TW202337434A - Cdk inhibitors and methods of use thereof - Google Patents

Abstract

The present disclosure relates to novel compounds and pharmaceutical compositions thereof, and methods for inhibiting the activity of CDK enzymes with the compounds and compositions of the disclosure. The present disclosure further relates to, but is not limited to, methods for treating disorders associated with CDK signaling with the compounds and compositions of the disclosure.

Description

CDK inhibitors and methods of use

Cyclin-dependent kinases (CDKs) are a family of serine/threonine kinases that are regulated by direct binding to cyclins. The originally discovered CDKs (CDK1, CDK2, CDK4, CDK6) bind to cognate cyclins during specific cell cycle stages, thereby activating their kinase activity and promoting cell cycle progression (Malumbres M. Genome Biology 2014). Relevant CDK family members (CDK7, CDK8, CDK9, CDK12, CDK13) are involved in other biological functions, such as transcriptional control (Chou J. et al., Cancer Discovery 2020).

The cell cycle is initiated following mitogenic stimuli that signal cyclin D expression, binding to CDK4/6 and kinase activation. The active CDK4/6-cyclin D complex monophosphorylates retinoblastoma protein (RB), a tumor suppressor, to initiate cyclin E expression and formation of the active CDK2-cyclin E complex. Activated CDK2-cyclin E hyperphosphorylates RB, triggering DNA replication, which is further promoted by CDK2-cyclin A. Finally, CDK1-cyclin B and CDK1-cyclin A coordinate the separation of replicated DNA in the mother cell to complete cell division and form two new daughter cells (Otto, T. and Sicinski, P. Nat Rev Cancer 2017).

Since continued cell proliferation is a hallmark of cancer, changes in the pathways that control cell cycle progression are often associated with cancer. In fact, CCNE1 (the gene encoding the cyclin E1 protein) is the most frequently amplified gene in a variety of cancers, including ovarian, endometrial, gastric, cervical, bladder, esophageal, lung and breast cancers. One (Sanchez-Vega F. et al., Cell 2018; Cerami E. et al., Cancer Discovery 2012). The amplified CCNE1 gene, which results in overexpression of the cyclin E1 protein, is thought to be an oncogenic driver in these tumors due to increased CDK2-cyclin E activity. Notably, CCNE1- amplified or overexpressed tumor cells are dependent on CDK2 activity, and thus provide a rationale for targeting CDK2 in this genetically defined patient population (McDonald ER et al., Cell 2017; Au-Yeung G. et al. People, Clin Cancer Research 2016). Furthermore, CDK2 activation via cyclin E1 amplification and overexpression is a common mechanism of resistance to several approved targeted therapies, such as CDK4/6 and HER2 modulators, and thus supports CDK2 and other validated cancer drivers. Combination targeting (Turner NC et al., J Clin Oncology 2019; Herrera-Abreu MT et al., Cancer Research 2016; Scaltriti M. et al., PNAS 2011).

Several pan-CDK inhibitors with activity against CDK2 and other CDKs have shown evidence of clinical activity, but they have also shown significant hematopoietic and gastrointestinal toxicity, possibly due to their inhibition of CDK1 (Otto, T. and Sicinski, P., Nat. Review Cancer 2017; Kumar, K.S. et al., Blood 2015; Shapiro G.I. et al., Clin Cancer Research 2001). Although CDK2 activity may not be important for normal cell function, CDK1 activity is critical in all cells, especially in highly proliferative cells of the intestinal and hematopoietic systems (Berthet C. et al., Current Biology 2003; Jayapal S.R. et al. People, Haematologica 2015; Santamaria D. et al., Nature 2007; Lu S. et al., Tox Sciences 2020).

In some embodiments, the present disclosure encompasses the recognition of the need for CDK selective inhibitor compounds, such as CDK2 selective inhibitor compounds, and methods of treating cancer and other disorders with such compounds.

In some embodiments, the present disclosure provides compounds of Formula I: I or a pharmaceutically acceptable salt thereof, wherein each of Cy ^A , Cy ^B , Cy ^C , Q and P is as defined in the Examples and classes and subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula IA: IA, or a pharmaceutically acceptable salt thereof, wherein each of Cy ^B , Cy ^C , Q, and P is as defined in the Examples and classes and subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula II or III: , III or a pharmaceutically acceptable salt thereof, wherein each of ^CyB , ^CyC , ^RP , Q, X and Y is as defined in the Examples and classes and subclasses herein.

In some embodiments, the disclosure provides compounds of Formula IV-a, IV-b, IV-c, Va, Vb, or Vc: , IV-a , IV-bIV-c Va , Vb Vc or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C , ^RP and Q is as defined in the Examples and Classes and Subclasses herein.

In some embodiments, the disclosure provides compounds of Formula VI, VII, VIII, IX, X, XI, XII, or XIII: , , VI VII , , VIII IX , , X XI , XII XIII or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C and ^RP is as defined in the Examples and classes and subclasses herein.

In some embodiments, the disclosure provides compounds of Formula XIV, XV, XVI, XVII, XVIII, or XIX: , , XIV XV , , XVI XVII , ^{XVIII _}

In some embodiments, the present disclosure provides compounds of formula XX, XXI, XXII: , , XX XXI XXII or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C , R ^{C 1} , ^RP and Q is as defined in the Examples and classes and subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula XXIII, XXIV, or XXV: , , XXIII XXIV XXV or a pharmaceutically acceptable salt thereof, wherein each of R ^C1 , ^RP and Q is as defined in the Examples and Classes and Subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, or XXVII-c: , XXVI-a , XXVI-b XXVI-c XXVII-a , XXVII-b XXVII-c or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C , ^RP and Q is as defined in the Examples and Classes and Subclasses herein.

In some embodiments, the disclosure provides compounds of Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof, wherein each of Cy ^A , Cy ^B , Cy ^C , Q, P, and ^RD is as defined in the Examples and classes and subclasses herein.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula XXIX or XXX: , XXIX XXX or a pharmaceutically acceptable salt thereof, wherein each of ^CyB , ^CyC , ^RD , ^Q ,

In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the present disclosure provides compounds comprising the present disclosure (e.g., Formulas I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX , X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, -b, a pharmaceutical composition of a compound of XXVII-c, XXVIII, XXIX or XXX) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant or diluent. In some embodiments, the disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula I-A) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or diluent. .

In some embodiments, the present disclosure provides methods of treating CDK2-mediated disorders comprising administering to a patient in need thereof a compound of Formula I, or a composition comprising the compound. In some embodiments, the disclosure provides methods of treating CDK2-mediated disorders, comprising administering to a patient in need thereof a compound of the disclosure (e.g., Formulas I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX or XXX) or a composition containing the compound. In some embodiments, the disclosure provides methods of treating CDK2-mediated disorders, comprising administering to a patient in need thereof a compound of the disclosure (e.g., Formulas I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX or XXX) or a composition containing the compound.

In some embodiments, the present disclosure provides methods for providing compounds of Formula I, or synthetic intermediates thereof. In some embodiments, the disclosure provides compounds of the disclosure (e.g., Formulas I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII , IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, , XXVII-b, XXVII-c, XXVIII, XXIX or XXX compounds) or methods of synthesizing intermediates thereof. In some embodiments, the disclosure provides compounds of the disclosure (e.g., Formulas I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII , IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, , XXVII-b, XXVII-c, XXVIII, XXIX or XXX compounds) or methods of synthesizing intermediates thereof.

In some embodiments, the present disclosure provides methods for providing pharmaceutical compositions comprising compounds of Formula I. In some embodiments, the present disclosure provides for providing compounds comprising the present disclosure (e.g., Formulas I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, a. Methods for pharmaceutical compositions of compounds of XXVII-b, XXVII-c, XXVIII, XXIX or XXX). In some embodiments, the present disclosure provides for providing compounds comprising the present disclosure (e.g., Formula I, I-A, II, III, IV-a, IV-b, IV-c, V-a, V-b, V-c, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, Methods for pharmaceutical compositions of compounds of XXVII-a, XXVII-b, XXVII-c, XXVIII, XXIX or XXX).

Cross-references to related applications

This application claims U.S. Provisional Application No. 63/309,213 filed on February 11, 2022, U.S. Provisional Application No. 63/325,284 filed on March 30, 2022, and U.S. Provisional Application No. 63/325,284 filed on June 3, 2022. U.S. Provisional Application No. 63/348,599 and U.S. Provisional Application No. 63/397,136 filed on August 11, 2022. Each of these U.S. Provisional Applications is incorporated by reference in its entirety. into this article. 1. General description of certain embodiments

The compounds provided herein and their pharmaceutical compositions can be used as inhibitors of CDK2. In some embodiments, the present disclosure provides compounds of Formula I: I or a pharmaceutically acceptable salt thereof, wherein: Q is L ¹ ; Cy ^A is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A is replaced by m instances of R ^A in addition to Q and Cy ^B ; Cy ^B is , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with ^P ; P is L ² -RP; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group, 1-4 3-10 membered saturated or partially unsaturated heterocycles having heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-5-membered heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 14-membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 in addition to L ² ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14-membered carbocyclic ring; having 1- 4 saturated or partially unsaturated 3-14 membered heterocycles with heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or 5 with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -14-membered heteroaryl; wherein Cy ^C is substituted by p instances of R ^C in addition to Q; R ^C is L ³ -R ^C1 or L ³ -H; R ^C1 is C _1-4 aliphatic group; benzene radical; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic heteroaryl ring; 3-7-membered saturated or partially unsaturated carbocyclic ring; 3-7-membered saturated or partially unsaturated monocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Cyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1- 0-4 instances of ₄ haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of R ^A or R ^B is independently R ¹ or R ² , where R ^A is replaced by q ^A instances of R ³ , R ^B is replaced by q ^B instances of R ³ , or two instances of R ^A , two instances of R ^B , two instances of R ^C , one instance of R ^A and an instance of R ^L , or an instance of R ^C and an instance of R ^L together with intervening atoms form a 4-8 membered saturated, moiety having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur Unsaturated or aromatic ring; wherein the ring is substituted by r instances of R ³ ; Each of L ¹ , L ² and L ³ is independently a covalent bond, or C _1-5 saturated or unsaturated, straight chain or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _{3 -6-} cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S (O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein each of the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group is deemed to be is substituted by one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² and is substituted by t instances of R ³ ; each instance of R ¹ is independently It is a side oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S (O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC( O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R) C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S( O) ₂ R; Each instance of R ² is independently a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic heterocyclic heterocyclic group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Aryl ring; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; having 1-2 A 3-7-membered saturated or partially unsaturated monocyclic heterocyclic ring with heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12-membered heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Saturated or partially unsaturated bicyclic heterocycle; Each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C( O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R )C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR) NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or optionally substituted groups selected from the following : C _1-6 aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 independently 5-6 membered heteroaryl rings selected from heteroatoms of nitrogen, oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from: C _1-6 aliphatic, saturated or Partially unsaturated 3-7 membered carbocyclic ring, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 independently A 5-6 membered heteroaryl ring selected from heteroatoms of nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen together with intervening atoms form 0-3 independent rings in addition to the nitrogen 4-7 membered saturated, partially unsaturated or heteroaryl rings selected from heteroatoms of nitrogen, oxygen and sulfur; and each of m, n, p, q ^A , q ^B , q ^P , r and t are independently 0, 1, 2, 3, or 4.

In some embodiments, the present disclosure provides compounds of Formula IA: IA, or a pharmaceutically acceptable salt thereof, wherein each of Cy ^B , Cy ^C , Q, and P is as defined in the Examples and classes and subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula II or III: , II III or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NR ^X and S; Y is selected from O, NR ^Y and S; Each instance of R ^X and R ^Y is independently R; Q series L ¹ ; Cy ^B series , , or ,in Represents a _covalent bond ^with 3-10 membered saturated or partially unsaturated heterocyclic rings having heteroatoms of nitrogen, oxygen and sulfur, and 5-14 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein ^{RP , in addition to _} , a saturated or partially unsaturated 3-14-membered heterocyclic ring with heteroatoms of oxygen and sulfur; phenyl; or a 5-14-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Wherein Cy ^C, in addition to Q, is also substituted by p instances of ^RC ; ^RC is L ³ -R ^C1 or L ³ -H; R ^C1 is a C _1-4 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryls with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1 -4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from nitrogen, oxygen and sulfur heteroatoms; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1- 0-4 instances of ₄ alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of ^RB is independently R ¹ or R ² , wherein ^RB is substituted with q ^B instances of R ³ , or two instances of R ^B , two instances of R ^C , or one instance of R ^C and one instance of R ^L together with intervening atoms form a heterogeneous mixture having 0-4 independently selected from nitrogen, oxygen, and sulfur. A 4-8 membered saturated, partially unsaturated or aromatic ring of atoms; wherein the ring is substituted by r instances of ^R3 ; each of ^L1 and ^L3 is independently a covalent bond, or _C1-5 Saturated or unsaturated, straight or branched hydrocarbon chains, in which one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH-, -N(R ^L )-, -NHC(O)- , -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O ) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O)O -, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group each of which is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² and substituted with t instances of R ³ ; R ¹ Each example is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S( O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R )OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R , -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or - N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic; phenyl; 5 having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -6-membered monocyclic heteroaryl ring; 8-10-membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7-membered saturated or partially unsaturated carbocyclic ring ; A 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 7-12 membered saturated or partially unsaturated bicyclic heterocycle of atoms; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S (O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O )R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N( R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or selected from the following Substituted groups: C _1-6 aliphatic group, phenyl group, 3-7 membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1-4 5-6 membered heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 Aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl group, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and A 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with the intervening atom form in addition to the nitrogen A 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of n, p, q ^B , q ^P , r and t One is independently 0, 1, 2, 3, or 4.

In some embodiments, the disclosure provides compounds of Formula IV-a, IV-b, IV-c, Va, Vb, or Vc: , IV-a , IV-bIV-c Va , Vb Vc or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C , ^RP and Q is as defined in the Examples and Classes and Subclasses herein.

In some embodiments, the disclosure provides compounds of Formula VI, VII, VIII, IX, X, XI, XII, or XIII: , , VI VII , , VIII IX , , X XI , XII XIII or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C and ^RP is as defined in the Examples and classes and subclasses herein.

In some embodiments, the disclosure provides compounds of Formula XIV, XV, XVI, XVII, XVIII, or XIX: , , XIV XV , , XVI XVII , ^{XVIII _}

In some embodiments, the present disclosure provides compounds of formula XX, XXI, XXII: , , XX XXI XXII or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C , R ^{C 1} , ^RP and Q is as defined in the Examples and classes and subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula XXIII, XXIV, or XXV: , , XXIII XXIV XXV or a pharmaceutically acceptable salt thereof, wherein each of R ^C1 , ^RP and Q is as defined in the Examples and Classes and Subclasses herein.

In some embodiments, the present disclosure provides compounds of Formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, or XXVII-c: , XXVI-a , XXVI-b XXVI-c XXVII-a , XXVII-b XXVII-c or a pharmaceutically acceptable salt thereof, wherein each of Cy ^C , ^RP and Q is as defined in the Examples and Classes and Subclasses herein.

In some embodiments, the disclosure provides compounds of Formula XXVIII: XXVIII or a pharmaceutically acceptable salt thereof, wherein each of Cy ^A , Cy ^B , Cy ^C , Q, P, and ^RD is as defined in the Examples and classes and subclasses herein.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula XXIX or XXX: , XXIX XXX or a pharmaceutically acceptable salt thereof, wherein each of ^CyB , ^CyC , ^RD , ^Q , 2. Compounds and definitions

Compounds described herein include those generally described herein and are further elucidated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements (CAS Edition), Handbook of Chemistry and Physics, 75th Edition. In addition, the general principles of organic chemistry are described in: "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, edited by Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. Chemical names, common names, and chemical structures are used interchangeably to describe the same structure. If both a chemical structure and a chemical name are used to refer to a compound, and there is an ambiguity between the structure and the name, the structure shall prevail.

The term "aliphatic" or "aliphatic group" as used herein means fully saturated or containing one or more unsaturated units, linear (i.e., unbranched) or branched, substituted or unbranched. Substituted hydrocarbon chains, monocyclic or bicyclic hydrocarbons that are either fully saturated or contain one or more unsaturated units, but are not aromatic (also referred to herein as "carbocyclic" or "alicyclic"), It has a single point of connection to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic") refers to a monocyclic C ₃ -C ₆ hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, and has a connecting to a single point on the rest of the molecule. In some cases, the carbocycle can be a bridged bicyclic or fused ring, such as, for example, ortho-fused carbocycles, spiro-fused carbocycles, and the like. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl) )alkyl or (cycloalkyl)alkenyl.

Unless otherwise indicated, the term "alkyl" as used herein refers to a monovalent aliphatic hydrocarbon group having a straight chain, a branched chain, a monocyclic moiety, or a polycyclic moiety, or a combination thereof, wherein the group is in the straight chain, as appropriate. , branched chain, monocyclic moiety or polycyclic moiety, or a combination thereof, one or more carbons are substituted with one or more substituents on each carbon, wherein the one or more substituents are independently C ₁ -C ₁₀ alkyl. Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclopropyl, Butyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like.

The term "lower alkyl" refers to C _1-4 linear or branched alkyl. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms. Exemplary haloalkyl groups are _-CF3 , _-CHF2 , _-CH2F , and the like.

The term "low carbon haloalkyl" refers to a C _1-4 linear or branched alkyl group substituted by one or more halogen atoms.

The term "alkoxy" refers to an alkyl group covalently attached to an oxygen atom, where the oxygen atom is the intervening atom between the alkyl group and another point of attachment. Exemplary alkoxy groups are -OMe (aka "methoxy"), -OEt (aka "ethoxy"), and the like.

The term "haloalkoxy" refers to an alkyl group substituted with one or more halogen atoms, wherein the alkyl group is covalently attached to an oxygen atom, and wherein the oxygen atom is an intervening atom between the alkyl group and another point of attachment. Exemplary haloalkoxy systems _{are -OCF3} , _-OCHF2 , _-OCH2CH2F , -OCH(F) _CH3 , and the like.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including any oxidized form of nitrogen, sulfur, phosphorus or silicon; any quaternary form of basic nitrogen; or heteroatom Substitutable nitrogen of the ring, such as N (as in 3,4-dihydro- 2H -pyrrolyl), NH (as in pyrrolidinyl) or NR ⁺ (as in N-substituted pyrrolidinyl) ).

The term "unsaturated" as used herein means a moiety having one or more unsaturated units.

The term "alkylene" refers to a divalent alkyl group. "Alkylene chain" is polymethylene, that is, -(CH ₂ ) _n -, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2 or 2 to 3. The substituted alkylene chain is a polymethylene in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenyl chains are polymethylenes containing at least one double bond in which one or more hydrogen atoms have been replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

The term "halogen" means F, Cl, Br or I.

The term "aryl" used alone or as part of a larger moiety refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring system in the system is aromatic and wherein the system Each ring contains 3 to 7 ring members. The term "aryl" is used interchangeably with the term "aryl ring." In certain embodiments of the compounds described herein, "aryl" refers to an aromatic ring system that may have one or more substituents, including but not limited to phenyl, naphthyl, anthracenyl, and the like. It is understood that an "aryl" group may contain carbon and heteroatom ring members.

Unless otherwise defined, the term "heteroaryl" or "heteroaromatic" as used herein refers to a monocyclic ring containing one or more heteroatoms (eg, 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur) Aromatic 5-6 membered rings, or 8-10 membered polycyclic systems containing one or more heteroatoms, in which at least one ring in the polycyclic system is aromatic, and the points of connection of the polycyclic system are via aromatic rings The ring atoms above. Heteroaryl rings can be linked to adjacent groups via carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isothiazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, and the like. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring if its point of attachment is through a benzo ring, for example: .

Unless otherwise defined, the term "heterocyclyl" or "heterocyclyl group" refers to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings (e.g., Ortho-fused bicyclic or spiro-fused bicyclic), and its ring system includes 1 to 4 heteroatoms, such as nitrogen, oxygen and sulfur. Heterocyclyl rings can be linked to adjacent groups via carbon or nitrogen.

Unless otherwise defined, the term "partially unsaturated" in the context of rings refers to a constituent ring within a monocyclic or polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the constituent ring contains at least one ring other than the ring Unsaturation beyond that provided by itself, but not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, and the like. In the case of a partially unsaturated ring system that is part of a polycyclic system, the other constituent rings in the polycyclic system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic system is at the partially unsaturated constituent ring. superior. For example, unless otherwise defined, if the point of attachment of 1,2,3,4-tetrahydroquinoline is via N-hexahydropyridinyl, it is a partially unsaturated ring, for example: .

Unless otherwise defined, the term "saturated" in the context of rings refers to 3-10 membered monocyclic or 7-14 membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring systems, where monocyclic or as used for polycyclic The points of connection of the ring system are composed of rings that do not contain additional unsaturation beyond that provided by the ring itself. Examples of monocyclic saturated rings include, but are not limited to, azetidine, oxetane, cyclohexane, and the like. In the case of a saturated ring system that is part of a polycyclic system, the other constituent rings in the polycyclic system may be saturated, partially unsaturated or aromatic, but the point of attachment to the polycyclic system is on the saturated constituent ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring if the point of attachment is via an azetidinyl ring, for example: .

As used herein, the terms "alkylene", "aryl", "cycloalkyl", "heteroaryl", "heterocycloalkyl" and other similar terms having the suffix "-alkylene" It refers to the bivalent bonding form of the group modified by the suffix. For example, "alkylene" is a divalent alkyl group attached to the group to which it is attached.

As used herein, the term "bridged bicyclic" refers to any bicyclic ring system having at least one bridge, that is, carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, "bridge" means an unbranched chain of atoms or atoms or bonds connecting two bridgeheads, where a "bridgehead" is any backbone bonded to three or more backbone atoms in a ring system atoms (excluding hydrogen). In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those described below, where each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, bridged bicyclic groups are optionally substituted with one or more substituents as described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen bridging the bicyclic group is optionally substituted. Examples of bridged second rings include:

As described herein, the compounds described herein may contain "optionally substituted" moieties. Generally speaking, the term "substituted" regardless of whether preceded by the term "optionally" means that one or more hydrogens of the specified moiety have been replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position on the group, and more than one position in any given structure may be substituted by more than one group selected from When a specified group of substituents is substituted, the substituents at each position may be the same or different. Combinations of substituents contemplated by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that does not, when subjected to conditions permitting its production, detection and, in certain embodiments, its recovery, purification and use for one or more purposes disclosed herein. substantial changes.

Suitable monovalent substituents on the substitutable carbon atoms of the "optionally substituted" group are independently halogen; -(CH ₂ ) _0-4 R°; -(CH ₂ ) _0-4 OR°; -O( CH ₂ ) _0-4 R°, -O-(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 CH(OR°) ₂ ; -(CH ₂ ) _0-4 SR °; -(CH ₂ ) _0-4 Ph, which may be substituted by R°; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph, which may be substituted by R°; -CH=CHPh, which Can be substituted by R°; -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl, which can be substituted by R°; -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _{0 -4} N(R°) ₂ ;-(CH ₂ ) _0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH ₂ ) _0-4 N(R°)C(O)NR° ₂ ;-N(R°)C(S)NR° ₂ ;-(CH ₂ ) _0-4 N(R°)C(O)OR°;-N( R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR° ₂ ; -N(R°)N(R°)C(O)OR °;-(CH ₂ ) _0-4 C(O)R°;-C(S)R°;-(CH ₂ ) _0-4 C(O)OR°;-(CH ₂ ) _0-4 C( O)SR°;-(CH ₂ ) _0-4 C(O)OSiR° ₃ ;-(CH ₂ ) _0-4 OC(O)R°;-OC(O)(CH ₂ ) _0-4 SR° ;-SC(S)SR°;-(CH ₂ ) _0-4 SC(O)R°;-(CH ₂ ) _0-4 C(O)NR° ₂ ;-C(S)NR° ₂ ;- C(S)SR°; -SC(S)SR°, -(CH ₂ ) _0-4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; -C(O)C (O)R°; -C(O)CH ₂ C(O)R°; -C(NOR°)R°; -(CH ₂ ) _0-4 SSR°; -(CH ₂ ) _0-4 S( O) ₂ R°;-(CH ₂ ) _0-4 S(O) ₂ OR°;-(CH ₂ ) _0-4 OS(O) ₂ R°;-S(O) ₂ NR° ₂ ;-( CH ₂ ) _0-4 S(O)R°; -N(R°)S(O) ₂ NR° ₂ ; -N(R°)S(O) ₂ R°; -N(OR°)R° ;-C(NH)NR° ₂ ;-P(O)(OR°)R°;-P(O)R° ₂ ;-OP(O)R° ₂ ;-OP(O)(OR°) ₂ ;-SiR° ₃ ;-(C _1-4 straight chain or branched alkylene group)ON(R°) ₂ ;or -(C _1-4 straight chain or branched alkylene group)C(O) ON(R°) ₂ , where each R° may be substituted as defined below and is independently hydrogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ -(5-6 membered heteroaryl ring), or 3-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or although As defined above, but two independently occurring R° together with intervening atoms form a 3-12 membered saturated, partially unsaturated or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. or bicyclic, which may be substituted as defined below.

Suitable monovalent substituents on R° (or a ring formed by two independently occurring R° together with an intervening atom) are independently halogen, -(CH ₂ ) _0-2 R ^l , -(halo R ^l ) , -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^l , -(CH ₂ ) _0-2 CH(OR ^l ) ₂ ; -O(halogen group R ^l ), -CN, - N ₃ , -(CH ₂ ) _0-2 C(O)R ^l , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^l , -(CH ₂ ) _0-2 SR ^l , -(CH ₂ ) _0-2 SH , -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^l , -(CH ₂ ) _0-2 NR ^l _2. -NO ₂ , -SiR ^l ₃ , -OSiR ^l ₃ , -C(O)SR ^l , -(C _1-4 linear or branched alkylene group)C(O)OR ^l or -SSR ^l , wherein each R ^l is unsubstituted or only substituted by one or more halogens when there is a "halogen group" in front, and is independently selected from C _1-4 aliphatic group, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on the saturated carbon atom of R° include =O and =S.

Suitable divalent substituents on the saturated carbon atom of the "optionally substituted" group include the following: =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , =NOR ^* , -O(C(R ^* ₂ )) _2-3 O- or -S(C(R ^* ₂ )) _2-3 S-, where Each independently occurring R ^* is selected from hydrogen, substituted C _1-6 aliphatic as defined below, or unsubstituted having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. 5 to 6 membered saturated, partially unsaturated or aryl ring. Suitable divalent substituents bonded to the ortho-substitutable carbon of the "optionally substituted" group include: -O(CR ^* ₂ ) _2-3O- , where each independently occurring R ^* is selected from hydrogen , may be a substituted C _1-6 aliphatic group as defined below or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic group having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. base ring.

Suitable substituents on the aliphatic group of R ^* include halogen, ^-Rl , -( ^haloRl ), -OH, ^-ORl , -O(haloRl ⁾ , -CN, -C(O) OH, -C(O)OR ^l , -NH ₂ , -NHR ^l , -NR ^l ₂ or -NO ₂ , where each R ^l is unsubstituted or only substituted by one or more Halogen substituted and independently C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or 5 having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur -6-membered saturated, partially unsaturated or aryl ring.

Suitable substituents on the substitutable nitrogen of the "optionally substituted" group include -R ^ , -NR ^ ₂ , -C(O)R ^ , -C(O)OR ^ , -C(O)C (O)R ^ , -C(O)CH ₂ C(O)R ^ , -S(O) ₂ R ^ , -S(O) ₂ NR ^ ₂ , -C(S)NR ^ ₂ , -C (NH)NR ^ ₂ or -N(R ^ )S(O) ₂ R ^ ; wherein each R ^ is independently hydrogen, substituted C _1-6 aliphatic group as defined below, unsubstituted -OPh or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or notwithstanding the above definition, two independently Occurrences of R ^† together with one or more intervening atoms form an unsubstituted 3-12 membered saturated, partially unsaturated or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur Or the second ring.

Suitable substituents on the aliphatic group of R ^† are independently halogen, -R ^l , -(halogen group R ^l ), -OH, -OR ^l , -O(halogen group R ^l ), -CN, -C( O)OH, -C(O)OR ^l , -NH ₂ , -NHR ^l , -NR ^l ₂ or -NO ₂ , in which each R ^l is unsubstituted or is preceded by only one or Multiple halogen substitutions, and are independently C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph or have 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur 5-6 membered saturated, partially unsaturated or aryl ring.

The term "isomers" as used herein refers to compounds that have the same chemical formula but different structures or optical configurations. The term "stereoisomers" as used herein refers to and includes isomeric molecules that have the same molecular formula but differ in the positioning of atoms and/or functional groups in space. All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbons on various substituents) (including enantiomer forms and diastereomer forms) are encompassed by the present disclosure. within the range. Therefore, unless otherwise indicated, single stereochemical isomers as well as mixtures of enantiomers, diastereomers, and geometric (or configurational) isomers of the compounds of the present invention are within the scope of the present disclosure.

The term "tautomer" as used herein refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It should be understood that tautomers encompass both valence tautomers and proton tautomers (also known as proton transfer tautomers). Valence tautomers involve interconversions by rearrangement of some of the bonding electrons. Protic tautomers include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. Unless otherwise stated, all tautomers of the compounds described herein are within the scope of this disclosure.

The term "isotopic substitution" as used herein refers to the substitution of an atom with its isotope. The term "isotope" as used herein refers to an atom that has the same atomic number as the atomic number of the atom that predominates in nature but has a different mass number (neutron number) than the mass number of the atom that predominates in nature. . It should be understood that a compound having isotopic substitution means a compound in which at least one of the atoms contained is substituted by its isotope. Atoms that may be substituted by their isotopes include, but are not limited to, hydrogen, carbon, and oxygen. Examples of isotopes of hydrogen atoms include ^2H (also represented as D) and ^3H . Examples of isotopes of carbon atoms include ¹³ C and ¹⁴ C. Examples of isotopes of oxygen atoms include ¹⁸ O. Unless otherwise stated, all isotopic substitutions of the compounds described herein are within the scope of this disclosure. In accordance with the present disclosure, such compounds may be used, for example, as analytical tools, probes in bioanalysis, or therapeutic agents.

As used herein, the term "pharmaceutically acceptable salts" means salts that are suitable, within the scope of reasonable medical judgment, for use in contact with tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, and the like and with reasonable The benefit/risk ratio of these salts is commensurate. Exemplary pharmaceutically acceptable salts are provided in, for example, Berge et al., J. Pharm. Sci. 1977, 66(1), 1; and Gould, PL, Int. J. Pharmaceutics 1986, 33, 201-217 (each hereby incorporated by reference) incorporated by reference in full).

Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amine groups with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid; or organic acids such as acetic acid, oxalic acid, Maleic acid, tartaric acid, citric acid, succinic acid or malonic acid; or salts formed by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphorsulfonate, citrate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, Glycerophosphate, gluconate, hemisulfate, enanthate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate , pectate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like.

Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium and the like. Other pharmaceutically acceptable salts include, where appropriate, formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates. Non-toxic ammonium, quaternary ammonium and amine cations.

Pharmaceutically acceptable salts are also intended to encompass half-salts in which the compound:acid ratio is 2:1 respectively. Exemplary half-salts are those derived from acids containing two carboxylic acid groups, such as malic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, glutaric acid, oxalic acid, adipic acid, and citric acid. salt. Other exemplary half-salts are those derived from diprotic inorganic acids such as sulfuric acid. Exemplary preferred half-salts include, but are not limited to, hemalenate, hemifumarate, and hemisuccinate.

As used herein, the term "about" is used herein to mean about, approximately, approximately, or approximately. When the term "about" is used in connection with a numerical range, it modifies the range by extending the boundaries above and below the stated numerical value. Generally speaking, the term "about" is used herein to modify a numerical value to vary up to 20% plus or minus (higher or lower) above and below the stated value.

As used herein, an "effective amount," "sufficient amount," or "therapeutically effective amount" is one that, when administered according to a therapeutic dosage regimen, is sufficient to treat an individual or population suffering from or susceptible to a disease, disorder, and/or disorder (e.g., , an amount of a compound that achieves a beneficial or desired result, including clinical results) for the disease, condition and/or disorder. Accordingly, an effective amount may be sufficient, for example, to reduce or ameliorate the severity and/or duration of a disorder or one or more symptoms thereof, to prevent the progression of a disorder or symptom associated with a CDK2 signaling-related disorder, or to enhance or reduce the severity of a disorder or symptom thereof. Other modalities modify one or more of the preventive or therapeutic effects of another therapy. An effective amount also includes an amount of a compound that avoids or substantially attenuates undesirable side effects.

As used herein and as well understood in the art, "treatment" refers to a method used to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, reduction in severity of a disease or illness, stabilization (i.e., non-exacerbation) of a disease or illness, prevention of spread, delay or slowdown of a disease or illness. Progression, amelioration or alleviation of disease or illness and alleviation (whether partial or total) of disease or illness, whether detectable or undetectable. "Treatment" also means prolonging survival compared to expected survival without treatment. In some embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (eg, due to a history of symptoms and/or due to genetic or other predisposing factors). Treatment may also be continued after symptoms have subsided, for example to prevent or delay their recurrence.

The phrase "in need" refers to the need for symptomatic or asymptomatic relief from a disorder associated with CDK2 signaling activity or ameliorated by the compounds and/or compositions of the present disclosure. 3. Description of exemplary embodiments

As generally described above, in some embodiments, the present disclosure provides compounds of Formula I: I or a pharmaceutically acceptable salt thereof, wherein: Q is L ¹ ; Cy ^A is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A is replaced by m instances of R ^A in addition to Q and Cy ^B ; Cy ^B is , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with ^P ; P is L ² -RP; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group, 1-4 3-10 membered saturated or partially unsaturated heterocycles having heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-5-membered heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 14-membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 in addition to L ² ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14-membered carbocyclic ring; having 1- 4 saturated or partially unsaturated 3-14 membered heterocycles with heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or 5 with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -14-membered heteroaryl; wherein Cy ^C is substituted by p instances of R ^C in addition to Q; R ^C is L ³ -R ^C1 or L ³ -H; R ^C1 is C _1-4 aliphatic group; benzene radical; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic heteroaryl ring; 3-7-membered saturated or partially unsaturated carbocyclic ring; 3-7-membered saturated or partially unsaturated monocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Cyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1- 0-4 instances of ₄ haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of R ^A or R ^B is independently R ¹ or R ² , where R ^A is replaced by q ^A instances of R ³ , and R ^B is replaced by q ^B instances of R ³ , or two instances of R ^A , two instances of R ^B , two instances of R ^C , one of R ^A Example and one example of R ^L , or one example of R ^C and one example of R ^L together with intervening atoms form a 4-8 membered saturated, Partially unsaturated or aromatic ring; wherein the ring is substituted by r instances of R ³ ; Each of L ¹ , L ² and L ³ is independently a covalent bond, or C _1-5 is saturated or unsaturated, Straight or branched hydrocarbon chains in which one or both methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6- membered cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, - S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S- , -S(O)- or -S(O) ₂ -; wherein each of the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group Optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; Each instance of R ^L is independently R ¹ or R ² and substituted with t instances of R ³ ; Each instance of R ¹ is independently Ground is a side oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, - S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC (O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R )C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S (O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Heteroaryl ring; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; having 1-2 A 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur A saturated or partially unsaturated bicyclic heterocycle; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C (O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N( R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR )NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or optionally substituted groups selected from the following Group: C _1-6 aliphatic group, phenyl group, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 independently is a 5-6 membered heteroaryl ring selected from heteroatoms of nitrogen, oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 aliphatic, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 A 5-6 membered heteroaryl ring independently selected from heteroatoms of nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen together with intervening atoms form 0-3 R groups in addition to the nitrogen 4-7 membered saturated, partially unsaturated or heteroaryl rings independently selected from heteroatoms of nitrogen, oxygen and sulfur; and each of m, n, p, q ^A , q ^B , q ^P , r and t One is independently 0, 1, 2, 3, or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula II or III: , II III or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NR ^X and S; Y is selected from O, NR ^Y and S; Each instance of R ^X and R ^Y is independently R; Q series L ¹ ; Cy ^B series , , or ,in Represents a _covalent bond ^with 3-10 membered saturated or partially unsaturated heterocyclic rings having heteroatoms of nitrogen, oxygen and sulfur, and 5-14 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein ^{RP , in addition to _} , a saturated or partially unsaturated 3-14-membered heterocyclic ring with heteroatoms of oxygen and sulfur; phenyl; or a 5-14-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Wherein Cy ^C, in addition to Q, is also substituted by p instances of ^RC ; ^RC is L ³ -R ^C1 or L ³ -H; R ^C1 is a C _1-4 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryls with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1 -4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from nitrogen, oxygen and sulfur heteroatoms; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1- 0-4 instances of ₄ alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of ^RB is independently R ¹ or R ² , wherein ^RB is substituted with q ^B instances of R ³ , or two instances of R ^B , two instances of R ^C , or one instance of R ^C and one instance of R ^L together with intervening atoms form a heterogeneous mixture having 0-4 independently selected from nitrogen, oxygen, and sulfur. A 4-8 membered saturated, partially unsaturated or aromatic ring of atoms; wherein the ring is substituted by r instances of ^R3 ; each of ^L1 and ^L3 is independently a covalent bond, or _C1-5 Saturated or unsaturated, straight or branched hydrocarbon chains, in which one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH-, -N(R ^L )-, -NHC(O)- , -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O ) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O)O -, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group each of which is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² and substituted with t instances of R ³ ; R ¹ Each example is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S( O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R )OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R , -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or - N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic; phenyl; 5 having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -6-membered monocyclic heteroaryl ring; 8-10-membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7-membered saturated or partially unsaturated carbocyclic ring ; A 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 7-12 membered saturated or partially unsaturated bicyclic heterocycle of atoms; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S (O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O )R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N( R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or selected from the following Substituted groups: C _1-6 aliphatic group, phenyl group, 3-7 membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and having 1-4 5-6 membered heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 Aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl group, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and A 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with the intervening atom form in addition to the nitrogen A 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of n, p, q ^B , q ^P , r and t One is independently 0, 1, 2, 3 or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula IV-a, IV-b, IV-c, Va, Vb, or Vc: , IV-a , IV-bIV-c Va , Vb Vc or its pharmaceutically acceptable salt, wherein: Q is L ¹ ; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, benzene radical, a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 3-10 membered saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 5-14-membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14-membered carbocyclic ring; having 1-4 independent A saturated or partially unsaturated 3-14-membered heterocycle with heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or a 5-14-membered heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Heteroaryl; wherein Cy ^C in addition to Q is also substituted by p instances of R ^C ; R ^C is L ^{3 -RC1} or L ³ -H; R ^C1 is C _1-4 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 members with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Bicyclic heteroaryl ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur ; Or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl , 0-4 instances of C _1-4 alkoxy and C _1-4 haloalkoxy groups are substituted; or two instances of R ^C , or one instance of R ^C and one instance of R ^L with intervening The atoms together form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is substituted by r instances of ^R3 ; ^L1 , Each of L ² and L ³ is independently a covalent bond, or a C _1-5 saturated or unsaturated, straight or branched hydrocarbon chain, with one or two methylene units in the chain as appropriate And independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered cycloalkyl group Heteroaryl, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N( R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O -, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) _2- ; wherein C _3-6 extends Each of cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl is optionally substituted with one instance of R ¹ or C _1-6 aliphatic group; each of R ^L Examples are independently R ¹ or R ² and are substituted by t instances of R ³ ; each instance of R ¹ is independently pendant oxy, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R , -S(O)NR ₂ , -C(O)R , -C(O)OR , -C (O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR , -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N( R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; Phenyl; 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 8-10 membered bicyclic heteroaryl ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Monocyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each instance of ^R3 is independently a pendant oxygen group , Halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F , -OS(O) ₂ F , -C(O)R , -C(O)OR , -C(O)NR ₂ , -C(NR)NR ₂ , -C (O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S (O)R, -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C _1-6 aliphatic, phenyl, having 1-2 independently selected from nitrogen , a 3-7 membered saturated or partially unsaturated heterocyclic ring having heteroatoms of oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, having 1-2 independently selected from 3-7 membered saturated or partially unsaturated heterocyclic rings with heteroatoms of nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or : Two R groups on the same nitrogen together with intervening atoms form a 4-7 membered saturated, partially unsaturated or Heteroaryl ring; and each of p, ^qP , r, and t is independently 0, 1, 2, 3, or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula VI, VII, VIII, IX, X, XI, XII, or XIII: , , VI VII , , VIII IX , , X XI , ^XII _{_} 4 3-10 membered saturated or partially unsaturated heterocycles having heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-14 members having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring; having 1 to 4 independently selected from nitrogen, A saturated or partially unsaturated 3-14-membered heterocyclic ring with heteroatoms of oxygen and sulfur; phenyl; or a 5-14-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C is substituted by p instances of R ^C ; R ^C is L ^{3 -RC1} or L ³ -H; R ^C1 is a C _1-4 aliphatic group; phenyl; having 1 to 4 independently selected from nitrogen, 5-6 membered monocyclic heteroaryl ring with heteroatoms of oxygen and sulfur; 8-10 membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 A saturated or partially unsaturated carbocyclic ring with 1-2 members; a 3-7-membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 1-4 membered monocyclic heterocyclic ring independently selected from nitrogen, oxygen and sulfur. A 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring composed of heteroatoms of nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1-4 alkoxy and C 0-4 instances of the _1-4 haloalkoxy group are substituted; two instances of R ^C , or one instance of R ^C and one instance of R ^L together with the intervening atom form a group having 0 to 4 independently selected A 4-8 membered saturated, partially unsaturated or aromatic ring derived from heteroatoms of nitrogen, oxygen and sulfur; wherein the ring is substituted by r instances of ^R3 ; each ^L3 is independently a covalent bond, or _{C1 -5} saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C( R ^L ) ₂ -, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, -NH-, -N(R ^L )-, -NHC(O )-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S (O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O )O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6- membered cycloalkyl, 3-6-membered heterocycloalkyl and 5-6-membered heterocycloalkyl Each of the aryl groups is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² and substituted with t instances of R ³ ; Each instance of R ¹ is independently a pendant oxy, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N (R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR )R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; phenyl; having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 5-6 membered monocyclic heteroaryl ring; 8-10 membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated Carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 7-12-membered saturated or partially unsaturated bicyclic heterocyclic heteroatom; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C (O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O )NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , - N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or selected from the following The optionally substituted group: C _1-6 aliphatic group, phenyl group, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from: C _{1 -6} aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl group, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur , and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with the intervening atom form a ring other than the nitrogen In addition, it also has a 4-7 membered saturated, partially unsaturated or heteroaryl ring with 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and each of p, q ^P , r and t is independent Land is 0, 1, 2, 3 or 4.

