3 (1 S ,3 R )-3-[3-({[6-(trifluoromethyl)pyridin-3-yl]acetyl}amino)-1 H -pyrazol-5-yl]cyclopentyl {[(1 S ,2 S )-2-(hydroxymethyl)cyclopropyl]methyl}carbamate 581

499.2 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl [(1-acetylpiperidin-4-yl)methyl ]carbamate 582

504.3 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl [(1-acetylpiperidin-4-yl)methyl]carbamate 583

492.1 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl {[(2ξ)-4-methyl-5-oxomorpholine -2-yl]methyl}carbamate - Isomer A 584

492.0 (1 S ,3 R )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl {[(2ξ)-4-methyl-5-oxomorpholine -2-yl]methyl}carbamate - Isomer B 585

372.9 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -imidazol-5-yl)carbonyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 2S )-2 -methylazetidine-1-carboxylate 586

374.3 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -1,2,3-triazol-5-yl)carbonyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-2-methylazetidine-1-carboxylate 587

386.9 (1 R ,3 S )-3-(3-{[(1-methyl-1 H -pyrazol-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R )-2 -methylazetidine-1-carboxylate 588

408.9 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-2 -methylazetidine-1-carboxylate 589

388.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -methylazetidine-1-carboxylate - Isomer A 590

388.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -methylazetidine-1-carboxylate - Isomer B 591

399.3 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )-2-methylazetidin-1- carboxylate 592

415.4 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (2 S )-2-methylazetidin-1- carboxylate 593

417.3 (1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 R )-2-methylazetidine-1-carboxylate 594

417.3 (1 R ,3 S )-3-[3-({[1-(2-methoxyethyl)-1 H -pyrazol-5-yl]carbonyl}amino)-1 H -pyrazol-5-yl]cyclopentyl (2 S )-2-methylazetidine-1-carboxylate 595

417.3 (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl- 1H -pyrazol-5-yl]carbonyl}amino)-1H - pyrazol-5-yl]cyclopentyl ( 2S )-2-methylazetidine-1-carboxylate 596

430.4 (1 R ,3 S )-3-{3-[({1-[2-(dimethylamino)ethyl] -1H -pyrazol-5-yl}carbonyl)amino] -1H -pyrazol-5-yl} cyclopentyl ( 2S )-2-methylazetidine-1-carboxylate 597

402.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -ethylazetidine-1-carboxylate - Isomer A 598

402.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -ethylazetidine-1-carboxylate - Isomer B 599

402.1 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -ethylazetidine-1-carboxylate - Isomer A 600

402.1 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -ethylazetidine-1-carboxylate - Isomer B 601

413.3 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine-1-carboxylate 602

429.3 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylazetidine-1-carboxylate 603

416.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -ethyl-2-methylazetidine-1-carboxylate - Isomer A 604

416.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2ξ)-2 -ethyl-2-methylazetidine-1-carboxylate - Isomer B 605

401.4 ( 1R , 3S )-3-(3-{[(1-methyl- 1H -pyrazol-4-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S , 4S )-2,4-dimethylazetidine-1-carboxylate 606

402.1 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,4 S )-2,4-dimethylazetidine-1-carboxylate 607

402.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R ,4 S )-2,4-dimethylazetidine-1-carboxylate 608

413.3 (1 R ,3 S )-3-(3-{[(5-methylpyrazin-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S , 4S )-2,4 -dimethylazetidine-1-carboxylate 609

428.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R ,4 R )-2,4 -dimethylazetidine-1-carboxylate 610

429.3 (1 R ,3 S )-3-(3-{[(5-methoxypyrazin-2-yl)acetyl]amino}-1 H- pyrazol-5-yl)cyclopentyl (2 S ,4 S )-2,4 -dimethylazetidine-1-carboxylate 611

430.3 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R ,3 S )-3-hydroxy -2-methylazetidine-1-carboxylate 612

430.4 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy -2-methylazetidine-1-carboxylate 613

430.4 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R ,3 S )-3-hydroxy -2-methylazetidine-1-carboxylate 614

430.4 (1 S ,3 R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S ,3 R )-3-hydroxy -2-methylazetidine-1-carboxylate 615

430.4 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy -2-methylazetidine-1-carboxylate 616

430.4 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R ,3 S )-3-hydroxy -2-methylazetidine-1-carboxylate 617

435.0 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy-2 -methylazetidine-1-carboxylate 618

418.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-methoxy-2-methylazetidine-1-carboxylate 619

443.9 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-methoxy -2-methylazetidine-1-carboxylate 620

444.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R ,3 S )-3-methoxy -2-methylazetidine-1-carboxylate 621

443.9 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-methoxy -2-methylazetidine-1-carboxylate 622

418.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy-2,3-dimethylazetidine-1-carboxylate 623

434.3 (1 R ,3 S )-3-(3-{[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy-2,3-dimethylazetidine-1-carboxylate 624

444.3 (1 S ,3 R )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy -2,3-dimethylazetidine-1-carboxylate 625

444.3 (1 R ,3 S )-3-(3-{[(2-methoxypyridin-4-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy -2,3-dimethylazetidine-1-carboxylate 626

444.3 (1 S ,3 R )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S ,3 R )-3-hydroxy -2,3-dimethylazetidine-1-carboxylate 627

444.3 (1 R ,3 S )-3-(3-{[(6-methoxypyridin-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,3 R )-3-hydroxy -2,3-dimethylazetidine-1-carboxylate 628

388.1 (1 R ,3 S )-3-{3-[(1,2-oxazol-3-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( 2S )-2-methylpyrrolidin-1-carboxylate 629

388.1 (1 R ,3 S )-3-{3-[(1,3-oxazol-5-ylacetyl)amino] -1H- pyrazol-5-yl}cyclopentyl ( 2S )-2-methylpyrrolidin-1-carboxylate 630

398.3 (1 R ,3 S )-3-{3-[(pyridin-2-ylacetyl)amino]-1H - pyrazol-5-yl}cyclopentyl ( 2S )-2-methylpyrrolidin-1-carboxylate 631

401.4 (1 R ,3 S )-3-(3-{[(1-methyl- 1H -pyrazol-3-yl)acetyl]amino}-1H - pyrazol-5-yl)cyclopentyl ( 2S )-2 -methylpyrrolidine-1-carboxylate 632

402.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpyrrolidine-1-carboxylate 633

401.9 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R )- 2-methylpyrrolidine-1-carboxylate 634

402.1 (1 R ,3 S )-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpyrrolidine-1-carboxylate 635

402.1 (1 R ,3 S )-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpyrrolidine-1-carboxylate 636

402.3 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-oxazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpyrrolidine-1-carboxylate 637

418.4 (1 R ,3 S )-3-(3-{[(4-methyl-1,3-thiazol-2-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpyrrolidine-1-carboxylate 638

416.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 S ,5 S )-2,5-dimethylpyrrolidine-1-carboxylate 639

415.4 (1 R ,3S)-3-(3-{[(1-methyl-1 H -pyrazol-3-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 2,2-dimethylpyrrolidin-1 -carboxylate 640

415.9 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl ( 2S )- 2-methylpiperidine-1-carboxylate 641

416.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (2 R )- 2-methylpiperidine-1-carboxylate 642

418.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3 S )- 3-methylmorpholine-4-carboxylate 643

418.4 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3 R )- 3-methylmorpholine-4-carboxylate 644

449.2 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( 3S )-3-methylmorpholine-4-carboxylate 645

449.2 (1 R ,3 S )-3-(3-{[(3,5-difluorophenyl)acetyl]amino} -1H -pyrazol-5-yl)cyclopentyl ( 3R )-3-methylmorpholine-4-carboxylate 646

450.1 (1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3 S )- 3-methylmorpholine-4-carboxylate 647

450.3 (1 R ,3 S )-3-(3-{[(2-methoxy-1,3-thiazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl (3 R )- 3-methylmorpholine-4-carboxylate 648

432.3 ( 1R , 3S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino} -1H- pyrazol-5-yl)cyclopentyl ( 3S ,5 S )-3,5-dimethylmorpholine-4-carboxylate 649

432.3 (1 R ,3 S )-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1 H -pyrazol-5-yl)cyclopentyl 3,3-dimethylmorpholine -4-carboxylate