As generally described above, in some embodiments, the disclosure provides compounds of Formula XIV, XV, XVI, XVII, XVIII, or XIX: , , XIV XV , , XVI XVII , ^{XVIII _ _ _} , a saturated or partially unsaturated 3-14-membered heterocyclic ring with heteroatoms of oxygen and sulfur; phenyl; or a 5-14-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Wherein Cy ^C, in addition to Q, is also substituted by p instances of ^RC ; ^RC is L ³ -R ^C1 or L ³ -H; R ^C1 is a C _1-4 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryls with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1 -4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from nitrogen, oxygen and sulfur heteroatoms; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1- 0-4 instances of ₄ alkoxy and C _1-4 haloalkoxy groups are substituted; two instances of R ^C , or one instance of R ^C and one instance of R ^L together with the intervening atom form a group having 0 - 4 4-8 membered saturated, partially unsaturated or aromatic rings independently selected from heteroatoms of nitrogen, oxygen and sulfur; wherein the ring is substituted by r instances of ^R3 ; each of ^L1 and ^L3 One is independently a covalent bond, or a C _1-5 saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by the following groups : -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS( O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)- , -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 members Each of the heterocycloalkyl and 5-6 membered heteroaryl groups is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; each instance of ^R is independently R ¹ or R ² , and substituted by t instances of R ³ ; each instance of R ¹ is independently a pendant oxy group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C (NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C( O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR _2. -N(R)S(O)R or -N(R)S(O) ₂ R; Each instance of R ² is independently a C _1-7 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryls with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1 -4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from heteroatoms of nitrogen, oxygen and sulfur; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR , -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, - N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N( R)S(O) ₂ R or an optionally substituted group selected from the following: C _1-6 aliphatic, phenyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated heterocyclic rings, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or selected from The following optionally substituted groups: C _1-6 aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl group, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated heterocyclic rings, and 5-6 membered heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R on the same nitrogen The group together with the intervening atom forms a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and p, Each of r and t is independently 0, 1, 2, 3 or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formulas XX, XXI, and XXII: , , XX XXI XXII or its pharmaceutically acceptable salt, wherein: Q is L ¹ ; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group , 3-10 membered saturated or partially unsaturated heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered saturated or partially unsaturated heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 5-14 membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring; having 1-4 independently Saturated or partially unsaturated 3-14-membered heterocycle with heteroatoms selected from nitrogen, oxygen and sulfur; phenyl; or 5-14-membered heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Aryl; R ^C1 is a C _1-4 aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; having 1-4 8-10 membered bicyclic heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; 3-7 membered saturated or partially unsaturated carbocyclic rings; 1-2 members independently selected from nitrogen, oxygen and A 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with sulfur heteroatoms; or a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Ring; wherein R ^C1 is substituted by 0-4 instances of groups independently selected from halogen, C _1-4 haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy; L ¹ is covalent bond, or a C _1-5 saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or both methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L ) -, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH-, -N(R ^L )- , -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N (R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)- , -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5 Each of the -6-membered heteroaryl groups is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² , and is substituted with one instance of R ³ Substituted by t instances; each instance of R ¹ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , - C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R) S(O)R or -N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; phenyl; having 1-4 independently selected from nitrogen, oxygen 5-6 membered monocyclic heteroaryl rings with heteroatoms of nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 members Saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 1-4 independently selected from 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring with heteroatoms of nitrogen, oxygen and sulfur; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR , -NR ₂ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R , -S(O)NR ₂ , -S(O) ₂ F , -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R , -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O )NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C _1-6 aliphatic, phenyl, 3-7 membered saturated or partially saturated with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated heterocycles, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or selected from the following optionally substituted Group: C _1-6 aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, 3-7 membered saturated or with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Partially unsaturated heterocycles, and 5-6 membered heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with an intervening atom Forming a 4-7 membered saturated, partially unsaturated or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen; and each of q ^P , r and t One is independently 0, 1, 2, 3, or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula XXIII, XXIV, or XXV: , , XXIII XXIV XXV or its pharmaceutically acceptable salt, wherein: Q is L ¹ ; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group , 3-10 membered saturated or partially unsaturated heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 3-10 membered saturated or partially unsaturated heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 5-14 membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 ; R ^P1 is R ³ ; R ^C1 is C _1-4 aliphatic group; phenyl; having 1 to 4 independently selected A 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1-4 7-12 membered saturated or partially unsaturated bicyclic heterocycle independently selected from heteroatoms of nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1-4 alkoxy 0-4 examples of substitution of C _1-4 haloalkoxy groups; L ¹ is a covalent bond, or C _1-5 saturated or unsaturated, linear or branched hydrocarbon chain, wherein the chain One or two methylene units are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl, 3-6 membered cycloalkyl Heterocycloalkyl, 5-6 membered heteroaryl, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O) NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) _2- ; wherein each of the C _3-6 cycloalkyl, 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl is optionally replaced by an instance of R ¹ or C _1-6 Aliphatic substitution; Each instance of R ^L is independently R ¹ or R ² and substituted by t instances of R ³ ; Each instance of R ¹ is independently a pendant oxy group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R , -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R) C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R; each instance of R ² is independent Ground is a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; having 1-4 independently selected 8-10 membered bicyclic heteroaryl ring with heteroatoms from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur R ³ Each example is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S( O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R) C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or optionally substituted groups selected from the following: C _1-6 aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated heterocycles having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5 having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -6-membered heteroaryl ring; each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl group , 3-7 membered saturated or partially unsaturated heterocyclic rings with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 5-6 membered heteroaryl ring, or: two R groups on the same nitrogen together with the intervening atom form a ring having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen 4-7 membered saturated, partially unsaturated or heteroaryl ring; and each of q ^P and t is independently 0, 1, 2, 3 or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula XXVIII: XXVIII or its pharmaceutically acceptable salt, wherein: ^RD is ^RD' , or ; ^RD' is a group capable of being cleaved; Each of ^RD1 and ^RD2 is independently hydrogen, ^R1, or ^R2 , wherein ^RD1 is substituted by q ^D1 instances of ^R3 , and ^RD2 is q ^D2 instances of ^R3 are substituted; or one instance of ^RD1 and one instance of ^RD2 together with intervening atoms form a 4-8 membered saturation having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. or a partially unsaturated ring; wherein the ring is substituted by q ^DD instances of R ³ ; ^RD3 is hydrogen, R ¹ or R ² , wherein ^RD3 is substituted by q D ³ instances of R ³ ; Q is L ¹ ; Cy ^A It is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A is also substituted by m instances of R ^A in addition to Q and Cy ^B ; Cy ^B department , , , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with ^P ; P is L ² -RP; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group, 1-4 3-10 membered saturated or partially unsaturated heterocycles having heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-5-membered heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 14-membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 in addition to L ² ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14-membered carbocyclic ring; having 1- 4 saturated or partially unsaturated 3-14 membered heterocycles with heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or 5 with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -14-membered heteroaryl; wherein Cy ^C is substituted by p instances of R ^C in addition to Q; R ^C is L ³ -R ^C1 or L ³ -H; R ^C1 is C _1-4 aliphatic group; benzene radical; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic heteroaryl ring; 3-7-membered saturated or partially unsaturated carbocyclic ring; 3-7-membered saturated or partially unsaturated monocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Cyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1- 0-4 instances of ₄ haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of R ^A or R ^B is independently R ¹ or R ² , where R ^A is replaced by q ^A instances of R ³ , and R ^B is replaced by q ^B instances of R ³ , or two instances of R ^A , two instances of R ^B , two instances of R ^C , one of R ^A Example and one example of R ^L , or one example of R ^C and one example of R ^L together with intervening atoms form a 4-8 membered saturated, Partially unsaturated or aromatic ring; wherein the ring is substituted by r instances of R ³ ; each of ^LD , L ¹ , L ² and L ³ is independently a covalent bond, or C _1-5 saturated or Unsaturated, straight or branched hydrocarbon chains, in which one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, phenyl, C _3-6 cycloalkyl, 3-6 heterocycloalkyl, 5-6 heteroaryl, -NH-, -N(R ^L )-, -NHC(O )-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S (O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O )O-, -S-, -S(O)- or -S(O) ₂ -; wherein the phenylene group, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5- Each of the 6-membered heteroaryl groups is substituted with 0-3 instances of R ¹ or C _1-6 aliphatic; each instance of R ^L is independently R ¹ or R ² and is substituted with 0 to ³ instances of R 1 Substituted by t instances; each instance of R ¹ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , - C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N( R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R) S(O)R or -N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; phenyl; having 1-4 independently selected from nitrogen, oxygen 5-6 membered monocyclic heteroaryl rings with heteroatoms of nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 members Saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 1-4 independently selected from 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring with heteroatoms of nitrogen, oxygen and sulfur; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR , -NR ₂ , -S(O) ₂ R , -S(O) ₂ NR ₂ , -S(O)R , -S(O)NR ₂ , -S(O) ₂ F , -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R , -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O )NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C _1-6 aliphatic, phenyl, 3-7 membered saturated or partially saturated with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Unsaturated heterocycles, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or selected from the following optionally substituted Group: C _1-6 aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, 3-7 membered saturated or with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Partially unsaturated heterocycles, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups together with the intervening atom form except the nitrogen In addition, it also has a 4-7 membered saturated, partially unsaturated or heteroaryl ring with 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and m, n, p, q ^A , q ^B , q Each of ^D1 , q ^D2 , q ^D3 , q ^DD , q ^P , r and t is independently 0, 1, 2, 3 or 4.

As generally described above, in some embodiments, the present disclosure provides compounds of Formula XXIX or XXX: , XXIX XXX or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NR ^X and S; Y is selected from O, ^{NR Y} and ^S ; Each instance of R R ^D is R ^D' , or ; ^RD' is a group capable of being cleaved; Each of ^RD1 and ^RD2 is independently hydrogen, ^R1, or ^R2 , wherein ^RD1 is substituted by q ^D1 instances of ^R3 , and ^RD2 is q ^D2 instances of ^R3 are substituted; or one instance of ^RD1 and one instance of ^RD2 together with intervening atoms form a 4-8 membered saturation having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Or a partially unsaturated ring; wherein the ring is substituted by q ^D instances of R ³ ; ^RD3 is hydrogen, R ¹ or R ² , wherein ^RD3 is substituted by q ^D instances of R ³ ; Q is L ¹ ; Cy ^B department , , , , or ,in represents the covalent bond with Cy ^A and Represents a _covalent bond ^with 3-10 membered saturated or partially unsaturated heterocyclic rings having heteroatoms of nitrogen, oxygen and sulfur, and 5-14 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein ^{RP , in addition to _} , a saturated or partially unsaturated 3-14-membered heterocyclic ring with heteroatoms of oxygen and sulfur; phenyl; or a 5-14-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Wherein Cy ^C, in addition to Q, is also substituted by p instances of ^RC ; ^RC is L ³ -R ^C1 or L ³ -H; R ^C1 is a C _1-4 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryls with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1 -4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from nitrogen, oxygen and sulfur heteroatoms; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1- 0-4 instances of ₄ alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of ^RB is independently R ¹ or R ² , wherein ^RB is substituted with q ^B instances of R ³ , or two instances of R ^B , two instances of R ^C , or one instance of R ^C and one instance of R ^L together with intervening atoms form a heterogeneous mixture having 0-4 independently selected from nitrogen, oxygen, and sulfur. A 4-8 membered saturated, partially unsaturated or aromatic ring of atoms; wherein the ring is substituted by r instances of R ³ ; each of ^LD , L ¹ and L ³ is independently a covalent bond, or C _1-5 saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C (R ^L ) ₂ -, phenyl group, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH-, -N(R ^L )- , -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N (R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)- , -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the phenyl group, C _3-6 cycloalkyl group, 3-6 membered heterocyclic group Each of alkyl and 5-6 membered heteroaryl is substituted with 0-3 instances of R ¹ or C _1-6 aliphatic; each instance of ^RL is independently R ¹ or R ² , and substituted by t instances of R ³ ; each instance of R ¹ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR )NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O) R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; phenyl; having 1-4 independently 5-6 membered monocyclic heteroaryl rings with heteroatoms selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur ; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1-4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from heteroatoms of nitrogen, oxygen and sulfur; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, - OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N( R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R) S(O) ₂ R or an optionally substituted group selected from the following: C _1-6 aliphatic, phenyl, 3- having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 7-membered saturated or partially unsaturated heterocyclic rings, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or selected from the following Optionally substituted groups: C _1-6 aliphatic group, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl group, 3 having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur -7-membered saturated or partially unsaturated heterocycles, and 5-6-membered heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups with intervening atoms Together, they form a 4-7 membered saturated, partially unsaturated, or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur in addition to the nitrogen; and n, p, q ^B , q Each of ^D1 , ^qD2 , ^qD3 , ^qDD , ^qP , r and t is independently 0, 1, 2, 3 or 4.

As generally defined above, Cy ^A is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A is also modified by R ^A in addition to Q and Cy ^B. m instances are replaced. In some embodiments, Cy ^A is , , , , , , , , , , or ,in represents the covalent bond with Q and Represents the covalent bond with Cy ^B. In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is . In some embodiments, Cy ^A is .

In some embodiments, Cy ^A is ,in Represents the covalent bond with Q, represents a covalent bond with Cy ^B , and Represents the covalent bond with R ^D.

In some embodiments, Cy ^A is selected from the groups depicted in the compounds in Table 1.

As generally defined above for example with respect to formulas I, IA and II, Cy ^B is , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with P. As described above for the general definitions of formulas XXVIII, XXIX and XXX, Cy ^B is , , , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with X.

In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is .

In some embodiments, Cy ^B is , , , , , , , , , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with P, X or Y. In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is . In some embodiments, Cy ^B is , in some embodiments, Cy ^B is , in some embodiments, Cy ^B is .

In some embodiments, Cy ^B , Cy ^A and P or X are in a trans relationship. In some embodiments, Cy ^B , Cy ^A and P or X are in a cis relationship. See, for example, the Cy ^B group shown in the compounds in Table 1.

In some embodiments, Cy ^B is selected from the groups depicted in the compounds in Table 1.

As generally defined above, P is L ^{2 -RP} , wherein each of L ² and ^RP is as defined in the Examples and classes and subclasses herein. In some embodiments, ^P is -L ² -RP. In some embodiments, ^P is -ORP, ^-NHRP , ^-SRP , -NHC(O) ^NHRP , -OC(O) ^NHRP , and -NHC(O) ^ORP .

In some embodiments, P is -XC(O) ^YRP , wherein each of X, Y, and ^RP is as defined in the Examples and classes and subclasses herein. In some embodiments, each P is selected from the groups depicted in the compounds in Table 1.

As generally defined above, R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group, having 1-4 independently selected from nitrogen, oxygen and 3-10 membered saturated or partially unsaturated heterocyclic heteroatoms of sulfur, and 5-14 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^P except In addition to L ² , it is also replaced by q ^P instances of R ^P1 .

In some embodiments, R ^P is a group selected from the group consisting of phenyl, a 3-10 membered saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and A 5-14 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein ^RP, in addition to ^L2 , is also substituted by ^qP instances of ^RP1 . In some embodiments, ^RP is a C _1-3 aliphatic substituted with q ^P instances of ^RP1 .

In some embodiments, ^RP is a C _1-8 aliphatic substituted with q ^P instances of ^RP1 . In some such embodiments, ^RP is a C _1-6 aliphatic substituted with q ^P instances of ^RP1 . In some such embodiments, ^RP is a C _1-4 aliphatic substituted with q ^P instances of ^RP1 . In some embodiments, ^RP is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , , or . In some embodiments, R ^P is . In some embodiments, R ^P is or . In some embodiments, R ^P is or . In some embodiments, R ^P is or .

In some embodiments, ^RP is a saturated or partially unsaturated 3-14 membered carbocyclic ring substituted with ^qP instances of ^RP1 . In some embodiments, ^RP is a saturated or partially unsaturated 4-14 membered carbocyclic ring substituted with ^qP instances of ^RP1 . In some embodiments, ^RP is a saturated 3-membered carbocyclic ring substituted with ^qP instances of ^RP1 . In some embodiments, ^RP is a saturated or partially unsaturated 4-membered carbocyclic ring substituted with ^qP instances of ^RP1 . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is . In some embodiments, R ^P is .

In some embodiments, ^RP is a phenyl ring substituted with q ^P instances of ^RP1 . In some embodiments, ^RP is a 3-10 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with ^qP instances of ^RP1 . In some embodiments, ^RP is a 4-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen, and sulfur substituted with q ^P instances of ^RP1 . In some such embodiments, R ^P is . In some such embodiments, R ^P is . In some such embodiments, R ^P is .

In some embodiments, ^RP is a 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with ^qP instances of ^RP1 . In some embodiments, R ^P is an optionally substituted 5-membered saturated or partially unsaturated heteroatom having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q ^P instances of R ^P1 ring. In some such embodiments, R ^P is or . In some such embodiments, R ^P is .

In some embodiments, ^RP is a 6-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q ^P instances of ^RP1 . In some such embodiments, R ^P is .

In some embodiments, ^RP is a 5-14 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur substituted with q ^P instances of ^RP1 . In some embodiments, ^RP is an optionally substituted 5-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, substituted with ^qP instances of ^RP1 . In some embodiments, ^RP is a 6-membered heteroaryl ring having 1-2 nitrogen atoms substituted with ^qP instances of ^RP1 . In some embodiments, ^RP is selected from isothiazolyl, pyridyl, or pyridyl substituted with q ^P instances of ^RP1 . In some such embodiments, R ^P is , , , , , , , , , , , , , .

In some embodiments, ^RP is selected from the groups depicted in the compounds in Table 1.

As generally defined above, L ² is a covalent bond, or a C _1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently Replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl , -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L ) -, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group , 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by one instance of R ¹ or C _1-6 aliphatic group.

In some embodiments, ^L2 is a covalent bond. In some embodiments, ^L2 is a _C1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently modified by Substitution: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH- , -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS (O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O) -, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 Each of the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group. In some embodiments, L ² is -CH ₂ -. In some embodiments, ^L2 is _-CH2O- .

In some embodiments, L ² is -O-, -NH-, -S-, -NHC(O)NH-, -N(CH ₃ )C(O)NH-*, -OC(O)NH- *, -OC(O)N(CH ₃ )-*, -NHC(O)O-*, -CH ₂ C(O)NH-*, -CH ₂ OC(O)NH-*, -C(O )NH-* and -C(O)O-*, )-, where "-*" represents the covalent bond with R ^P. In some embodiments, L ² is -O-, -NH-, -S-, -NHC(O)NH-, -N(CH ₃ )C(O)NH-*, -OC(O)NH- *, -OC(O)N(CH ₃ )-*, -NHC(O)O-*, -CH ₂ C(O)NH-*, -NHC(O)CH ₂ -*, -CH ₂ OC( O)NH-*, -C(O)NH-*, -NHC(O)-*, -C(O)O-*, -OC(O)-*, -NHS(O) ₂ -*, - NHS(O) ₂ NH-* and -OC(O)N( ⁱ Pr)-*, where "-*" represents the covalent bond with R ^P. In some embodiments, ^L2 is -O-. In some embodiments, ^L2 is -NH-. In some embodiments, ^L2 is -S-. In some embodiments, ^L2 is -NHC(O)NH-. In some embodiments, ^L2 is -N( _CH3 )C(O)NH-*. In some embodiments, ^L2 is -OC(O)NH-*. In some embodiments, ^L2 is -NHC(O)O-*. In some embodiments, ^L2 is _-CH2C (O)NH-*. In some embodiments, L ² is -CH ₂ OC(O)NH-*. In some embodiments, ^L2 is -C(O)NH-*. In some embodiments, ^L2 is -NHC(O)-*. In some embodiments, ^L2 is -C(O)O-*. In some embodiments, ^L2 is -OC(O)-*. In some embodiments, L ² is -NHC(O)CH ₂ -*. In some embodiments, L ² is -NHS(O) ₂ -*. In some embodiments, L ² is -NHS(O) ₂ NH-*. In some embodiments, ^L2 is -OC(O)N( ^iPr )-*. In some embodiments, L ² is a covalent bond, -CH ₂ -, -NH-, -O-, -NHC(O)NH-, , , , , , , , , , , , , , , , , , or ,in represents the covalent bond with Cy ^B and Represents the covalent bond with R ^P. In some embodiments, ^L2 is ,in represents the covalent bond with Cy ^B and Represents the covalent bond with R ^P. In some embodiments, ^L2 is ,in represents the covalent bond with Cy ^B and Represents the covalent bond with R ^P.

In some embodiments, ^L2 is -XC(O)Y-, wherein each of X and Y are as defined in the Examples and classes and subclasses herein. In some embodiments, X is -O-. In some embodiments, X is ^-NRX- . In some embodiments, X is -NH-. In some embodiments, X is -N( _CH3 )-. In some embodiments, X is -S-. In some embodiments, Y is -O-. In some embodiments, Y is ^-NRY- . In some embodiments, Y is -NH-. In some embodiments, Y is -N( _CH3 )-. In some embodiments, Y is -S-.

In some embodiments, each ^L is selected from the groups depicted in the compounds in Table 1.

As generally defined above, Q is L ¹ , where L ¹ is as defined in the Examples and classes and subclasses herein. In some embodiments, Q is a covalent bond, or a C _1-5 saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently Group substitution: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, - NH-, -N(R ^L )-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ - , -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC( O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl Each of the 5-6 membered heteroaryl group and the 5-6 membered heteroaryl group is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group. In some embodiments, Q is -NH-, , or ,in represents the covalent bond with Cy ^A and Represents the covalent bond with Cy ^C. In some embodiments, Q is -NH-. In some embodiments, Q is -O-. In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is . In some embodiments, Q is -NHC(O)NH-. In some embodiments, Q is . In some embodiments, Q is .

In some embodiments, Q is selected from the groups depicted in the compounds in Table 1.

As generally defined above, L ¹ is a covalent bond, or C _1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently Replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl , -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L ) -, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group , 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by one instance of R ¹ or C _1-6 aliphatic group.

In some embodiments, ^L1 is a covalent bond. In some embodiments, ^L is a C _1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently modified by Substitution: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH- , -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS (O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O) -, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 Each of the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group.

In some embodiments, ^L is -NH-, , , , , , ,in represents the covalent bond with Cy ^A and Represents the covalent bond with Cy ^C. In some embodiments, L ¹ is -NH-. In some embodiments, L ¹ is -O-. In some embodiments, L ¹ is . In some embodiments, L ¹ is . In some embodiments, L ¹ is . In some embodiments, L ¹ is . In some embodiments, L ¹ is . In some embodiments, L ¹ is .

In some embodiments, L ¹ is selected from the groups depicted in the compounds in Table 1.

As generally defined above, each instance of R ^L is independently R ¹ or R ² , substituted by t instances of R ³ . In some embodiments, R ^L is R ¹ . In some embodiments, R ^L is R ² .

As generally defined above, each instance of ^RA and ^RB is independently R ¹ or R ² , where ^RA is substituted by q ^A instances of R ³ and R ^B is substituted by q ^B instances of R ³ . In some embodiments, R ^A is R ¹ . In some embodiments, R ^B is R ¹ . In some embodiments, ^RA is ^R2 . In some embodiments, R ^B is R ² .

As generally defined above, R ^C is L ^{3 -RC1} or L ³ -H. In some embodiments, ^RC is L ^{3 -RC1} . In some embodiments, R ^C is L ³ -H.

In some embodiments, R ^C is selected from the groups depicted in the compounds in Table 1.

As generally defined above, L ³ is a covalent bond, or a C _1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently Replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl , -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L ) -, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, - C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group , 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, each of which is optionally substituted by one instance of R ¹ or C _1-6 aliphatic group.

In some embodiments, ^L3 is a covalent bond. In some embodiments, L ³ is a C _1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently modified by Substitution: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH- , -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS (O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O) -, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 Each of the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group.

In some embodiments, L ³ is -OCH ₂ -* or -CH ₂ O-*, where "-*" represents a covalent bond to R ^C1 or -H. In some embodiments, L ³ is -OCH ₂ -*. In some embodiments, L ³ is -CH ₂ O-*.

In some embodiments, ^L3 is selected from the groups depicted in the compounds in Table 1.

As generally defined above, ^LD is a covalent bond, or a C _1-5 saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently Group substitution: -CH(R ^L )-, -C(R ^L ) ₂ -, phenyl group, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heterocycloalkyl group Aryl, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O- , -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the phenylene group, C ₃ Each of _-6- membered cycloalkyl, 3-6-membered heterocycloalkyl and 5-6-membered heteroaryl is substituted with 0-3 instances of ^R1 or _C1-6 aliphatic group.

In some embodiments, ^LD is a covalent bond. In some embodiments, ^LD is a C _1-5 divalent saturated or unsaturated, straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently modified by the following groups Substitution: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH- , -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS (O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O) -, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 Each of the 5-6-membered heterocycloalkyl and 5-6-membered heteroaryl is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group.

In some embodiments, ^LD is -OC _1-4alkyl- *, -OC _1-3alkyl- *, -OC _2-3alkyl- *, or -OC _1-2alkyl- *, wherein "-*" indicates covalent bond with Cy ^A. In some embodiments, ^LD is -OC _1-4alkyl- *. In some embodiments, ^LD is -OC _1-3alkyl- *. In some embodiments, ^LD is -OC _2-3alkyl- *. In some embodiments, ^LD is -OC _1-2alkyl- *.

In some embodiments, ^LD is -OCH ₂ -* or -CH ₂ O-*, where "-*" represents a covalent bond with Cy ^A. In some embodiments, ^LD is _-OCH2- *. In some embodiments, ^LD is -CH ₂ O-*.

In some embodiments, ^LD is -C _1-4 alkyl-, -C _1-3 alkyl-, -C _2-3 alkyl-, or -C _1-2 alkyl-. In some embodiments, ^LD is -C _1-4 alkyl-. In some embodiments, ^LD is -C _1-3 alkyl-. In some embodiments, ^LD is -C _2-3 alkyl-. In some embodiments, ^LD is -C _1-2 alkyl-.

In some embodiments, ^LD is -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ CH ₂ -O-CH ₂ -*, -CH ₂ -O-CH ₂ -, -CH ₂ -O- CH ₂ CH ₂ -* or -CH ₂ CH ₂ CH ₂ -, where "-*" represents the covalent bond with Cy ^A. In some embodiments, ^LD is _-CH2- . In some _embodiments , ^LD is _-CH2CH2- . In some embodiments, ^LD is _-CH2CH2 -O- _{CH2 .} In some embodiments, ^LD is -CH ₂ -O-CH ₂ -. In some embodiments _, ^LD is _-CH2 -O- _CH2CH2- . In some embodiments, ^LD _{is -CH2CH2CH2- .}

In some embodiments, the ^LD system , , or . In some embodiments, the ^LD system . In some embodiments, the ^LD system . In some embodiments, the ^LD system . In some embodiments, the ^LD system .

In some embodiments, ^LD is selected from the groups depicted in the compounds in Table 1.

As generally defined above, R ^C1 is a C _1-4 aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; having 1 - 4 8-10 membered bicyclic heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; 3-7 membered saturated or partially unsaturated carbocyclic rings; 1-2 independently selected from nitrogen, A 3-7-membered saturated or partially unsaturated monocyclic heterocyclic ring with heteroatoms of oxygen and sulfur; or a 7-12-membered saturated or partially unsaturated monocyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Cyclic heterocycle; wherein R ^C1 is substituted with 0 to 4 instances of groups independently selected from halogen, C _1-4 haloalkyl, C _1-4 alkoxy, and C _1-4 haloalkoxy.

In some embodiments, R ^C1 is C substituted with 0-4 instances of groups independently selected from halogen, C _1-4 haloalkyl, C _1-4 alkoxy, and C _1-4 haloalkoxy. _1-4 aliphatic groups. In some embodiments, R ^C1 is methyl. In some embodiments, R ^C1 is ethyl.

In some embodiments, R ^C1 is C _1-4 haloalkyl. In some embodiments, R ^C1 is -CF ₃ . In some embodiments, R ^C1 is -CHF ₂ . In some embodiments, R ^C1 is -CH ₂ F. In some embodiments, R ^C1 is -CCIF ₂ .

As generally defined above, each instance of R ¹ (e.g., the R ¹ group of RA, the R ¹ group of ^RB ) is independently ^a pendant oxy group, halogen, -CN, -NO ₂ , -OR, - SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C(O) OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C (O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R. In some embodiments, ^R1 is pendant oxy. In some embodiments, each R ¹ is independently halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N (R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR )R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R.

In some embodiments, ^R1 is halogen, -CN, or _-NO2 . In some embodiments, R ¹ is -OR, -SR, or -NR ₂ . In some embodiments, R ¹ is -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C (O)OR, -C(O)NR ₂ , -C(NR)NR ₂ or -C(O)N(R)OR. In some embodiments, R ¹ is -S(O) ₂ R, -S(O) ₂ N(H)R, -S(O)R, -S(O)N(H)R, -C( O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R or -C(O)N(H)OR. In some embodiments, R ¹ is -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S (O)R or -N(R)S(O) ₂ R. In some embodiments, R ¹ is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, - N(H)C(NH)R, -N(H)C(O)NR ₂ , -N(H)C(NH)NR ₂ , -N(H)S(O) ₂ NR ₂ , -N( H)S(O)R or -N(H)S(O) ₂ R. In some embodiments, ^RA is halogen. In some embodiments, ^RB is halogen. In some embodiments, R ^B is -C≡N. In some embodiments, R ^C is -S(O) ₂ R. In some embodiments, R ^C is -S(O) ₂ CH ₃ . In some embodiments, R ^C is -OR. In some embodiments, R ^C is -OCH ₃ . In some embodiments, R ^C is a pendant oxy group. In some embodiments, R ^C is -N(R)C(O)R. In some such embodiments, R ^C is -N(H)C(O)R. In some embodiments, R ^C is -C≡N.

As generally defined above, each instance of R ² (e.g., the R ² group of ^RA , the R ² group of ^RB , or the R ² group of ^RC ) is independently a C _1-7 aliphatic group; benzene radical; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic heteroaryl ring; 3-7-membered saturated or partially unsaturated carbocyclic ring; 3-7-membered saturated or partially unsaturated monocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Cyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ² is a C _1-7 aliphatic. In some embodiments, R ² is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 heteroatoms independently selected from 8-10 membered bicyclic heteroaryl ring with heteroatoms of nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated monocyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ^R2 is phenyl. In some embodiments, ^R2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ² is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ^R2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^A is a C _1-7 aliphatic. In some such embodiments, ^RA is _-CH3 . In some embodiments, ^RA is -C(CH ₃ ) ₃ .

In some embodiments, R ^B is a C _1-7 aliphatic. In some such embodiments, ^RB is _-CH3 . In some embodiments, R ^B is selected from -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , and . In some embodiments, ^RB is a C _1-7 aliphatic substituted with R ³ . In some embodiments, ^RB is a C _1-7 aliphatic substituted with R ³ , wherein R ³ is -OR. In some embodiments, ^RB is a C _1-2 aliphatic substituted with R ³ , wherein R ³ is -OR. In some embodiments, ^RB is _-CH2OH . In some embodiments, ^RB is a pendant oxy group. In some embodiments, R ^B is -OR, wherein R is a C _1-6 aliphatic. In some embodiments, ^RB is _-OCH3 .

In some embodiments, R ^C is a C _1-7 aliphatic. In some such embodiments, R ^C is -CH ₃ or -C(CH ₃ ) ₃ . In some embodiments, R ^C is -CH ₂ C(CH ₃ ) ₃ . In some embodiments, R ^C is a C _1-7 aliphatic group substituted with R ³ . In some embodiments, R ^C is a C _1-7 aliphatic substituted with R ³ , wherein R ³ is -OR. In some embodiments, R ^C is a C _1-2 aliphatic substituted with R ³ , wherein R ³ is -OR. In some embodiments, R ^C is -CH ₂ OCH ₃ . In some embodiments, R ^C is . In some embodiments, R ^C is -N(H)C(O)CH ₃ . In some embodiments, R ^C is -C(O)OR. In some embodiments, R ^C is -C(O)OR, wherein R is a C _1-6 aliphatic. In some embodiments, R ^C is -C(O)OCH ₂ CH ₃ . In some embodiments, R ^C is a C _1-7 aliphatic group substituted with R ³ , wherein R ³ is halogen. In some embodiments, R ^C is a C _1-7 aliphatic group substituted with R ³ , wherein R ³ is fluoro. In some embodiments, R ^C is -CF ₃ . In some embodiments, R ^C is a pendant oxy group. In some embodiments, R ^C is -OR substituted with R ³ . In some embodiments, R ^C is -OR substituted with R ³ , wherein R is a C _1-6 aliphatic and R ³ is -OR. In some embodiments, R ^C is -OCH ₂ CH ₂ OH. In some embodiments, R ^C is a C _1-7 aliphatic substituted with R ³ , wherein R ³ is -OR. In some embodiments, R ^C is a C _1-7 aliphatic substituted with R ³ , wherein R ³ is -OR. In some embodiments, R ^C is a C _1-7 aliphatic group substituted with R ³ , wherein R ³ is -OR and R is a C _1-6 aliphatic group optionally substituted with halogen.

In some embodiments, R ^C is -OCH ₂ CF ₃ . In some embodiments, R ^C is -OCH ₂ CHF ₂ . In some embodiments, R ^C is -CH ₂ OCF ₃ . In some embodiments, R ^C is -CH ₂ OCHF ₂ .

As generally defined above, each instance of R ³ is independently pendant oxy, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C(O)OR, - C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O) OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N (R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or an optionally substituted group selected from the following: C _1-6 Aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 heteroatoms independently selected from nitrogen, oxygen And 5-6 membered heteroaryl ring of sulfur heteroatom. In some embodiments, ^R3 is pendant oxy. In some embodiments, R ³ is halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O) R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C (NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C( O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR _2. -N(R)S(O)R, -N(R)S(O) ₂ R or optionally substituted groups selected from the following: C _1-6 aliphatic group, phenyl group, having 1 - 2 3-7 membered saturated or partially unsaturated heterocycles with heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 members with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Member heteroaryl ring. In some embodiments, ^R3 is halogen, -CN, or _-NO2 . In some embodiments, R ³ is -OR, -SR, or -NR ₂ . In some embodiments, R ³ is -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, - OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ or -C(O)N(R)OR. In some embodiments, ^R3 is -S(O) _2R , -S(O) _2N (H)R, -S(O)R, -S(O)N(H)R, -S( O) ₂ F, -OS(O) ₂ F, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)NR ₂ or -C(O )N(H)OR. In some embodiments, R ³ is OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R) C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S( O)R or -N(R)S(O) ₂ R. In some embodiments, R ^is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, - N(H)C(NH)R, -N(H)C(O)NR ₂ , -N(H)C(NH)NR ₂ , -N(H)S(O) ₂ NR ₂ , -N( H)S(O)R or -N(H)S(O) ₂ R. In some embodiments, R ³ is selected from the following optionally substituted groups: C _1-6 aliphatic, phenyl, having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 3-7 membered saturated or partially unsaturated heterocyclic rings, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ³ is optionally substituted C _1-6 aliphatic. In some embodiments, ^R3 is optionally substituted phenyl. In some embodiments, ^R3 is an optionally substituted 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^R3 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As generally defined above, Cy ^C is a saturated or partially unsaturated 3-14-membered carbocyclic ring; a saturated or partially unsaturated 3-14-membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or 5-14 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C is also substituted by p instances of ^RC in addition to Q. In some embodiments, Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring. In some embodiments, Cy ^C is a saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring. In some embodiments, Cy ^C is cyclopropyl.

In some embodiments, Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring; a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. ; Phenyl; or 6-14 membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C, in addition to Q, is also substituted by p instances of ^RC . In some embodiments, Cy ^C is a saturated or partially unsaturated 3-14 membered heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is phenyl. In some embodiments, Cy ^C is a 5-14 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is a 6-14 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, Cy ^C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is a 5-membered heteroaryl ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen or sulfur. In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is .

In some embodiments, Cy ^C is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. In some embodiments, Cy ^C is pyridyl. In some embodiments, Cy ^C is pyrimidinyl. In some embodiments, ^CyC is hydroxyl. In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is .

In some embodiments, Cy ^C is a 9-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is a 9-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy ^C is a 9-10 membered heteroaryl group having 2-4 nitrogen atoms. In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is . In some embodiments, Cy ^C is .

As generally defined above, R ^D is R ^D' , or , where ^LD , ^RD1 , ^RD2 and ^RD3 are as defined herein. In some embodiments, R ^D is . In some embodiments, R ^D is .