Biochemical analyzes

Full-length CDK2/cyclin E1 mobility change assay

The aim of the CDK2/cyclin E1 assay is to evaluate the inhibition (% inhibition, K _iapp and K _i values) of small molecule inhibitors using a fluorescence-based microfluidic mobility change assay. Full-length CDK2/cyclin E1 catalyzes the production of ADP from ATP, which accompanies the transfer of phosphoryl to the peptide substrate FL-Peptide-18 (5-FAM-QSPKKG-CONH ₂ , CPC Scientific, Sunnyvale, CA) (SEQ ID NO:1). The mobility change assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) after the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % substrate to product conversion using a LabChip EZ reader. The CDK2 wild-type/full-length cyclin E1 wild-type enzyme complex was generated in situ (baculovirus expression, LJIC-2080/LJIC-2103) and phosphorylated with the CDK7/cyclin H1/Mat1 enzyme complex with CDK2:CDK7 at a ratio of 50:1 (mg/mL concentration ) in the presence of 10 mM MgCl ₂ and 5 mM ATP at room temperature for one hour. Typical reaction solutions (50 µl final reaction volume) contained 2% DMSO (± inhibitor), 4 mM MgCl ₂ , 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 competent active site) phosphorylated wild-type full-length CDK2/cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15. The assay was started with the addition of ATP, after a fifteen minute pre-incubation of enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 45 minutes at room temperature by adding 50 μl of 80 mM EDTA. The K _i value was determined by fitting the data to Morrison's tight coupling equation for competitive inhibition with enzyme concentration as variable ^{1, 2} .

GSK3beta (GSK3β) mobility change analysis

The purpose of the GSK3β assay is to evaluate the inhibition (% inhibition, K _iapp and K _i values) of small molecule inhibitors using a fluorescence-based microfluidic mobility change assay. GSK3β catalyses the production of ADP from ATP, which accompanies the transfer of phosphoryl to the peptide substrate FL-Peptide-15 (5-FAM-KRREILSRRPpSYR-COOH, CPC Scientific, Sunnyvale, CA) (SEQ ID NO:2). The mobility change assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) after the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % substrate to product conversion using a LabChip EZ reader. Active GSK3β (H350L) was purchased from Upstate/Millipore. Typical reaction solutions (50 µl final reaction volume) contained 2% DMSO (± inhibitor), 4 mM MgCl ₂ , 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 in 25 mM HEPES buffer at pH 7.5. The analysis was started with the addition of ATP, after 15 minutes of pre-incubation of the enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 30 minutes at room temperature by adding 50 μl of 80 mM EDTA. The K _i value was determined by fitting the data to Morrison's tight coupling equation for competitive inhibition with enzyme concentration as a variable. See Morrison, JF (1969) Kinetics of the reversible inhibition 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: an in silico study of experimental error and assay design, Analytical biochemistry 327 , 61-67.

CDK4/cyclin D ₁ mobility change assay

The aim of the CDK4/cyclin D ₁ assay is to evaluate inhibition (% inhibition, K _iapp and K _i values) in the presence of small molecule inhibitors using a fluorescence-based microfluidic mobility change assay. CDK4/cyclin D ₃ catalyzes the production of ADP from ATP, which accompanies the transfer of phosphoryl to the peptide substrate 5-FAM-Dyrktide (5-FAM-RRRFASPLRGPPK) (SEQ ID NO:3). The mobility change assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) after the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % substrate to product conversion using a LabChip EZ reader. Representative reaction solutions contained 2% DMSO (± inhibitor), 10 mM MgCl ₂ , 1 mM DTT, 3.5 mM ATP, 0.005% TW-20, 3 μM 5-FAM-Dyrktide, 3 nM (active sites) activated CDK4/ cyclin D ₁ in 40 mM HEPES buffer at pH 7.5.

K _i inhibitor determinations for activated CDK4/cyclin D ₁ (2007 E1/2008 +PO4) were initiated by the addition of ATP (50 μl final reaction volume), after an eighteen minute pre-incubation of enzyme and inhibitor at 22° C. in the reaction mixture. The reaction was stopped after 195 minutes by adding 50 μl of 30 mM EDTA. The K _i determinations were made from a plot of fractional rate as a function of inhibitor concentration corresponding to the Morrison equation with enzyme concentration as a variable.

CDK6/cyclin D ₃ mobility change assay

The aim of the CDK6/cyclin D ₃ assay is to evaluate inhibition (% inhibition, K _iapp and K _i values) in the presence of small molecule inhibitors using a fluorescence-based microfluidic mobility change assay. CDK6/cyclin D ₃ catalyses the production of ADP from ATP, which accompanies the transfer of phosphoryl to the peptide substrate 5-FAM-Dyrktide (5-FAM-RRRFASPLRGPPK) (SEQ ID NO:3). The mobility change assay electrophoretically separates the fluorescently labeled peptides (substrate and phosphorylated product) after the kinase reaction. Both substrate and product are measured and the ratio of these values is used to generate % substrate to product conversion using a LabChip EZ reader. Typical reaction solutions contained 2% DMSO (± inhibitor), 2% glycerol, 10 mM MgCl ₂ , 1 mM DTT, 3.5 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide, 4 nM (active sites) of activated CDK6/cyclin D ₃ in 40 mM HEPES buffer at pH 7.5.