In some embodiments, R ^D is . In some embodiments, R ^D is . In some embodiments, R ^D is .

As generally defined above, RD ^' is a group capable of being cleaved upon administration to an individual. In some embodiments, RD ^' contains a phosphate group. In some embodiments, RD ^' contains an amino acid group. In some embodiments, RD ^' contains a disulfide group. In some embodiments, RD ^' contains a glucuronidyl group.

As generally defined above, each of ^RD1 and ^RD2 is independently hydrogen, ^R1 or ^R2 , wherein ^RD1 is substituted by qD1 instances ^{of R3} and ^RD2 is substituted by ^qD2 instances of ^R3 ; Or one instance of ^RD1 and one instance of ^RD2 together with intervening atoms form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the The loop is replaced by q ^DD instances of R ³ .

In some embodiments, R ^D1 is hydrogen, R ¹ or R ² , wherein R ^D1 is substituted with q ^D1 instances of R ³ . In some embodiments, ^RD1 is hydrogen. In some embodiments, R ^D1 is R ¹ , wherein R ^D1 is replaced with q ^D1 instances of R ³ . In some embodiments, R ^D1 is R ² , wherein R ^D1 is replaced with q ^D1 instances of R ³ .

In some embodiments, R ^D1 is a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 8-10 membered bicyclic heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; 3-7 membered saturated or partially unsaturated carbocyclic rings; 1-2 independently selected from nitrogen , 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with heteroatoms of oxygen and sulfur; or 7-12 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Bicyclic heterocycle. In some embodiments, R ^D1 is a C _1-7 aliphatic. In some embodiments, R ^D1 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 heteroatoms independently selected from 8-10 membered bicyclic heteroaryl ring with heteroatoms of nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated monocyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R ^D1 is phenyl. In some embodiments, R ^D1 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ^D1 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R ^D1 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ^RD1 is a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD1 is a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, R ^D1 is a pendant oxy group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N (R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR )R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R. In some embodiments, ^RD1 is a pendant oxy group. In some embodiments, each ^RD1 is halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _{2NR2 ,} -S( O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R )OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R , -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or - N(R)S(O) ₂ R.

In some embodiments, ^RD1 is halogen, -CN, or _-NO2 . In some embodiments, ^RD1 is -OR, -SR, or _-NR2 . In some embodiments, R ^D1 is -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C (O)OR, -C(O)NR ₂ , -C(NR)NR ₂ or -C(O)N(R)OR. In some embodiments, R ^D1 is -S(O) ₂ R, -S(O) ₂ N(H)R, -S(O)R, -S(O)N(H)R, -C( O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R or -C(O)N(H)OR. In some embodiments, R ^D1 is -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S (O)R or -N(R)S(O) ₂ R. In some embodiments, R ^D1 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, - N(H)C(NH)R, -N(H)C(O)NR ₂ , -N(H)C(NH)NR ₂ , -N(H)S(O) ₂ NR ₂ , -N( H)S(O)R or -N(H)S(O) ₂ R.

In some embodiments, R ^D1 is a C _1-7 aliphatic. In some embodiments, R ^D1 is a C _1-4 aliphatic. In some embodiments, R ^D1 is methyl. In some embodiments, R ^D1 is ethyl. In some embodiments, ^RD1 is n-propyl. In some embodiments, ^RD1 is isopropyl. In some embodiments, ^RD1 is n-butyl. In some embodiments, R ^D1 is second butyl. In some embodiments, R ^D1 is tert-butyl.

In some embodiments, ^RD2 is hydrogen, ^R1 , or ^R2 , wherein ^RD2 is substituted with ^qD2 instances of ^R3 . In some embodiments, ^RD2 is hydrogen. In some embodiments, ^RD2 is R ¹ , wherein ^RD2 is replaced with q ^D2 instances of R ³ . In some embodiments, R ^D1 is R ² , wherein R ^D2 is replaced with q ^D2 instances of R ³ .

In some embodiments, ^RD2 is a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 8-10 membered bicyclic heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; 3-7 membered saturated or partially unsaturated carbocyclic rings; 1-2 independently selected from nitrogen , 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with heteroatoms of oxygen and sulfur; or 7-12 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Bicyclic heterocycle. In some embodiments, ^RD2 is a C _1-7 aliphatic. In some embodiments, ^RD2 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 heteroatoms independently selected from 8-10 membered bicyclic heteroaryl ring with heteroatoms of nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated monocyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ^RD2 is phenyl. In some embodiments, ^RD2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD2 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ^RD2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^RD2 is a pendant oxy group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N (R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR )R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R. In some embodiments, ^RD2 is a pendant oxy group. In some embodiments, each ^RD2 is halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _{2NR2 ,} -S( O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R )OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R , -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or - N(R)S(O) ₂ R.

In some embodiments, ^RD2 is halogen, -CN, or _-NO2 . In some embodiments, ^RD2 is -OR, -SR, or _-NR2 . In some embodiments, ^RD2 is -S(O) _2R , -S(O) _2NR2 , -S( _O )R, -S(O) _NR2 , -C(O)R, -C (O)OR, -C(O)NR ₂ , -C(NR)NR ₂ or -C(O)N(R)OR. In some embodiments, ^RD2 is -S(O) _2R , -S(O) _2N (H)R, -S(O)R, -S(O)N(H)R, -C( O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R or -C(O)N(H)OR. In some embodiments, ^RD2 is -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S (O)R or -N(R)S(O) ₂ R. In some embodiments, ^RD2 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, - N(H)C(NH)R, -N(H)C(O)NR ₂ , -N(H)C(NH)NR ₂ , -N(H)S(O) ₂ NR ₂ , -N( H)S(O)R or -N(H)S(O) ₂ R.

In some embodiments, ^RD2 is a C _1-7 aliphatic. In some embodiments, ^RD2 is a C _1-4 aliphatic. In some embodiments, ^RD2 is methyl. In some embodiments, ^RD2 is ethyl. In some embodiments, ^RD2 is n-propyl. In some embodiments, ^RD2 is isopropyl. In some embodiments, ^RD2 is n-butyl. In some embodiments, ^RD2 is sec-butyl. In some embodiments, ^RD2 is tert-butyl.

In some embodiments, one instance of ^RD1 and one instance of ^RD2 together with intervening atoms form a 4-8 membered saturated or partially unsaturated chain having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Ring; wherein the ring is substituted by q ^DD instances of R ³ . In some embodiments, one instance of ^RD1 and one instance of ^RD2 , together with intervening atoms, form a 4-membered saturated ring substituted with q ^DD instances of ^R3 . In some embodiments, one instance of ^RD1 and one instance of ^RD2 , together with intervening atoms, form a 5-membered saturated ring substituted with q ^DD instances of ^R3 . In some embodiments, one instance of ^RD1 and one instance of ^RD2 , together with intervening atoms, form a 5-6 membered saturated ring substituted with q ^DD instances of ^R3 . In some embodiments, one instance of ^RD1 and one instance of ^RD2 , together with intervening atoms, form a 6-membered saturated ring substituted with q ^DD instances of ^R3 . In some embodiments, one instance of ^RD1 and one instance of ^RD2 , together with intervening atoms, form a 7-membered saturated ring substituted with q ^DD instances of ^R3 . In some embodiments, one instance of ^RD1 and one instance of ^RD2 , together with intervening atoms, form an 8-membered saturated ring substituted with q ^DD instances of ^R3 .

As generally defined above, R ^D3 is hydrogen, R ¹ or R ² , wherein R ^D3 is substituted with q ^D3 instances of R ³ . In some embodiments, ^RD3 is hydrogen. In some embodiments, ^RD3 is R ¹ , wherein ^RD3 is replaced with q ^D3 instances of R ³ . In some ^embodiments , ^RD3 is ^R2 , wherein ^RD3 is substituted with ^qD3 instances of R3.

In some embodiments, ^RD3 is a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 8-10 membered bicyclic heteroaryl rings independently selected from nitrogen, oxygen and sulfur heteroatoms; 3-7 membered saturated or partially unsaturated carbocyclic rings; 1-2 independently selected from nitrogen , 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with heteroatoms of oxygen and sulfur; or 7-12 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Bicyclic heterocycle. In some embodiments, ^RD3 is a C _1-7 aliphatic. In some embodiments, ^RD3 is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; having 1-4 heteroatoms independently selected from 8-10 membered bicyclic heteroaryl ring with heteroatoms of nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-7 membered saturated or partially unsaturated monocyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, ^RD3 is phenyl. In some embodiments, ^RD3 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD3 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD3 is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, ^RD3 is a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, ^RD3 is a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

In some embodiments, ^RD3 is a pendant oxy group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , - S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N (R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR )R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S(O) ₂ R. In some embodiments, ^RD3 is a pendant oxy group. In some embodiments, each ^RD3 is halogen, -CN, _-NO2 , -OR, -SR, _-NR2 , -S(O) _2R , -S(O) _{2NR2 ,} -S( O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R )OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R , -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or - N(R)S(O) ₂ R.

In some embodiments, ^RD3 is halogen, -CN or _-NO2 . In some embodiments, ^RD3 is -OR, -SR, or _-NR2 . In some embodiments, ^RD3 is -S(O) _2R , -S(O) _2NR2 , -S( _O )R, -S(O) _NR2 , -C(O)R, -C (O)OR, -C(O)NR ₂ , -C(NR)NR ₂ or -C(O)N(R)OR. In some embodiments, ^RD3 is -S(O) ₂ R, -S(O) ₂ N(H)R, -S(O)R, -S(O)N(H)R, -C( O)R, -C(O)OR, -C(O)N(H)R, -C(NH)N(H)R or -C(O)N(H)OR. In some embodiments, ^RD3 is -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R )C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S (O)R or -N(R)S(O) ₂ R. In some embodiments, ^RD3 is -OC(O)R, -OC(O)N(H)R, -N(H)C(O)OR, -N(H)C(O)R, - N(H)C(NH)R, -N(H)C(O)NR ₂ , -N(H)C(NH)NR ₂ , -N(H)S(O) ₂ NR ₂ , -N( H)S(O)R or -N(H)S(O) ₂ R.

In some embodiments, ^RD3 is a C _1-7 aliphatic. In some embodiments, ^RD3 is a C _1-4 aliphatic. In some embodiments, ^RD3 is methyl. In some embodiments, ^RD3 is ethyl. In some embodiments, ^RD3 is n-propyl. In some embodiments, ^RD3 is isopropyl. In some embodiments, ^RD3 is n-butyl. In some embodiments, ^RD3 is sec-butyl. In some embodiments, ^RD3 is tert-butyl.

As generally defined above, each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 aliphatic, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, having 1 - 2 3-7 membered saturated or partially unsaturated heterocycles with heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 members with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Member heteroaryl ring, or: two R groups on the same nitrogen together with the intervening atom form 4-7 which, in addition to the nitrogen, also has 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. Member saturated, partially unsaturated or heteroaryl ring. In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from the following: C _1-6 aliphatic, saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, having 1-2 independently 3-7 membered saturated or partially unsaturated heterocyclic rings with heteroatoms selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur , or: the two R groups on the same nitrogen together with the intervening atoms form a 4-7 membered saturated, partially non-unionized heteroatom with 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to the nitrogen. Saturated or heteroaryl rings. In some embodiments, R is optionally substituted C _1-6 aliphatic. In some embodiments, R is an optionally substituted saturated or partially unsaturated 3-7 membered carbocyclic ring. In some embodiments, R is optionally substituted phenyl. In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

As generally defined above, m is 0, 1, 2, 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 0 or 1. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 or 2. In some embodiments, m is 1, 2, or 3. In some embodiments, m is 1, 2, 3, or 4. In some embodiments, m is 2 or 3. In some embodiments, m is 2, 3, or 4. In some embodiments, m is 3 or 4. In some embodiments, m is selected from the values represented among the compounds in Table 1.

As generally defined above, n is 0, 1, 2, 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 0 or 1. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1, 2, or 3. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 2 or 3. In some embodiments, n is 2, 3, or 4. In some embodiments, n is 3 or 4. In some embodiments, n is selected from the values represented among the compounds in Table 1.

As generally defined above, p is 0, 1, 2, 3 or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 0 or 1. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 1 or 2. In some embodiments, p is 1, 2, or 3. In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 2 or 3. In some embodiments, p is 2, 3, or 4. In some embodiments, p is 3 or 4. In some embodiments, p is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^A is 0, 1, 2, 3 or 4. In some embodiments, q ^A is zero. In some embodiments, q ^A is 1. In some embodiments, q ^A is 2. In some embodiments, q ^A is 3. In some embodiments, q ^A is 4. In some embodiments, q ^A is 0 or 1. In some embodiments, q ^A is 0, 1, or 2. In some embodiments, q ^A is 0, 1, 2, or 3. In some embodiments, q ^A is 1 or 2. In some embodiments, q ^A is 1, 2, or 3. In some embodiments, q ^A is 1, 2, 3, or 4. In some embodiments, q ^A is 2 or 3. In some embodiments, q ^A is 2, 3, or 4. In some embodiments, q ^A is 3 or 4. In some embodiments, q ^A is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^B is 0, 1, 2, 3 or 4. In some embodiments, ^qB is zero. In some embodiments, ^qB is 1. In some embodiments, ^qB is 2. In some embodiments, ^qB is 3. In some embodiments, ^qB is 4. In some embodiments, ^qB is 0 or 1. In some embodiments, ^qB is 0, 1, or 2. In some embodiments, ^qB is 0, 1, 2, or 3. In some embodiments, ^qB is 1 or 2. In some embodiments, ^qB is 1, 2, or 3. In some embodiments, ^qB is 1, 2, 3, or 4. In some embodiments, ^qB is 2 or 3. In some embodiments, ^qB is 2, 3, or 4. In some embodiments, ^qB is 3 or 4. In some embodiments, q ^B is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^D1 is 0, 1, 2, 3 or 4. In some embodiments, q ^D1 is zero. In some embodiments, q ^D1 is 1. In some embodiments, q ^D1 is 2. In some embodiments, q ^D1 is 3. In some embodiments, q ^D1 is 4. In some embodiments, q ^D1 is 0 or 1. In some embodiments, q ^D1 is 0, 1, or 2. In some embodiments, q ^D1 is 0, 1, 2, or 3. In some embodiments, q ^D1 is 1 or 2. In some embodiments, q ^D1 is 1, 2, or 3. In some embodiments, q ^D1 is 1, 2, 3, or 4. In some embodiments, q ^D1 is 2 or 3. In some embodiments, q ^D1 is 2, 3, or 4. In some embodiments, q ^D1 is 3 or 4. In some embodiments, q ^D1 is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^D2 is 0, 1, 2, 3 or 4. In some embodiments, q ^D2 is zero. In some embodiments, q ^D2 is 1. In some embodiments, q ^D2 is 2. In some embodiments, q ^D2 is 3. In some embodiments, q ^D2 is 4. In some embodiments, q ^D2 is 0 or 1. In some embodiments, q ^D2 is 0, 1, or 2. In some embodiments, q ^D2 is 0, 1, 2, or 3. In some embodiments, q ^D2 is 1 or 2. In some embodiments, q ^D2 is 1, 2, or 3. In some embodiments, q ^D2 is 1, 2, 3, or 4. In some embodiments, q ^D2 is 2 or 3. In some embodiments, q ^D2 is 2, 3, or 4. In some embodiments, q ^D2 is 3 or 4. In some embodiments, q ^D2 is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^D3 is 0, 1, 2, 3 or 4. In some embodiments, q ^D3 is zero. In some embodiments, q ^D3 is 1. In some embodiments, q ^D3 is 2. In some embodiments, q ^D3 is 3. In some embodiments, q ^D3 is 4. In some embodiments, q ^D3 is 0 or 1. In some embodiments, q ^D3 is 0, 1, or 2. In some embodiments, q ^D3 is 0, 1, 2, or 3. In some embodiments, q ^D3 is 1 or 2. In some embodiments, q ^D3 is 1, 2, or 3. In some embodiments, q ^D3 is 1, 2, 3, or 4. In some embodiments, q ^D3 is 2 or 3. In some embodiments, q ^D3 is 2, 3, or 4. In some embodiments, q ^D3 is 3 or 4. In some embodiments, q ^D3 is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^DD is 0, 1, 2, 3 or 4. In some embodiments, q ^DD is zero. In some embodiments, ^qDD is 1. In some embodiments, ^qDD is 2. In some embodiments, q ^DD is 3. In some embodiments, q ^DD is 4. In some embodiments, q ^DD is 0 or 1. In some embodiments, q ^DD is 0, 1, or 2. In some embodiments, q ^DD is 0, 1, 2, or 3. In some embodiments, q ^DD is 1 or 2. In some embodiments, q ^DD is 1, 2, or 3. In some embodiments, q ^DD is 1, 2, 3, or 4. In some embodiments, q ^DD is 2 or 3. In some embodiments, q ^DD is 2, 3, or 4. In some embodiments, q ^DD is 3 or 4. In some embodiments, q ^DD is selected from the values represented among the compounds in Table 1.

As generally defined above, q ^P is 0, 1, 2, 3 or 4. In some embodiments, ^qP is zero. In some embodiments, ^qP is 1. In some embodiments, ^qP is 2. In some embodiments, ^qP is 3. In some embodiments, ^qP is 4. In some embodiments, ^qP is 0 or 1. In some embodiments, ^qP is 0, 1, or 2. In some embodiments, ^qP is 0, 1, 2, or 3. In some embodiments, ^qP is 1 or 2. In some embodiments, ^qP is 1, 2, or 3. In some embodiments, ^qP is 1, 2, 3, or 4. In some embodiments, ^qP is 2 or 3. In some embodiments, ^qP is 2, 3, or 4. In some embodiments, ^qP is 3 or 4. In some embodiments, ^qP is selected from the values represented among the compounds in Table 1.

As generally defined above, r is 0, 1, 2, 3 or 4. In some embodiments, r is 0. In some embodiments, r is 1. In some embodiments, r is 2. In some embodiments, r is 3. In some embodiments, r is 4. In some embodiments, r is 0 or 1. In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0, 1, 2, or 3. In some embodiments, r is 1 or 2. In some embodiments, r is 1, 2, or 3. In some embodiments, r is 1, 2, 3, or 4. In some embodiments, r is 2 or 3. In some embodiments, r is 2, 3, or 4. In some embodiments, r is 3 or 4. In some embodiments, r is selected from the values represented in the compounds in Table 1.

As generally defined above, t is 0, 1, 2, 3 or 4. In some embodiments, t is zero. In some embodiments, t is 1. In some embodiments, t is 2. In some embodiments, t is 3. In some embodiments, t is 4. In some embodiments, t is 0 or 1. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 1 or 2. In some embodiments, t is 1, 2, or 3. In some embodiments, t is 1, 2, 3, or 4. In some embodiments, t is 2 or 3. In some embodiments, t is 2, 3, or 4. In some embodiments, t is 3 or 4. In some embodiments, t is selected from the values represented among the compounds in Table 1.

Examples of compounds described herein include those listed in the Tables and Examples herein, or pharmaceutically acceptable salts, stereoisomers or mixtures of stereoisomers thereof. In some embodiments, the present disclosure includes compounds selected from those shown in Table 1 below, or pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof. In some embodiments, the present disclosure provides compounds listed in Table 1 below, or pharmaceutically acceptable salts thereof. In some embodiments, the present disclosure provides compounds listed in Table 1 below. surface 1. Representative compounds and bioactivity data. Example structure Biochemistry CDK2/ Cyclin E Caliper IC50 Cell nanoBRET IC50 1 A 2 A 3 A 4 A 5 A 6 A 7 A 8 A 9 A 10 A 11 B 12 A 13 A 14 A 15 A 16 A 17 A 18 A 19 A 20 C twenty one A twenty two C twenty three D twenty four A 25 A 26 A 27 A 28 A 29 A 30 A 31 A 32 A 33 A 34 A 35 A 36 A 37 A 38 A 39 A 40 A 41 42 43 A 44 A 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 A 98 A 99 A 100 A 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 A 142 143 144 A A 145 A 146 147 148 A A 149 150 151 152 153 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 C 204 205 C 206 207 D 208 209 D 210 211 B 212 213 B 214 215 C 216 217 C 218 219 B 220 221 B 222 223 A 224 225 B 226 227 A 228 229 A 230 231 B 232 233 A 234 235 B 236 237 A 238 D 239 D 240 A 241 A A 242 A 243 A 244 A 245 A A 246 A 247 A 248 A 249 A 250 A 251 A 252 A 253 A 254 A 255 A 256 D 257 A 258 A 259 C 260 B 261 D 262 A 263 A 264 C 265 B 266 C 267 B 268 B 269 D 270 B 271 B 272 B 273 D 274 D 275 B 276 D 277 A 278 B 279 B 280 B 281 B 282 B 283 B 284 A 285 A 286 A 287 C 288 C 289 B 290 B 291 B 292 C 293 D 294 D 295 A 296 A 297 B 298 A 299 B 300 D 301 B 302 C 303 A 304 A 305 A 306 A 307 A 308 A 309 A 310 A 311 A 312 A A 313 A 314 A 315 A 316 A 317 A 318 A 319 A 320 A 321 A 322 A 323 A 324 B 325 C 326 327 A 328 A 329 A 330 A 331 332 333 A 344 A 345 346 347 348 349 350 351 A 352 A 353 A 354 C 355 D 356 A 357 A 358 C 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378 379 380 381 382 383 384 385 386 387 388 389 390 391 392 393 D 394 395 396 397 398 399 400 401 402 403 404 405 406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 B 445 446 A 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 A 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 A 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 608 609 610 611 612 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628 629 630 631 632 633 634 635 636 637 638 639 640 641 642 643 644 645 646 647 648 649 650 651 652 653 654 655 656 657 658 659 660 661 662 663 664 665 666 667 668 669 670 671 672 673 674 675 676 677 678 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 708 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 785 786 787 788 789 790 791 792 793 794 795 796 797 798 799 800 801 802 803 804 805 806 807 808 809 810 811 812 813 814 815 816 817 818 819 820 821 822 823 824 825 826 827 828 829 830 831 832 833 834 835 836 837 838 839 840 841 842 843 844 845 846 847 848 849 850 851 852 853 854 855 856 857 858 859 860 861 862 863 864 865 866 867 868 869 870 871 872 873 874 875 876 877 878 879 880 881 882 883 884 885 886 887 888 889 890 891 892 893 894 895 896 897 898 899 900 901 902 903 904 905 906 907 908 909 910 911 912 913 914 915 916 917 918 919 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1936 1937 1938 1939 1940 1941 1942 1943 1944 1945 1946 1947 1948 1949 1950 1951 1952 1953 1954 1955 1956 1957 1958 1959 1960 1961 1962 1963 1964 1965 1966 1967 1968 1969 A 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030 2031 2032 2033 2034 2035 2036 2037 2038 2039 2040 2041 2042 2043 2044 2045 2046 2047 2048 2049 2050 2051 2052 2053 2054 2055 2056 2057 2058 2059 2060 2061 2062 2063 2064 2065 2066 2067 2068 2069 2070 2071 2072 2073 2074 2075 2076 2077 2078 2079 2080 2081 2082 2083 2084 2085 2086 2087 2088 2089 2090 2091 2092 2093 2094 2095 2096 2097 2098 2099 2100 2101 2102 2103 2104 2105 2106 2107 2108 2109 2110 2111 2112 2113 2114 2115 2116 2117 2118 2119 2120 2121 2122 2123 2124 2125 2126 2127 2128 2129 2130 2131 2132 2133 2134 2135 2136 2137 2138 2139 2140 2141 2142 2143 2144 2145 2146 2147 2148 2149 2150 2151 2152 2153 2154 2155 2156 2157 2158 2159 2160 2161 2162 2163 2164 2165 2166 2167 2168 2169 2170 2171 2172 2173 2174 2175 2176 2177 2178 2179 2180 2181 2182 2183 2184 2185 2186 2187 2188 2189 2190 2191 2192 2193 2194 2195 2196 2197 2198 2199 2200 2201 2202 2203 2204 2205 2206 2207 2208 2209 2210 2211 2212 2213 2214 2215 2216 2217 2218 2219 2220 2221 2222 2223 2224 2225 2226 2227 2228 2229 2230 2231 2232 2233 2234 2235 2236 2237 2238 2239 2240 2241 2242 2243 2244 2245 2246 2247 2248 2249 2250 2251 2252 2253 2254 2255 2256 2257 2258 2259 2260 2261 2262 2263 2264 2265 2266 2267 2268 2269 2270 2271 2272 2273 2274 2275 2276 2277 2278 2279 2280 2281 2282 2283 2284 2285 2286 2287 2288 2289 2290 2291 2292 2293 2294 2295 2296 2297 2298 2299 2300 2301 2302 2303 2304 2305 2306 2307 2308 2309 2310 2311 2312 2313 2314 2315 2316 2317 2318 2319 2320 2321 2322 2323 2324 2325 2326 2327 2328 2329 2330 2331 2332 2333 2334 2335 2336 2337 2338 2339 2340 2341 2342 2343 2344 2345 2346 2347 2348 2349 2350 2351 2352 2353 2354 2355 2356 2357 2358 2359 2360 2361 2362 2363 2364 2365 2366 2367 2368 2369 2370 2371 2372 2373 2374 2375 2376 2377 2378 2379 2380 2381 2382 2383 2384 2385 2386 2387 2388 2389 2390 2391 A 2392 2393 2394 2395 2396 2397 2398 2399 2400 2401 2402 2403 2404 2405 2406 2407 2408 2409 2410 2411 2412 2413 2414 2415 2416 2417 2418 2419 2420 2421 2422 2423 2424 2425 2426 2427 2428 2429 2430 2431 2432 2433 2434 2435 2436 2437 2438 2439 2440 2441 2442 2443 2444 2445 2446 2447 2448 2449 2450 2451 2452 2453 2454 2455 2456 2457 2458 2459 2460 2461 2462 2463 2464 2465 2466 2467 2468 2469 2470 2471 2472 2473 2474 2475 2476 2477 2478 2479 2480 2481 2482 2483 2484 2485 2486 2487 2488 2489 2490 2491 2492 2493 2494 2495 2496 2497 2498 2499 2500 2501 2502 2503 2504 2505 2506 2507 2508 2509 2510 2511 2512 2513 2514 2515 2516 2517 2518 2519 2520 2521 2522 2523 2524 2525 2526 2527 2528 2529 2530 2531 2532 2533 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2733 2734 2735 2736 2737 2738 2739 2740 2741 2742 2743 2744 2745 2746 2747 2748 2749 2750 2751 2752 2753 2754 2755 2756 2757 2758 2759 2760 2761 2762 2763 2764 2765 2766 2767 2768 2769 2770 2771 2772 2773 2774 2775 2776 2777 2778 2779 2780 2781 2782 2783 2784 2785 2786 2787 2788 2789 2790 2791 2792 2793 2794 2795 2796 2797 2798 2799 2800 2801 2802 2803 2804 2805 2806 2807 2808 2809 2810 2811 2812 2813 2814 2815 2816 2817 2818 2819 2820 2821 2822 2823 2824 2825 2826 2827 2828 2829 2830 2831 2832 2833 2834 2835 2836 2837 2838 2839 2840 2841 2842 2843 2844 2845 2846 2847 2848 2849 2850 2851 2852 2853 2854 2855 2856 2857 2858 2859 2860 2861 2862 2863 2864 2865 2866 2867 2868 2869 2870 2871 2872 2873 2874 2875 2876 2877 2878 2879 2880 2881 2882 2883 2884 2885 2886 2887 2888 2889 2890 2891 2892 2893 2894 2895 2896 2897 2898 2899 2900 2901 2902 2903 2904 2905 2906 2907 2908 2909 2910 2911 2912 2913 2914 2915 2916 2917 2918 2919 2920 2921 2922 2923 2924 2925 2926 2927 2928 2929 2930 2931 2932 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3133 3134 3135 3136 3137 3138 3139 3140 3141 3142 3143 3144 3145 3146 3147 3148 3149 3150 3151 3152 3153 3154 3155 3156 3157 3158 3159 3160 3161 3162 3163 3164 3165 3166 3167 3168 3169 3170 3171 3172 3173 3174 3175 3176 3177 3178 3179 3180 3181 3182 3183 3184 3185 3186 3187 3188 3189 3190 3191 3192 3193 3194 3195 3196 3197 3198 3199 3200 3201 3202 3203 3204 3205 3206 3207 3208 3209 3210 3211 3212 3213 3214 3215 3216 3217 3218 3219 3220 3221 3222 3223 3224 3225 3226 3227 3228 3229 3230 3231 3232 3233 3234 3235 3236 3237 3238 3239 3240 3241 3242 3243 3244 3245 3246 3247 3248 3249 3250 3251 3252 3253 3254 3255 3256 3257 3258 3259 3260 3261 3262 3263 3264 3265 3266 3267 3268 3269 3270 3271 3272 3273 3274 3275 3276 3277 3278 3279 3280 3281 3282 3283 3284 3285 3286 3287 3288 3289 3290 3291 3292 3293 3294 3295 3296 3297 3298 3299 3300 3301 3302 3303 3304 3305 3306 3307 3308 3309 3310 3311 3312 3313 3314 3315 3316 3317 3318 3319 3320 3321 3322 3323 3324 3325 3326 3327 3328 3329 3330 3331 3332 3333 3334 3335 3336 3337 3338 3339 3340 3341 3342 3343 3344 3345 3346 3347 3348 3349 3350 3351 3352 3353 3354 3355 3356 3357 3358 3359 3360 3361 3362 3363 3364 3365 3366 3367 3368 3369 3370 3371 3372 3373 3374 3375 3376 3377 3378 3379 3380 3381 3382 3383 3384 3385 3386 3387 3388 3389 3390 3391 3392 3393 3394 3395 3396 C 3397 B 3398 3399 3400 3401 3402 3403 B 3404 B 3405 D 3406 D 3407

In the chemical structures in Table 1 above, when a stereocenter is depicted with a dashed line or wedge bond and labeled "abs" (or unlabeled), the compound at that stereocenter is essentially a single isomer ( rather than an equimolar mixture), and the absolute stereochemistry is as shown in the chemical structure. (See, e.g., the structure of Example 1.) When a stereocenter is drawn with a dashed line or wedge bond and is also labeled "or1" or "or2", the compound is a single isomer at that stereocenter, but the The absolute stereochemistry of the stereocenter has not yet been determined. (See, e.g., the structure of Example 203.) When a stereocenter is drawn with a dashed line or wedge bond and is also labeled "and1" or "&1", the compound is a mixture of two isomers at that stereocenter : The structure as shown, and the isomer with the opposite configuration of the stereocenter.

Certain compounds depicted in Table 1 above exist in solution at room temperature as non-interrotating atropisomers across biaryl bonds. When one atom of the biaryl bond is labeled "or1", this means that the compound exists in solution as a non-interrotating atropisomer at room temperature and that the compound is essentially a single atropisomer (rather than an equimolar mixture).

In some embodiments, the present disclosure provides a compound in Table 1 above, wherein the compound is represented as a biochemical CDK2 Caliper _IC50 with "A". In some embodiments, the present disclosure provides a compound in Table 1 above, wherein the compound is represented as a biochemical CDK2 Caliper _IC50 with "A" or "B." In some embodiments, the present disclosure provides a compound in Table 1 above, wherein the compound is represented as a biochemical CDK2 Caliper _IC50 with "A", "B" or "C".

In some embodiments, the present disclosure provides a compound in Table 1 above, wherein the compound is represented as Cell nanoBRET _IC50 with "A". In some embodiments, the present disclosure provides a compound in Table 1 above, wherein the compound is represented as a Cell nanoBRET _IC50 with "A" or "B." In some embodiments, the present disclosure provides a compound in Table 1 above, wherein the compound is represented as a Cell nanoBRET _IC50 with "A", "B" or "C". 4. General methods for providing compounds of the invention

The compounds described herein may generally be prepared or isolated by synthetic and/or semisynthetic methods known to those skilled in the art for similar compounds and by methods detailed in the Examples herein.

In some embodiments, the present disclosure provides methods of preparing compounds of Formula I or salts thereof: I, wherein Cy ^A , Cy ^B , Cy ^C , Q and P are as defined and described above and herein, the method includes the following steps: making a compound of formula XXVIII: XXVIII or a salt thereof, wherein Cy ^A , Cy ^B , Cy ^C , Q, P and ^RD are as defined and illustrated above and herein, react under suitable reaction conditions to provide a compound of formula I or a salt thereof.

In some embodiments, provided methods further comprise administering a compound of Formula XXVIII, or a salt thereof, to an individual or patient as defined and illustrated herein. In some embodiments, provided methods include reacting a compound of Formula XXVIII, or a salt thereof, upon administration to an individual or patient as defined and illustrated herein. In some embodiments, provided methods include reacting a compound of Formula XXVIII, or a salt thereof, in an individual or patient as defined and illustrated herein. In some embodiments, provided methods include reacting a compound of Formula XXVIII or a salt thereof in vivo. 5. Usage, preparation and administration of pharmaceutically acceptable compositions

According to another embodiment, the present disclosure provides compositions comprising a compound described herein, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier, adjuvant, or excipient. In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable carrier. The amount of compound in the compositions described herein is effective to measurably inhibit CDK2 protein kinase or mutants thereof in a biological sample or patient. In certain embodiments, the amount of compound in the compositions described herein is such that it is effective to measurably inhibit CDK2 protein kinase or a mutant thereof in a biological sample or patient. In certain embodiments, a composition described herein is formulated for administration to a patient in need of the composition. In some embodiments, the compositions described herein are formulated for oral administration to a patient.

The terms "individual" and "patient" as used herein mean an animal (ie, a member of the animal kingdom), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the individual system is human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or excipients that may be used in the compositions described herein include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphates), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, phosphoric acid Potassium hydroxide, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes , polyethylene-polyoxypropylene block polymer, polyethylene glycol and lanolin.

"Pharmaceutically acceptable derivative" means any non-toxic salt, ester, or ester of a compound described herein that is capable of directly or indirectly providing the compound described herein or inhibiting active metabolites or residues thereof upon administration to a recipient. Salts or other derivatives.

As used herein, the term "inhibitively active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of CDK2 protein kinase or a mutant thereof.

The compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously.

Sterile injectable forms of the compositions described herein may be aqueous or oily suspensions. Such suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are often used as the solvent or suspending medium.

For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated forms. Such oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants such as carboxymethylcellulose or similar dispersants commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants commonly used in the preparation of pharmaceutically acceptable solid, liquid or other dosage forms (such as Tween, Span and other emulsifiers or bioavailability enhancers) may also be used for formulation purposes.

The pharmaceutically acceptable compositions described herein may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, lozenges, aqueous suspensions, or solutions. In the case of tablets for oral use, common carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also often added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredients are combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions described herein may be administered as suppositories for rectal or vaginal administration. Such compositions may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal or vaginal temperatures and will therefore be absorbed in the rectum or vagina. Melt to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycol.

The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes a site or organ that is readily accessible by topical administration (including diseases of the eye, skin, or lower intestinal tract). Suitable topical formulations are readily prepared for each of these sites or organs.

Topical application for the lower intestinal tract may be accomplished in the form of a rectal suppository formulation (see above) or in a suitable enema formulation. Topical transdermal patches may also be used.

For topical application, the provided pharmaceutically acceptable compositions can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical administration of compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying waxes, and water. Alternatively, the provided pharmaceutically acceptable compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

For ophthalmic use, the provided pharmaceutically acceptable compositions may be formulated as a micronized suspension in isotonic, pH-adjusted sterile saline, or preferably as a micronized suspension in isotonic, pH-adjusted sterile saline. Solutions in sterile saline with or without preservatives such as benzylalkonium chloride. Alternatively, for ophthalmic uses, a pharmaceutically acceptable composition may be formulated into an ointment such as petroleum jelly.

The pharmaceutically acceptable compositions described herein may also be administered via nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the field of pharmaceutical formulations and may be prepared using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and/or other conventional solubilizers or dispersants. into a solution in salt water.

Preferably, the pharmaceutically acceptable compositions described herein are formulated for oral administration. The formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food.

The amount of a compound described herein that can be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient treated, and the particular mode of administration. Preferably, the provided compositions should be formulated such that a dose of between 0.01-100 mg/kg body weight/day of the inhibitor can be administered to a patient receiving the compositions.

It is also understood that the specific dosage and treatment regimen used in any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, excretion rate, drug combination and the judgment of the treating physician and the severity of the specific condition being treated. The amount of compounds described herein in the composition will also depend on the particular compound in the composition.

The precise dosage contemplated for the compositions will also depend on the route of administration and should be determined according to the practitioner's judgment and each individual's circumstances. In specific embodiments of the present disclosure, suitable dosage ranges for oral administration of compounds of the present disclosure generally range from about 1 mg/day to about 1000 mg/day. In some embodiments, the oral dosage ranges from about 1 mg/day to about 800 mg/day. In some embodiments, the oral dosage ranges from about 1 mg/day to about 500 mg/day. In some embodiments, the oral dosage ranges from about 1 mg/day to about 250 mg/day. In some embodiments, the oral dosage ranges from about 1 mg/day to about 100 mg/day. In some embodiments, the oral dosage is about 5 mg/day to about 50 mg/day. In some embodiments, the oral dosage is about 5 mg/day. In some embodiments, the oral dosage is about 10 mg/day. In some embodiments, the oral dosage is about 20 mg/day. In some embodiments, the oral dosage is about 30 mg/day. In some embodiments, the oral dosage is about 40 mg/day. In some embodiments, the oral dosage is about 50 mg/day. In some embodiments, the oral dosage is about 60 mg/day. In some embodiments, the oral dosage is about 70 mg/day. In some embodiments, the oral dosage is about 100 mg/day. It will be appreciated that any dose listed herein may constitute an upper or lower limit of a dosage range, and may be combined with any other dose to constitute a dosage range inclusive of the upper or lower limits.

In some embodiments, pharmaceutically acceptable compositions contain a provided compound and/or a pharmaceutically acceptable salt thereof at a concentration in the following range: about 0.01 wt% to about 90 wt%, about 0.01 wt % to about 80 wt%, about 0.01 wt% to about 70 wt%, about 0.01 wt% to about 60 wt%, about 0.01 wt% to about 50 wt%, about 0.01 wt% to about 40 wt%, about 0.01 wt % to about 30 wt%, about 0.01 wt% to about 20 wt%, about 0.01 wt% to about 2.0 wt%, about 0.01 wt% to about 1 wt%, about 0.05 wt% to about 0.5 wt%, about 1 wt % to about 30 wt% or about 1 wt% to about 20 wt%. The compositions may be formulated as solutions, suspensions, ointments or capsules and the like. Pharmaceutical compositions may be prepared as aqueous solutions and may contain additional components such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity adjusting ingredients, and the like.

Pharmaceutically acceptable carriers are well known to those skilled in the art and include, for example, adjuvants, diluents, excipients, fillers, lubricants and vehicles. In some embodiments, the carrier is a diluent, adjuvant, excipient, or vehicle. In some embodiments, the carrier is a diluent, adjuvant or excipient. In some embodiments, the carrier is a diluent or adjuvant. In some embodiments, the carrier is an excipient.

Examples of pharmaceutically acceptable carriers may include, for example, water or saline solutions, polymers such as polyethylene glycol, carbohydrates and derivatives thereof, oils, fatty acids or alcohols. Non-limiting examples of oils as pharmaceutical carriers include oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Pharmaceutical carriers may also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants can be used. Other examples of suitable pharmaceutical carriers are described in, for example, Remington's: The Science and Practice of Pharmacy, 22nd edition (edited by Allen, Loyd V., Jr., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5th edition ( Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th Edition (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. Editor, Pharmaceutical Press (2012)) (each of which is hereby incorporated by reference in its entirety).