K _i inhibitor determinations for activated CDK6/cyclin D ₃ (LJIC-2009G1/2010 +PO ₄ ) were initiated by the addition of ATP (50 μl final reaction volume), after an eighteen minute pre-incubation of enzyme and inhibitor at 22° C. in the reaction mixture. The reaction was stopped after 95 minutes by adding 50 μl of 30 mM EDTA. The K _i determinations were made from a plot of fractional rate as a function of inhibitor concentration corresponding to the Morrison equation with enzyme concentration as a variable.

For tight-binding inhibitor data fitting from CDK4 and CDK6 mobility alteration assays, equations and principles are taken from Morrison, JF (1969) Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimica et 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.

Biological activity data

Biological activity data for representative compounds of the invention are presented in Table 4 below.

Table 4 Example No. CDK2/cyclin E ₁ Ki (nM) GSK3β Ki (nM) 1 0.55 26.18 2 0.31 40.43 3 0.34 10.04 4 0.10 109.99 5 0.40 39.40 6 0.38 32.29 7 0.61 8 0.50 666.56 9 1.14 >95.31 10 0.25 100.53 eleven 0.32 36.21 12 0.13 4.86 13 1.16 537.81 14 0.27 293.53 15 0.17 29.30 16 0.37 51.67 17 0.33 65.76 18 0.17 19 0.17 20.83 20 0.21 27.85 21 0.25 4.20 22 0.23 >190.72 23 0.11 2.45 24 0.26 20.55 25 2.70 135.07 26 0.21 13.69 27 0.24 3.57 28 0.18 4.50 29 0.16 19.73 thirty 0.16 20.55 31 0.16 45.12 32 0.36 35.67 33 0.17 26.35 34 0.33 31.21 35 0.22 12.49 36 0.17 21.26 37 0.19 23.39 38 0.18 69.70 39 0.14 23.95 40 0.24 64.47 41 0.20 342.89 42 0.05 34.42 43 0.04 45.43 44 0.21 47.75 45 0.11 61.35 46 0.18 20.56 47 0.11 10.16 48 0.17 9.58 49 0.19 50 0.17 116.87 51 0.20 54.01 52 0.20 10.91 53 0.10 45.70 54 0.24 9.25 55 0.10 10.37 56 0.25 42.81 57 3.54 58 0.21 9.86 59 0.15 2.89 60 0.33 92.52 61 0.11 42.27 62 0.21 24.01 63 1.25 64 0.14 18.73 65 2.21 66 0.17 17.88 67 1.50 68 0.36 16.30 69 4.26 70 0.35 31.34 71 1.01 33.82 72 0.15 12.81 73 2.31 74 0.30 13.21 75 0.26 9.59 76 0.10 4.96 77 0.39 19.72 78 0.15 8.90 79 0.54 16.46 80 0.15 8.85 81 1.48 32.94 82 0.19 12.61 83 0.69 33.29 84 0.10 12.03 85 1.06 86 0.25 12.89 87 1.32 88 0.15 89 0.85 90 0.23 2.36 91 0.09 28.14 92 0.10 16.59 93 0.22 7.64 94 0.15 95 0.25 32.23 96 2.05 97 0.39 18.00 98 0.33 21.59 99 0.09 100 0.43 41.69 101 0.28 20.91 102 0.39 9.90 103 1.37 >47.63 104 0.17 >47.63 105 0.47 >47.63 106 0.76 107 0.19 27.09 108 0.15 38.75 109 0.68 39.20 110 0.29 111 0.38 771.75 112 0.15 40.19 113 0.16 11.10 114 0.19 5.65 115 0.23 116 0.13 8.86 117 0.14 15.91 118 0.22 17.78 119 0.13 19.28 120 0.09 34.89 121 0.08 19.36 122 0.22 12.73 123 0.13 8.87 124 0.19 80.65 125 0.34 126 0.27 26.56 127 0.23 20.12 128 0.15 55.36 129 0.20 31.57 130 0.25 131 0.20 132 0.19 133 0.11 7.00 134 0.12 7.12 135 0.19 11.72 136 0.22 8.22 137 0.09 6.07 138 0.23 7.06 139 0.21 8.48 140 0.19 15.27 141 0.08 5.75 142 0.22 17.74 143 0.25 15.82 144 0.10 1.26 145 0.12 0.95 146 0.07 3.47 147 0.25 6.87 148 0.24 5.57 149 0.06 5.58 150 0.25 8.35 151 0.15 3.89 152 