The pharmaceutically acceptable carrier used herein can be selected from various organic or inorganic materials, which are used as materials for pharmaceutical formulations and as analgesics, buffers, binders, disintegrants, diluents, Emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and tackifiers are incorporated. Pharmaceutical additives such as antioxidants, fragrances, colorants, flavor improvers, preservatives and sweeteners may also be added. Examples of acceptable pharmaceutical carriers include, inter alia, carboxymethylcellulose, crystalline cellulose, glycerol, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose , starch, talc and water. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of the federal or state government or listed in the United States Pharmacopeia or other recognized pharmacopeia for use in animals, and more specifically for use in humans.

Surfactants (such as, for example, detergents) are also suitable for use in the formulations. Specific examples of surfactants include polyvinylpyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerin, sorbitol or sorbitol. Polyoxyethylated esters of alcohol anhydrides; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates and others; anionic surfactants, such as alkaline stearates, especially stearin Sodium stearate, potassium stearate or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, especially sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecyl benzene sulfonate or Sodium dioctyl sulfosuccinate; or fatty acids, especially those derived from coconut oil; cationic surfactants, such as water-soluble ones of the formula N ⁺ R'R''R'''R''''Y ^- Quaternary ammonium salts, in which the R groups are the same or different optionally hydroxylated hydrocarbon groups and Y ^- is an anion of a strong acid, such as halide, sulfate and sulfonate anions; cetyltrimethylammonium bromide can One of the cationic surfactants used, an amine salt of the formula N ⁺ R'R''R''', in which the R groups are the same or different optionally hydroxylated hydrocarbon groups; octadecylamine hydrochloride Salts are one of the cationic surfactants that can be used, non-ionic surfactants, such as optionally polyoxyethylenated esters of sorbitan, especially polysorbate 80, or polyoxyethylated alkyl ethers; Polyethylene glycol stearate, polyoxyethylene derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants, Substituted lauryl compounds such as betaine.

Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica, sodium stearate, glyceryl monostearate, talc, sodium chloride , skimmed milk powder, glycerin, propylene, glycol, polyethylene glycol 300, water, ethanol, polysorbate 20 and the like. If desired, the compositions of the present invention may also contain wetting or emulsifying agents or pH buffering agents.

Tablet and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers or lubricants, each of which is known in the art. Examples of this include carbohydrates (such as lactose or sucrose), anhydrous calcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearates, Silicon oxide, talc, sodium starch glycolate, gum arabic, flavoring agents, preservatives, buffers, disintegrating agents and coloring agents. Compositions for oral administration may contain one or more optional agents, such as sweetening agents, such as fructose, aspartame, or saccharin; flavoring agents, such as peppermint, oil of wintergreen, or cherry; coloring agents; and preservatives. , to provide pharmaceutically delicious preparations. Uses of compounds and pharmaceutically acceptable compositions

The compounds and compositions described herein are generally useful for inhibiting kinases or mutants thereof. In some embodiments, the kinase inhibited by the compounds and compositions described herein is a cyclin-dependent kinase (CDK). In some embodiments, the kinase inhibited by the compounds and compositions described herein is one or more of CDK1, CDK2, CDK4, and CDK6. In some embodiments, the kinase inhibited by the compounds and compositions described herein is CDK2.

Compounds or compositions of the present disclosure may be used in applications that would benefit from inhibition of the CDK2 enzyme. For example, the CDK2 inhibitors described herein are generally useful in treating proliferative diseases.

CDK2 is known to be a factor in tumor formation and proliferation in many cancer types, including lung, liver, colon and breast cancer (Opyrchal, Int J Oncol 2014; Shi, PLoS One 2015; Lim, Cancer Prev Res 2014). There is evidence that CDK2 is functionally associated with hyperproliferation of a variety of cancer cells and is a potential therapeutic target for cancer therapy (Chohan, Curr Med Chem 2015).

CDK2 plays a role in malignant transformation of breast epithelial cells. Inhibiting CDK2 activity can effectively inhibit the proliferation of human breast cancer cells (Ali, Cancer Res 2009). Active CDK2 in the form of a cyclin D1/CDK2 fusion protein induces tumors containing an aggressive component that exhibits several characteristics common to human basal-like tumors and tumor-derived cell lines (Corsino, Neoplasia 2008). Cyclin D1/CDK2 complexes have been detected in human breast cancer cell lines (Sweeney, Oncogene 1998), and the levels of these complexes correlate closely with the extent of cyclin D1 overexpression.

The role of cyclin E and its related kinase CDK2 in ovarian cancer has been studied by screening primary, metastatic, recurrent and benign ovarian tumors. Using gene amplification, it has been shown that cyclin E is amplified in 21% of cases analyzed and CDK2 is amplified in 6.4% of cases analyzed. Additionally, cyclin E RNA was overexpressed in 29.5% of ovarian tumors tested, and CDK2 was overexpressed in 6.5% of ovarian tumors tested. Cyclin E and CDK2 are predominantly overexpressed in primary ovarian cancer (32% and 10%, respectively) compared with metastatic and recurrent disease (Marone, Int J Cancer 1998).

CDK2 has been found to be significantly elevated in glioma tumors, especially in glioblastoma multiforme (GBM), and is functionally required for GBM cell proliferation and tumor formation (Wang, Transl Oncol 2016). CDK2 expression was identified as significantly enriched in GBM tumors and is required for tumor proliferation both in vitro and in vivo. Furthermore, high CDK2 expression is associated with poor prognosis in GBM patients. Radioresistance is a major factor in poor clinical prognosis and tumor recurrence in GBM patients. CDK2 was found to be one of the most upregulated kinase-encoding genes in GBM after radiotherapy. CDK2-dependent radioresistance is indispensable for GBM tumor formation and recurrence after therapeutic treatment (ibid.).

Elevated levels of CDK2 expression have been observed in human cholangiocarcinoma tissues, where apoptosis-related protein 1-dependent inhibition of CDK2 induces cell cycle arrest and inhibits tumor growth (Zheng, Oncol Rep 2016).

CDK2 overexpression in oral squamous cell carcinoma (SCC) increases pRB phosphorylation and allows cancer cells to enter S phase faster. In the clinicopathological investigation of oral SCC, the incidence of CDK2 expression was higher in poorly differentiated lesions and was related to tumor invasion pattern, lymph node involvement, and survival, indicating that changes in CDK2 expression are related to oral cancer progression (Mihara, Jpn J Cancer Res 2001). CDK2 expression was significantly associated with lymph node involvement, tumor differentiation, tumor invasion pattern, and shorter survival. Therefore, increased expression of CDK2 is a factor in the progression of oral cancer and a negative predictive marker for patient prognosis (ibid.).

CDK2 has been found to play a role in cell proliferation in non-small cell lung cancer (Kawana, Am J Pathol 1998). CDK2 has also been found to play a role in prostate cancer cell proliferation (Flores, Endocrinology 2010).

The activity of compounds described herein as inhibitors of CDK kinases (eg, CDK2 or mutants thereof) can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays to determine the phosphorylation activity and/or subsequent functional consequences or inhibition of ATPase activity of activated CDK2 or mutants thereof. An alternative in vitro assay to quantify the ability of an inhibitor to bind to CDK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor/CDK2 complex, and determining the amount of radiolabel bound. Alternatively, inhibitor binding can be determined by running competition experiments in which new inhibitors are incubated with CDK2 bound to a known radioligand. Representative in vitro and in vivo assays that can be used to analyze CDK2 inhibitors include those described and disclosed in the patents and scientific publications described herein. Detailed conditions for the analysis of compounds described herein as inhibitors of CDK2 or mutants thereof are set forth in the Examples below. Treatment of disease

The provided compounds are inhibitors of CDK2 and thus may be used to treat one or more conditions associated with the activity of CDK2 or mutants thereof. Accordingly, in certain embodiments, the present disclosure provides methods of treating a CDK2-mediated disorder in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable version thereof. salt, or a pharmaceutically acceptable composition of any of the foregoing. In certain embodiments, the present disclosure provides methods of treating a CDK2-mediated disorder in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable composition thereof .

As used herein, the term "CDK2-mediated" disorder, disease and/or disorder means any disease or other deleterious disorder in which CDK2 or mutants thereof are known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or reducing the severity of one or more diseases in which CDK2 or mutants thereof are known to play a role. Such CDK2-mediated disorders include, but are not limited to, proliferative disorders (eg, cancer).

In some embodiments, the present disclosure provides methods for treating one or more disorders, wherein the disorders are selected from the group consisting of proliferative disorders and craniosynostosis syndrome, comprising administering to a patient in need thereof a therapeutically effective amount The compound of the present disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing. In some embodiments, the present disclosure provides methods for treating one or more disorders, wherein the disorders are selected from the group consisting of proliferative disorders and craniosynostosis syndrome, comprising administering to a patient in need thereof a therapeutically effective amount The compounds of this disclosure or their pharmaceutically acceptable compositions.

In some embodiments, the disorder is associated with CDK2 signaling. CDK2 is known to have multiple upstream and downstream signaling pathways, and inhibition of CDK2 can be used to treat conditions associated with abnormal signaling within these pathways. In some embodiments, the disorder is associated with cyclin E, cyclin El, or retinoblastoma protein (RB) signaling.

In some embodiments, methods of treatment include the steps of: i) identifying an individual in need of such treatment; (ii) providing a disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) administering a therapeutically effective amount The provided compounds are used to treat, inhibit and/or prevent disease states or disorders in individuals in need of such treatment.

In some embodiments, methods of treatment include the steps of: i) identifying an individual in need of such treatment; (ii) providing a composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof; and (iii) treating The composition is administered in an effective amount to treat, suppress, and/or prevent a disease state or disorder in an individual in need of such treatment.

Another aspect of the present disclosure provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, for use in the treatment of a disorder described herein. Another aspect of the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any of the foregoing, for the treatment of a disorder described herein. Similarly, the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder described herein. proliferative disorder

In some embodiments, the disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is ovarian cancer, breast cancer, lung cancer, colorectal cancer, or a combination thereof. In some embodiments, the proliferative disorder is leukemia. In some embodiments, the proliferative disorder is breast cancer. In some embodiments, the proliferative disorder is lung cancer. In some embodiments, the proliferative disorder is colorectal cancer.

In some embodiments, the proliferative disorder is breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, ovarian cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, or bladder cancer. In some embodiments, the proliferative disorder is intrahepatic cholangiocarcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, lung squamous cell carcinoma, thyroid cancer, gastric cancer, or ovarian cancer. In some embodiments, the proliferative disorder is gastric cancer, breast cancer, triple negative breast cancer, or rectal cancer. In some embodiments, the proliferative disorder is endometrial cancer, non-small cell lung cancer, lung squamous cell carcinoma, gastric cancer, breast cancer, or urothelial cancer.

In some embodiments, the condition is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, Multiple myeloma, colorectal, rectal, skin or pancreatic cancer. In some embodiments, the bladder cancer is urothelial cancer. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the lung cancer is pulmonary squamous cell carcinoma or non-small cell lung cancer. In some embodiments, the laryngeal cancer is laryngeal squamous cell carcinoma. In some embodiments, the skin cancer is melanoma.

In some embodiments, the proliferative disorder is associated with deregulation of CDK2 or cyclin E. In some embodiments, deregulation of CDK2 is overexpression of CDK2 or cyclin E. In some embodiments, deregulation of cyclin E is overexpression of CDK2 or cyclin E. In some embodiments, the proliferative disorder is associated with deregulation of CDK2 and cyclin E. In some embodiments, deregulation of CDK2 and cyclin E is overexpression of CDK2 and cyclin E.

In some embodiments, the proliferative disorder is associated with one or more activating mutations in CDK2. In some embodiments, the activating mutation in CDK2 is a mutation in one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutation in CDK2 is a mutation in the intracellular kinase domain. Route of administration and dosage form

According to the methods described herein, the compounds and compositions may be administered in any manner that is effective in treating a condition (e.g., a proliferative disorder or craniosynostosis syndrome) or reducing the severity of a condition (e.g., a proliferative disorder or craniosynostosis syndrome) Invest in any amount and through any investment method. The exact amount required will vary from individual to individual, depending on the species, age and general condition of the individual; the severity of the infection, the specific agent, its mode of administration, and the like. For ease of administration and uniformity of dosage, the compounds described herein are preferably formulated in dosage unit form. The expression "dosage unit form" as used herein refers to physically discrete units of dosage suitable for the treatment of the patient intended. However, it should be understood that the total daily dosage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage levels for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; and the age, weight, and general health of the patient. , gender and diet; the time of administration, route of administration and rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field.

The pharmaceutically acceptable compositions described herein may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., via powder, ointment, or drops), bucally, as an oral or nasal spray, or the like to humans and other animals. In certain embodiments, the compounds described herein may be administered orally or parenterally at a dosage level of about 0.01 mg/kg to about 50 mg/kg, and preferably about 1 mg/kg to about 25 mg/kg of body weight of the subject per day. Administer one or more times daily to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, liquid dosage forms may also contain inert diluents customary in the art, such as, for example, water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol. , Benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oil (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), Fatty acid esters of glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitan and their mixtures. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, such as sterile injectable aqueous or oily suspensions, may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are often used as the solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

Injectable formulations can be sterilized, for example, by filtering through a bacteria-retaining filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or another sterile injectable medium before use.

In order to prolong the effects of the compounds described herein, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using liquid suspensions of crystalline or amorphous materials with poor water solubility. The rate of absorption of a compound depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered compound forms is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of compound to polymer and the properties of the particular polymer used, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Preferred suppository formulations of compositions for rectal or vaginal administration may be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol, or suppository wax. For preparation, these excipients or carriers are solid at ambient temperature but liquid at body temperature and will therefore melt and release the active compound in the rectal or vaginal cavity.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier (such as sodium citrate or dicalcium phosphate) and/or the following: a) fillers or extenders Dosing agents, such as starch, lactose, sucrose, glucose, mannitol and silicic acid; b) binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants, such as glycerol; d) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) retarder, such as paraffin; f) absorption accelerators , such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glyceryl monostearate, h) absorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, hard Magnesium fatty acid, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. It may optionally contain a devitrification agent, and may also have a composition that allows it to release one or more active ingredients only (or preferentially) in a certain part of the intestinal tract in a delayed manner, as the case may be. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions may also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose and high molecular weight polyethylene glycols and the like.

The active compounds may also be in microencapsulated form with one or more excipients as mentioned above. Solid dosage forms of tablets, dragees, capsules, pills, and granules may be prepared with coatings and shells such as enteric coatings, release control coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. Such dosage forms may also contain, in accordance with common practice, additional substances besides the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. It may optionally contain a devitrification agent, and may also have a composition that allows it to release one or more active ingredients only (or preferentially) in a certain part of the intestinal tract in a delayed manner, as the case may be. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of the compounds described herein include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be necessary. Ophthalmic formulations, ear drops, and eye drops are also included within the scope of this disclosure. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of controlled delivery of compounds to the body. Such dosage forms can be prepared by dissolving or distributing the compound in an appropriate medium. Absorption enhancers may also be used to increase the flux of compounds across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Dosage amount and schedule

According to the methods of the present disclosure, a compound of the present disclosure is administered to an individual in a therapeutically effective amount, for example, to reduce or ameliorate the symptoms of a disorder in the individual. This amount is readily determined by one skilled in the art based on known procedures including analysis of titration curves established in vivo and the methods and analyzes disclosed herein.

In some embodiments, the methods include administering a therapeutically effective dose of a compound of the present disclosure. In some embodiments, the therapeutically effective dose is at least about 0.0001 mg/kg body weight, at least about 0.001 mg/kg body weight, at least about 0.01 mg/kg body weight, at least about 0.05 mg/kg body weight, at least about 0.1 mg/kg body weight, At least about 0.25 mg/kg body weight, at least about 0.3 mg/kg body weight, at least about 0.5 mg/kg body weight, at least about 0.75 mg/kg body weight, at least about 1 mg/kg body weight, at least about 2 mg/kg body weight, at least about 3 mg/kg body weight, at least about 4 mg/kg body weight, at least about 5 mg/kg body weight, at least about 6 mg/kg body weight, at least about 7 mg/kg body weight, at least about 8 mg/kg body weight, at least about 9 mg /kg body weight, at least about 10 mg/kg body weight, at least about 15 mg/kg body weight, at least about 20 mg/kg body weight, at least about 25 mg/kg body weight, at least about 30 mg/kg body weight, at least about 40 mg/kg Body weight, at least about 50 mg/kg body weight, at least about 75 mg/kg body weight, at least about 100 mg/kg body weight, at least about 200 mg/kg body weight, at least about 250 mg/kg body weight, at least about 300 mg/kg body weight, At least about 350 mg/kg body weight, at least about 400 mg/kg body weight, at least about 450 mg/kg body weight, at least about 500 mg/kg body weight, at least about 550 mg/kg body weight, at least about 600 mg/kg body weight, at least about 650 mg/kg body weight, at least about 700 mg/kg body weight, at least about 750 mg/kg body weight, at least about 800 mg/kg body weight, at least about 900 mg/kg body weight, or at least about 1000 mg/kg body weight. It will be appreciated that any dose listed herein may constitute an upper or lower limit of a dosage range, and may be combined with any other dose to constitute a dosage range inclusive of the upper or lower limits.

In some embodiments, the therapeutically effective dose is from about 0.1 mg to about 10 mg/kg body weight, from about 0.1 mg to about 6 mg/kg body weight, from about 0.1 mg to about 4 mg/kg body weight, or from about 0.1 mg to about 2 mg. /kg body weight.

In some embodiments, the therapeutically effective dose is about 1 to 500 mg, about 2 to 150 mg, about 2 to 120 mg, about 2 to 80 mg, about 2 to 40 mg, about 5 to 150 mg, about 5 to 120 mg mg, about 5 to 80 mg, about 10 to 150 mg, about 10 to 120 mg, about 10 to 80 mg, about 10 to 40 mg, about 20 to 150 mg, about 20 to 120 mg, about 20 to 80 mg, In the range of about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg, or about 40 to 80 mg.

In some embodiments, the methods include a single administration or administration (eg, as a single injection or deposition). Alternatively, in some embodiments, the methods include administering to an individual in need thereof once a day, twice a day, three times a day, or four times a day for about 2 to about 28 days, or about 7 to about 10 days, or About 7 to about 15 days, or longer. In some embodiments, the methods include long-term administration. In other embodiments, the methods include administration over the course of weeks, months, years, or decades. In other embodiments, the methods include administration over the course of several weeks. In other embodiments, the methods include administration over the course of several months. In other embodiments, the methods include administration over the course of several years. In other embodiments, the methods include investments over the course of decades.

The dosage administered may vary depending on known factors, such as the pharmacodynamic characteristics of the active ingredient and its mode and route of administration; the time of administration of the active ingredient; the age, sex, health and weight of the recipient; symptoms the nature and extent of concurrent treatment; the type, frequency and expected effects of concurrent treatment; and the rate of excretion. These factors can be readily determined and used by those skilled in the art to adjust or titrate dosage and/or dosing regimens. protein kinase inhibition

According to one embodiment, the present disclosure relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound described herein or a composition comprising the compound.

According to another embodiment, the present disclosure relates to a method of inhibiting the activity of CDK2 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound described herein or a composition comprising the compound. In certain embodiments, the present disclosure relates to methods of reversibly inhibiting the activity of CDK2 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound described herein or a composition comprising the compound. .

In another embodiment, the disclosure provides methods of selectively inhibiting CDK2 relative to one or more of CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, compounds described herein are more than 5-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, compounds described herein are more than 10-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, compounds described herein are more than 50-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, compounds described herein are more than 100-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, compounds described herein are more than 200-fold selective for CDK2 over CDK1, CDK4, CDK5, CDK6, and CDK9.

The term "biological sample" as used herein includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from mammals or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids, or its extracts.

Inhibition of the activity of CDK2 (or mutants thereof) in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusions, organ transplants, biological sample storage, and biological analysis.

Another embodiment of the present disclosure is directed to a method of inhibiting protein kinase activity in a patient, comprising the step of administering to the patient a compound described herein, or a composition comprising the compound.

According to another embodiment, the present disclosure is directed to a method of inhibiting the activity of CDK2 or a mutant thereof in a patient, comprising the step of administering to the patient a compound described herein or a composition comprising the compound. According to certain embodiments, the present disclosure is directed to methods of reversibly inhibiting the activity of one or more CDK2s or mutants thereof in a patient, comprising the step of administering to the patient a compound described herein, or a composition comprising the compound.

According to another embodiment, the present disclosure provides methods for treating a disorder mediated by CDK2 or a mutant thereof in a patient in need thereof, the method comprising administering to the patient a compound described herein or a pharmaceutically acceptable compound thereof The steps of composition. These conditions are described in detail herein. In some embodiments, the present disclosure provides methods for treating a disorder mediated by CDK2 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound described herein or a pharmaceutically acceptable compound thereof. A step of the composition wherein the compound reversibly inhibits CDK2 or a mutant thereof.

According to another embodiment, the present disclosure provides a method of inhibiting the signaling activity of CDK2 or a mutant thereof in an individual, the method comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable version thereof. composition. In some embodiments, the present disclosure provides methods of inhibiting CDK2 signaling activity in an individual, comprising administering to an individual in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable composition thereof.

In some embodiments, the present disclosure provides methods for treating a disorder mediated by CDK2 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound described herein or a pharmaceutically acceptable compound thereof. A step of the composition wherein the compound reversibly inhibits CDK2 or a mutant thereof.

Compounds described herein may also inhibit CDK2 function by incorporation into agents that catalyze CDK2 destruction. For example, these compounds can be incorporated into proteolysis targeting chimeras (PROTACs). PROTACs are bifunctional molecules, one part of which is capable of engaging E3 ubiquitin ligase, and the other part has the ability to bind to a target protein intended for degradation by the cellular protein quality control machinery. Recruitment of target proteins to specific E3 ligases results in their being marked for destruction (i.e., ubiquitination) and subsequent degradation by the proteasome. Any E3 ligase can be used. The portion of PROTAC that engages the E3 ligase is linked to the portion of PROTAC that engages the target protein via a linker consisting of a chain of variable atoms. Therefore, recruitment of CDK2 to E3 ligase will lead to the destruction of CDK2 protein. Variable atom chains may include, for example, rings, heteroatoms, and/or repeating polymer units. It can be rigid or flexible. It can be connected to the above two parts using standard techniques in the field of organic synthesis. combination therapy

Depending on the particular condition, disorder, or disease being treated, additional therapeutic agents typically administered to treat that condition may be administered in combination with the compounds and compositions described herein. As used herein, an additional therapeutic agent that is typically administered to treat a specific disease or disorder is referred to as "appropriate for the disease or disorder being treated."

Thus, in certain embodiments, methods of treatment include administering a compound or composition described herein in combination with one or more additional therapeutic agents. In certain other embodiments, methods of treatment include administering a compound or composition described herein as the sole therapeutic agent.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulators, and histone deacetylase inhibitors. In some embodiments, one or more additional therapeutic agents are selected from the following agents or pharmaceutically acceptable salts thereof: BCR-ABL inhibitors: for example, imatinib, inilotinib, Nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, seca saracatinib, PF03814735; ALK inhibitors (see Dardaei et al., 2018, Nat Med.; 24(4):512-517): such as crizotinib, NVP-TAE684, ceritinib (ceritinib), alectinib (alectinib), brigatinib (brigatinib), entrecinib (entrecinib), lorlatinib (lorlatinib); BRAF inhibitors (see Prahallad et al., 2015, Cell Rep. 12, 1978-1985): such as vemurafenib, dabrafenib; FGFR inhibitors: such as infigratinib, dovitinib, erdafitinib (erdafitinib), BLU-554, AZD4547; FLT3 inhibitors: such as sunitinib, midostaurin, tanutinib, sorafenib, lestatinib lestaurtinib, quizartinib, and crenolanib; MEK inhibitors (see Fedele et al., 2018, BioRxiv 307876; Torres-Ayuso et al., 2018, Cancer Discov. 8, 1210- 1212; and Wong et al., 2016, Oncotarget. 2016 Oct 4;7(40):65676-65695): such as trametinib, cobimetinib, binimetinib ), selumetinib; ERK inhibitors: such as ulixertinib, MK-8353, LY-3214996; VEGF receptor inhibitors: such as bevacizumab, axitinib (axitinib), aflibercept, brivanib, motesanib, pasireotide, sorafenib; tyrosine kinase inhibitors: e.g. Rotinib (erlotinib), linifanib (linifanib), sunitinib, pazopanib (pazopanib); epidermal growth factor receptor (EGFR) inhibitors: gefitnib (gefitnib), osimertinib osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors: such as trastuzumab, neratinib, lapatinib (lapatinib), lapatinib; MET inhibitors: such as crizotinib, cabozantinib (cabozantinib); CD20 antibodies: such as rituximab (rituximab), tositumomab (tositumomab), ofatumumab; DNA synthesis inhibitors: such as capecitabine, gemcitabine, nelarabine, hydroxyurea; anti-tumor agents: such as oxaliplatin, Cisplatin; HER dimerization inhibitors: such as pertuzumab; human granule colony-stimulating factor (G-CSF) modulators: such as filgrastim; immunomodulators: such as av afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: such as dacetuzumab; pro-apoptotic receptors PARA: such as dulanermin; heat shock protein (HSP) inhibitor: such as tanespimycin (17-allylamino-17-desmethoxygeld) (17-allylamino-17-desmethoxygeldanamycin); Hedgehog antagonist: such as vismodegib; proteasome inhibitor: such as bortezomib; PI3K inhibitor: such as pictilisib ), dactolisib, buparlisib, taselisib, idelalisib, duvelisib, umbralisib; Phospholipase A2 inhibitors: such as anagrelide; BCL-2 inhibitors: such as venetoclax; aromatase inhibitors: exemestane, letrozole, A Nastrozole, faslodex, tamoxifen; topoisomerase I inhibitors: such as irinotecan, topotecan; topoisomerase Enzyme II inhibitors: such as etoposide, teniposide; mTOR inhibitors: such as temsirolimus, ridaforolimus, everolimus , sirolimus; osteoclast bone resorption inhibitors: such as zoledronic acid; CD33 antibody drug conjugates: such as gemtuzumab ozogamicin; CD22 antibody drug conjugates : For example, inotuzumab ozogamicin; CD20 antibody drug conjugates: such as ibritumomab tiuxetan; Somatostain analogs: such as octreotide; interleukin- 11 (IL-11): such as oprelvekin; synthetic erythropoietin: such as darbepoetin alfa; receptor activator of nuclear factor kappa B (RANK) inhibitor: such as De Denosumab; thrombopoietin mimetic peptides: such as romiplostim; cell growth stimulators: such as palifermin; resistance to insulin-like growth factor-1 receptor (IGF-1R) Antibodies: such as figitumumab; anti-CS1 antibodies: such as elotuzumab; CD52 antibodies: such as alemtuzumab; CTLA-4 inhibitors: such as temtuzumab (tremelimumab), ipilimumab (ipilimumab); PD1 inhibitors: such as nivolumab (nivolumab), pembrolizumab (pembrolizumab); immune adhesins; such as pidilizumab (pidilizumab), AMP- 224; PDL1 inhibitors: such as MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C or MDX-1105; LAG-3 inhibitors: such as BMS-986016; GITR agonists; GITR fusion proteins and anti- GITR antibodies; histone deacetylase inhibitors (HDI): such as voninostat; anti-CTLA4 antibodies: such as tremelimumab, ipilimumab; alkylating agents : For example, temozolomide, dactinomycin, melphalan, altretamine carmustine, bendamustine, busulfan, carbamide Platinum, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine , methyldi(chloroethyl)amine (mechlorethamine), nitrogen mustard and bis(chloroethyl)methylamine (mechloroethamine), streptozocin, thiotepa; biological response modifiers: such as bacillus calmette-guerin, denileukin diftitox; anti-tumor antibiotics: such as doxorubicin, bleomycin, daunorubicin, daunorubicin Liposomes, mitoxantrone, epirubicin, idarubicin, mitomycin C; anti-microtubule agents: such as estramustine; cell autolysis Enzyme K inhibitors: such as odanacatib; Epothilone analogues: such as ixabepilone; TpoR agonists: such as eltrombopag; antimitotic agents : such as docetaxel; adrenal steroid inhibitors: such as aminoglutethimide; anti-androgens: such as nilutamide; androgen receptor inhibitors: such as enzalutamide ), abiraterone acetate, orteronel, galeterone, seviteronel, bicalutamide, flutamide ; Androgens: such as fluoxymesterone; CDK1 inhibitors: such as alvocidib, palbociclib, ribociclib, trilaciclib ), abemaciclib; gonadotropin-releasing hormone (GnRH) receptor agonists: such as leuprolide or leuprolide acetate; taxane anti-tumor agents: such as cabazitaxel ), larotaxel; 5-HTla receptor agonists: such as xaliproden; HPV vaccines: such as Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; iron chelators: such as Deferasirox; antimetabolites: such as claribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine Liposomes, decitabine, hydroxyurea, fludarabine, fluuridine, cladribine, methotrexate, pentostatin; bisphosphonates Acid salts: such as pamidronate; demethylating agents: such as 5-azacitidine, decitabine; anti-tumor plant alkaloids: such as protein-bound paclitaxel (paclitaxel protein-bound); vinblastine, vincristine, vinorelbine, paclitaxel; retinoids: such as alitretinoin, tretinoin , isotretinoin, bexarotene; glucocorticoids: such as hydrocortisone, dexamethasone, prednisolone, prednisone, Methylprednisolone; cytokines: such as interleukin-2, interleukin-11 (oprevelkin), alpha interferon alpha (IFN-α); under estrogen receptors Adjustments: fulvestrant; anti-estrogens: such as tamoxifen, toremifene; selective estrogen receptor modulators (SERM): such as raloxifene; corpus luteum LHRH agonists: such as goserelin; progesterone: such as megestrol; cytotoxic agents: arsenic trioxide, aspartase (also known as L- Aspartase, Erwinia L-aspartase; antiemetics: such as NK-1 receptor antagonists (such as casopitant); cytoprotective agents: For example, amifostine, leucovorin; and immune checkpoint inhibitors. The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. Immune checkpoint molecules include, but are not limited to, programmed death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD 137, CD40 and LAG3. Immunotherapeutic agents that can serve as immune checkpoint inhibitors that can be used in the methods of the present disclosure include, but are not limited to, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD 160, Inhibitors of 2B4 and/or TGFRβ.

In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of: anti-CDK2 antibodies; cytotoxic agents; estrogen receptor-targeted or other endocrine therapies, immune checkpoint inhibitors, other CDK inhibitors, receptor casein Amino acid kinase inhibitors, BRAF inhibitors, MEK inhibitors, PI3K inhibitors, SHP2 inhibitors and SRC inhibitors. (See M. Katoh, Nat. Rev. Clin. Oncol. 2019, 16:105-122; Y.K. Chae et al., Oncotarget 2017, 8:16052-16074; L. Formisano et al., Nat. Comm. 2019, 10: 1373-1386; and documents cited therein.)

The structures of active compounds identified by code, common name or trade name can be obtained from the current version of the standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

The compounds described herein may also be used in combination with known treatments, such as the administration of hormones or radiation. In certain embodiments, provided compounds are used as radiosensitizers, particularly for the treatment of tumors that exhibit poor sensitivity to radiotherapy.

The compounds described herein may be administered alone or in combination with one or more other therapeutic compounds. Possible combination therapies may take the form of fixed combinations or staggered administration of compounds described herein and one or more other therapeutic compounds or administered independently of each other, or in combination with one or more other therapeutic compounds. The compounds described herein may be administered in addition to or in combination with chemotherapy, radiation therapy, immunotherapy, phototherapy, surgical intervention, or combinations thereof, particularly for oncology therapy. Long-term therapy is equally possible as adjuvant therapy in the context of other treatment strategies as mentioned above. Other possible treatments are therapies to maintain the patient's status after tumor regression, or even chemopreventive therapies, for example in at-risk patients.

Such additional doses can be administered separately from compositions containing the provided compounds as part of a multiple-dose regimen. Alternatively, the agents can be part of a single dosage form mixed in a single composition with the compounds described herein. If administered as part of a multiple-dose regimen, the two active agents can be administered simultaneously, sequentially, or within time of each other, usually within five hours of each other.

As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents in accordance with the present disclosure. For example, a compound described herein can be administered with another therapeutic agent simultaneously or sequentially, in separate unit dosage forms, or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a compound described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or excipient.

The amounts of both a compound described herein and an additional therapeutic agent (in those compositions including additional therapeutic agents, as described above) that can be combined with the carrier materials to produce a single dosage form will depend upon the host treated and the particular administration. changes in ways. Preferably, the compositions described herein should be formulated such that a dose of between 0.01-100 mg/kg body weight/day of a compound described herein can be administered.

In compositions containing an additional therapeutic agent, the additional therapeutic agent and the compounds described herein may act synergistically. Therefore, the amount of additional therapeutic agent in such compositions will be less than that required in monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent may be administered at a dose between 0.01-1,000 μg/kg body weight/day.

The amount of additional therapeutic agent present in the compositions described herein will not exceed the amount normally administered in a composition containing the therapeutic agent as the sole active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount typically present in a composition containing such agent as the sole therapeutically active agent.

The compounds described herein, or pharmaceutical compositions thereof, may also be incorporated into compositions for coating implantable medical devices, such as prosthetics, artificial valves, vascular grafts, stents, and catheters. Vascular stents, for example, have been used to overcome restenosis (re-narrowing of the vessel wall after injury). However, patients using stents or other implantable devices are at risk for clot formation or platelet activation. These undesirable effects can be prevented or mitigated by precoating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. Implantable devices coated with compounds described herein are also contemplated by this disclosure.

Any compounds and/or compositions of the present disclosure may be provided in kits containing such compounds and/or compositions. Accordingly, in some embodiments, compounds and/or compositions of the present disclosure are provided in a kit.

The present disclosure is further illustrated by the following non-limiting examples. Example

This article provides examples to facilitate a more complete understanding of the present disclosure. The following examples serve to illustrate illustrative modes of making and practicing the subject matter of the present disclosure. However, the scope of the present disclosure should not be construed as being limited to the specific embodiments disclosed in these examples, which are illustrative only.

As described in the Examples below, in certain illustrative embodiments, compounds are prepared according to the following general procedures. It should be understood that although the general methods illustrate the synthesis of certain compounds described herein, the following general methods and other methods known to those skilled in the art may be applicable to other classes of each of these compounds as described herein. and subcategories and categories. Additional compounds described herein are prepared by methods substantially similar to those described in the Examples herein and by methods known to those skilled in the art.

In the description of the synthetic methods described below, unless otherwise indicated, it is understood that all reaction conditions (e.g., reaction solvent, atmosphere, temperature, duration, and processing procedures) are selected from the standards used for the reaction. condition. In a general approach, those skilled in the art of organic synthesis will understand that the functional groups present on different parts of the molecule should be compatible with the reagents and reactions proposed. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art and will therefore indicate alternative approaches (eg, use of protecting groups or substitution reactions). Starting materials used in the examples are either commercially available or can be readily prepared from known materials by standard methods.

It is contemplated that at least some of the compounds identified herein as "intermediates" are compounds of the present disclosure. Example 1 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl ) tetrahydrofuran -3- base ester (1-( tert-butyl )-3-((2R,4R)-4-(( tert-butyldimethylsilyl ) oxy ) tetrahydrofuran -2- yl )-1H- pyrazole -5 -Benzyl carbamate _ _

Step 1 : Charge 1-(tert-butyl)-3-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2- into a round-bottomed flask. base)-1H-pyrazol-5-amine (9.56 g, 28.2 mmol), NaHCO ₃ (11.8 g, 141 mmol), MeCN (100 mL) and stirring rod. Then benzyl chloroformate (14.4 g, 84.5 mmol) was added at 0°C. The solution was stirred at 25°C for 16 hours. Concentrate in vacuo. The mixture was diluted with water (150 mL), and the aqueous phase was extracted with EA (3*150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo yielded (1-(tert-butyl)-3-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)oxy)tetrahydrofuran- as a yellow oil 2-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (22 g, 23 mmol, 82%, 50% purity) (crude). m/z (ES ⁺ ) [M+H] ⁺ =474.40; HPLC tR = 1.237 min. (1-( tert-Butyl )-3-((2R,4R)-4- hydroxytetrahydrofuran -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 2 : Put (1-(tert-butyl)-3-((2R,4R)-4-((tert-butyldimethylsilyl)oxy)oxy)tetrahydrofuran-2 into the round-bottomed flask. Benzyl-1H-pyrazol-5-yl)carbamate (22 g, 50% purity, 28 mmol), 4-toluenesulfonic acid (14 g, 84 mmol) in ACN (200 mL) and stirring rod. The solution was stirred at 25°C for 2 hours. LCMS is normal. The resulting mixture was concentrated in vacuo. Neutralize the mixture to approximately pH 7. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted three times with EA (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was recrystallized from EA (100 ml) to give (1-(tert-butyl)-3-((2R,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyridine as a white solid Benzyl azol-5-yl)carbamate (8.51 g, 23.7 mmol, 85%). m/z (ES ⁺ ) [M+H] ⁺ =360.35; HPLC tR = 0.760 min. (1-( tert-butyl )-3-((2R,4R)-4-(((4- nitrophenoxy ) carbonyl ) oxy ) tetrahydrofuran -2- yl )-1H- pyrazole -5 -Benzyl carbamate _ _

Step 3 : To (1-(tert-butyl)-3-((2R,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate benzyl at 0°C To a stirred solution of the ester (4.45 g, 12.4 mmol) in DCM (40 mL) were added pyridine (2.94 g, 37.1 mmol) and N,N-lutidine-4-amine (303 mg, 2.48 mmol). To the above reaction was added 4-nitrophenyl chloroformate (3.74 g, 18.6 mmol) under _N2 . The reaction was stirred at 25°C for 4 hours. The resulting mixture was concentrated under vacuum to obtain crude (1-(tert-butyl)-3-((2R,4R)-4-((4-nitrophenoxy)carbonyl) as a light yellow oil) )oxy)tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (6.2 g, 5.9 mmol, 48%, 50% purity). m/z (ES ⁺ ) [M+H] ⁺ =525.30; HPLC tR = 1.020 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H - pyrazole- 3- yl ) tetrahydrofuran -3- yl ester

Step 4 : Put (1-(tert-butyl)-3-((2R,4R)-4-(((4-nitrophenoxy)carbonyl)oxy)tetrahydrofuran-2 into the round-bottom flask -1H-pyrazol-5-yl)carbamic acid benzyl ester (6.2 g, 12 mmol), 1-methylcyclopropan-1-amine hydrochloride (2.5 g, 24 mmol), THF (60 mL), DIEA (6.1 g, 8.2 mL, 47 mmol) and stirring rod. The solution was stirred at 25°C under nitrogen atmosphere for 3 hours. The resulting mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. Concentration in vacuo yielded (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-(((benzyloxy)carbonyl)amino)-1-( tert-Butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (4.6 g, 10 mmol, 85%). m/z (ES ⁺ ) [M+H] ⁺ =457.35; HPLC tR = 0.694 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 5 : (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H- A solution of pyrazol-3-yl)tetrahydrofuran-3-yl ester (9.2 g, 20 mmol) in EA/THF=2:1 (90 mL) was bubbled of nitrogen through the reaction mixture 3 times. Then Pd/C (920 mg) was added. After this time _H2 was bubbled through the reaction mixture 3 times. The mixture was stirred with _H2 at room temperature for 3 h. The mixture was evaporated and (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazole-3 was obtained as a white solid -yl)tetrahydrofuran-3-yl ester (6.4 g, 19 mmol, 94%, 95% purity), which was used directly in the next step without purification. m/z (ES+) [M+H] ⁺ =323.35; HPLC tR = 0.528 min. Example 2 (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H-pyra Azole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester Lithium 3- bromo -1- methyl -1H- pyrazole -5- carboxylate

Step 1. Stir 3-bromo-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (500 mg, 1 Eq, 2.28 mmol) in THF (5 mL) at room temperature under nitrogen atmosphere. LiOH (104 mg, 4.34 mL, 1 molar concentration, 1.9 Eq, 4.34 mmol) in water was added to the solution. The resulting mixture was stirred at 50°C for 0.5 hours. The mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 0% to 10% in 15 min; detector, UV 254 nm, in vacuum Concentration yielded lithium 3-bromo-1-methyl-1H-pyrazole-5-carboxylate (400 mg, 1.9 mmol, 60%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ =207.07; HPLC tR = 0.992 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-(1- methyl -3-(( trifluoromethoxy ) methyl) )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 2. To lithium 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylate (25 mg, 0.12 mmol) and (1-methylcyclopropyl)amine (3R,5R)-5-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl carboxylate (49 mg, 0.15 mmol) in ethyl acetate To a solution in ester (1 mL) was added DIEA (160 mg, 1.2 mmol). To the above reaction was added _T3P (620 mg, 50% Wt in EA, 0.98 mmol) at 0°C. The reaction was stirred at 75°C overnight. The mixture was quenched with water, filtered and extracted with EA (3*20 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 60% gradient in 30 min; detector, UV 254 nm, to obtain a white solid ( 1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl) -1H-pyrazol-5-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (60 mg, 120 μmol, 97%). m/z (ES ⁺ ) [M+H] ⁺ =509.37; HPLC tR = 1.41 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-3-(1- methyl -3-(2-( trifluoromethoxy )) Ethyl )-1H- pyrazole -5- carboxamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 3. Add NiCl ₂ diglyme (1.1 mg, 4.9 µmol), 4,4-di-tert-butyl-2,2-bipyridine (1.3 mg, 4.9 µmol), (4,4'-di-tert-butyl-2,2'-bipyridyl)bis[3,5-difluoro-2-(5-trifluoromethyl-2-pyridyl-kN)phenyl- kC]iridium(III) hexafluorophosphate (1.1 mg, 0.98 µmol) and (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(3-bromo-1-methyl) -1H-pyrazol-5-methamide)-1-(tert-butyl)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (50 mg, 98 µmol). The reaction was capped and purged with nitrogen 3 times, then the solid was dissolved in 1,4-dioxane (1.00 mL). To the solution add all 1-bromo-2-(trifluoromethoxy)ethane (38 mg, 26 µL, 0.20 mmol), tris(trimethylsilyl)silane (24 mg, 30 µL, 1 Eq , 98 µmol) and 2,6-lutidine (32 mg, 34 µL, 3 Eq, 0.29 mmol) while purging with nitrogen. The reactants were then inserted into a Merck photoreactor and reacted at 100% light intensity for 150 minutes. The reaction was filtered through a pad of celite, then concentrated and redissolved in DMSO and placed on the AccQ preparative system. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 60% gradient in 30 min; detector, UV 254 nm, yielding (1-methyl Cyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (4 mg, 7 µmol, 8%) m/z (ES ⁺ ) [M+H] ⁺ =543.48; HPLC tR = 1.47 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1- methyl -3-(2-( trifluoromethoxy ) ethyl )-1H - pyrazole- 5- Formamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 4. To (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy) FA (2 mL) was added to the residue (5 mg, 7 μmol) of (methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester. . The reaction was stirred at 75 °C for 1 h. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 60% gradient in 30 min; detector, UV 254 nm. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)) as a white solid )-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (1.3 mg, 2.7 μmol, 26%, 99.4% purity). m/z (ES ⁺ ) [M+H] ⁺ =487.31; HPLC tR = 1.288 min.

Additional compounds prepared according to the method of Example 2 are shown in Table 2 below. Table 2. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] (1-Methylcyclopropyl)carbamic acid (3S,5S)-5-(3-(1-methyl-3-(2-(trifluoromethoxy)ethyl)-1H-pyrazole- 5-Formamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.51 (s, 1H), 10.81 (s, 1H), 7.52 (s, 1H), 7.05 (s, 1H), 6.54 (s, 1H), 5.19 (d, J = 25.2 Hz, 1H), 5.03 - 4.78 (m, 1H), 4.31 (t, J = 6.5 Hz, 2H), 4.04 (s, 3H), 3.84 (d, J = 5.4 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), 2.70 (dt, J = 14.4, 7.6 Hz, 1H), 1.95 (d, J - 9.8 Hz, 1H), 1.25 (s, 3H), 0.62 (d, J = 5.2 Hz, 2H), 0.48 (q, J = 4.7 Hz, 2H). 487.15 Example 3 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-((S*)-1- methoxyethyl )) pyrazolo [1,5 -a] pyrid - 4- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-( 3-((2-((R*)-1- methoxyethyl ) pyrazolo [1,5-a] pyrazol -4- yl ) amino )-1H- pyrazol - 5 - yl ) Tetrahydrofuran -3- yl ester 4- Chloro -2-(1- methoxyvinyl ) pyrazolo [ 1,5-a] pyrazolo

Step 1. A stirred solution of 4-chloropyrazolo[1,5-a]pyridox-2-carboxylic acid methyl ester (1 g, 1 Eq, 5 mmol) in THF (14 mL) was cooled to 0°C and Treat with Tebbe's Reagent (1 eq, 9.4 mL, 0.5 M in toluene) under _N2 . The reaction was stirred at 0 °C for 30 min. After 30 min, the solution was warmed to room temperature and stirred for 1 h. The mixture was carefully quenched with (0.1 N) NaOH solution at 0°C. The mixture was treated with hexanes and the solids were removed by filtration through a pad of celite. The solids were washed with hexanes and the filtrate was passed through a second pad of celite to remove any newly formed solids. The organic layer was dried over _Na2SO4 and concentrated _under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 53% gradient in 8 min; detector, UV 254 nm, to obtain 4 as a white solid -Chloro-2-(1-methoxyvinyl)pyrazolo[1,5-a]pyrazole (460 mg, 2.19 mmol, 50%). m/z (ES+) [M+H] ⁺ = 210.20; HPLC tR = 0.887 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-((2-(1- methoxyvinyl ) pyrazolo [1 ,5-a] pyridin - 4- yl ) amino )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 2. Add 4-chloro-2-(1-methoxyvinyl)pyrazolo[1,5-a]pyrazolo(100 mg, 1 Eq, 477 μmol) _and (1-methyl cyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (154 mg, To a stirred solution of 1 Eq, 477 μmol) in DMF (3 mL) was added Cs ₂ CO ₃ (466 mg, 3 Eq, 1.43 mmol) and PdCl ₂ (dppf)-CH ₂ Cl ₂ adduct (77.9 mg, 0.2 Eq, 95.4 μmol). The reaction was stirred at 80°C overnight. The mixture was diluted with water, and the aqueous phase was extracted with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm, resulting in colorless (1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-(1-methoxyvinyl)pyridine)) as oil Azolo[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (80 mg, 0.16 mmol, 34%). m/z (ES ⁺ ) [M+H] ⁺ =496.20; HPLC tR = 0.824 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-((2-(1- methoxyethyl ) pyrazolo [1 ,5-a] pyridin - 4- yl ) amino )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 3. Add (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-(1-methoxy)) under _N Vinyl)pyrazolo[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (230 mg, 1 Eq, 464 μmol) in To a stirred solution in THF (5 mL) and ethyl acetate (5 mL) was added Pd/C (49.4 mg, 1 Eq, 464 μmol). The reaction was stirred under H at room temperature for ₁ h. The mixture was filtered and concentrated to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-( 1-Methoxyethyl)pyrazolo[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (160 mg, 322 μmol , 69.3%). m/z (ES ⁺ ) [M+H] ⁺ =498.25; HPLC tR = 0.746 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(5-((2-(1- methoxyethyl )) pyrazolo [1,5-a] pyrazolo - 4 -yl ) amino )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 4. To (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-(1-methoxyethyl)pyridine) FA (5 mL). The reaction was stirred at 80 °C for 1 h. The mixture was concentrated and purified by reversed phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 51% gradient in 8 min; detector, UV 254 nm, yielding a colorless oil (1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazolo) -4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (90 mg, 0.20 mmol, 63%). m/z (ES ⁺ ) [M+H] ⁺ =442.35; HPLC tR = 0.603 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-((S*)-1- methoxyethyl )) pyrazolo [1,5-a ] Pyramide - 4- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3- ((2-((R*)-1- methoxyethyl ) pyrazolo [1,5-a] pyrid - 4 - yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran- 3- yl ester

Step 5. Make (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a] Pyramide-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (90 mg, 1 Eq, 0.20 mmol) was subjected to preparative HPLC (column: CHIRALPAK IG, 2 *25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min; gradient: 13 min 50% B to 50% B; Wavelength: 220/254 nm; RT1(min): 6.04; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.8 mL; Number of runs: 3). Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-((2-((S*)-1-methoxyethyl)pyrazole) as a white solid) And[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (28.9 mg, 64.7 μmol, 64%, 98.9% purity). m/z (ES ⁺ ) [M+H] ⁺ =442.15; HPLC tR = 1.377 min. 1H NMR (400 MHz, DMSO-d6) 12.36 (s, 1H), 10.00 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.41-7.23 (m, 2H), 6.79 (s , 1H), 5.17 (s, 1H), 4.84 (s, 1H), 4.55 (q, J = 6.5 Hz, 1H), 3.85 (s, 2H), 3.22 (s, 3H), 2.68 (s, 1H) , 1.93 (d, J = 15.3 Hz, 1H), 1.47 (d, J = 6.5 Hz, 3H), 1.25 (s, 3H), 0.61 (s, 2H), 0.48 (q, J = 4.6 Hz, 2H) .

(1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-((2-(1-methoxyethyl)pyrazolo[1,5-a]pyrazolo)- 4-yl)Amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (90 mg, 1 Eq, 0.20 mmol) was subjected to preparative HPLC (column: CHIRALPAK IG, 2*25 cm , 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH: DCM=1: 1--HPLC; flow rate: 20 mL/min; gradient: 50% within 13 minutes B to 50% B; Wavelength: 220/254 nm; RT2(min): 9.67; Sample solvent: EtOH: DCM=1: 1--HPLC; Injection volume: 0.8 mL; Number of runs: 3). Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-((2-((R*)-1-methoxyethyl)) as a white amorphous solid) Pyrazolo[1,5-a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (31.1 mg, 63.1 μmol, 62%, 89.6% purity) . m/z (ES ⁺ ) [M+H] ⁺ =442.15; HPLC tR = 1.377 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.36 (s, 1H), 10.18 (d, J = 131.9 Hz, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.42-7.17 (m , 2H), 6.79 (s, 1H), 5.17 (s, 1H), 4.84 (s, 1H), 4.55 (q, J = 6.5 Hz, 1H), 3.85 (s, 2H), 3.22 (s, 3H) , 2.71 (s, 1H), 1.96 (s, 1H), 1.47 (d, J = 6.5 Hz, 3H), 1.25 (s, 3H), 0.60 (d, J = 5.1 Hz, 2H), 0.48 (q, J = 4.5 Hz, 2H). Example 4 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-( trifluoromethyl ) imidazo [1,2-c] pyrimidin -5- yl ) Amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5S)-5-(3-((2-( trifluoromethyl yl ) imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester 7- Chloro -5-( methylthio )-2-( trifluoromethyl ) imidazo [1,2-c] pyrimidine

Step 1. Put 6-chloro-2-(methylthio)pyrimidin-4-amine (5 g, 1 Eq, 0.03 mol) and DMF (20 mL) into a round-bottomed flask, and add 3-chloro-1, 1,1-trifluoropropan-2-one (6 g, 1.5 Eq, 0.04 mol), and the solution was stirred at 120°C for 16 hours. The residue was concentrated in vacuo and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase (acetonitrile/water), gradient 0% to 100% in 45 min; detector, UV 254 nm. Concentration in vacuo yielded 7-chloro-5-(methylthio)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (3.4 g, 13 mmol, 40%) as a yellow amorphous solid ). m/z (ES ⁺ ) [M+H] ⁺ = 267.85; HPLC tR = 0.875 min. 7- Chloro -2-( trifluoromethyl ) imidazo [1,2-c] pyrimidin -5- ol

Step 2. Charge 7-chloro-5-(methylthio)-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (3.4 g, 1 Eq, 13 mmol) into the round-bottomed flask. , MeOH:H ₂ O=2:1 (20 mL), LiOH (1.2 g, 4 Eq, 51 mmol) was added, and the solution was stirred at 25°C for 3 hours. The pH of the reaction mixture was adjusted to 7-8 using 1 N HCl solution. The residue was concentrated in vacuo and diluted with water (15 mL), and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave 7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-ol (2.9 g, 12 mmol, 96%) as a brown amorphous solid. m/z (ES ⁺ ) [M+H] ⁺ = 237.90; HPLC tR = 0.700 min. 5,7- Dichloro -2-( trifluoromethyl ) imidazo [1,2-c] pyrimidine

Step 3. Charge 7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidin-5-ol (1 g, 1 Eq, 4 mmol), POCl ₃ ( 15 mL), DIEA (3 g, 4 mL, 5 Eq, 0.02 mol) was added, and the solution was stirred at 80°C for 3 hours. The solution was concentrated in vacuo and quenched with _NaHCO3 solution (0°C) and the pH was adjusted to 7-8 with _NaHCO3 . The aqueous phase was extracted three times with EA (40 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave 5,7-dichloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (840 mg, 3.28 mmol, 80%) as a brown oil. m/z (ES ⁺ ) [M+H] ⁺ = 255.90; HPLC tR = 0.842 min. 5- bromo -7- chloro -2-( trifluoromethyl ) imidazo [1,2-c] pyrimidine

Step 4. Charge 5,7-dichloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (700 mg, 1 Eq, 2.73 mmol) and ACN (10 mL) into the round-bottomed flask. ), TMSBr (837 mg, 2 Eq, 5.47 mmol) was added, and the solution was stirred at 40°C for 3 hours. The crude product was purified by silica gel chromatography (10 g column; elution with PE/EA (ratio: 15/1)). Concentration in vacuo gave 5-bromo-7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (720 mg, 2.40 mmol, 87.6%) as a brown amorphous solid. m/z (ES ⁺ ) [M+H] ⁺ = 299.80; HPLC tR = 0.867 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-((7- chloro -2-( trifluoromethyl ) imidazo [1 ,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 5. Fill the resealable reaction vial with 5-bromo-7-chloro-2-(trifluoromethyl)imidazo[1,2-c]pyrimidine (550 mg, 1 Eq, 1.83 mmol), DMF (5 mL), (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran -3-yl ester (885 mg, 1.5 Eq, 2.75 mmol), potassium carbonate (1.01 g, 4 Eq, 7.32 mmol), and PdCl ₂ (dppf) (201 mg, 0.15 Eq, 275 μmol) was added. The resulting mixture was stirred at 80°C under nitrogen atmosphere for 2.5 hours. The residue was concentrated in vacuo and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase (acetonitrile/water), gradient 0% to 100% in 45 min; detector, UV 254 nm. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((7-chloro-2-()) as a yellow amorphous solid Trifluoromethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (295 mg, 0.33 mmol, 18%, 60 % purity). m/z (ES ⁺ ) [M+H] ⁺ = 542.05; HPLC tR = 0.900 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-( trifluoromethyl ) imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5S)-5-(3-((2-( trifluoromethyl )) Imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 6. Charge (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-(trifluoromethyl)) into a round-bottomed flask. yl)imidazo[1,2c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (140 mg, 1 Eq, 276 μmol), add FA (6 mL ), and the solution was stirred at 100°C for 16 hours. The residue was concentrated in vacuo and analyzed by preparative HPLC (column: Xselect CSH C18 OBD column 30*150mm 5 μm, n; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL/min; Gradient: 32% B to 44% B, 44% B in 8 minutes; Wavelength: 254; 220 nm; RT1(min): 6.5, 7.48(min)) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-((2-(trifluoromethyl)imidazo[1,2-c)) as a gray-white amorphous solid ]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (1.9 mg, 4.2 μmol, 1.5%, m/z (ES ⁺ ) [M+H] ⁺ = 452.15; HPLC tR = 1.178 min) and (1-methylcyclopropyl)carbamic acid (3R,5S)-5-(3-((2-(trifluoromethyl)imidazo) as a white amorphous solid [1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (2 mg, 4 μmol, 2%, m/z (ES ⁺ ) [ M+H] ⁺ = 452.15; HPLC tR = 1.258 min). Example 5 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1- methyl- 3-( trifluoromethoxy )-1H- pyrazole -5- carboxylic acid) Amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(3-( chlorodifluoromethyl) Oxy )-1- methyl -1H- pyrazole -5- carboxamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester 3-( Bromodifluoromethoxy )-1- methyl -1H- pyrazole -5- carboxylic acid methyl ester 3-( chlorodifluoromethoxy )-1- methyl -1H- pyrazole - 5- carboxylic acid Methyl ester

Step 1. Add a mixture of 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (400 mg, 2.56 mmol) and dihexane (5 mL) in a nitrogen atmosphere at 25°C. Add NaH (0.18 g, 7.69 mmol). The mixture was stirred at 25°C for 30 min, then 2-bromo-2,2-difluoroacetic acid sodium salt (608 mg, 3.07 mmol) was added. The mixture was stirred at 25 °C for 30 h. Filter out the solids. The filtrate was concentrated in vacuo. HCl in dihexane (5 mL) was added and concentrated in vacuo. DCM (5 mL) and XeF ₂ (1.31 g, 7.69 mmol) were added, and the mixture was stirred at 25 °C for 30 min. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo yielded 3-(bromodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester and 3-(chlorodifluoromethoxy)-1 as yellow oils -Mixture of methyl-1H-pyrazole-5-carboxylate (180 mg, 26.8%).

3-(Bromodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 224.95; HPLC tR = 0.875 min.

3-(Chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 240.90; HPLC tR = 0.875 min. 1- Methyl -3-( trifluoromethoxy )-1H- pyrazole -5- carboxylic acid 3-( chlorodifluoromethoxy )-1- methyl -1H- pyrazole - 5- carboxylic acid

Step 2. Charge 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid methyl ester and 3-(chlorodifluoromethoxy)-1 into a resealable reaction vial. - A mixture of methyl-1H-pyrazole-5-carboxylate (160 mg, 0.70 mmol), NaOH (0.86 mL, 0.86 mmol), MeOH (5 mL) and stir bar, then evacuated and purged with nitrogen three times , and the mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with H ₂ O (20 mL), and the aqueous phase was extracted three times with EA (20 mL), then adjusted to pH 1~3 with 1 M HCl, and the aqueous phase was extracted three times with EA (30 mL) . The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuum yields 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid and 3-(chlorodifluoromethoxy)-1-methyl as colorless oils -Mixture of 1H-pyrazole-5-carboxylic acid (120 mg, 80%).

1-Methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid: m/z (ES ⁺ ) [M+H] ⁺ = 210.95; HPLC tR = 0.750 min.

3-(Chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid: m/z (ES ⁺ ) [M+H] ⁺ = 226.90; HPLC tR = 0.750 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-(1- methyl -3-( trifluoromethoxy )-1H- Pyrazole -5- methamide )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-(3-( chlorodifluoromethoxy )-1- methyl -1H- pyrazole -5- methamide )-1H- pyrazole -3- yl ) tetrahydrofuran -3 -Basic ester

Step 3. Add 1-methyl-3-(trifluoromethoxy)-1H-pyrazole-5-carboxylic acid and 3-(chlorodifluoromethoxy)-1-methyl at 0°C under nitrogen atmosphere. 1H-pyrazole-5-carboxylic acid (109 mg, 0.50 mmol), DIEA (0.41 g, 0.55 mL, 3.1 mmol) and (1-methylcyclopropyl)carbamic acid (3R,5R)-5- To a mixture of (5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (0.10 g, 0.31 mmol) in EA (5 mL) was added dropwise _T3P (1.60 g, 50% wt, 2.5 mmol in EA). The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo yielded (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3) as a yellow oil) -(Trifluoromethoxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester and (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-methamide)- A mixture of 1H-pyrazol-3-yl)tetrahydrofuran-3-yl esters (300 mg, crude).

(1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-(trifluoromethoxy)-1H- Pyrazole-5-methamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester: m/z (ES ⁺ ) [M+H] ⁺ =515.15; HPLC tR = 1.158 min.

(1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H -pyrazole-5-methamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester: m/z (ES ⁺ ) [M+H] ⁺ = 531.10; HPLC tR = 1.178 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1- methyl -3-( trifluoromethoxy )-1H- pyrazole -5- methamide) )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(3-( chlorodifluoromethoxy) )-1- Methyl -1H- pyrazole -5- carboxamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 4. Charge the resealable reaction vial with (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl- 3-(Trifluoromethoxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester and (1-methylcyclopropyl)amine Formic acid (3R,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-methamide) A mixture of -1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (190 mg, crude product), FA (5 mL) and stirring rod were then evacuated and purged with nitrogen three times, and the mixture was heated at 70°C Stir for 1.5 h. The reaction was concentrated in vacuo. The obtained crude material was analyzed by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; Flow: 60 mL/min; Gradient: 25% B to 55% B, 55% B in 7 minutes; Wavelength: 220 nm; RT1(min): 7.27) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(trifluoromethoxy)-1H-) as a white amorphous solid Pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (38.6 mg, 22.8%). m/z (ES ⁺ ) [M+H] ⁺ =459.15; HPLC tR = 1.318 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 7.52 (s, 1H), 7.12 (s, 1H), 6.54 (s, 1H), 5.16 (s, 1H), 4.84 (t , J = 7.9 Hz, 1H), 4.06 (s, 3H), 3.84 (d, J = 4.6 Hz, 2H), 2.70 (dt, J = 14.4, 7.5 Hz, 1H), 1.93 (t, J = 10.3 Hz , 1H), 1.25 (s, 3H), 0.61 (d, J = 5.1 Hz, 2H), 0.48 (q, J = 4.6 Hz, 2H).

Charge the resealable reaction vial with (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3-( Trifluoromethoxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester and (1-methylcyclopropyl)carbamic acid (3R ,5R)-5-(1-(tert-butyl)-5-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H- A mixture of pyrazol-3-yl)tetrahydrofuran-3-yl ester (190 mg, crude product), FA (5 mL) and stirring rod were then evacuated and purged with nitrogen three times, and the mixture was stirred at 70°C for 1.5 h. . The reaction was concentrated in vacuo. The obtained crude material was analyzed by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; Flow: 60 mL/min; Gradient: 25% B to 55% B, 55% B in 7 minutes; Wavelength: 220 nm; RT1(min): 7.27) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(3-(chlorodifluoromethoxy)-1-methyl-1H) as a white amorphous solid -pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (50 mg, crude). The obtained crude material was analyzed by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: MeOH- -HPLC; Flow: 60 mL/min; Gradient: 49% B to 67% B, 67% B in 8 min; Wavelength: 254 nm; RT1(min): 7.85) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(3-(chlorodifluoromethoxy)-1-methyl-1H) as a white amorphous solid -Pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (9.3 mg, 21%). m/z (ES ⁺ ) [M+H] ⁺ =475.15; HPLC tR = 0.876 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 11.03 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.56 (s, 1H), 5.16 (s , 1H), 4.85 (s, 1H), 4.07 (s, 3H), 3.85 (s, 2H), 2.70 (dt, J = 14.0, 7.2 Hz, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.48 (s, 2H).

Additional compounds prepared according to the method of Example 5 are shown in Table 3 below. Table 3. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] (1-Methylcyclopropyl)carbamic acid (3S,5S)-5-(3-(3-(chlorodifluoromethoxy)-1-methyl-1H-pyrazole-5-methamide (yl)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.57 (s, 1H), 11.02 (s, 1H), 7.51 (s, 1H), 7.17 (s, 1H), 6.57 (s, 1H), 5.16 (s, 1H) , 4.93 (d, J = 57.3 Hz, 1H), 4.07 (s, 3H), 3.85 (s, 2H), 2.71 (dd, J = 14.1, 7.3 Hz, 1H), 1.93 (s, 1H), 1.25 ( s, 3H), 0.62 (s, 2H), 0.48 (q, J = 5.0, 4.6 Hz, 2H). 475.25 Example 6 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1- methyl- 3-((S*))-2,2,2- trifluoro -1- Methoxyethyl )-1H- pyrazole -5- methamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R, 5R)-5-(3-(1- methyl- 3-((R*)-2,2,2- trifluoro -1- methoxyethyl )-1H- pyrazole -5- methamide (yl )-1H- pyrazol -5- yl ) tetrahydrofuran -3-yl ester 1- Methyl -3-(2,2,2- trifluoro -1- hydroxyethyl )-1H- pyrazole -5- carboxylic acid methyl ester

Step 1. Charge 3-formyl-1-methyl-1H-pyrazole-5-carboxylic acid methyl ester (500 mg, 2.97 mmol), trimethyl (trifluoromethyl) into a resealable reaction vial. Silane (719 mg, 5.06 mmol), TBAF (155 mg, 0.60 mmol), THF (5 mL) and stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 25°C for 3 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. Concentration in vacuo yielded 1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole-5-carboxylic acid methyl ester as a colorless oil (400 mg, crude ). m/z (ES ⁺ ) [M+H] ⁺ = 239.20; HPLC tR = 0.720 min. 1- Methyl -3-(2,2,2- trifluoro -1- methoxyethyl )-1H- pyrazole -5- carboxylic acid methyl ester

Step 2. To 1-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-pyrazole-5-carboxylic acid methyl ester (390 mg, To a mixture of 1.64 mmol) in DMF (5 mL) was added NaH (0.12 g, 4.91 mmol) portionwise. The mixture was stirred at 0°C for 5 min, then methyl iodide (697 mg, 4.91 mmol) was added. The mixture was stirred at 25 °C for 1 h. The reaction solution was used directly in the next step. m/z (ES ⁺ ) [M+H] ⁺ = 253.00; HPLC tR = 0.788 min. 1- Methyl -3-(2,2,2- trifluoro -1- methoxyethyl )-1H- pyrazole -5- carboxylic acid

Step 3. Add NaOH (3.27 mL, 3.27 mmol) to the above reaction solution and stir at 25°C for 1 h. The reaction mixture was diluted with H ₂ O (20 mL), and the aqueous phase was extracted three times with EA (30 mL), then adjusted to pH 1~3 with 1 M HCl, and the aqueous phase was extracted three times with EA (30 mL) . The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo gave 1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxylic acid (180 mg, 46.2 %). m/z (ES ⁺ ) [M+H] ⁺ = 239.20; HPLC tR = 0.720 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert -butyl )-5-(1- methyl -3-(2,2,2- trifluoro- 1- methoxyethyl )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 4. Add 1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl)-1H-pyrazole-5-carboxylic acid (160 mg, 0.67 mmol), DIEA (722 mg, 5.58 mmol) and (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H- To a mixture of pyrazol-3-yl)tetrahydrofuran-3-yl ester (180 mg, 0.56 mmol) in EA (5 mL) was added T ₃ P (6.39 g, 10.00 mmol) dropwise. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with _H2O (30 mL), and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo yielded (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl-3) as a yellow oil) -(2,2,2-Trifluoro-1-methoxyethyl)-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (400 mg, crude product). m/z (ES ⁺ ) [M+H] ⁺ = 543.45; HPLC tR = 0.945 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1- methyl -3-(2,2,2- trifluoro -1- methoxyethyl )- 1H- pyrazole -5- methamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 5. Charge the resealable reaction vial with (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-methyl- 3-(2,2,2-Trifluoro-1-methoxyethyl)-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester ( 380 mg, 0.70 mmol), FA (5 mL) and stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 75°C for 2 h. The reaction was concentrated in vacuo. The obtained crude material was analyzed by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; Flow: 60 mL/min; Gradient: 26% B to 44% B, 44% B in 8 minutes; Wavelength: 220 nm; RT1(min): 7.35) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1- Methoxyethyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (190 mg, 55.8%). m/z (ES ⁺ ) [M+H] ⁺ = 487.30; HPLC tR = 0.820 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1- methyl -3-((S*))-2,2,2- trifluoro -1- methoxy Ethyl )-1H- pyrazole -5- carboxamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5R) -5-(3-(1- methyl- 3-((R*)-2,2,2- trifluoro -1- methoxyethyl )-1H- pyrazole -5- methamide ) -1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 6. Combine (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1-methoxy) Ethyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (189 mg, 0.39 mmol) was analyzed by preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min ; Gradient: 40% B to 40% B in 10 min; Wavelength: 220/254 nm; RT1(min): 5.27; RT2(min): 7.46; Sample solvent: EtOH: DCM=1:1-HPLC; Injection volume :0.45 mL; number of runs: 5) Purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((S*)-2,2,)) as an amorphous white solid. 2-Trifluoro-1-methoxyethyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (47.5 mg, 50.3%). m/z (ES ⁺ ) [M+H] ⁺ =487.20; HPLC tR = 0.948 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.94 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 6.56 (s, 1H), 5.16 (s , 1H), 5.03 (q, J = 6.9 Hz, 1H), 4.85 (s, 1H), 4.11 (s, 3H), 3.85 (s, 2H), 3.35 (s, 3H), 2.71 (dd, J = 14.3, 7.5 Hz, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.48 (q, J = 5.1, 4.7 Hz, 2H).

(1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoro-1-methoxyethyl) -1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (189 mg, 0.39 mmol) was analyzed by palm preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min; gradient: 40% B to 40% B in 10 minutes; Wavelength: 220/254 nm; RT1(min): 5.27; RT2(min): 7.46; Sample solvent: EtOH: DCM=1:1-HPLC; Injection volume: 0.45 mL ;Number of runs: 5) Purification. Lyophilization gave (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((R*)-2,2, 2-Trifluoro-1-methoxyethyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (38.6 mg, 40.8%). m/z (ES ⁺ ) [M+H] ⁺ = 487.20; HPLC tR = 0.948 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.50 (s, 1H), 10.94 (s, 1H), 7.50 (s, 1H), 7.30 (s, 1H), 6.56 (s, 1H), 5.16 (s , 1H), 5.03 (q, J = 7.0 Hz, 1H), 4.85 (s, 1H), 4.11 (s, 3H), 3.85 (s, 2H), 3.35 (s, 3H), 2.71 (dd, J = 14.4, 7.4 Hz, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.55 (d, J = 13.0 Hz, 1H), 0.48 (q, J = 5.1, 4.7 Hz, 2H). Example 7 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(3-( methoxymethyl )-1-( trifluoromethyl )-1H - pyrazole- 5- Formamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester 3-( Chloromethyl )-1H- pyrazole -5- carboxylic acid ethyl ester

Step 1. Place 3-(hydroxymethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (2.00 g, 0.01 mol), SOCl ₂ (20 mL) and stirring rod into a resealable reaction vial, and then evacuate The mixture was purged three times with nitrogen, and the mixture was stirred at 80 °C for 2 h. The reaction was concentrated in vacuo. The residue was diluted with water, and then adjusted to pH 6~7 with sodium bicarbonate. The aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Concentration in vacuo gave 3-(chloromethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (2.20 g, crude) as a colorless oil. m/z (ES ⁺ ) [M+H] ⁺ = 189.20; HPLC tR = 0.645 min. 3-( methoxymethyl )-1H- pyrazole -5- carboxylic acid ethyl ester

Step 2. To a mixture of 3-(chloromethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (2.20 g, 12.00 mmol) in MeOH (20 mL) was added portionwise at 0°C under nitrogen atmosphere. NaOMe (0.82 g, 15.00 mmol). The mixture was stirred at 25 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. Concentration in vacuo gave 3-(methoxymethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (1.60 g, 74%) as a colorless oil. m/z (ES ⁺ ) [M+H] ⁺ = 185.05; HPLC tR = 0.633 min. 3-( methoxymethyl )-1-( trifluoromethyl )-1H- pyrazole -5- carboxylic acid ethyl ester

Step 3. To SiO ₂ -OH (34 mg, 0.42 mmol) was added dropwise ClSO ₃ H (49 mg, 0.42 mmol) at 25°C under nitrogen atmosphere. The mixture was stirred at 25 °C for 2 h. Add 3-(methoxymethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (600 mg, 3.26 mmol), HDMS (10 mL) and a stir bar to a resealable reaction vial, then evacuate and use Nitrogen was purged three times, and the mixture was stirred at 125 °C for 2 h. Strain out the solids. The filtrate was concentrated in vacuo. Add DCM (10 mL) followed by 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-1l3-benzo[d][1,2]iodooxolane (iodaoxole) (1.40 g, 4.20 mmol), LiNTf ₂ (0.15 g, 0.51 mmol) and HNTf ₂ (0.14 g, 0.51 mmol), then evacuated and purged with nitrogen three times, and the mixture was stirred at 40°C for 16 h. . The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm. Concentration in vacuo gave ethyl 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylate as a colorless oil (140 mg, crude). m/z (ES ⁺ ) [M+H] ⁺ = 253.005; HPLC tR = 0.867 min. 3-( methoxymethyl )-1-( trifluoromethyl )-1H- pyrazole -5- carboxylic acid

Step 4. Charge 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid ethyl ester (180 mg, 0.21 mmol) and NaOH into a resealable reaction vial. (428 µL, 428 µmol), MeOH (5 mL) and stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with _H2O (20 mL), and the aqueous phase was extracted three times with EA (20 mL), followed by adjusting to pH 1~3 with 1 M HCl. The aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo gave 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (50 mg, crude) as a colorless oil. m/z (ES ⁺ ) [M+H] ⁺ = 225.05; HPLC tR = 0.567 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-(3-( methoxymethyl )-1-( trifluoromethyl) )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 5. Add 3-(methoxymethyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid (119 mg, 0.53 mmol), DIEA (625 mg, 4.84 mmol) and (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl) To a mixture of tetrahydrofuran-3-yl ester (156 mg, 0.48 mmol) in EA (5 mL) was added _T3P (4.92 g, 50% wt, 3.87 mmol in EA) dropwise. The mixture was stirred at 80 °C for 12 h. The reaction mixture was diluted with _H2O (20 mL), and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo yielded (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(3-(methoxy)) as a yellow oil. Methyl)-1-(trifluoromethyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (200 mg, 78.2%). m/z (ES ⁺ ) [M+H] ⁺ = 529.10; HPLC tR = 0.850 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(3-( methoxymethyl )-1-( trifluoromethyl )-1H- pyrazole -5- Formamide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 6. Charge the resealable reaction vial with (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(3-(methoxy (Methyl)-1-(trifluoromethyl)-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (250 mg, 0.47 mmol), FA (5 mL) and stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 70 °C for 3 h. The reaction was concentrated in vacuo. The obtained crude material was analyzed by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; Flow: 60 mL/min; Gradient: 20% B to 45% B, 45% B in 7 minutes; Wavelength: 220 nm; RT1(min): 7.63) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(3-(methoxymethyl)-1-(trifluoromethyl)-) as an off-white solid 1H-pyrazol-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (86.8 mg, 38.8%). m/z (ES ⁺ ) [M+H] ⁺ = 473.15; HPLC tR = 0.903 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 11.36 (s, 1H), 7.52 (s, 1H), 7.17 (s, 1H), 6.55 (s, 1H), 5.16 (s , 1H), 4.85 (s, 1H), 4.47 (s, 2H), 3.85 (s, 2H), 3.33 (s, 3H), 2.74 - 2.66 (m, 1H), 1.92 (s, 1H), 1.24 ( s, 3H), 0.67 - 0.43 (m, 4H). Example 8 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1-(2-( trifluoromethoxy ) ethyl )-1H- pyrazole -4- methyl amide )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester 1-(2-( Trifluoromethoxy ) ethyl )-1H- pyrazole -4- carboxylic acid methyl ester

Step 1. To a mixture of 1H-pyrazole-4-carboxylic acid methyl ester (110 mg, 0.87 mmol) in DMF (5 mL) was added 1-bromo-2-(trifluoromethoxy)ethane (252 mg , 1.31 mmol) and K ₂ CO ₃ (362 mg, 2.62 mmol). The mixture was stirred at 50°C for 1 hour. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. Concentration in vacuo gave 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid methyl ester (170 mg, 81.8%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 238.95; HPLC tR = 0.742 min. 1-(2-( trifluoromethoxy ) ethyl )-1H- pyrazole -4- carboxylic acid

Step 2. Charge 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid methyl ester (160 mg, 0.67 mmol) and NaOH (54 mg) into a resealable reaction vial. , 1.34 mmol), MeOH (4 mL) and a stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). Adjust the pH value of the aqueous layer to 1~3 with 1 M HCl. The aqueous layer was extracted with 3×30 mL ethyl acetate. The organic layers were combined, washed with brine and dried. Concentration in vacuo gave 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (100 mg, 66.4%) as a white solid. m/z (ES ⁺ ) [M+H] ⁺ = 224.95; HPLC tR = 0.458 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-(1-(2-( trifluoromethoxy ) ethyl )-1H -pyrazole -4- methamide )-1H- pyrazol - 3- yl ) tetrahydrofuran -3- yl ester

Step 3. 1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid (91 mg, 0.41 mmol) in EA (5 mL) at 0 °C under nitrogen atmosphere Add (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)tetrahydrofuran- 3-yl ester (110 mg, 0.34 mmol) and DIEA (441 mg, 3.41 mmol), followed by dropwise addition of _T3P (2.6 g, 50 wt, 2.04 mmol in EA). The mixture was stirred at 80 °C for 2.5 h. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. Concentration in vacuo yielded (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-(2-(trifluoro)) as a white solid Methoxy)ethyl)-1H-pyrazole-4-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (150 mg, 83.2%). m/z (ES ⁺ ) [M+H] ⁺ = 529.15; HPLC tR = 0.783 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-(1-(2-( trifluoromethoxy ) ethyl )-1H - pyrazole -4- carboxamide (yl )-1H- pyrazol -5- yl ) tetrahydrofuran -3-yl ester

Step 4. Charge the resealable reaction vial with (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-(1-(2- (Trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxamide)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (145 mg, 0.27 mmol), FA (6 mL) and stir bar, then evacuated and purged with nitrogen three times, and the mixture was stirred at 75°C for 1.5 hours. The reaction was concentrated in vacuo. The obtained crude material was analyzed by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.1% NH ₃ .H ₂ O), mobile phase B: ACN; flow rate: 60 mL/min; gradient: 20% B to 40% B, 40% B in 8 minutes; wavelength: 254 nm; RT1 (min): 7.57) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(1-(2-(trifluoromethoxy)ethyl)-1H) as a white amorphous solid -pyrazole-4-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (72.1 mg, 55.6%). m/z (ES ⁺ ) [M+H] ⁺ = 473.35; HPLC tR = 0.687 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.39 (s, 1H), 10.49 (s, 1H), 8.41 (s, 1H), 8.13 (s, 1H), 7.53 (s, 1H), 6.54 (s , 1H), 5.16 (s, 1H), 4.81 (s, 1H), 4.51 - 4.44 (m, 4H), 3.84 (s, 2H), 2.75 (s, 1H), 1.91 (s, 1H), 1.25 ( s, 3H), 0.61 (s, 2H), 0.48 (s, 2H).