1.06 153 0.22 9.15 154 1.77 155 0.13 1.63 156 2.21 157 1.86 158 0.17 0.78 159 3.63 160 0.15 1.72 161 0.15 5.93 162 3.01 163 0.32 16.64 164 0.72 44.74 165 2.28 166 0.40 24.29 167 1.40 33.85 168 0.36 25.84 169 1.63 29.63 170 1.37 >190.72 171 1.73 18.22 172 1.20 101.69 173 2.29 >190.72 174 3.00 >95.33 175 0.82 39.66 176 2.50 46.08 177 0.43 19.04 178 1.10 21.38 179 0.54 13.50 180 0.81 >95.33 181 3.91 >190.72 182 0.82 90.62 183 3.68 >95.33 184 1.35 >95.33 185 0.71 13.02 186 1.03 9.64 187 4.59 23.93 188 0.44 9.32 189 0.38 11.41 190 0.81 26.12 191 3.33 192 0.70 >190.72 193 0.41 194 0.80 195 4.39 196 1.44 197 0.49 >190.72 198 0.28 52.14 199 3.45 200 2.87 201 1.91 202 1.85 203 0.29 34.19 204 1.13 205 0.76 97.69 206 1.22 >95.33 207 0.66 208 3.18 209 1.21 210 3.80 211 4.87 212 0.67 77.19 213 0.32 183.00 214 0.37 131.31 215 1.26 216 0.86 28.16 217 2.22 218 2.09 30.64 219 3.81 220 3.26 221 1.73 222 2.93 223 2.33 224 0.31 225 2.67 226 3.72 131.65 227 1.21 18.92 228 1.84 229 2.06 230 1.55 48.59 231 1.18 15.57 232 1.54 34.13 233 0.85 43.44 234 4.11 235 2.33 236 3.16 237 0.64 5.23 238 1.13 14.73 239 1.15 9.44 240 0.73 16.08 241 1.04 13.36 242 0.81 9.70 243 0.75 5.35 244 0.57 3.70 245 0.53 19.18 246 3.29 247 1.36 12.15 248 2.41 249 2.32 250 1.62 27.37 251 1.83 252 1.39 10.56 253 1.26 28.80 254 2.17 255 1.69 256 2.58 257 4.20 258 0.74 10.69 259 0.68 17.38 260 2.89 261 1.00 121.36 262 0.64 >47.63 263 0.52 31.91 264 1.83 265 1.91 266 0.39 32.63 267 3.02 268 0.97 269 1.68 270 0.86 39.88 271 1.57 272 2.63 40.85 273 3.08 274 2.62 275 0.49 53.15 276 0.64 33.09 277 0.98 278 0.52 56.69 279 0.32 53.18 280 2.12 281 0.33 24.42 282 2.34 283 4.60 284 0.60 285 3.97 286 4.14 287 2.26 288 0.39 289 0.49 10.63 290 1.45 291 0.43 >47.63 292 0.86 293 0.85 >95.31 294 0.62 31.97 295 0.38 56.13 296 0.30 297 1.17 298 0.68 72.02 299 0.26 29.89 300 0.65 301 0.55 302 0.50 303 0.33 304 1.41 305 0.52 306 1.09 307 0.73 308 0.30 89.06 309 1.55 310 0.69 311 0.36 312 0.43 313 0.63 314 0.41 40.58 315 0.65 132.72 316 1.30 317 0.26 45.99 318 0.53 319 0.39 123.24 320 2.95 321 0.63 >190.68 322 0.93 81.21 323 1.07 74.13 324 0.54 94.28 325 0.81 54.02 326 1.17 72.42 327 0.44 57.75 328 1.77 329 1.02 107.07 330 0.55 85.98 331 1.49 332 1.05 61.28 333 0.41 63.16 334 1.60 335 0.41 23.86 336 0.39 53.47 337 0.58 94.93 338 1.58 94.40 339 0.66 340 2.24 341 0.64 342 0.74 40.03 343 0.77 26.14 344 0.58 345 2.66 346 0.26 10.74 347 0.37 45.60 348 0.59 54.15 349 0.40 57.31 350 3.45 351 2.77 352 0.82 58.42 353 0.50 29.47 354 3.74 355 1.13 18.13 356 0.67 148.05 357 4.08 358 1.65 359 0.39 28.46 360 1.46 361 0.94 25.61 362 0.84 363 0.35 52.03 364 0.82 59.92 365 2.08 366 1.79 367 0.27 23.52 368 0.41 369 0.84 370 0.28 50.81 371 0.32 160.53 372 0.85 114.62 373 0.47 74.30 374 0.32 10.83 375 0.31 115.98 376 0.40 99.35 377 1.14 378 0.83 379 3.05 380 0.63 381 3.11 382 0.77 74.18 383 1.34 43.17 384 1.24 385 0.52 25.86 386 0.66 45.93 387 0.30 388 2.34 36.88 389 0.83 18.31 390 3.74 391 1.38 37.96 392 3.14 393 