Additional compounds prepared according to the method of Example 8 are shown in Table 4 below. Table 4. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] (1-Methylcyclopropyl)carbamic acid ((3S,5S)-5-(3-(1-(2-(trifluoromethoxy)ethyl)-1H-pyrazole-4-carboxylic acid) Amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.39 (s, 1H), 10.49 (s, 1H), 8.41 (s, 1H), 8.14 (s, 1H), 7.53 (s, 1H), 6.54 (s, 1H) , 5.16 (s, 1H), 4.83 (t, J = 7.6 Hz, 1H), 4.54 - 4.43 (m, 4H), 3.84 (s, 2H), 2.70 (dt, J = 14.2, 7.3 Hz, 1H), 1.91 (s, 1H), 1.25 (s, 3H), 0.61 (s, 2H), 0.48 (q, J = 4.5 Hz, 2H). 473.20 Example 9 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-(( trifluoromethoxy ) methyl ) pyrazolo [1,5-a] Pyramide -4- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester 4- Bromo - 2-( bromomethyl ) pyrazolo [1,5-a] pyrazolo

Step 1. Add (4-chloropyrazolo[1,5-a]pyridin-2-yl)methanol (2 g, 1 Eq, 0.01 mol) to MeCN (20 mL) at 0°C under nitrogen atmosphere. Add PBr3 (4 g, 2 mL, 1.5Eq, 0.02 mol) to the stirring solution. The resulting mixture was stirred at 70°C for 1 hour. The mixture was adjusted to pH=7 and extracted with EtOAc (3×40 mL). The combined organic layers were washed with brine (1×40 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 4-bromo-2-(bromomethyl)pyrazolo[1,5-a]pyrazole (1.5 g, 5.2 mmol, 50%) as a yellow solid. . m/z (ES ⁺ ) [M+H] ⁺ = 290.80; HPLC tR = 0.850 min. 4- Bromo - 2-(( trifluoromethoxy ) methyl ) pyrazolo [1,5-a] pyrazolo

Step 2. To a stirred solution of silver fluoride (2.0 g, 0.34 mL, 3 Eq, 15 mmol) in MeCN (30 mL) was added trifluoromethanesulfonate under nitrogen atmosphere at -30°C. (4.5 g, 4 Eq, 21mmol). The mixture was stirred at -30 °C for 1 h. Next, 4-bromo-2-(bromomethyl)pyrazolo[1,5-a]pyrazamide (1.5 g, 1 Eq, 5.2 mmol) was added. The resulting mixture was stirred at 25°C for 16 hours. The resulting mixture was filtered. The residue was purified by silica gel chromatography using the following conditions: EtOAc in PE, gradient from 0% to 25% in 20 min to obtain 4-bromo-2-((trifluoromethoxy)) as a yellow oil Methyl)pyrazolo[1,5-a]pyrazamide (600 mg, 2.03 mmol, 39%). m/z (ES ⁺ ) [M+H] ⁺ = 295.80; HPLC tR = 0.848 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-((2-(( trifluoromethoxy ) methyl ) pyrazolo ) [1,5-a] pyrid -4- yl ) amino )-1H- pyrazol - 3- yl ) tetrahydrofuran -3- yl ester

Step 3. Add (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyridine to (1-methylcyclopropyl)carbamate at room temperature under nitrogen atmosphere. To a stirred solution of oxazol-3-yl)tetrahydrofuran-3-yl ester (327 mg, 1Eq, 1.01 mmol) in 1,4-dihexane (3 mL) was added 4-bromo-2-((trifluoromethyl) Oxy)methyl)pyrazolo[1,5-a]pyrazole (300 mg, 1 Eq, 1.01mmol), K ₂ CO ₃ (420 mg, 3 Eq, 3.04 mmol), xantphos (235 mg, 0.4 Eq, 405 μmol), Pd ₂ (dba) ₃ (186 mg, 0.2 Eq, 203 μmol). The resulting mixture was stirred at 60°C for 1 hour. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 90% in 15 min; detector, UV 254 nm. Concentration in vacuum yielded (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-((tert-butyl))-5-((2-((tributyl))) as a yellow oil) Fluoromethoxy)methyl)pyrazolo[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (160 mg, 298 μmol , 29.4%). m/z (ES ⁺ ) [M+H] ⁺ = 538.15; HPLC tR = 0.888 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-(( trifluoromethoxy ) methyl ) pyrazolo [1,5-a] pyrazolo ) -4- yl ) amino )-1H- pyrazol - 5- yl ) tetrahydrofuran -3- yl ester

Step 4. To (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-((trifluoromethoxy)methyl) FA was added to )pyrazolo[1,5-a]pyridin-4-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (150 mg, 1 Eq, 279 μmol) (3 mL). The reaction was stirred at 70°C for 1 hour. The mixture was concentrated and analyzed by preparative HPLC (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL/min; Gradient: 18% B to 40% B in 8 minutes, 40% B; Wavelength: 254 nm; RT1(min): 6.65) purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-((2-((trifluoromethoxy)methyl)pyrazolo[1)) as a white solid ,5-a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (12.5 mg, 26.0 μmol, 9.30%). m/z (ES ⁺ ) [M+H] ⁺ = 482.20; HPLC tR = 0.696 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.39 (s, 1H), 10.16 (s, 1H), 8.10 (s, 1H), 7.58-7.21 (m, 3H), 6.80 (s, 1H), 5.35 (s, 2H), 5.17 (s, 1H), 4.92 (d, J = 49.7 Hz, 1H), 3.86 (s, 2H), 2.73 (dd, J = 14.7, 7.2 Hz, 1H), 1.96 (d, J = 11.2 Hz, 1H), 1.25 (s, 3H), 0.60 (d, J = 5.3 Hz, 2H), 0.48 (q, J = 4.5 Hz, 2H).

Additional compounds prepared according to the method of Example 9 are shown in Table 5 below. Table 5. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] (1-Methylcyclopropyl)carbamic acid (3S,5S)-5-(3-((2-((trifluoromethoxy)methyl)pyrazolo[1,5-a]pyrazolo) -4-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.40 (s, 1H), 10.21 (s, 1H), 8.11 (d, J = 4.7 Hz, 1H), 7.59-7.39 (m, 3H), 6.77 (s, 1H) , 5.35 (s, 2H), 5.17 (s, 1H), 4.84 (s, 1H), 3.85 (d, J = 6.3 Hz, 2H), 2.72 (dd, J = 14.3, 7.7 Hz, 1H), 1.97 ( d, J = 12.7 Hz, 1H), 1.25 (s, 3H), 0.60 (d, J = 5.2 Hz, 2H), 0.48 (q, J = 5.0, 4.5 Hz, 2H). 482.20 Example 10 (1- methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-( methoxymethyl ) imidazo [1,2-c] pyrimidin -5- yl) ) Amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester (1- methylcyclopropyl ) carbamic acid (3R,5S)-5-(3-((2-( methoxy methyl ) imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester 7- Chloro -5- hydroxyimidazo [1,2-c] pyrimidine -2- carboxylic acid ethyl ester

Step 1. Charge 2,6-dichloropyrimidin-4-amine (3 g, 0.02 mol), ethyl 3-bromo-2-oxypropionate (9 g, 0.05 mol) and Stirring stick. AcOH (32 mL) was added and the solution was stirred at 120°C for 3 hours. The mixture was concentrated in vacuo. Adjust the pH of the mixture to 6-7. The aqueous phase was extracted three times with DCM (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (10 g column; elution with DCM/MEOH (ratio: 30/1)). Concentrate in vacuo. The precipitated solid was collected by filtration and washed with EA (20 mL) to give ethyl 7-chloro-5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate (1.09 g, 4.51) as a light pink solid. mmol, 20%). m/z (ES ⁺ ) [M+H] ⁺ = 242.05; HPLC tR = 0.467 min. 5- Hydroxyimidazo [1,2-c] pyrimidine -2- carboxylic acid ethyl ester

Step 2. Combine 7-chloro-5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (1.09 g, 4.51 mmol) and Pd/C (120 mg, 1.13 mmol) at 25°C. The stirred mixture in MeOH (15 mL) was treated with _H2 for 1 h. The reaction mixture was filtered through a pad of celite, the pad was washed with MeOH (50 ml), and the filtrate was concentrated in vacuo to give 5-hydroxyimidazo[1,2-c]pyrimidine-2- as a yellow solid Ethyl formate (910 mg, 4.39 mmol, 97.4%). m/z (ES ⁺ ) [M+H] ⁺ = 208.05; HPLC tR = 0.615 min. 2-( Hydroxymethyl ) imidazo [1,2-c] pyrimidin -5- ol

Step 3. To a mixture of 5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (500 mg, 2.41 mmol) in THF (15 mL) was added dropwise at 0 °C under nitrogen atmosphere. LAH (3.62 mL of 1 M solution in THF, 3.62 mmol) was added. The mixture was stirred at 25°C for 12 hours. The mixture was quenched with _{Na2SO4 · 10H2O} . The reaction mixture was filtered, washed with slightly heated DCM/MeOH=4/1 (100 ml) and MeOH/H ₂ O=4/1 (100 ml), and the filtrate was concentrated in vacuo to obtain 2 as a brown solid. -(Hydroxymethyl)imidazo[1,2-c]pyrimidin-5-ol (480 mg, 2.91 mmol, crude). m/z (ES ⁺ ) [M+H] ⁺ = 166.05; HPLC tR = 0.233 min. 2-( Chloromethyl ) imidazo [1,2-c] pyrimidin -5- ol

Step 4. Put 2-(hydroxymethyl)imidazo[1,2-c]pyrimidin-5-ol (2.7 g, 16 mmol) and SOCl ₂ (19 g, 12 mL, 0.16 mol) into the round-bottomed flask. ), DMF (0.01 mL), toluene (30 mL) and stirring rod. The solution was stirred at 110°C for 5 hours. The mixture was concentrated in vacuo to give 2-(chloromethyl)imidazo[1,2-c]pyrimidin-5-ol (2.1 g, 11 mmol, crude) as a brown solid. m/z (ES ⁺ ) [M+H] ⁺ = 184.00; HPLC tR = 0.565 min. 2-( methoxymethyl ) imidazo [1,2-c] pyrimidin -5- ol

Step 5. Put 2-(chloromethyl)imidazo[1,2-c]pyrimidin-5-ol (2.1 g, 11 mmol) and sodium methoxide (10 g, 11 mL, 30%) into the round-bottomed flask. Wt, 57 mmol) and stirring rod. MeOH (40 mL) was added and the solution was stirred at 25°C for 16 hours. The mixture was concentrated in vacuo. The pH of the mixture was adjusted to 6-7 with 2 M HCl. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 20% gradient in 25 min; detector, UV 254 nm, resulting in a white color 2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-ol, amorphous solid (380 mg, 2.12 mmol, 19%). m/z (ES ⁺ ) [M+H] ⁺ = 180.05; HPLC tR = 0.432 min. 5- Chloro -2-( methoxymethyl ) imidazo [1,2-c] pyrimidine

Step 6. Charge 2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-ol (380 mg, 2.12 mmol) and DIEA (5.48 g, 7.39 mL, 42.4) into the round-bottomed flask. mmol), POCl ₃ (25 mL) and stirring rod. The solution was stirred at 100°C for 6 hours. The mixture was concentrated in vacuo. Adjust the pH of the mixture to 6-7 with _NaHCO3 . The reaction mixture was diluted with water (20 mL), and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 50% gradient in 18 min; detector, UV 254 nm, resulting in a white color 5-Chloro-2-(methoxymethyl)imidazo[1,2-c]pyrimidine, solid (320 mg, 1.62 mmol, 76.4%). m/z (ES ⁺ ) [M+H] ⁺ = 198.00; HPLC tR = 0.656 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(1-( tert-butyl )-5-((2-( methoxymethyl ) imidazo [1,2- c] pyrimidin -5- yl ) amino )-1H- pyrazol -3- yl ) tetrahydrofuran -3- yl ester

Step 7. Charge the resealable reaction vial with (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(5-amino-1-(tert-butyl)-1H-pyridine Azol-3-yl)tetrahydrofuran-3-yl ester (475 mg, 1.47 mmol), 5-chloro-2-(methoxymethyl)imidazo[1,2-c]pyrimidine (320 mg, 1.62 mmol) , xantphos (426 mg, 736 µmol), Pd ₂ (dba) ₃ (270 mg, 294 µmol), K ₂ CO ₃ (610 mg, 4.42 mmol) and stir bar, then evacuated and purged with nitrogen three times. 1,4-dioctane (8 mL) was added and the mixture was stirred at 80°C for 12 hours. The mixture was quenched with water (20 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 80% gradient in 18 min; detector, UV 254 nm, resulting in a white color Solid (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-(methoxymethyl)imidazo[1, 2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (260 mg, 538 µmol, 36.5%). m/z (ES ⁺ ) [M+H] ⁺ = 484.30; HPLC tR = 0.913 min. (1- Methylcyclopropyl ) carbamic acid (3R,5R)-5-(3-((2-( methoxymethyl ) imidazo [1,2-c] pyrimidin -5- yl ) amine ( 3R, 5S ) -5-( 3- ((2- ( methoxymethyl) )- 1H - pyrazol -5 -yl ) tetrahydrofuran -3-yl ester (1 -methylcyclopropyl)carbamic acid yl ) imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) tetrahydrofuran -3- yl ester

Step 8. Charge (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(1-(tert-butyl)-5-((2-(methoxy)) into the round-bottom flask Methyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)tetrahydrofuran-3-yl ester (300 mg, 620 µmol) and stirring rod. HCOOH (8 mL) was added and the solution was stirred at 100°C for 5 hours. Adjust the pH of the mixture to 6-7. The aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The obtained crude material was analyzed by preparative HPLC (column: XBridge Shield RP18 OBD column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ ), mobile phase B: ACN; Flow: 60 mL/min; Gradient: 6% B to 32% B in 11 min, 32% B to 40% B, 40% B in 12 min; Wavelength: 220 nm; RT1(min): 10.47/11.2) Purification . Lyophilized to obtain (1-methylcyclopropyl)carbamic acid (3R,5R)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]) as a white solid) Pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (49.2 mg, 115 µmol, 18.6%) and (1-methylcyclopropyl)carbamic acid (3R ,5S)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)tetrahydrofuran- 3-yl ester (57.4 mg, 134 µmol, 21.6%).

(1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amine 1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester: m/z (ES ⁺ ) [M+H] ⁺ = 428.20; HPLC tR = 1.218 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.12 (s, 1H), 8.31 (s, 1H), 7.59 (d, J = 37.8 Hz, 2H), 7.08 (d, J = 130.3 Hz, 1H), 6.67 (d, J = 245.9 Hz, 1H), 5.17 (s, 1H), 4.86 (s, 1H), 4.50 (s, 2H), 3.85 (d, J = 5.0 Hz, 2H ), 3.35 (s, 3H), 2.69 (d, J = 14.6 Hz, 1H), 2.02 (d, J = 50.7 Hz, 1H), 1.24 (s, 3H), 0.60 (d, J = 5.1 Hz, 2H ), 0.52-0.36 (m, 2H).

(1-Methylcyclopropyl)carbamic acid (3R,5S)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amine (1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester: m/z (ES ⁺ ) [M+H] ⁺ = 428.20; HPLC tR =1.306 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.13 (s, 1H), 8.31 (s, 1H), 8.02-7.14 (m, 2H), 6.92 (d, J = 6.4 Hz , 1H), 6.69 (d, J = 251.5 Hz, 1H), 5.25 (s, 1H), 5.03 (s, 1H), 4.50 (s, 2H), 4.13 (d, J = 15.7 Hz, 1H), 3.74 (d, J = 10.3 Hz, 1H), 3.36 (s, 3H), 2.30 (d, J = 24.5 Hz, 2H), 1.27 (s, 3H), 0.69-0.59 (m, 2H), 0.51 (d, J = 5.3 Hz, 2H).

Additional compounds prepared according to the method of Example 10 are shown in Table 6 below. Table 6. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] (1-Methylcyclopropyl)carbamic acid (3S,5S)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amine (yl)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.51 (s, 1H), 10.13 (s, 1H), 8.31 (s, 1H), 7.59 (d, J = 39.8 Hz, 2H), 7.08 (d, J = 129.3 Hz , 1H), 6.67 (d, J = 248.4 Hz, 1H), 5.18 (s, 1H), 4.92 (d, J = 46.2 Hz, 1H), 4.50 (s, 2H), 3.86 (s, 2H), 3.35 (s, 3H), 2.70 (d, J = 15.3 Hz, 1H), 2.04 (d, J = 67.7 Hz, 1H), 1.24 (s, 3H), 0.60 (s, 2H), 0.48 (s, 2H) . 428.20 (1-Methylcyclopropyl)carbamic acid (3S,5R)-5-(3-((2-(methoxymethyl)imidazo[1,2-c]pyrimidin-5-yl)amine (yl)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d6) 12.58 (s, 1H), 10.14 (s, 1H), 8.31 (s, 1H), 7.61 (s, 2H), 6.92 (s, 1H), 6.70 (s, 1H), 5.25 (s, 1H), 5.03 (s, 1H), 4.50 (s, 2H), 4.11 (d, J = 10.2 Hz, 1H), 3.74 (d, J = 10.3 Hz, 1H), 3.35 (s, 3H ), 2.31 (d, J = 24.0 Hz, 2H), 1.27 (s, 3H), 0.74-0.58 (m, 2H), 0.51 (s, 2H). 428.20 Example 11

Additional compounds listed in Table 7 were synthesized according to the procedures described herein. Table 7. Additional exemplary compounds compound structure Proton NMR MS [M+1] Bicyclo[1.1.1]pentan-1-ylcarbamate (3S,5S)-5-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole) -5-Formamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.55 (s, 1H), 10.80 (s, 1H), 7.94 (s, 1H), 6.69 - 6.49 (m, 2H), 6.38 (t, J = 3.5 Hz , 1H), 5.16 (d, J = 3.4 Hz, 1H), 4.86 (s, 1H), 4.38 (td, J = 14.9, 3.5 Hz, 2H), 3.96 (s, 3H), 3.86 (s, 2H) , 2.70 (d, J = 14.8 Hz, 1H), 2.37 (s, 1H), 1.92 (s, 7H). 467.15 Bicyclo[1.1.1]pentan-1-ylcarbamate (3S,5S)-5-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.55 (s, 1H), 10.83 (s, 1H), 7.92 (s, 1H), 6.63 (d, J = 44.6 Hz, 2H), 5.17 (dd, J = 7.4, 3.8 Hz, 1H), 4.81 (q, J = 14.4, 8.9 Hz, 3H), 4.31-3.68 (m, 5H), 2.71 (q, J = 7.5 Hz, 1H), 2.36 (s, 1H) , 2.07-1.69 (m, 7H) 484.15 Bicyclo[1.1.1]pentan-1-ylcarbamate (3R,5R)-5-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole) -5-Formamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.53 (s, 1H), 10.63 (s, 1H), 7.91 (s, 1H), 6.68 - 6.47 (m, 2H), 6.38 (t, J = 3.5 Hz , 1H), 5.17 (dt, J = 7.3, 3.5 Hz, 1H), 4.86 (s, 1H), 4.38 (td, J = 14.9, 3.5 Hz, 2H), 3.96 (s, 3H), 3.86 (s, 2H), 2.70 (dt, J = 13.6, 7.6 Hz, 1H), 2.36 (s, 1H), 1.92 (s, 7H). 467.20 Bicyclo[1.1.1]pentan-1-ylcarbamate (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.54 (s, 1H), 10.83 (s, 1H), 7.92 (s, 1H), 6.63 (d, J = 45.6 Hz, 2H), 5.16 (t, J = 4.1 Hz, 1H), 4.80 (q, J = 8.9 Hz, 3H), 3.97 (s, 3H), 3.86 (s, 2H), 2.71 (dd, J = 14.4, 7.7 Hz, 1H), 2.35 (d , J = 11.4 Hz, 1H), 1.92 (s, 7H). 485.15 (2-cyanoprop-2-yl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole- 5-Formamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.56 (s, 1H), 10.93 (s, 1H), 8.09 (s, 1H), 7.29 (s, 1H), 6.58 (s, 1H), 5.26 (dp , J = 7.6, 2.4 Hz, 1H), 5.12 (s, 2H), 4.87 (s, 1H), 4.10 (s, 3H), 4.00-3.74 (m, 2H), 2.77 (dt, J = 12.8, 6.7 Hz, 1H), 2.00 (d, J = 12.2 Hz, 1H), 1.56 (d, J = 4.2 Hz, 6H). 486.15 (1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide) )-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.50 (s, 1H), 10.80 (s, 1H), 7.52 (s, 1H), 7.13 (s, 1H), 6.56 (s, 1H), 5.16 (s , 1H), 4.85 (s, 1H), 4.35 (s, 2H), 4.06 (s, 3H), 3.85 (s, 2H), 3.28 (s, 3H), 2.70 (s, 1H), 1.93 (s, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.48 (s, 2H). 419.10 Cuban-1-ylcarbamate (3R,5R)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-methamide (yl)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.52 (s, 1H), 10.91 (s, 1H), 7.90 (d, J = 105.4 Hz, 1H), 7.29 (s, 1H), 6.58 (s, 1H ), 5.15 (d, J = 28.2 Hz, 3H), 4.88 (s, 1H), 4.10 (s, 3H), 4.03 (s, 2H), 3.97-3.78 (m, 6H), 3.74 (s, 1H) , 2.72 (t, J = 7.2 Hz, 1H), 2.03 (d, J = 39.4 Hz, 1H). 521.10 (1-(methoxymethyl)cyclopropyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.50 (s, 1H), 10.91 (s, 1H), 7.59 (s, 1H), 7.29 (s, 1H), 6.57 (s, 1H), 5.14 (d , J = 19.2 Hz, 3H), 4.86 (s, 1H), 4.10 (s, 3H), 3.85 (s, 2H), 3.29 (s, 2H), 3.24 (s, 3H), 2.70 (s, 1H) , 1.93 (s, 1H), 0.65 (d, J = 4.7 Hz, 4H). 503.10 (3-Methyloxetan-3-yl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H -pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.53 (s, 1H), 10.91 (s, 1H), 7.78 (s, 1H), 7.29 (s, 1H), 6.58 (s, 1H), 5.20 (t , J = 4.4 Hz, 1H), 5.12 (s, 2H), 4.87 (s, 1H), 4.59 (s, 2H), 4.25 (s, 2H), 4.10 (s, 3H), 3.90 (d, J = 11.1 Hz, 2H), 2.70 (d, J = 15.0 Hz, 1H), 2.04 (d, J = 34.3 Hz, 1H), 1.49 (s, 3H). 489.15 (3-Methyloxetan-3-yl)carbamic acid (3S,5S)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H -pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.55 (s, 1H), 10.93 (s, 1H), 7.79 (s, 1H), 7.29 (s, 1H), 6.59 (s, 1H), 5.19 (dq , J = 7.2, 3.2 Hz, 1H), 5.12 (s, 2H), 4.87 (s, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.25 (d, J = 6.0 Hz, 2H), 4.10 (s, 3H), 3.95-3.78 (m, 2H), 2.72 (s, 1H), 2.00 (d, J = 10.8 Hz, 1H), 1.49 (s, 3H). 489.20 (1-(methoxymethyl)cyclopropyl)carbamic acid (3S,5S)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.50 (s, 1H), 10.92 (s, 1H), 7.59 (s, 1H), 7.29 (s, 1H), 6.57 (s, 1H), 5.12 (s , 4H), 4.10 (s, 3H), 3.85 (s, 2H), 3.30 (d, J = 7.1 Hz, 2H), 3.24 (s, 3H), 2.69 (d, J = 6.7 Hz, 1H), 1.93 (s, 1H), 0.65 (d, J = 4.5 Hz, 4H). 503.20 N-(5-((2R,4R)-4-((4-isopropyl-1H-pyrazol-5-yl)oxy)tetrahydrofuran-2-yl)-1H-pyrazol-3-yl) -3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.49 (br. s, 1H), 11.54 (s, 1H), 10.78 (br. s, 1H), 7.26 (s, 1H), 7.11 (s, 1H) , 6.58 (br. s, 1H), 5.25 - 5.17 (m, 1H), 5.02 - 4.88 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 4.04 - 3.91 (m, 2H) , 3.27 (immersion, s, 3H), 2.79 - 2.62 (m, 2H), 2.14 (ddd, J = 13.4, 6.5, 2.8 Hz, 1H), 1.08 (d, J = 6.8 Hz, 6H). 430.30 (1-Methylcyclopropyl)carbamic acid (3R,5R)-5-(3-(3-(hydroxymethyl)-1-methyl-1H-pyrazole-5-methamide)- 1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.48 (s, 1H), 10.76 (s, 1H), 7.51 (s, 1H), 7.09 (s, 1H), 6.56 (s, 1H), 5.14 (d , J = 19.0 Hz, 2H), 4.85 (s, 1H), 4.41 (d, J = 5.7 Hz, 2H), 4.04 (s, 3H), 3.85 (s, 2H), 2.71 (d, J = 7.1 Hz , 1H), 2.01 (d, J = 59.5 Hz, 1H), 1.25 (s, 3H), 0.62 (s, 2H), 0.48 (q, J = 4.6 Hz, 2H). 405.05 (1-Methylcyclopropyl)carbamic acid rel-(3R,5R)-5-(2-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole- 5-methamide)thiazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.75 (s, 1H), 7.56 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 5.14 (s, 4H), 4.14 (s , 3H), 3.85 (dd, J = 19.4, 7.9 Hz, 2H), 2.76 (dd, J = 14.1, 7.2 Hz, 1H), 1.89 (s, 1H), 1.24 (d, J = 6.7 Hz, 3H) , 0.63 (s, 2H), 0.49 (s, 2H). 490.15 ((R)-1-cyclopropylethyl)carbamic acid (3R,5R)-5-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyra Azole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.53 (s, 1H), 10.76 (d, J = 4.6 Hz, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.64 (s, 1H), 6.54 (s, 1H), 6.38 (tt, J = 54.5, 3.4 Hz, 1H), 5.16 (s, 1H), 4.85 (t, J = 7.7 Hz, 1H), 4.38 (td, J = 14.9, 3.5 Hz , 2H), 3.96 (s, 3H), 3.86 (d, J = 9.4 Hz, 2H), 2.99 (d, J = 7.4 Hz, 1H), 2.77-2.66 (m, 1H), 1.95 (s, 1H) , 1.10 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 5.6 Hz, 1H), 0.45-0.21 (m, 3H), 0.10 (d, J = 4.5 Hz, 1H). 469.10 ((S)-1-Cyclopropylethyl)carbamic acid (3R,5R)-5-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyra Azole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.59 - 12.54 (m, 1H), 10.81 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.66 (s, 1H), 6.58 (s , 1H), 6.38 (tt, J = 54.5, 3.4 Hz, 1H), 5.16 (s, 1H), 4.86 (t, J = 7.7 Hz, 1H), 4.38 (td, J = 14.9, 3.5 Hz, 2H) , 3.96 (s, 3H), 3.87 (q, J = 6.5, 4.9 Hz, 2H), 3.00 (q, J = 7.5 Hz, 1H), 2.77 - 2.67 (m, 1H), 1.96 (d, J = 11.6 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.82 (dd, J = 8.2, 4.6 Hz, 1H), 0.42 - 0.21 (m, 3H), 0.11 (dd, J = 9.4, 4.7 Hz , 1H). 469.10 ((R)-1-Cyclopropylethyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H -pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.56 (s, 1H), 10.84 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.58 (s, 1H ), 5.17 (s, 1H), 4.80 (q, J = 8.9 Hz, 3H), 3.97 (s, 3H), 3.86 (s, 2H), 3.00 (d, J = 7.1 Hz, 1H), 2.72 (s , 1H), 1.96 (s, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.82 (s, 1H), 0.43-0.20 (m, 3H), 0.12 (d, J = 7.3 Hz, 1H) . 487.15 ((S)-1-Cyclopropylethyl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H -pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.57 (s, 1H), 10.85 (s, 1H), 7.18 (d, J = 8.5 Hz, 1H), 6.69 (s, 1H), 6.58 (s, 1H ), 5.16 (s, 1H), 4.81 (p, J = 9.0 Hz, 3H), 3.97 (s, 3H), 3.89 - 3.84 (m, 2H), 3.07 - 2.64 (m, 2H), 1.95 (s, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.82 (d, J = 7.0 Hz, 1H), 0.54 - 0.15 (m, 3H), 0.15 - 0.08 (m, 1H). 487.20 (3-Methoxybicyclo[1.1.1]pentan-1-yl)carbamic acid (3S,5S)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl) (yl)-1H-pyrazole-5-carboxamide base)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.53 (s, 1H), 10.92 (s, 1H), 7.99 (s, 1H), 7.30 (s, 1H), 6.58 (s, 1H), 5.18 (dd , J = 7.4, 3.7 Hz, 1H), 5.12 (s, 2H), 4.87 (s, 1H), 4.10 (s, 3H), 3.87 (s, 2H), 3.18 (s, 3H), 2.70 (dd, J = 13.9, 7.2 Hz, 1H), 2.14-1.98 (m, 6H), 1.96 (s, 1H). 515.15 (3-cyanobicyclo[1.1.1]pentan-1-yl)carbamic acid (3S,5S)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl) )-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.53 (s, 1H), 10.92 (s, 1H), 8.25 (s, 1H), 7.29 (s, 1H), 6.57 (s, 1H), 5.18 (s , 1H), 5.11 (s, 2H), 4.86 (s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 2.69-2.65 (m, 1H), 2.44-2.18 (m, 6H), 1.94 (s, 1H). 510.05 (3-Methoxybicyclo[1.1.1]pentan-1-yl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl) (yl)-1H-pyrazole-5-carboxamide base)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.54 (s, 1H), 10.91 (s, 1H), 7.84 (d, J = 127.7 Hz, 1H), 7.29 (s, 1H), 6.55 (s, 1H ), 5.18 (dt, J = 7.2, 3.6 Hz, 1H), 5.12 (s, 2H), 4.92 (d, J = 47.5 Hz, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 3.18 (s, 3H), 2.77-2.60 (m, 1H), 2.11-1.72 (m, 7H). 515.15 (3-cyanobicyclo[1.1.1]pentan-1-yl)carbamic acid (3R,5R)-5-(3-(1-methyl-3-((trifluoromethoxy)methyl) )-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.54 (s, 1H), 10.92 (s, 1H), 8.25 (s, 1H), 7.29 (s, 1H), 6.57 (s, 1H), 5.18 (s , 1H), 5.11 (s, 2H), 4.86 (s, 1H), 4.10 (s, 3H), 3.86 (s, 2H), 2.67 (dd, J = 3.7, 1.9 Hz, 1H), 2.41 (s, 4H), 2.35-2.13 (m, 2H), 1.94 (s, 1H). 510.30 Example 12 (1- Methylcyclopropyl ) carbamic acid rel-(1S,2R,4R)-2- fluoro -4-(3-(1- methyl- 3-(( trifluoromethoxy ) methyl) base )-1H- pyrazole -5- carboxylic acid )-1H- pyrazole -5- yl ) cyclopentyl ester (1- methylcyclopropyl ) carbamic acid rel-(1R,2S,4S) -2- Fluoro -4-(3-(1- methyl -3-(( trifluoromethoxy ) methyl )-1H - pyrazole -5- methamide )-1H- pyrazole -5- cyclopentyl ester _ 1- Methyl -3-(( trifluoromethoxy ) methyl )-1H- pyrazole -5- carboxylic acid ethyl ester

Step 1. Add 3-( _{hydroxymethyl} )-1-methyl-1H-pyrazole-5-carboxylic acid ethyl ester (1 g, 5 mmol), silver (I) trifluoromethanesulfonate (3 g, 0.01 mol), KF (0.9 g, 0.02 mol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-diom To a stirred solution of tetrafluoroborate (3 g, 8 mmol) in ethyl acetate (35 mL) were added 2-fluoropyridine (1 g, 0.01 mol) and trimethyl (trifluoromethyl)silane (2 g , 0.01 mol). The reaction was stirred at room temperature overnight in the dark. The mixture was filtered and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 55% to 60% gradient in 10 min; detector, UV 220 nm, to obtain a 1-Methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylic acid ethyl ester as a white solid (1.2 g, 2.4 mmol, 40%, 50% purity). m/z (ES+) [M+H]+ =253.00; HPLC tR = 0.987 min. Lithium 1- methyl -3-(( trifluoromethoxy ) methyl )-1H- pyrazole -5- carboxylate

Step 2. Add 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylic acid ethyl ester (1.2 g, 50% Wt, 2.4 mmol) in MeOH (10 mL) To the stirred solution was added a solution of LiOH (85 mg, 3.6 mmol) in H ₂ O (4 mL). The reaction was stirred at room temperature for 30 min. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 0% gradient in 8 min; detector, UV 254 nm, to obtain a white solid Lithium 1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-carboxylate (230 mg, 1.00 mmol, 42%). m/z (ES+) [M+H]+ =225.25; HPLC tR = 0.717 min. 3-( Cyclopent - 3- en -1- yl )-3- Pendantoxypropionitrile

Step 3. To a mixture of CH ₃ CN (12.00 g, 0.29 mol) in THF (200 mL) was added dropwise n-BuLi (0.14 L, 0.36 mol) at -78 °C under nitrogen atmosphere. The mixture was stirred at -78 °C for 2 h, then cyclopent-3-ene-1-carboxylic acid ethyl ester (20.00 g, 0.14 mol) was added. The mixture was stirred at 50 °C for 4 h. The reaction mixture was diluted with H ₂ O (50 mL), then adjusted to pH 6~7 with 1M HCl, and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Concentration in vacuo gave 3-(cyclopent-3-en-1-yl)-3-pentoxypropionitrile (27.40 g, 70%) as a yellow oil. m/z (ES ⁺ ) [M+H] ⁺ = No signal in LCMS. 1-( tert-butyl )-3-( cyclopent -3- en -1- yl )-1H- pyrazole -5- amine

Step 4. Charge 3-(cyclopent-3-en-1-yl)-3-side oxypropionitrile (27.40 g, 203.00 mmol) and tert-butylhydrazine (60.80 g) into the resealable reaction vial. , 689.00 mmol), DIEA (126.00 g, 973.00 mmol), IPA (300 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the mixture was stirred at 80°C for 12 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (50.00 g column; elution with PE/EA (ratio: 10/1)). Concentration in vacuo gave 1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-amine as a white solid (23.00 g, 55%). m/z (ES ⁺ ) [M+H] ⁺ =206.20; HPLC tR = 0.398 min. (1-( tert-Butyl )-3-( cyclopent -3 - en -1- yl )-1H- pyrazol -5- yl ) carbamate benzyl ester

Step 5. To 1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazole-5-amine (17.60 g, 85.70 mmol) at 0°C under nitrogen atmosphere ) and NaHCO ₃ (36.00 g, 429.00 mmol) in ACN (200 mL) was added benzyl chloroformate (43.90 g, 257.00 mmol) dropwise. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40.00 g column; elution with PE/EA (ratio: 8/1)). Concentration in vacuo gave benzyl (1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-yl)carbamate (25.6) as a white solid g, 88.0%). m/z (ES ⁺ ) [M+H] ⁺ = 340.15; HPLC tR = 0.950 min. (3-((1R,3s,5S)-6- oxabicyclo [3.1.0] hex -3- yl )-1-( tert-butyl )-1H- pyrazol -5- yl ) amine Benzyl formate

Step 6. Charge the resealable reaction vial with benzyl (1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-yl)carbamate Esters (25.00 g, 74.00 mmol), H ₂ O ₂ (36.00 g, 35% Wt, 0.37 mol), Na ₂ WO ₄ (2.20 g, 7.40 mmol), PhP(O)(OH) ₂ (600 mg, 3.70 mmol), Me(nC ₈ H ₁₇ ) ₃ N]HSO ₄ (3.40 g, 7.40 mmol), i-PrOAc (300 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the mixture was heated at 25°C Stir for 24 hours. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). Na ₂ S ₂ O ₃ (50.00 g, 316 mmol) was added and the mixture was stirred at 25 °C for 15 min. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (10 g column; elution with PE/EA (ratio: 4/1)). Concentration in vacuo yielded (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl)-1H- as a white solid Benzyl pyrazol-5-yl)carbamate (11.00 g, 42%). m/z (ES ⁺ ) [M+H] ⁺ = 356.20; HPLC tR = 0.917 min. (1-( tert-Butyl )-3-( racemic- (1R,3R,4R)-3- fluoro -4- hydroxycyclopentyl )-1H- pyrazol -5- yl ) benzylcarbamate ester

Step 7. Charge the resealable reaction vial with (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl) -1H-pyrazol-5-yl)benzylcarbamate (20.00 g, 56.00 mmol), Et ₃ N-HF (200 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the mixture was heated at 60 Stir for 12 h at ℃. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (60.00 g column; elution with PE/EA (ratio: 4/1)). Concentration in vacuo yielded (1-(tert-butyl)-3-(racemic-(1R,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazole as a white solid Benzyl-5-yl)carbamate (13.00 g, 62%). m/z (ES ⁺ ) [M+H] ⁺ = 376.15; HPLC tR = 0.851 min. Racemic -4- nitrobenzoic acid (1S,2R,4R)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H - pyrazole- 3- yl )-2- fluorocyclopentyl ester

Step 8. Add (1-(tert-butyl)-3-(racemic-(1R, 3R, 4R)-3-fluoro-4-hydroxycyclopentyl)-1H at 0°C under nitrogen atmosphere -Benzyl-pyrazol-5-yl)carbamate (13.00 g, 35.00 mmol), 4-nitrobenzoic acid (6.90 g, 42.00 mmol) and Ph ₃ P (21.00 g, 80.00 mmol) in THF (130 mL ) was added dropwise to the mixture in DIAD (16.00 g, 80.00 mmol). The mixture was stirred at 0 °C for 1 h. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with H ₂ O (20 mL), then adjusted to pH 7~8 with 1 M HCl, and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (40.00 g column; elution with PE/EA (ratio: 4/1)). Concentration in vacuo yielded racemic-4-nitrobenzoic acid (1S,2R,4R)-4-(5-((benzyloxy)carbonyl)amine)-1-(tertiary) as a white solid Butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (15.80 g, 87%). m/z (ES ⁺ ) [M+H] ⁺ =525.35; HPLC tR = 1.294 min. (1-( tert-Butyl )-3-( racemic- (1R,3R,4S)-3- fluoro -4- hydroxycyclopentyl )-1H- pyrazol -5- yl ) benzylcarbamate ester

Step 9. Charge the resealable reaction vial with racemic-4-nitrobenzoic acid (1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1- (tert-Butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (15.80 g, 30.10 mmol), LiOH (90.40 mL, 1 M, 90.40 mmol), THF/MeOH (150 mL ) and stirring rod, then evacuated and purged with nitrogen three times, and the mixture was stirred at 25°C for 1 h. The residue was diluted with water, then adjusted to pH 6~7 with 1M HCl, and the aqueous phase was extracted three times with EA (40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 10 min; detector, UV 254 nm, in vacuum Concentration yielded (1-(tert-butyl)-3-(racemic-(1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazole-5- as a white solid Benzyl carbamate (5.20 g, 46%). m/z (ES ⁺ ) [M+H] ⁺ = 376.10; HPLC tR = 0.783 min. (1-( tert-butyl )-3-( rac- (1R,3R,4S)-3- fluoro -4-(((4- nitrophenoxy ) carbonyl ) oxy ) cyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 10. Charge the resealable reaction vial with (1-(tert-butyl)-3-(rac-(1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H -Benzyl-pyrazol-5-yl)carbamate (5.20 g, 14.00 mmol), DMAP (0.34 g, 2.80 mmol), Py (3.30 g, 42.00 mmol), DCM (52 mL) and stirring rod, then evacuated and purged with nitrogen three times, then 4-nitrophenyl chloroformate (4.20 g, 21.00 mmol) was added dropwise at 0°C and the mixture was stirred at 25°C for 1 h. The reaction mixture was diluted with _H2O (20 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (15.00 g column; elution with PE/EA (ratio: 2/1)). Concentration in vacuo yielded (1-(tert-butyl)-3-(racemic-(1R,3R,4S)-3-fluoro-4-((4-nitrophenoxy) as a white solid )carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (7.20 g, 96%). m/z (ES ⁺ ) [M+H] ⁺ = 541.10; HPLC tR = 0.917 min. Racemic- (1- methylcyclopropyl ) carbamic acid (1S,2R,4R)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl ) -1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 11. Charge (1-(tert-butyl)-3-(racemic-(1R,3R,4S)-3-fluoro-4-(((4-nitrophenoxy)) into a round-bottom flask base)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (2.00 g, 4.00 mmol), 1-methylcyclo-propan-1-amine hydrochloride (0.80 g, 7.00 mmol), DIEA (2.00 g, 0.02 mol), DMAP (0.05 g, 0.40 mmol), THF (20 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the solution was stirred at 25°C 2 hours. The reaction mixture was diluted with _H2O (30 mL), and the aqueous phase was extracted three times with EA (90 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 30% to 80% gradient in 15 min; detector, UV 254 nm, in vacuum Concentration yields racemic-(1-methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1- as a white solid (tert-Butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (1.70 g, 97%). m/z (ES ⁺ ) [M+H] ⁺ = 473.30; HPLC tR = 0.915 min. Racemic- (1- methylcyclopropyl ) carbamic acid (1S,2R,4R)-4-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl ) -2- fluorocyclopentyl ester

Step 12. Combine racemic-(1-methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)- 1-(tert-Butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (1.70 g, 3.60 mmol) and Pd/C (0.11 g, 1.10 mmol) in EA (10 mL) and THF (10 mL) was treated with H for ₂ h. The mixture was filtered through a pad of celite. Concentration in vacuo yielded racemic -(1-methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-) as a white solid 1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (1.10 g, 90%). m/z (ES ⁺ ) [M+H] ⁺ = 339.20; HPLC tR = 0.665 min. Racemic- (1- methylcyclopropyl ) carbamic acid (1S,2R,4R)-4-(1-( tert-butyl )-5-(1- methyl -3-(( trifluoro Methoxy ) methyl )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 13. Racemize -(1-methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(5-amino-1-(tert-butyl) at 0°C under nitrogen atmosphere To a mixture of 1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (140 mg, 414 µmol) in EA (2 mL) was added dropwise Fluoromethoxy)methyl)-1H-pyrazole-5-carboxylic acid (102 mg, 455 µmol) and DIEA (535 mg, 4.14 mmol), followed by T ₃ P (4.20 g, 50% Wt, 6.62 mmol) . The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (MeOH/DCM; ratio: 1/20) to give racemic -(1-methylcyclopropyl)carbamic acid (1S,2R,4R)- as a yellow solid 4-(1-(tert-butyl)-5-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazole Azol-3-yl)-2-fluorocyclopentyl ester (218 mg, 96.8%). m/z (ES ⁺ ) [M+H] ⁺ =545.40; HPLC tR = 1.158 min. (1- Methylcyclopropyl ) carbamic acid rel-(1S,2R,4R)-2- fluoro -4-(3-(1- methyl -3-(( trifluoromethoxy ) methyl )) -1H- pyrazole -5- methamide )-1H- pyrazol -5- yl ) cyclopentyl ester

Step 14. Racemize -(1-methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(1-(tert-butyl)-5-(1-methyl-3- ((Trifluoromethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (200 mg, 367 µmol) in FA (4 mL) in a mixture. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 15 min; detector, UV 254 nm, and concentrated to obtain a (1-Methylcyclopropyl)carbamic acid rel-(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)) as a white solid Methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)cyclopentyl ester (110 mg, 61.3%). m/z (ES ⁺ ) [M+H] ⁺ = 489.15; HPLC tR = 1.042 min. (1- Methylcyclopropyl ) carbamic acid rel-(1S,2R,4R)-2- fluoro -4-(3-(1- methyl -3-(( trifluoromethoxy ) methyl )) -1H- pyrazole -5- methamide )-1H- pyrazol -5- yl ) cyclopentyl ester and (1- methylcyclopropyl ) carbamic acid rel-(1R,2S,4S)- 2- Fluoro -4-(3-(1- methyl -3-(( trifluoromethoxy ) methyl )-1H- pyrazole -5- methamide )-1H- pyrazol -5- yl ) cyclopentyl ester

Racemic-(1-methylcyclopropyl)carbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)) Methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)cyclopentyl ester (110 mg, 225 µmol) by palm preparative HPLC (column: CHIRALPAK IH , 2*25 cm, 5 μm; mobile phase A: Hex(0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min; gradient : 20% B to 20% B in 10.5 min; Wavelength: 220/254 nm; RT1(min): 6.72; RT2(min): 8.39; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.3 mL; number of runs: 10) Purification.