0.97 34.05 394 0.42 42.71 395 1.43 396 2.10 139.07 397 1.87 155.22 398 0.65 44.11 399 0.47 68.80 400 1.29 401 0.34 32.95 402 1.54 403 1.76 76.11 404 1.38 84.27 405 1.37 97.90 406 1.81 73.33 407 1.16 408 0.29 17.91 409 4.15 410 0.42 55.54 411 2.58 412 0.19 413 0.44 14.69 414 0.42 3.44 415 1.48 26.45 416 2.27 417 0.81 12.56 418 2.69 419 0.36 420 0.54 421 0.94 422 0.55 423 0.60 424 0.51 14.40 425 1.05 426 0.53 17.04 427 1.78 428 0.40 30.11 429 1.15 430 1.14 431 1.19 432 1.25 433 0.50 17.12 434 0.48 39.83 435 1.49 436 3.30 437 0.51 15.87 438 2.50 439 2.37 440 1.47 441 1.42 442 0.37 443 0.36 444 1.41 445 0.60 446 1.70 447 0.36 >47.63 448 0.29 449 0.39 450 0.38 451 0.46 452 0.51 453 0.29 454 0.48 455 0.47 21.28 456 0.38 457 0.38 458 3.07 459 0.32 460 1.62 39.91 461 1.75 462 1.74 463 0.55 28.32 464 2.63 465 1.95 466 1.02 467 1.20 468 0.35 469 0.31 470 0.83 471 1.43 472 1.17 473 0.36 66.25 474 0.44 475 0.83 23.95 476 0.45 30.89 477 1.04 59.19 478 1.13 479 0.89 480 2.01 481 0.53 44.64 482 0.55 36.16 483 0.32 484 0.32 30.32 485 1.41 486 1.46 487 0.67 >47.63 488 1.40 489 3.71 490 3.68 491 3.87 492 2.39 493 0.98 156.95 494 1.02 53.29 495 1.79 496 2.25 497 4.38 498 4.28 499 2.55 500 2.36 501 1.43 12.54 502 3.71 503 2.13 504 3.64 505 1.60 506 0.76 77.63 507 3.69 508 1.46 509 0.50 30.23 510 0.19 13.98 511 1.52 4.74 512 3.20 513 3.19 514 2.78 515 1.25 11.30 516 3.24 517 1.29 518 1.43 519 0.56 520 2.88 521 1.95 522 3.05 523 2.49 524 1.69 10.88 525 1.24 7.01 526 3.95 527 2.63 528 1.11 3.60 529 0.73 3.92 530 2.03 531 1.51 532 0.89 2.97 533 0.77 1.41 534 0.85 4.63 535 1.21 3.80 536 2.07 537 1.34 10.73 538 2.72 539 2.35 540 2.65 541 1.85 542 2.41 543 1.96 544 0.54 1.96 545 0.39 2.20 546 1.85 3.51 547 0.61 3.62 548 0.39 2.10 549 0.90 3.24 550 0.36 3.12 551 0.34 2.94 552 0.29 2.41 553 0.41 1.90 554 1.76 5.11 555 0.37 3.58 556 0.46 1.85 557 1.01 2.60 558 0.41 18.59 559 1.44 8.58 560 0.60 9.84 561 1.80 562 0.43 4.85 563 1.80 4.35 564 0.37 10.07 565 1.24 4.07 566 0.79 37.61 567 1.61 568 0.41 5.12 569 1.25 4.31 570 0.35 3.29 571 1.08 2.28 572 0.37 24.23 573 0.83 14.08 574 4.07 575 2.28 576 1.99 577 3.36 578 3.64 579 2.41 580 3.38 581 2.62 582 2.23 583 2.71 584 3.84 585 2.57 586 0.88 51.55 587 2.77 588 0.75 589 0.59 18.16 590 2.86 591 1.67 592 2.27 593 2.21 594 0.62 14.35 595 1.52 596 1.75 597 0.54 20.86 598 0.78 16.39 599 1.38 600 2.12 601 0.39 7.32 602 0.30 603 0.07 13.82 604 0.08 5.00 605 0.32 9.89 606 0.63 11.50 607 1.90 608 1.11 609 4.81 610 1.04 611 1.67 13.94 612 0.45 8.01 613 2.98 614 1.66 6.58 615 1.99 616 0.28 4.05 617 0.27 7.18 618 0.78 8.57 619 0.42 5.75 620 3.91 621 0.36 2.77 622 4.00 623 1.17 6.31 624 4.18 16.26 625 0.45 4.97 626 4.73 627 0.51 2.76 628 0.92 20.77 629 0.40 10.58 630 1.43 631 1.12 11.78 632 0.36 12.67 633 2.11 634 0.99 14.37 635 0.53 16.29 636 0.83 637 1.47 638 0.28 14.94 639 0.47 6.34 640 0.48 13.27 641 0.59 14.45 642 1.37 10.33 643 1.84 644 0.33 8.71 645 0.37 7.23 646 1.03 5.18 647 1.08 3.39 648 0.47 12.25 649 0.31 9.20