The fractions eluted at RT1 (min): 6.72 were freeze-dried to obtain (1-methylcyclopropyl)carbamic acid rel-(1S,2R,4R)-2-fluoro- as a white amorphous solid. 4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester (26.7 mg, 49%). m/z (ES ⁺ ) [M+H] ⁺ =489.15; HPLC tR =1.512 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 10.87 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.43 (s, 1H), 5.11 (s , 3H), 4.99 (s, 1H), 4.09 (s, 3H), 3.22 (t, 1H), 2.68 (p, 1H), 2.41 (dd, 1H), 1.87 (dq, 2H), 1.26 (s, 3H), 0.63 (q, 2H), 0.50 (q, 2H).

The fractions eluted at RT2 (min): 8.39 were freeze-dried to obtain (1-methylcyclopropyl)carbamic acid rel-(1R,2S,4S)-2-fluoro- as a white amorphous solid. 4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester (29.3 mg, 53%). m/z (ES ⁺ ) [M+H] ⁺ =489.20; HPLC tR =1.512 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.86 (s, 1H), 7.64 (s, 1H), 7.29 (s, 1H), 6.44 (s, 1H), 5.11 (s , 3H), 4.91 - 4.80 (m, 1H), 4.09 (s, 3H), 3.22 (s, 1H), 2.68 (s, 1H), 2.41 (s, 1H), 2.10 - 1.76 (m, 2H), 1.26 (s, 3H), 0.62 (t, 2H), 0.50 (d, 2H). Example 13

Additional compounds listed in Table 8 were synthesized according to the procedures described herein. Table 8. Additional exemplary compounds compound structure Proton NMR MS [M+1] [α] ²⁵ _D (C=0.1, MeOH) Isopropylcarbamic acid rel-(1R,2R,4S)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid) Amino)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.32 (s, 1H), 10.78 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 6.47 (s, 1H ), 5.16-4.98 (m, 2H), 4.34 (s, 2H), 4.06 (s, 3H), 3.60 (dt, J = 13.7, 6.7 Hz, 1H), 3.41 (d, J = 25.3 Hz, 1H) , 3.27 (s, 3H), 2.62 (dd, J = 14.2, 7.3 Hz, 1H), 2.28 (d, J = 21.1 Hz, 1H), 2.08-1.92 (m, 1H), 1.64 (t, J = 15.0 Hz, 1H), 1.06 (dd, J = 6.6, 1.9 Hz, 6H). 423.20 Isopropylcarbamic acid rel-(1R,2R,4S)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid) Amino)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.32 (s, 1H), 10.84-10.76 (m, 1H), 7.21 (d, J = 7.7 Hz, 1H), 7.13 (s, 1H), 6.47 (s , 1H), 5.16-4.98 (m, 2H), 4.34 (s, 2H), 4.06 (s, 3H), 3.60 (h, J = 6.6 Hz, 1H), 3.38 (s, 1H), 3.27 (s, 3H), 2.63 (dt, J = 14.6, 7.9 Hz, 1H), 2.37-2.24 (m, 1H), 2.09-1.91 (m, 1H), 1.64 (t, J = 15.0 Hz, 1H), 1.06 (dd , J = 6.6, 1.8 Hz, 6H). 423.20 Isopropylcarbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid) Amino)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.30 (s, 1H), 10.76 (s, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.44 (s, 1H ), 5.00 (s, 1H), 4.91-4.81 (m, 1H), 4.34 (s, 2H), 4.06 (s, 3H), 3.62 (dt, J = 13.7, 6.8 Hz, 1H), 3.27 (s, 3H), 3.21 (d, J = 8.7 Hz, 1H), 2.57 (s, 1H), 2.41 (dt, J = 12.9, 7.9 Hz, 1H), 1.89 (dt, J = 36.3, 9.8 Hz, 2H), 1.06 (d, J = 6.5 Hz, 6H) 423.15 Isopropylcarbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid) Amino)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.29 (s, 1H), 10.76 (s, 1H), 7.27 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 6.43 (s, 1H ), 5.17-4.96 (m, 1H), 4.95-4.78 (m, 1H), 4.34 (s, 2H), 4.06 (s, 3H), 3.61 (dq, J = 13.5, 6.7 Hz, 1H), 3.27 ( s, 3H), 3.25-3.18 (m, 1H), 2.63-2.54 (m, 1H), 2.41 (dt, J = 13.7, 7.3 Hz, 1H), 1.98-1.78 (m, 2H), 1.06 (d, J = 6.5 Hz, 6H). 423.10 (1-Methylcyclopropyl)carbamic acid (1S,2R,4R)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole- 5-Methodamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.29 (s, 1H), 10.75 (s, 1H), 7.65 (s, 1H), 7.11 (s, 1H), 6.42 (s, 1H), 5.05 (d , J = 55.4 Hz, 1H), 4.91-4.77 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.27 (s, 3H), 3.20 (d, J = 8.4 Hz, 1H) , 2.61-2.53 (m, 1H), 2.40 (dd, J = 12.6, 6.9 Hz, 1H), 1.96-1.75 (m, 2H), 1.26 (s, 3H), 0.62 (t, J = 3.2 Hz, 2H ), 0.49 (q, J = 4.4, 3.8 Hz, 2H). 430.10 (1-Methylcyclopropyl)carbamic acid (1R,2S,4S)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole- 5-Methodamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.29 (s, 1H), 10.75 (s, 1H), 7.65 (s, 1H), 7.11 (s, 1H), 6.43 (s, 1H), 5.05 (d , J = 55.5 Hz, 1H), 4.91-4.79 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.27 (s, 3H), 3.21 (s, 1H), 2.56 (s, 1H), 2.45-2.32 (m, 1H), 1.97-1.75 (m, 2H), 1.26 (s, 3H), 0.62 (t, J = 3.2 Hz, 2H), 0.50 (q, J = 4.5, 3.9 Hz , 2H). 435.15 Racemic-(1-(tert-butyl)-3-((1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 9.09 (s, 1H), 7.42 - 7.31 (m, 5H), 5.89 (s, 1H), 5.12 (s, 2H), 4.98 (d, J = 6.2 Hz , 1H), 4.77 (d, J = 55.5 Hz, 1H), 3.99 - 3.83 (m, 1H), 2.98 (ddd, J = 17.8, 10.2, 7.6 Hz, 1H), 2.32 (dddd, J = 31.7, 15.2 , 10.0, 5.1 Hz, 1H), 2.13 (dt, J = 13.9, 7.2 Hz, 1H), 1.85 (ddt, J = 29.0, 13.3, 7.8 Hz, 1H), 1.69 (q, J = 10.9 Hz, 1H) , 1.48 (s, 9H). 376.20 Racemic-(1-(tert-butyl)-3-((1R,3R,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 9.09 (s, 1H), 7.37 (dd, J = 17.8, 5.1 Hz, 5H), 5.90 (s, 1H), 5.12 (s, 2H), 4.98 (d , J = 6.2 Hz, 1H), 4.88 - 4.68 (m, 1H), 3.99 - 3.82 (m, 1H), 2.98 (tt, J = 10.2, 7.5 Hz, 1H), 2.32 (dddd, J = 32.1, 15.0 , 10.1, 5.1 Hz, 1H), 2.13 (dt, J = 12.0, 7.0 Hz, 1H), 1.85 (dddd, J = 30.4, 14.9, 7.2, 2.5 Hz, 1H), 1.70 (dtd, J = 12.4, 10.4 , 2.1 Hz, 1H), 1.48 (s, 9H). 376.20 (1-Methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole- 5-Methodamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.31 (s, 1H), 10.73 (s, 1H), 7.63 (s, 1H), 6.64 (s, 1H), 6.56-6.19 (m, 2H), 5.05 (d, J = 55.5 Hz, 1H), 4.85 (d, J = 21.0 Hz, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.21 (s, 1H) , 2.64-2.52 (m, 1H), 2.40 (s, 1H), 1.81 (d, J = 11.3 Hz, 2H), 1.26 (s, 3H), 0.61 (d, J = 4.2 Hz, 2H), 0.49 ( d, J = 2.5 Hz, 2H). 471.10 +487 (1-Methylcyclopropyl)carbamic acid (1R,2S,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole- 5-Methodamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.31 (s, 1H), 10.74 (s, 1H), 7.63 (s, 1H), 6.63 (s, 1H), 6.36 (tt, J = 54.5, 3.5 Hz , 2H), 5.05 (d, J = 55.5 Hz, 1H), 4.95-4.79 (m, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.28-3.13 ( m, 1H), 2.64-2.52 (m, 1H), 2.44-2.32 (m, 1H), 2.04-1.73 (m, 2H), 1.26 (s, 3H), 0.62 (q, J = 3.2 Hz, 2H) , 0.49 (q, J = 4.5, 3.9 Hz, 2H). 471.10 +17 Bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.31 (s, 1H), 10.74 (s, 1H), 8.05 (s, 1H), 6.64 (s, 1H), 6.47 - 6.19 (m, 2H), 5.12 (s , 1H), 5.02 - 4.77 (m, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.21 (t, J = 8.7 Hz, 1H), 2.49 (s, 1H), 2.37 (s, 2H), 1.92 (s, 8H). 483.15 18 Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2S,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.32 (s, 1H), 10.73 (s, 1H), 8.05 (s, 1H), 6.64 (s, 1H), 6.47 - 6.34 (m, 2H), 5.12 (s , 1H), 4.99 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.25 - 3.13 (m, 1H), 2.49 (d, J = 2.1 Hz, 1H), 2.37 (s, 2H), 1.92 (s, 8H). 483.15 159 Isopropylcarbamic acid (1S,2R,4R)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide) )-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.34 (s, 1H), 10.80 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.16 (s, 1H), 6.48 (s, 1H ), 5.12 (d, J = 55.2 Hz, 1H), 4.98-4.85 (m, 1H), 4.40 (s, 2H), 4.11 (s, 3H), 3.67 (q, J = 6.8 Hz, 1H), 3.33 (s, 3H), 3.26 (d, J = 9.0 Hz, 1H), 2.64 (d, J = 15.0 Hz, 1H), 2.47 (p, J = 7.6, 7.2 Hz, 1H), 2.05-1.84 (m, 2H), 1.12 (d, J = 6.6 Hz, 6H). ). 423.10 -6 Isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide) )-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.33 (s, 1H), 10.80 (s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.17 (s, 1H), 6.49 (s, 1H ), 5.11 (dd, J = 55.3, 5.6 Hz, 1H), 4.98-4.86 (m, 1H), 4.40 (s, 2H), 4.11 (s, 3H), 3.67 (h, J = 6.7 Hz, 1H) , 3.33 (s, 3H), 3.30-3.23 (m, 1H), 2.68-2.58 (m, 1H), 2.47 (dt, J = 14.2, 7.8 Hz, 1H), 1.94 (dq, J = 33.4, 12.4, 11.2 Hz, 2H), 1.11 (d, J = 6.6 Hz, 6H) 423.10 -15 Isopropylcarbamic acid (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((2,2,2-trifluoroethoxy)methyl)-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6)12.29 (s, 1H), 10.79 (s, 1H), 7.40 - 7.09 (m, 2H), 6.44 (s, 1H), 5.06 (d, J = 55.0 Hz, 1H ), 4.93 - 4.80 (m, 1H), 4.60 (s, 2H), 4.23 - 4.02 (m, 5H), 3.61 (dq, J = 13.6, 6.8 Hz, 1H), 3.22 (t, J = 8.7 Hz, 1H), 2.69 - 2.55 (m, 1H), 2.46 - 2.31 (m, 1H), 1.87 (dq, J = 22.3, 12.6, 11.3 Hz, 2H), 1.06 (d, J = 6.5 Hz, 6H). 491.20 10 Isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((2,2,2-trifluoroethoxy)methyl)-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.29 (s, 1H), 10.79 (s, 1H), 7.20 (d, J = 32.9 Hz, 2H), 6.44 (s, 1H), 5.20 - 4.79 (m, 2H ), 4.60 (s, 2H), 4.08 (d, J = 12.9 Hz, 5H), 3.61 (s, 1H), 3.22 (s, 1H), 2.60 - 2.55 (m, 1H), 2.42-2.39 (m, 1H), 2.08 - 1.78 (m, 2H), 1.21 - 0.98 (m, 6H). 491.20 -16 Isopropylcarbamic acid (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- Formamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.32 (s, 1H), 10.88 (s, 1H), 7.27 (d, J = 7.7 Hz, 2H), 6.44 (s, 1H), 5.25-4.73 (s , 4H), 4.09 (d, 3H), 3.61 (dt, J = 13.5, 6.7 Hz, 1H), 3.22 (t, J = 8.9 Hz, 1H), 2.70-2.56 (m, 1H), 2.46-2.28 ( m, 1H), 2.01-1.71 (m, 2H), 1.05 (d, J = 6.5 Hz, 6H). 477.10 3 Isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H-pyrazole-5- Formamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.32 (s, 1H), 10.88 (s, 1H), 7.27 (d, J = 7.2 Hz, 2H), 6.43 (s, 1H), 5.25-4.73 (s , 4H), 4.09 (s, 3H), 3.60 (h, J = 6.7 Hz, 1H), 3.22 (t, J = 8.6 Hz, 1H), 2.67 (q, J = 1.9 Hz, 1H), 2.42 (s , 1H), 2.05-1.65 (m, 2H), 1.05 (d, J = 6.5 Hz, 6H). 477.15 -9 Bicyclo[1.1.1]pentan-1-ylcarbamate(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((2,2,2-trifluoro Ethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.30 (s, 1H), 10.80 (s, 1H), 8.06 (s, 1H), 7.18 (s, 1H), 6.45 (s, 1H), 5.19-4.94 (m, 1H), 4.88 (d, J = 15.1 Hz, 1H), 4.60 (s, 2H), 4.09 (d, J = 13.5 Hz, 5H), 3.33 (s, 1H), 2.71-2.56 (m, 1H), 2.39 (d, J = 13.7 Hz, 2H), 1.93 (s, 8H). 515.15 48 Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((2,2,2-trifluoro Ethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.30 (s, 1H), 10.81 (s, 1H), 8.06 (s, 1H), 7.17 (s, 1H), 6.44 (s, 1H), 5.06 (dq , J = 55.1, 5.3, 4.0 Hz, 1H), 4.87 (d, J = 17.2 Hz, 1H), 4.60 (s, 2H), 4.25-3.97 (m, 5H), 3.23 (q, J = 8.8 Hz, 1H), 2.73-2.54 (m, 1H), 2.37 (s, 2H), 1.93 (s, 8H). 515.15 -20 Bicyclo[1.1.1]pentan-1-ylcarbamate(1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl) )-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.31 (s, 1H), 10.86 (s, 1H), 8.05 (s, 1H), 7.28 (s, 1H), 6.44 (s, 1H), 5.11 (s, 3H ), 4.87 (s, 1H), 4.09 (s, 3H), 3.21 (s, 1H), 2.56 (s, 1H), 2.37 (s, 2H), 1.93 (s, 8H). 501.15 14 Bicyclo[1.1.1]pentan-1-ylcarbamate(1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl) )-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.31 (s, 1H), 10.86 (s, 1H), 8.05 (s, 1H), 7.28 (s, 1H), 6.44 (s, 1H), 5.11 (s, 3H ), 4.87 (s, 1H), 4.09 (s, 3H), 3.22 (s, 1H), 2.56 (s, 1H), 2.37 (s, 2H), 1.93 (s, 8H). 501.10 -13 Isopropylcarbamic acid (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazole- 5-Methodamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.33 (s, 1H), 10.78 (s, 1H), 7.26 (d, J = 7.7 Hz, 1H), 6.68 (s, 1H), 6.44 (s, 1H ), 5.06 (d, J = 55.4 Hz, 1H), 4.79 (q, J = 9.0 Hz, 3H), 3.96 (s, 3H), 3.61 (dq, J = 13.5, 6.8 Hz, 1H), 3.22 (dt , J = 16.1, 8.5 Hz, 1H), 2.50-2.35 (m, 2H), 2.00-1.73 (m, 2H), 1.06 (d, J = 6.6 Hz, 6H). 477.05 14 Isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazole- 5-Methodamide)-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.33 (s, 1H), 10.78 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.68 (s, 1H), 6.44 (s, 1H ), 5.06 (d, J = 55.3 Hz, 1H), 4.79 (q, J = 9.0 Hz, 3H), 3.96 (s, 3H), 3.61 (dq, J = 13.4, 6.7 Hz, 1H), 3.21 (q , J = 8.2 Hz, 1H), 2.41 (dt, J = 13.7, 7.7 Hz, 2H), 1.86 (qd, J = 24.4, 23.3, 10.0 Hz, 2H), 1.06 (d, J = 6.6 Hz, 6H) . 477.10 -8 Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2S,4S)-4-(3-(3-((2,2-difluoroethoxy)methyl)-1-methyl (1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 10.79 (s, 1H), 8.06 (s, 1H), 7.15 (s, 1H), 6.44 (s, 1H), 6.17 (tt, J = 55.0, 3.7 Hz, 1H), 5.06 (d, J = 54.9 Hz, 1H), 4.87 (d, J = 18.4 Hz, 1H), 4.53 (s, 2H), 4.07 (s, 3H), 3.73 (td , J = 15.2, 3.8 Hz, 2H), 3.22 (t, J = 8.9 Hz, 1H), 2.59 (d, J = 14.7 Hz, 1H), 2.39 (d, J = 14.4 Hz, 2H), 1.93 (s , 7H), 1.83 (d, J = 11.0 Hz, 1H). 479.15 4 Bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(3-(3-((2,2-difluoroethoxy)methyl)-1-methyl (1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.30 (s, 1H), 10.80 (s, 1H), 8.06 (s, 1H), 7.15 (s, 1H), 6.43 (s, 1H), 6.17 (tt , J = 55.0, 3.8 Hz, 1H), 5.06 (d, J = 55.0 Hz, 1H), 4.88 (s, 1H), 4.53 (s, 2H), 4.07 (s, 3H), 3.73 (td, J = 15.2, 3.7 Hz, 2H), 3.20 (q, J = 9.4, 8.8 Hz, 1H), 2.63-2.53 (m, 1H), 2.37 (m, 2H), 1.93 (s, 8H). 497.15 -9 (1-Methylcyclopropyl)carbamic acid (1S,2R,4R)-4-(3-(3-((2,2-difluoroethoxy)methyl)-1-methyl-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.28 (s, 1H), 10.77 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 6.43 (s, 1H), 6.16 (tt , J = 54.9, 3.7 Hz, 1H), 5.05 (d, J = 55.0 Hz, 1H), 4.85 (d, J = 22.7 Hz, 1H), 4.53 (s, 2H), 4.06 (s, 3H), 3.72 (td, J = 15.2, 3.8 Hz, 2H), 3.21 (s, 1H), 2.58 (s, 1H), 2.40 (s, 1H), 1.85 (dd, J = 27.2, 16.7 Hz, 2H), 1.26 ( s, 3H), 0.62 (q, J = 3.2 Hz, 2H), 0.49 (q, J = 4.6, 4.0 Hz, 2H). 485.10 -7 (1-Methylcyclopropyl)carbamic acid (1R,2S,4S)-4-(3-(3-((2,2-difluoroethoxy)methyl)-1-methyl-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.28 (s, 1H), 10.77 (s, 1H), 7.62 (s, 1H), 7.14 (s, 1H), 6.42 (s, 1H), 6.16 (tt , J = 55.0, 3.8 Hz, 1H), 5.05 (d, J = 55.1 Hz, 1H), 4.85 (d, J = 24.0 Hz, 1H), 4.52 (s, 2H), 4.06 (s, 3H), 3.72 (td, J = 15.2, 3.8 Hz, 2H), 3.22 (d, J = 8.4 Hz, 1H), 2.57 (s, 1H), 2.41 (s, 1H), 2.00-1.75 (m, 2H), 1.26 ( s, 3H), 0.62 (d, J = 3.2 Hz, 2H), 0.50 (t, J = 3.1 Hz, 2H). 485.10 8 Isopropylcarbamic acid (1S,2R,4R)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide )-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.32 (s, 1H), 10.74 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 6.63 (s, 1H), 6.55-6.12 (m, 2H ), 5.06 (d, J = 55.2 Hz, 1H), 4.89-4.73 (m, 1H), 4.37 (td, J = 15.0, 3.5 Hz, 2H), 3.95 (s, 3H), 3.60 (dq, J = 13.5, 6.7 Hz, 1H), 3.21 (t, J = 8.4 Hz, 1H), 2.67 (s, 1H), 2.44-2.20 (m, 1H), 2.07-1.45 (m, 2H), 1.05 (d, J = 6.5 Hz, 6H). 459.10 25 Isopropylcarbamic acid (1R,2S,4S)-4-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide )-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6)12.32 (s, 1H), 10.74 (s, 1H), 7.26 (d, J = 7.8 Hz, 1H), 6.63 (s, 1H), 6.36 (tt, J = 54.5 , 3.5 Hz, 2H), 5.15-4.94 (m, 1H), 4.91-4.77 (m, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.67-3.54 ( m, 1H), 3.26-3.13 (m, 1H), 2.57 (q, J = 5.0 Hz, 1H), 2.40 (dt, J = 12.0, 7.3 Hz, 1H), 2.11-1.74 (m, 2H), 1.05 (d, J = 6.6 Hz, 6H). 459.15 -6 (1-Methylcyclopropyl)carbamic acid (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((2,2,2-trifluoroethoxy) )Methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 10.80 (s, 1H), 7.65 (s, 1H), 7.17 (s, 1H), 6.43 (s, 1H), 5.06 (d, J = 55.4 Hz, 1H), 4.85 (d, J = 22.1 Hz, 1H), 4.60 (s, 2H), 4.23-4.04 (m, 5H), 3.22 (s, 1H), 2.53 (s, 1H), 2.42 (s, 1H), 1.98-1.68 (m, 2H), 1.26 (s, 3H), 0.62 (s, 2H), 0.50 (s, 2H). 503.20 -12 (1-Methylcyclopropyl)carbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((2,2,2-trifluoroethoxy) )Methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 10.80 (s, 1H), 7.65 (s, 1H), 7.17 (s, 1H), 6.43 (s, 1H), 5.06 (d, J = 55.3 Hz, 1H), 4.90-4.80 (m, 1H), 4.60 (s, 2H), 4.13-4.04 (m, 5H), 3.21 (s, 1H), 2.56 (s, 1H), 2.40 (d, J = 9.4 Hz, 1H), 1.85 (dq, J = 33.1, 13.4, 11.0 Hz, 2H), 1.26 (s, 3H), 0.62 (q, J = 3.3 Hz, 2H), 0.50 (q, J = 4.6 , 4.0 Hz, 2H). 503.25 8 (1-Methylcyclopropyl)carbamic acid (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)) -1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.33 (s, 1H), 10.78 (s, 1H), 7.65 (s, 1H), 6.67 (s, 1H), 6.43 (s, 1H), 5.05 (d, J = 55.6 Hz, 1H), 4.79 (q, J = 8.9 Hz, 3H), 3.96 (s, 3H), 3.21 (s, 1H), 2.37 (d, J = 27.5 Hz, 2H), 2.12 - 1.71 (m , 2H), 1.26 (s, 3H), 0.62 (s, 2H), 0.50 (s, 2H). 489.20 -13 (1-Methylcyclopropyl)carbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-(2,2,2-trifluoroethoxy)) -1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.33 (s, 1H), 10.78 (s, 1H), 7.65 (s, 1H), 6.68 (s, 1H), 6.43 (s, 1H), 5.05 (d, J = 55.6 Hz, 1H), 4.79 (q, J = 8.9 Hz, 3H), 3.96 (s, 3H), 3.21 (s, 1H), 2.40 (s, 2H), 1.98 - 1.70 (m, 2H), 1.26 (s, 3H), 0.62 (s, 2H), 0.50 (s, 2H). 489.20 +28 (1-Methylcyclopropyl)carbamic acid (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.30 (s, 1H), 10.87 (s, 1H), 7.64 (s, 1H), 7.28 (s, 1H), 6.43 (s, 1H), 5.11 (s, 3H ), 4.99 (s, 1H), 4.09 (s, 3H), 3.22 (t, J = 8.9 Hz, 1H), 2.68 (p, J = 1.8 Hz, 1H), 2.41 (dd, J = 12.8, 6.9 Hz , 1H), 1.87 (dq, J = 44.6, 11.2, 9.2 Hz, 2H), 1.26 (s, 3H), 0.63 (q, J = 3.3 Hz, 2H), 0.50 (q, J = 4.4, 3.8 Hz, 2H). 489.15 -4 (1-Methylcyclopropyl)carbamic acid (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-((trifluoromethoxy)methyl)-1H -Pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.31 (s, 1H), 10.86 (s, 1H), 7.64 (s, 1H), 7.29 (s, 1H), 6.44 (s, 1H), 5.11 (s, 3H ), 4.91 - 4.80 (m, 1H), 4.09 (s, 3H), 3.22 (s, 1H), 2.68 (s, 1H), 2.41 (s, 1H), 2.10 - 1.76 (m, 2H), 1.26 ( s, 3H), 0.62 (t, J = 3.3 Hz, 2H), 0.50 (d, J = 2.3 Hz, 2H). 489.20 13 Bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-2-fluoro-4-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.34 (s, 1H), 10.80 (s, 1H), 8.07 (s, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 5.06 (d, J = 55.1 Hz, 1H), 4.80 (q, J = 8.9 Hz, 3H), 3.97 (s, 3H), 3.26 - 3.17 (m, 1H), 2.52 (s, 1H), 2.38 (s, 2H), 1.93 (s, 7H), 1.89 - 1.79 (m, 1H). 501.20 +200 Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2S,4S)-2-fluoro-4-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.34 (s, 1H), 10.80 (s, 1H), 8.07 (s, 1H), 6.68 (s, 1H), 6.44 (s, 1H), 5.06 (d, J = 55.1 Hz, 1H), 4.80 (q, J = 8.9 Hz, 3H), 3.96 (s, 3H), 3.26 - 3.17 (m, 1H), 2.52 (s, 1H), 2.38 (s, 2H), 1.93 (s, 7H), 1.88 - 1.79 (m, 1H). 501.20 -2 Isopropylcarbamic acid (1R,2S,4S)-4-(3-(3-((2,2-difluoroethoxy)methyl)-1-methyl-1H-pyrazole-5- Formamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.28 (s, 1H), 10.78 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.14 (s, 1H), 6.48 (d, J = 33.4 Hz, 1H), 6.16 (tt, J = 54.9, 3.8 Hz, 1H), 5.06 (d, J = 55.3 Hz, 1H), 4.96-4.69 (m, 1H), 4.53 (s, 2H), 4.06 (s , 3H), 3.72 (td, J = 15.2, 3.7 Hz, 2H), 3.61 (dq, J = 13.7, 6.8 Hz, 1H), 3.22 (s, 1H), 2.54 (d, J = 1.1 Hz, 1H) , 2.46-2.35 (m, 1H), 2.10-1.65 (m, 2H), 1.05 (d, J = 6.6 Hz, 6H). 473.25 -6.2 Isopropylcarbamic acid (1S,2R,4R)-4-(3-(3-((2,2-difluoroethoxy)methyl)-1-methyl-1H-pyrazole-5- Formamide)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.28 (s, 1H), 10.78 (s, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.14 (s, 1H), 6.43 (s, 1H), 6.16 (tt, J = 55.0, 3.8 Hz, 1H), 5.06 (d, J = 55.2 Hz, 1H), 4.94-4.75 (m, 1H), 4.53 (s, 2H), 4.06 (s, 3H), 3.72 (td, J = 15.2, 3.7 Hz, 2H), 3.66-3.50 (m, 1H), 3.28-3.14 (m, 1H), 2.55 (d, J = 10.0 Hz, 1H), 2.45-2.36 (m, 1H ), 2.10-1.71 (m, 2H), 1.06 (d, J = 6.6 Hz, 6H). 473.25 10.67 (1-Methylcyclopropyl)carbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-(2-(3-methylisoethazol-5-yl)acetamide) (yl)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.18 (s, 1H), 10.66 (s, 1H), 7.65 (s, 1H), 6.30 (s, 1H), 6.23 (s, 1H), 5.04 (d, J = 55.5 Hz, 1H), 4.86 (s, 1H), 3.83 (s, 2H), 3.18 (s, 1H), 2.62 (d, J = 2.2 Hz, 1H), 2.34 (s, 1H), 2.20 (s , 3H), 1.77 (d, J = 10.6 Hz, 2H), 1.25 (s, 3H), 0.61 (s, 2H), 0.49 (d, J = 2.4 Hz, 2H). 406.20 -3.3 (1-Methylcyclopropyl)carbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-(2-(3-methylisoethazol-5-yl)acetamide) (yl)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.18 (s, 1H), 10.66 (s, 1H), 7.65 (s, 1H), 6.30 (s, 1H), 6.23 (s, 1H), 5.04 (d, J = 55.6 Hz, 1H), 4.86 (s, 1H), 3.83 (s, 2H), 3.18 (s, 1H), 2.52 (s, 1H), 2.33 (d, J = 2.0 Hz, 1H), 2.20 (s , 3H), 1.79 (t, J = 11.6 Hz, 2H), 1.25 (s, 3H), 0.61 (s, 2H), 0.49 (d, J = 2.4 Hz, 2H). 406.20 3.57 Bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1 ,5-a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.15 (s, 1H), 9.99 (s, 1H), 8.02 (d, J = 5.7 Hz, 2H), 7.41-7.23 (m, 2H), 6.63 (s, 1H ), 5.07 (d, J = 55.0 Hz, 1H), 4.88 (s, 1H), 4.56 (s, 2H), 3.33 (s, 3H), 3.25-3.19 (m, 1H), 2.62 (d, J = 40.3 Hz, 1H), 2.38 (d, J = 11.2 Hz, 2H), 1.93 (s, 8H). 456.30 12 Bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1 ,5-a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.16 (s, 1H), 9.96 (s, 1H), 8.03 (d, J = 10.7 Hz, 2H), 7.41-7.25 (m, 2H), 6.66 (s, 1H ), 5.07 (dd, J = 56.1, 5.2 Hz, 1H), 4.87 (s, 1H), 4.56 (s, 2H), 3.32 (s, 3H), 3.22 (s, 1H), 2.68 (s, 1H) , 2.39 (d, J = 12.9 Hz, 2H), 1.93 (s, 8H). 456.25 -11 (1-Methylcyclopropyl)carbamate rel-(1R,2R,4S)-2-fluoro-4-(3-(2-(3-methylisoethazol-5-yl)acetamide) (yl)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.18 (s, 1H), 10.65 (s, 1H), 7.56 (s, 1H), 6.26 (d, J = 41.0 Hz, 2H), 5.15 - 4.91 (m, 2H ), 3.82 (s, 2H), 2.58 (dd, J = 14.2, 7.5 Hz, 1H), 2.20 (s, 4H), 1.97 (s, 1H), 1.87 (s, 1H), 1.24 (s, 4H) , 0.61 (s, 2H), 0.48 (d, J = 2.2 Hz, 2H). 406.15 29 (1-Methylcyclopropyl)carbamate rel-(1R,2R,4S)-2-fluoro-4-(3-(2-(3-methylisoethazol-5-yl)acetamide) (yl)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.18 (s, 1H), 10.64 (s, 1H), 7.56 (s, 1H), 6.26 (d, J = 41.1 Hz, 2H), 5.21 - 4.91 (m, 2H ), 3.82 (s, 2H), 2.63 - 2.55 (m, 1H), 2.20 (s, 4H), 1.96 (s, 1H), 1.57 (s, 1H), 1.24 (s, 4H), 0.61 (s, 2H), 0.48 (d, J = 2.1 Hz, 2H). 406.15 -20 Isopropylcarbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazolo-4) -yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.17 (s, 1H), 9.97 (s, 1H), 8.02 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 9.4 Hz, 2H), 6.66 (s, 1H), 5.17 - 4.97 (m, 1H), 4.91 - 4.81 (m, 1H), 4.56 (s, 2H), 3.61 (dq, J = 13.5, 6.7 Hz, 1H) , 3.32 (s, 3H), 3.22 (s, 1H), 2.51 (s, 1H), 2.49 (s, 1H), 1.88 (q, J = 11.2 Hz, 2H), 1.06 (dd, J = 6.5, 1.2 Hz, 6H). 432.25 +5 Isopropylcarbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazolo-4) -yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.17 (s, 1H), 9.99 (s, 1H), 8.02 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.26 (d, J = 8.9 Hz, 2H), 6.65 (s, 1H), 5.07 (d, J = 55.2 Hz, 1H), 4.91 - 4.81 (m, 1H), 4.56 (s, 2H), 3.61 (dq, J = 13.5, 6.7 Hz , 1H), 3.32 (s, 3H), 3.23 (d, J = 9.2 Hz, 1H), 2.51 (s, 1H), 2.41 (s, 1H), 1.88 (d, J = 11.0 Hz, 2H), 1.06 (dd, J = 6.6, 1.2 Hz, 6H). 432.20 -4 (1-Methylcyclopropyl)carbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5- a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.18 (s, 1H), 10.03 (s, 1H), 8.03 (s, 1H), 7.63 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.28 (s, 1H), 6.62 (s, 1H), 5.06 (d, J = 55.3 Hz, 1H), 4.95-4.78 (m, 1H), 4.56 (s, 2H), 3.37 (s, 3H), 3.22 (t, J = 8.6 Hz, 1H), 2.57 (s, 1H), 2.46-2.31 (m, 1H), 1.87 (p, J = 13.9, 11.7 Hz, 2H), 1.26 (s, 3H), 0.62 ( s, 2H), 0.50 (s, 2H). 444.30 13 (1-Methylcyclopropyl)carbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1,5- a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester 1H NMR (400 MHz, DMSO-d6) 12.18 (s, 1H), 10.05 (s, 1H), 8.03 (s, 1H), 7.63 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.28 (s, 1H), 6.62 (s, 1H), 5.06 (d, J = 55.4 Hz, 1H), 4.85 (d, J = 22.8 Hz, 1H), 4.56 (s, 2H), 3.41 (s, 3H ), 3.23 (d, J = 8.7 Hz, 1H), 2.57 (s, 1H), 2.46-2.29 (m, 1H), 1.89 (dd, J = 28.4, 17.0 Hz, 2H), 1.26 (s, 3H) , 0.63 (d, J = 4.9 Hz, 2H), 0.50 (s, 2H). 444.30 -5 Example 14 Bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl Bicyclo [ 1.1.1 ] pentan - 1 - ylcarbamate rel _ _ _ _ _ _ _ -(1S,2R,4S)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl -1H- pyrazole -5- methamide )-1H- pyrazole Azol -5- yl )-2- methoxycyclopentyl ester Racemic- (1-( tert-butyl )-3-((1R,3R,4R)-3- hydroxy -4- methoxycyclopentyl )-1H- pyrazol -5- yl ) amine Benzyl formate