Additional biological activity data for selected compounds are presented in Table 5 below.

Table 5 Example No. Biochemical analysis Ki (nM) 13 CDK1/cyclin A ₂ 110 13 CDK4/cyclin D ₁ 238 13 CDK6/cyclin D ₃ 465 13 CDK9 177 15 CDK1/cyclin A ₂ 16.4 15 CDK4/cyclin D ₁ 26.6 15 CDK6/cyclin D ₃ 58.6 15 CDK9 6.3

All publications and patent applications cited in this specification are incorporated herein by reference in their entirety. Those skilled in the art will appreciate that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

--->

SEQUENCE LIST

<110> Pfizer Inc.

Behenna, Douglas C

Freeman-Cook, Kevin D

Hoffman, Robert L

Nagata, Asako

Ninkovic, Sacha

Sutton, Scott C

<120> CDK2 INHIBITORS

<130> PC72484

<160> 3

<170>PatentIn version 3.5

<210> 1

<211> 6

<212> PROTEIN

<213> Artificial

<220>

<223> Synthetic construction

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> 5-FAM labeled glutamine

<220>

<221> MOD_RES_AMIDATION

<222>(6)..(6)

<223> Amidation of glycine

<400> 1

Gln Ser Pro Lys Lys Gly

15

<210> 2

<211> 13

<212> PROTEIN

<213> Artificial

<220>

<223> Synthetic construction

<220>

<221> MISC_FEATURE

<222> (1)..(1)

<223> 5-FAM labeled lysine

<220>

<221> MOD_RES_PHOSPHORYLATION

<222> (11)..(11)

<223> Serine phosphorylated

<400> 2

Lys Arg Arg Glu Ile Leu Ser Arg Arg Pro Ser Tyr Arg

1 5 10

<210> 3

<211> 15

<212> PROTEIN

<213> Artificial

<220>

<223> Synthetic construction

<220>

<221> MISC_FEATURE

<222> (1)..(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 (44)

1. Compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ is -L ¹ -(5-10 membered heteroaryl containing 1-4 heteroatoms, each selected from N, O and S) or -L ¹ -(C ₆ -C ₁₂ aryl), where the specified 5-10 -membered heteroaryl or C ₆ -C ₁₂ aryl is optionally substituted with one or two R ⁴ ; R ² and R ³ are independently H, C ₁ -C ₆ alkyl, C ₁ -C ₆ fluoroalkyl, -L ² -(C ₃ -C ₇ cycloalkyl), or -L ² -(4-7 membered heterocyclyl containing 1-2 heteroatoms, each selected from N or O), where each specified C ₁ -C ₆ alkyl and C ₁ -C ₆ fluoroalkyl is optionally substituted with one R ⁵ and each specified C ₃ -C ₇ cycloalkyl and 4-7-membered heterocyclyl optionally substituted with one or two R ⁶ ; or R ² and R ³ are taken together with the N-atom to which they are attached to form a 4-6 membered heterocyclyl optionally containing an additional heteroatom that is O as a ring member, wherein said 4-6 membered heterocyclyl optionally substituted with one to three R ⁸ ; each L ¹ and L ² is independently a bond or C ₁ -C ₂ alkylene; each R ⁴ is independently F, Cl, OH, CN, C ₁ -C ₄ alkyl, C ₁ -C ₄ fluoroalkyl, C ₁ -C ₄ alkoxy, C ₁ -C ₄ fluoroalkoxy, C ₃ -C ₈ cycloalkyl, SO ₂ R ¹² , or SO ₂ NR ¹⁰ R ¹¹ , where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with one R ¹³ ; each R ⁵ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁰ R ¹¹ ; each R ⁶ is independently F, OH, C ₁ -C ₄ alkyl or C ₁ -C ₄ fluoroalkyl, where each C ₁ -C ₄ alkyl and C ₁ -C ₄ fluoroalkyl is optionally substituted with one R ¹³ ; each R ⁸ is independently F, OH, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, or CN; each R ¹⁰ and R ¹¹ independently represents H or C ₁ -C ₄ alkyl; each R ¹² is C ₁ -C ₄ alkyl or C ₃ -C ₆ cycloalkyl; each R ¹³ is independently OH, C ₁ -C ₄ alkoxy or NR ¹⁴ R ¹⁵ ; And each R ¹⁴ and R ¹⁵ is independently H or C ₁ -C ₄ alkyl. 2. The compound according to claim 1, having the formula (II):

or a pharmaceutically acceptable salt or solvate thereof. 3. The compound according to claim 1, having the formula (III):

or a pharmaceutically acceptable salt or solvate thereof. 4. The compound according to any one of paragraphs 1-3 or its pharmaceutically acceptable salt or solvate, where R ¹ represents -L ¹ - (5-10-membered heteroaryl containing 1-4 heteroatoms, each selected from N, O and S), wherein said 5-10 membered heteroaryl is optionally substituted with one or two R ⁴ . 5. A compound according to claim 4 or a pharmaceutically acceptable salt or solvate thereof, wherein said 5-10 membered heteroaryl is pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, indazolyl, or benzimidazolyl, where said 5 -10-membered heteroaryl is optionally substituted with one or two R ⁴ . 6. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein said 5- to 10-membered heteroaryl is pyrazolyl optionally substituted with one or two R ⁴ . 7. The compound of claim 5, or a pharmaceutically acceptable salt or solvate thereof, wherein said 5- to 10-membered heteroaryl is isoxazolyl optionally substituted with one or two R ⁴ . 8. Connection according to any one of paragraphs. 1-7 or a pharmaceutically acceptable salt or solvate thereof, wherein L ¹ is a bond or methylene. 9. Connection according to any one of paragraphs. 1-8 or a pharmaceutically acceptable salt or solvate thereof, wherein each R ⁴ is independently C ₁ -C ₄ alkyl or C ₁ -C ₄ alkoxy, where each C ₁ -C ₄ alkyl is optionally substituted with one R ¹³ . 10. Connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H and R ³ is C ₁ -C ₆ alkyl. 11. The connection according to any one of paragraphs. 1-9 or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is H and R ³ is -L ² -(C ₃ -C ₇ cycloalkyl), wherein said C ₃ -C ₇ cycloalkyl is optionally substituted with one or two R ⁶ . 12. The compound of claim 11, or a pharmaceutically acceptable salt or solvate thereof, wherein L ² is a bond or methylene. 13. A compound selected from the group consisting of: (1 R ,3 S )-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. The compound according to claim 13, which is (1 R ,3 S )-3-[3-({[3-(methoxymethyl)-1-methyl-1 H -pyrazol-5-yl]carbonyl}amino) -1 H -pyrazol-5-yl]cyclopentyl propan-2-ylcarbamate. 15. The compound of claim 13 which is (1R,3S)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1H-pyrazole-5- yl)cyclopentyl (1-methylcyclopropyl)carbamate. 16. A compound having the structure:

, or a pharmaceutically acceptable solvate thereof. 17. A compound having the structure:

, or a pharmaceutically acceptable solvate thereof. 18. Pharmaceutical composition for inhibition of CDK2, containing an effective amount of the compound according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier or excipient. 19. A method of treating cancer associated with inhibition of CDK2 activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or solvate thereof, wherein the cancer is selected from breast cancer , ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and thyroid cancer. 20. The use of a compound according to any one of paragraphs. 1-17 or a pharmaceutically acceptable salt or solvate thereof, for the treatment of cancer associated with inhibition of CDK2 activity in a subject in need thereof, wherein the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, cancer lung, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer and thyroid cancer.

Images