Step 1. To (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl)-1H-pyrazole-5- To a stirred solution of benzyl carbamate (2.5 g, 1 Eq, 7.0 mmol) in MeOH (20 mL) was added concentrated H ₂ SO ₄ (69 mg, 37 μL, 0.1 Eq, 0.70 mmol). The reaction was stirred at room temperature overnight. The mixture was adjusted to pH 7 with _NaHCO3 (aq.) and extracted three times with DCM. The combined organic layers were concentrated and purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 40% to 60% gradient in 10 min; detector, UV 220 nm , obtaining racemic -(1-(tert-butyl)-3-((1R,3R,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyridine as a colorless oily substance Benzyl azol-5-yl)carbamate (2.2 g, 5.7 mmol, 81%). m/z (ES ⁺ ) [M+H] ⁺ = 388.40; HPLC tR = 0.792 min. Racemic -4- nitrobenzoic acid (1S,2R,4S)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H - pyrazole- 3- yl )-2- methoxycyclopentyl ester

Step 2. Racemize -(1-(tert-butyl)-3-((1R,3R,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyridine under _N To a stirred solution of benzylazol-5-yl)carbamate (2.2 g, 1 Eq, 5.7 mmol) and 4-nitrobenzoic acid (1.1 g, 1.2 Eq, 6.8 mmol) in THF (25 mL) was added Ph ₃ P (4.5 g, 3 Eq, 17 mmol). To the above reaction, DIAD (3.4 g, 3.3 mL, 3 Eq, 17 mmol) was added at 0°C. The reaction was stirred at room temperature for 3 h. The mixture was concentrated and purified by reversed phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 70% gradient in 8 min; detector, UV 220 nm, to obtain a Yellow oil racemic-4-nitrobenzoic acid (1S, 2R, 4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)- 1H-pyrazol-3-yl)-2-methoxycyclopentyl ester (1.9 g, 3.5 mmol, 62%). m/z (ES ⁺ ) [M+H] ⁺ =537.40; HPLC tR = 1.075 min. Racemic- (1-( tert-butyl )-3-((1R,3S,4R)-3- hydroxy -4- methoxycyclopentyl )-1H- pyrazol -5- yl ) amine Benzyl formate

Step 3. To 4-nitrobenzoic acid (1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazole- To a stirred solution of 3-yl)-2-methoxycyclopentyl ester (1.9 g, 1 Eq, 3.5 mmol) in MeOH/THF (10 mL) was added LiOH (0.13 g, 1.5 Eq, 5.3 mmol). Solution in H ₂ O (2 mL). The reaction was stirred at room temperature for 1 h. The mixture was adjusted to pH 6-7 with HCl (1 M), extracted three times with EA and concentrated. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 50% gradient in 8 min; detector, UV 220 nm, resulting in a yellow color Oil racemic -(1-(tert-butyl)-3-((1R,3S,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyrazole-5- Benzyl carbamate (1.0 g, 2.6 mmol, 73%). m/z (ES ⁺ ) [M+H] ⁺ = 388.30; HPLC tR =1.030 min. Racemic- (1-( tert-butyl )-3-((1S,3R,4S)-3- methoxy -4-(((4- nitrophenoxy ) carbonyl ) oxy ) ring Pentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 4. Racemize -(1-(tert-butyl)-3-((1R,3S,4R)-3-hydroxy-4-methoxycyclopentyl)-1H-pyrazole-5- To a stirred solution of benzyl carbamate (1 g, 1 Eq, 3 mmol) in DCM (10 mL) was added pyridine (0.6 g, 0.6 mL, 3 Eq, 8 mmol). To the above reaction was added 4-nitrophenyl chloroformate (0.8 g, 1.5 Eq, 4 mmol) at 0°C. The reaction was stirred at room temperature overnight. The mixture was concentrated and purified by reversed phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 60% to 100% gradient in 8 min; detector, UV 220 nm, to obtain a Colorless oil racemic -(1-(tert-butyl)-3-((1S,3R,4S)-3-methoxy-4-((4-nitrophenoxy)carbonyl) )oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (660 mg, 1.19 mmol, 50%). m/z (ES ⁺ ) [M+H] ⁺ = 553.40; HPLC tR = 1.067 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tertiary Butyl )-1H pyrazol -3- yl )-2- methoxycyclopentyl ester

Step 5. Racemize -(1-(tert-butyl)-3-((1S,3R,4S)-3-methoxy-4-((4-nitrophenoxy)carbonyl) To a stirred solution of benzyl (oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (660 mg, 1 Eq, 1.19 mmol) in THF (10 mL) was added DIEA (926 mg, 1.25 mL, 6 Eq, 7.17 mmol) and bicyclo[1.1.1]pentan-1-amine hydrochloride (429 mg, 3 Eq, 3.58 mmol). The reaction was stirred at room temperature overnight. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 60% to 100% gradient in 10 min; detector, UV 220 nm, to obtain a Yellow oil, racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amine)- 1-(tert-Butyl)-1H pyrazol-3-yl)-2-methoxycyclopentyl ester (400 mg, 805 μmol, 67.4%). m/z (ES ⁺ ) [M+H] ⁺ = 497.40; HPLC tR = 1.186 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tertiary Butyl )-1H pyrazol -3- yl )-2- methoxycyclopentyl ester

Step 6. Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(((benzyloxy)carbonyl)amine) at room temperature (390 mg, 1 Eq, 785 μmol) and Pd/C (41.8 mg, 0.5 A stirred mixture of Eq, 393 μmol) in THF/EA (10 mL) was treated with H for ₁ h. The mixture was filtered and concentrated. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 8 min; detector, UV 220 nm, resulting in a white color Solid racemic-bicyclo[1.1.1]pentan-1-ylcarbamic acid (1S,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazole -3-yl)-2-methoxycyclopentyl ester (240 mg, 662 μmol, 84.3%). m/z (ES ⁺ ) [M+H] ⁺ = 363.15; HPLC tR = 0.658 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(1-( tert-butyl )-5-(3-(2,2- di Fluoroethoxy )-1- methyl -1H- pyrazole - 5 -methamide )-1H- pyrazol -3- yl )-2- methoxycyclopentyl ester

Step 7. Racemize -bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-amino-1-(tert-butyl)-1H- Pyrazol-3-yl)-2-methoxycyclopentyl ester (120 mg, 1 Eq, 331 μmol) and 3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazol To a solution of azole-5-carboxylic acid (68.2 mg, 1 Eq, 331 μmol) in EA (5 mL) was added DIEA (214 mg, 288 μL, 5 Eq, 1.66 mmol). To the above reaction was added T ₃ P/EA (632 mg, 50% Wt, 3 Eq, 993 μmol)) at 0°C. The reaction was stirred at 80°C for 2 hours. The mixture was quenched with water, filtered and extracted three times with EA. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 50% to 80% gradient in 10 min; detector, UV 254 nm, resulting in colorless Oil racemic-bicyclo[1.1.1]pentan-1-ylcarbamic acid (1S,2R,4S)-4-(1-(tert-butyl)-5-(3-(2) ,2-Difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-methoxycyclopentyl ester (170 mg , 309 μmol, 93.3%). m/z (ES ⁺ ) [M+H] ⁺ = 551.30; HPLC tR = 1.152 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2 -difluoroethoxy )-1- methyl ( 1H- pyrazole -5- methamide )-1H- pyrazol -3- yl )-2- methoxycyclopentyl ester

Step 8. Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(1-(tert-butyl)-5-(3-(2) ,2-Difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-methoxycyclopentyl ester (165 mg , 1 Eq, 300 μmol) was dissolved in FA (5 mL). The reaction was stirred at 80°C for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 60% to 80% gradient in 8 min; detector, UV 254 nm, to obtain a White solid racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)- 1-Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-methoxycyclopentyl ester (130 mg, 263 μmol, 87.7%). m/z (ES ⁺ ) [M+H] ⁺ = 495.40; HPLC tR = 0.817 min. Bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2 -difluoroethoxy )-1 - methyl- 1H- pyrazole -5- methamide )-1H- pyrazol -5- yl )-2- methoxycyclopentyl ester bicyclo [1.1.1] pentan -1- ylcarbamate rel-( 1S,2R,4S)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl -1H- pyrazole -5- methamide )-1H - pyrazole- 5- yl )-2- methoxycyclopentyl ester

Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1- Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-methoxycyclopentyl ester (130 mg, 1 Eq, 263 μmol) was prepared by preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate :20 mL/min; Gradient: 50% B to 50% B in 11 minutes; Wavelength: 220/254 nm; RT1(min): 6.98; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.3 mL; Runs: 9) Purification. Lyophilization gave bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethyl)) as a white amorphous solid. Oxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)-2-methoxycyclopentyl ester (35.8 mg, 71.5 μmol, 54% , 98.8% purity). m/z (ES ⁺ ) [M+H] ⁺ =495.25; HPLC tR = 1.248 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.22 (s, 1H), 10.72 (s, 1H), 7.87 (s, 1H), 6.64 (s, 1H), 6.52-6.22 (m, 2H), 4.96 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.72 (q, J = 6.1, 5.6 Hz, 1H), 3.26 (s, 3H), 3.10 ( d, J = 10.0 Hz, 1H), 2.42-2.26 (m, 3H), 1.91 (s, 6H), 1.74 (s, 2H).

Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1- Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-methoxycyclopentyl ester (130 mg, 1 Eq, 263 μmol) was prepared by preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate :20 mL/min; Gradient: 50% B to 50% B in 11 minutes; Wavelength: 220/254 nm; RT2(min): 8.70; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.3 mL; number of runs: 9) Purification. Lyophilization gave bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethyl)) as a white amorphous solid. Oxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)-2-methoxycyclopentyl ester (37.3 mg, 75.0 μmol, 57% , 99.4% purity). m/z (ES ⁺ ) [M+H] ⁺ =495.20; HPLC tR = 0.826 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) 12.22 (s, 1H), 10.72 (s, 1H), 7.88 (s, 1H), 6.64 (s, 1H), 6.53-6.20 (m, 2H), 4.96 (s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.72 (q, J = 6.2, 5.6 Hz, 1H), 3.26 (s, 3H), 3.11 ( d, J = 9.9 Hz, 1H), 2.45-2.23 (m, 3H), 1.91 (s, 6H), 1.74 (s, 2H). Example 15 Bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl 1H - pyrazole - 5 - carboxylic acid rel- ( _ _ _ _ _ _ _ 1S,2R,4S)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl -1H- pyrazole -5- methamide )-1H - pyrazole- 5- yl )-2- hydroxycyclopentyl ester Racemic - acetic acid (1R,2R,4R)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H- pyrazol -3- yl )- 2- hydroxycyclopentyl ester

Step 1. Charge (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl)-1H into a round-bottomed flask. -Benzyl-pyrazol-5-yl)carbamate (1 g, 3 mmol), BF ₃ OEt ₂ (0.6 g, 4 mmol), AcOH (10 mL) and stir bar, then evacuated and purged with nitrogen three times , and the solution was stirred at 0°C for 2 h. The solution was quenched with saturated _NH4Cl . The solution was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 20% to 60% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-acetic acid (1R,2R,4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H as a white solid -pyrazol-3-yl)-2-hydroxycyclopentyl ester (950 mg, 80%). m/z (ES ⁺ ) [M+H] ⁺ = 416.40; HPLC tR = 0.825 min. Racemic -4- nitrobenzoic acid (1S,2R,4S)-2- acetyloxy -4-(5-(( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 2. Racemize -acetic acid (1R, 2R, 4R)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl) at 0°C under nitrogen atmosphere )-1H-pyrazol-3-yl)-2-hydroxycyclopentyl ester (0.95 g, 2.29 mmol), 4-nitrobenzoic acid (459 mg, 2.74 mmol) and PPh ₃ (1.38 g, 5.26 mmol) To the mixture in THF (10 mL) was added DIAD (1.06 g, 5.26 mmol) dropwise. The mixture was stirred at 0 °C for 1 h. The mixture was stirred at 25 °C for an additional 12 h. The reaction mixture was diluted with _H2O (60 mL), and the aqueous phase was extracted three times with EA (90 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 30% to 70% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-4-nitrobenzoic acid (1S,2R,4S)-2-acetyloxy-4-(5-((benzyloxy)carbonyl)amine as a yellow solid )-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (1.16 g, 89.9%). m/z (ES ⁺ ) [M+H] ⁺ =565.40; HPLC tR = 1.278 min. Racemic- (1-( tert-butyl )-3-((1r,3R,4S)-3,4 -dihydroxycyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 3. Charge racemic-4-nitrobenzoic acid (1S,2R,4S)-2-acetyloxy-4-(5-((benzyloxy)carbonyl)amine into the round bottom flask (1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ester (1.16 g, 2.05 mmol), LiOH (3.08 mL, 1M, 3.08 mmol), MeOH/THF (12 mL ) and stirring rod, then evacuated and purged with nitrogen three times, and the solution was stirred at 25°C for 1 h. The residue was diluted with water, then adjusted to pH 7~8 with 1 M HCl, and the aqueous phase was extracted three times with EA (150 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 70% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic -(1-(tert-butyl)-3-((1r,3R,4S)-3,4-dihydroxycyclopentyl)-1H-pyrazole- as a white solid) 5-yl)benzylcarbamate (0.56 g, 73.0%). m/z (ES ⁺ ) [M+H] ⁺ = 374.40; HPLC tR = 0.725 min. Racemic- (1-( tert-butyl )-3-((1S,3S,4R)-3-(( tert-butyldiphenylsilyl ) oxy )-4- hydroxycyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 4. Racemize -(1-(tert-butyl)-3-((1r,3R,4S)-3,4-dihydroxycyclopentyl)-1H- at 0°C under nitrogen atmosphere To a mixture of benzyl pyrazol-5-yl)carbamate (460 mg, 1.23 mmol) and 1-methylimidazole (607 mg, 7.39 mmol) in DCM (5 mL) was added portionwise TBDPSCl (675 mg, 2.46 mmol). The mixture was stirred at 25 °C for 5 h. The reaction mixture was diluted with _H2O (30 mL), and the aqueous phase was extracted three times with EA (60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo gave racemic -(1-(tert-butyl)-3-((1S,3S,4R)-3-((tert-butyldiphenylsilyl)oxy) as a white solid Benzyl)-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (765 mg, 91%). m/z (ES ⁺ ) [M+H] ⁺ = 612.50; HPLC tR = 1.486 min. Racemic- (1-( tert-butyl )-3-((1R,3R,4S)-3-(( tert-butyldiphenylsilyl ) oxy )-4-(((4 -Nitrophenoxy ) carbonyl ) oxy ) cyclopentyl )-1H- pyrazol - 5- yl ) carbamic acid benzyl ester

Step 5. Racemize -(1-(tert-butyl)-3-((1R,3R,4S)-3-((tert-butyldiphenylmethane) at 0°C under nitrogen atmosphere Benzyl)oxy)-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamate (800 mg, 1.31 mmol), DMAP (32 mg, 0.26 mmol) and pyridine (310 mg, To a mixture of 3.92 mmol) in THF (9 mL) was added portionwise 4-nitrophenyl chloroformate (527 mg, 2.61 mmol). The mixture was stirred at 25 °C for 4 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo gave racemic -(1-(tert-butyl)-3-((1R,3R,4S)-3-((tert-butyldiphenylsilyl)oxy) as a yellow solid Benzyl)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (820 mg, 80.7%). m/z (ES ⁺ ) [M+H] ⁺ = 777.60; HPLC tR = 1.572 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tertiary Butyl )-1H- pyrazol -3- yl )-2-(( tert-butyldiphenylsilyl ) oxy ) cyclopentyl ester

Step 6. Charge the resealable reaction vial with racemic-(1-(tert-butyl)-3-((1R,3R,4S)-3-((tert-butyldiphenylmethane) Benzyl)oxy)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (800 mg, 1.03 mmol) , bicyclo[1.1.1]pentan-1-amine hydrochloride (246 mg, 2.06 mmol), DMAP (12.6 mg, 0.10 mmol), DIEA (665 mg, 5.15 mmol), THF (10 mL) and stirring rod , then evacuated and purged with nitrogen three times, and the mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-((benzyloxy)carbonyl) as a white solid Amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl ester (600 mg, 80.8 %). m/z (ES ⁺ ) [M+H] ⁺ = 721.65; HPLC tR = 1.092 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(5- amino -1-( tert-butyl )-1H- pyrazole -3 -yl )-2 - (( tert-butyldiphenylsilyl ) oxy ) cyclopentyl ester

Step 7. Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-((benzyloxy)carbonyl)amine at 25°C yl)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl ester (780 mg, 1.08 mmol ) and Pd/C (11.5 mg, 0.11 mmol) in THF/EA (10 mL) was treated with H ₂ for 1 h. The reaction mixture was filtered through a pad of celite, the pad was washed with EA, and the filtrate was concentrated in vacuo. Concentration in vacuo yielded racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-amino-1-(tert-butyl) as a white solid yl)-1H-pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl ester (470 mg, 74.0%). m/z (ES ⁺ ) [M+H] ⁺ = 587.55; HPLC tR = 1.244 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(1-( tert-butyl )-5-(3-(2,2- di Fluoroethoxy )-1- methyl - 1Hpyrazole - 5- methamide )-1H- pyrazol -3- yl )-2-(( tert-butyldiphenylsilyl ) oxy ) cyclopentyl ester

Step 8. Racemize -bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-amino-1-( tert-Butyl)-1H-pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl ester (450 mg, 0.77 mmol), DIEA (991 mg , 7.67 mmol) and 3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-carboxylic acid (174 mg, 0.84 mmol) in EA (10 mL), T ₃ P (3.90 g, , 50% Wt, 6.13 mmol) was added dropwise. The mixture was stirred at 80 °C for 2 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (PE/EA; ratio: 20/1) to give racemic-bicyclo[1.1.1]pentan-1-ylcarbamic acid (1S,2R, 4R)-4-(1-(tert-butyl)-5-(3-(2,2-difluoroethoxy)-1-methyl-1H pyrazole-5-methamide)-1H -pyrazol-3-yl)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl ester (500 mg, 84.1%). m/z (ES ⁺ ) [M+H] ⁺ = 775.60; HPLC tR = 1.519 min. Racemic - Formic acid (1R,2S,4S)-2-(( bicyclo [1.1.1] pent -1- ylaminoformyl ) oxy )-4-(5-(3-(2, 2 -Difluoroethoxy )-1- methyl -1H- pyrazole -5 -methamide )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 9. Charge the resealable reaction vial with racemic-bicyclo[1.1.1]pentan-1-ylcarbamic acid (1S,2R,4R)-4-(1-(tert-butyl) -5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazole-3-yl)-2-(( 3-Butyldiphenylsilyloxy)cyclopentyl ester (450 mg, 0.58 mmol), FA (3 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the mixture was heated at 80°C Stir for 3 hours. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-formic acid (1R,2S,4S)-2-((bicyclo[1.1.1]pent-1-ylaminoformyl)oxy)-4- as a white solid (5-(3-(2,2-Difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)cyclopentyl ester ( 190 mg, 64.4%). m/z (ES ⁺ ) [M+H] ⁺ = 509.30; HPLC tR = 1.036 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2 -difluoroethoxy )-1- methyl ( 1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) -2hydroxycyclopentyl ester

Step 10. Charge the resealable reaction vial with racemic-formic acid (1R,2S,4S)-2-((bicyclo[1.1.1]pentan-1-ylaminoformyl)oxy) -4-(5-(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)cyclopentan ester (180 mg, 354 μmol), LiOH (0.35 mL, 1M, 354 μmol), THF/MeOH (3 mL) and a stirring rod, then evacuated and purged with nitrogen three times, and the mixture was stirred at 25°C for 1 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Lyophilized to obtain racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethyl)) as a white solid Oxy)-1-methyl-1Hpyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2hydroxycyclopentyl ester (160 mg, 94.1%). m/z (ES ⁺ ) [M+H] ⁺ =481.30; HPLC tR = 0.953 min. Bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2 -difluoroethoxy )-1 - methyl- 1H- pyrazole -5- methamide )-1H- pyrazol -5- yl )-2- hydroxycyclopentyl ester bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1S, 2R,4S)-4-(3-(3-(2,2- difluoroethoxy )-1- methyl -1H- pyrazole -5- methamide )-1H- pyrazole -5- hydroxy )-2- hydroxycyclopentyl ester

Step 11. Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy) -1-Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-hydroxycyclopentyl ester (130 mg, 271 μmol) by preparative HPLC (Column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min; Gradient: 90% B to 90% B in 30 minutes; Wavelength: 220/254 nm; RT1(min): 3.44; RT2(min): 14.45; Sample solvent: EtOH:DCM=1:1-- HPLC; injection volume: 2.4 mL; number of runs: 1) Purification. Lyophilization gave bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethyl)) as a white amorphous solid. Oxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)-2-hydroxycyclopentyl ester (42.1 mg, 65%). m/z (ES ⁺ ) [M+H] ⁺ = 481.25; HPLC tR = 1.418 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.72 (s, 1H), 7.77 (s, 1H), 6.64 (s, 1H), 6.54 - 6.19 (m, 2H), 4.78 (dd, 2H), 4.37 (td, 2H), 4.08 - 4.00 (m, 1H), 3.95 (s, 3H), 3.09 - 3.01 (m, 1H), 2.44 - 2.21 (m, 3H), 1.92 (s , 6H), 1.72 (d, 2H).

Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1- Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-hydroxycyclopentyl ester (130 mg, 271 μmol) was analyzed by preparative HPLC (column : CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min ;Gradient: 90% B to 90% B in 30 minutes; Wavelength: 220/254 nm; RT1(min): 3.44; RT2(min): 14.45; Sample solvent: EtOH:DCM=1:1--HPLC; Injection Volume: 2.4 mL; Number of runs: 1) Purification. Lyophilization gave bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethyl)) as a white amorphous solid. Oxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)-2-hydroxycyclopentyl ester (43.2 mg, 66%). m/z (ES ⁺ ) [M+H] ⁺ =481.20; HPLC tR =1.418 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.72 (s, 1H), 7.77 (s, 1H), 6.64 (s, 1H), 6.55 - 6.19 (m, 2H), 4.78 (dd, 2H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 4.08 - 3.99 (m, 1H), 3.95 (s, 3H), 3.10 - 3.01 (m, 1H), 2.39 - 2.22 (m , 3H), 1.92 (s, 6H), 1.72 (d, 2H). Example 16 Isopropylcarbamic acid rel-(1R,2S,4S)-2- fluoro -4-(3-((2-( methoxymethyl ) pyrazolo [1,5-a] pyrazamide ) -4- yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester isopropylcarbamate rel-(1S,2R,4R)-2- fluoro -4-(3-((2 -( Methoxymethyl ) pyrazolo [1,5-a] pyrid -4- yl ) amino )-1H- pyrazol - 5- yl ) cyclopentyl ester Racemic- (1-( tert-butyl )-3-((1S,3S,4S)-3- fluoro -4- hydroxycyclopentyl )-1H pyrazol -5- yl ) carbamic acid benzyl ester

Step 1. Charge (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl)-1H into a round-bottomed flask. -pyrazol-5-yl)benzyl carbamate (8.00 g, 0.02 mol), Et ₃ N-3HF (80 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the mixture was heated at 60°C Stir for 12 hours. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo gave racemic -(1-(tert-butyl)-3-((1S,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H pyrazole- as a white solid 5-yl)benzylcarbamate (6.00 g, 70%). m/z (ES ⁺ ) [M+H] ⁺ = 376.20; HPLC tR = 1.042 min. Racemic -4- nitrobenzoic acid (1R,2S,4S)-4-(5-(( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H - pyrazole- 3- yl )-2- fluorocyclopentyl ester

Step 2. Racemize -(1-(tert-butyl)-3-((1S,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H at 0°C under nitrogen atmosphere -Benzyl-pyrazol-5-yl)carbamate (6.00 g, 0.02 mol) and 4-nitrobenzoic acid (3.00 g, 0.02 mol), Ph ₃ P (10.00 g, 0.04 mol) in THF (60 mL ), DIAD (7.00 g, 0.04 mol) was added dropwise to the mixture. The mixture was stirred at 0 °C for 1 h. The mixture was stirred at 25 °C for an additional 12 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-4-nitrobenzoic acid (1R,2S,4S)-4-(5-((benzyloxy)carbonyl)amine)-1-(tertiary) as a white solid Butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (7.60 g, 90%). m/z (ES ⁺ ) [M+H] ⁺ = 525.25; HPLC tR = 1.332 min. Racemic- (1-( tert-butyl )-3-((1S,3S,4R)-3- fluoro -4- hydroxycyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 3. Charge racemic-4-nitrobenzoic acid (1R,2S,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(No. Tributyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (7.60 g, 14.00 mmol), LiOH (43 mL, 1 M, 43.00 mmol), THF/MeOH (80 mL) and Stir bar, then evacuate and purge with nitrogen three times. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with H ₂ O (50 mL), the pH value of the solution was adjusted to 6~8 with 1 M HCl, and the aqueous phase was extracted three times with EA (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 90% gradient in 15 min; detector, UV 254 nm. Concentration in vacuo gave racemic -(1-(tert-butyl)-3-((1S,3S,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazole as a white solid Benzyl-5-yl)carbamate (3.68 g, 68%). m/z (ES ⁺ ) [M+H] ⁺ = 376.20; HPLC tR = 1.012 min. Racemic- (1-( tert-butyl )-3-((1S,3R,4S)-3-(( tert-butyldimethylsilyl ) oxy )-4- fluorocyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 4. Racemize -(1-(tert-butyl)-3-((1S,3S,4R)-3-fluoro-4-hydroxycyclopentyl)-1H at 0°C under nitrogen atmosphere To a mixture of benzyl-pyrazol-5-yl)carbamate (4.10 g, 11.00 mmol) and 1H-imidazole (5.40 g, 66.00 mmol) in DMF (50 mL) was added dropwise tert-butyldichloride Methylsilane (6.60 g, 44.00 mmol). The mixture was stirred at 25 °C for 2 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic -(1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethylsilyl)oxy) as a white solid Benzyl)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)carbamate (4.60 g, 86%). m/z (ES ⁺ ) [M+H] ⁺ = 409.30; HPLC tR = 1.502 min. Racemic -1-( tert-butyl )-3-((1S,3R,4S)-3-(( tert-butyldimethylsilyl ) oxy )-4- fluorocyclopentyl ) -1H- pyrazole -5- amine

Step 5. Combine racemic-(1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethylsilyl)oxy) at 25°C )-4-fluorocyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (4.60 g, 9.40 mmol) and Pd/C (0.10 g, 0.94 mmol) in THF/EA (40 mL) The stirred mixture was treated with _H2 for 1 h. The reaction mixture was filtered through a pad of celite, the pad was washed with EA, and the filtrate was concentrated in vacuo. This produces racemic-1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethylsilyl)oxy)-4 as a white solid -Fluorocyclopentyl)-1H-pyrazole-5-amine (3.10 g, 93%). m/z (ES ⁺ ) [M+H] ⁺ = 356.20; HPLC tR = 1.358 min. Racemic -N-(1-( tert-butyl )-3-((1S,3R,4S)-3-(( tert-butyldimethylsilyl ) oxy )-4- fluorocyclic Pentyl )-1H- pyrazol -5- yl )-2-( methoxymethyl ) pyrazolo [1,5-a] pyrazol - 4- amine

Step 6. Racemize -1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethylsilyl) at 0°C under nitrogen atmosphere )Oxy)-4-fluorocyclopentyl)-1H-pyrazole-5-amine (1.00 g, 3.00 mmol) in DMF (10 mL) was added portion-wise NaH (0.40 g, 60% Wt, 0.01 mol). The mixture was stirred at 0°C for 5 min, followed by the addition of 4-chloro-2-(methoxymethyl)pyrazolo[1,5-a]pyrazolin (1.50 g, 6.00 mmol). The mixture was stirred at 25 °C for 8 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-N-(1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethylsilyl)) as a white solid )oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(methoxymethyl)pyrazolo[1,5-a]pyrazol-4-amine (0.60 g, 40%). m/z (ES+) [M+H] + = 517.25; HPLC tR = 1.428 min. Racemic- (1R,2S,4S)-4-(1-( tert-butyl )-5-((2-( methoxymethyl ) pyrazolo [1,5-a] pyra 𠯤 - 4- yl ) amino )-1H- pyrazol -3- yl )-2- fluorocyclopent -1- ol

Step 7. Charge the resealable reaction vial with racemic-N-(1-(tert-butyl)-3-((1S,3R,4S)-3-((tert-butyldimethyl) Silyl)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(methoxymethyl)pyrazolo[1,5-a]pyrazolo-4- Amine (1.00 g, 2.00 mmol), 4-toluenesulfonic acid (0.40 g, 2.00 mmol), MeCN (10 mL) and stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo gave racemic -(1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[ 1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopent-1-ol (0.60 g, 80%). m/z (ES ⁺ ) [M+H] ⁺ = 403.20; HPLC tR = 0.822 min. Racemic - carbonic acid (1R,2S,4S)-4-(1-( tert-butyl )-5-((2-( methoxymethyl ) pyrazolo [1,5-a] pyrazolo ) -4- yl ) amino )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester (4- nitrophenyl ) ester

Step 8. Racemize -(1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyridine) at 0°C under nitrogen atmosphere Azolo[1,5-a]pyridin-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopent-1-ol (580 mg, 1.44 mmol), Py (342 mg, 4.32 mmol) and DMAP (35 mg, 0.29 mmol) in DCM (10 mL) was added dropwise 4-nitrophenyl chloroformate (436 mg, 2.16 mmol) in 10 mL DCM. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-carbonic acid (1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo)) as a white solid [1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (4-nitrophenyl) ester (700 mg, 85.6% ). m/z (ES ⁺ ) [M+H] ⁺ = 568.25; HPLC tR = 1.202 min. Racemic - isopropylcarbamic acid (1R,2S,4S)-4-(1-( tert-butyl )-5-((2-( methoxymethyl ) pyrazolo [1,5 -a] pyrid -4- yl ) amino )-1H- pyrazol - 3- yl )-2- fluorocyclopentyl ester

Step 9. Charge the resealable reaction vial with racemic-carbonic acid (1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)) Pyrazolo[1,5-a]pyridin-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (4-nitrophenyl) ester (300 mg , 0.53 mmol), propyl-2-amine (63 mg, 1.06 mmol), DIEA (342 mg, 2.64 mmol), THF (5 mL) and stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 25 °C for 1 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-isopropylcarbamic acid (1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methoxymethyl)) as a white solid (yl)pyrazolo[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (270 mg, 90%). m/z (ES ⁺ ) [M+H] ⁺ = 488.50; HPLC tR = 0.969 min. Racemic - isopropylcarbamic acid (1R,2S,4S)-2- fluoro -4-(5-((2-( methoxymethyl ) pyrazolo [1,5-a] pyrazolo ) -4- yl ) amino )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 10. Charge the resealable reaction vial with racemic-isopropylcarbamic acid (1R,2S,4S)-4-(1-(tert-butyl)-5-((2-(methyl) Oxymethyl)pyrazolo[1,5-a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (270 mg, 0.55 mmol) , FA (5 mL) and stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 80 °C for 2 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 10% to 50% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(5-((2-(methoxymethyl)pyrazolo) as a white solid [1,5-a]pyridin-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (150 mg, 62.8%). m/z (ES ⁺ ) [M+H] ⁺ = 432.35; HPLC tR = 0.836 min. Isopropylcarbamic acid rel-(1R,2S,4S)-2- fluoro - 4-(3-((2-( methoxymethyl ) pyrazolo [1,5-a] pyrazolo -4) -yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester isopropylcarbamate rel- (1S,2R,4R)-2- fluoro -4-(3-((2-( Methoxymethyl ) pyrazolo [1,5-a] pyrid - 4- yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester

Step 11. Racemic-isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(5-((2-(methoxymethyl)pyrazolo[1,5- a]pyrid-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (150 mg, 0.35 mmol) by palm preparative HPLC (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min; gradient: 65 within 11.5 min % B to 65% B; Wavelength: 220/254 nm; RT1(min): 6.26; RT2(min): 8.13; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.3 mL; Number of runs :11) Purification. Lyophilization produces isopropylcarbamic acid rel-(1R,2S,4S)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1)) as a white amorphous solid ,5-a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (45.8 mg, 61%). m/z (ES ⁺ ) [M+H] ⁺ = 432.25; HPLC tR = 0.892 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.97 (s, 1H), 8.02 (s, 1H), 7.39 (d, , 1H), 7.26 (d, Hz, 2H), 6.66 (s, 1H), 5.17 - 4.97 (m, 1H), 4.91 - 4.81 (m, 1H), 4.56 (s, 2H), 3.61 (dq, 1H), 3.32 (s, 3H), 3.22 (s, 1H), 2.51 (s, 1H), 2.49 (s, 1H), 1.88 (q, 2H), 1.06 (dd, 6H).

Racemic-isopropylcarbamic acid (1R,2S,4S)-2-fluoro-4-(5-((2-(methoxymethyl)pyrazolo[1,5-a]pyra 𠯤-4-yl)amino)-1H-pyrazol-3-yl)cyclopentyl ester (150 mg, 0.35 mmol) was analyzed by palm preparative HPLC (column: CHIRALPAK IE, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH3-MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL/min; gradient: 65% B to 11.5 min 65% B; Wavelength: 220/254 nm; RT1(min): 6.26; RT2(min): 8.13; Sample solvent: EtOH:DCM=1:1--HPLC; Injection volume: 0.3 mL; Number of runs: 11) Purification. Lyophilization produces isopropylcarbamate rel-(1S,2R,4R)-2-fluoro-4-(3-((2-(methoxymethyl)pyrazolo[1)) as a white amorphous solid ,5-a]pyridin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (38.2 mg, 51%). m/z (ES ⁺ ) [M+H] ⁺ = 432.20; HPLC tR =0.892 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.99 (s, 1H), 8.02 (s, 1H), 7.39 (d, 1H), 7.26 (d, 2H), 6.65 (s , 1H), 5.07 (d, 1H), 4.91 - 4.81 (m, 1H), 4.56 (s, 2H), 3.61 (dq, 1H), 3.32 (s, 3H), 3.23 (d, 1H), 2.51 ( s, 1H), 2.41 (s, 1H), 1.88 (d, 2H), 1.06 (dd, 6H). Example 17 Bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl Bicyclo [ 1.1.1 ] pentan - 1 - ylcarbamate rel- _ _ _ _ _ _ _ (1S,2R,4S)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl -1H- pyrazole -5 -methamide )-1H- pyrazole -5- yl )-2- methylcyclopentyl ester Racemic- (1-( tert-butyl )-3-((1S,3R,4R)-3- hydroxy -4- methylcyclopentyl )-1H- pyrazol -5- yl ) carbamic acid Benzyl ester

Step 1. Overlay the CuI mixture (13.00 g, 68.00 mmol) with anhydrous THF (30 mL) and cool the reaction to -20°C. After a few minutes, methylmagnesium chloride solution (5.6 mL, 3 molar in THF, 17.00 mmol) was added to the reaction over approximately 3 h. During the addition, care was taken to maintain the temperature of the external bath between -20°C and -25°C. The reaction was stirred at -25°C for 20 min, and (3-((1R,3s,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl) was added A solution of benzyl)-1H-pyrazol-5-yl)carbamate (1.50 g, 4.20 mmol) in THF (20 mL). The mixture was stirred at -18°C for 2 hours. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (120 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 0% to 60% in 20 min; detector, UV 254 nm. Concentration in vacuo gave racemic -(1-(tert-butyl)-3-((1S,3R,4R)-3-hydroxy-4-methylcyclopentyl)-1H-pyridine as a yellow solid Benzyl azol-5-yl)carbamate (1.20 g, 77%). m/z (ES ⁺ ) [M+H] ⁺ = 372.10; HPLC tR = 0.862 min. Racemic -4- nitrobenzoic acid (1S,2R,4S)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H - pyrazole- 3- yl )-2- methylcyclopentyl ester

Step 2. Racemize -(1-(tert-butyl)-3-((1S,3R,4R)-3-hydroxy-4-methylcyclopentyl)- at 0°C under nitrogen atmosphere 1H-pyrazol-5-yl)carbamic acid benzyl ester (1.49 g, 4.01 mmol), 4-nitrobenzoic acid (0.80 g, 4.81 mmol) and PPh3 (2.42 g, 9.23 mmol) in THF (15 mL) DIAD (1.87 g, 9.23 mmol) was added dropwise to the mixture. The mixture was stirred at 0 °C for 1 h. The mixture was stirred at 25 °C for 6 h. The reaction mixture was diluted with _H2O (30 mL), and the aqueous phase was extracted three times with EA (90 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-4-nitrobenzoic acid (1S,2R,4S)-4-(5-((benzyloxy)carbonyl)amine)-1-(tertiary) as a yellow solid Butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (1.60 g, 77%). m/z (ES ⁺ ) [M+H] ⁺ = 521.25; HPLC tR = 1.158 min. Racemic- (1-( tert-butyl )-3-((1S,3S,4R)-3- hydroxy -4- methylcyclopentyl )-1H- pyrazol -5- yl ) carbamic acid Benzyl ester

Step 3. Charge racemic-4-nitrobenzoic acid (1S, 2R, 4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(No. Tributyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (1.60 g, 3.10 mmol), LiOH (4.60 mL, 1 M, 4.60 mmol), THF/MeOH (20 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the solution was stirred at 25°C for 1 h. The residue was diluted with water (30 mL), then adjusted to pH 6~7 with 1 M HCl, and the aqueous phase was extracted three times with EA (90 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 60% to 90% gradient in 20 min; detector, UV 254 nm, in vacuum Concentration gave racemic -(1-(tert-butyl)-3-((1S,3S,4R)-3-hydroxy-4-methylcyclopentyl)-1H-pyrazole-5 as a yellow solid -Benzyl carbamate (0.90 g, 79%). m/z (ES ⁺ ) [M+H] ⁺ = 372.30; HPLC tR = 1.111 min. Racemic- (1-( tert-butyl )-3-((1S,3R,4S)-3- methyl -4-(((4- nitrophenoxy ) carbonyl ) oxy ) cyclopentyl Benzyl )-1H- pyrazol -5- yl ) carbamate

Step 4. Racemize -(1-(tert-butyl)-3-((1S,3S, 4R)-3-hydroxy-4-methylcyclopentyl)- at 0°C under nitrogen atmosphere To a mixture of benzyl 1H-pyrazol-5-yl)carbamate (292.00 mg, 0.79 mmol) and pyridine (187.00 mg, 2.36 mmol) in THF (3 mL) was added dropwise 4-nitrobenzene chloroformate. ester (317.00 mg, 1.57 mmol). The mixture was stirred at 50°C for 1 hour. Concentrate in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 30% to 90% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic -(1-(tert-butyl)-3-((1S,3R,4S)-3-methyl-4-(((4-nitrophenoxy)) as a white solid Benzyl)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamate (200.00 mg, 47.4%). m/z (ES ⁺ ) [M+H] ⁺ = 537.40; HPLC tR = 1.319 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tertiary Butyl )-1H- pyrazol -3- yl )-2- methylcyclopentyl ester

Step 5. Charge racemic-(1-(tert-butyl)-3-((1S,3R,4S)-3-methyl-4-(((4-nitrobenzene)) into the round bottom flask Oxy)carbonyl)oxy)cyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (580.00 mg, 1.08 mmol), bicyclo[1.1.1]pentan-1-amine hydrochloride (259.00 mg, 2.16 mmol), DIEA (838.00 mg, 6.49 mmol) and DMAP (66.00 mg, 0.54 mmol), THF (6 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the solution was heated at 25°C Stir for 1.5 hours. The reaction mixture was diluted with _H2O (30 mL), and the aqueous phase was extracted three times with EA (90 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 80% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-((benzyloxy)carbonyl) as a white solid Amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (409.00 mg, 78.7%). m/z (ES ⁺ ) [M+H] ⁺ = 481.35; HPLC tR = 0.965 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5- amino -1-( tert-butyl )-1H- pyrazole -3 -yl )-2- methylcyclopentyl ester

Step 6. Combine racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S, 2R, 4S)-4-(5-((benzyloxy)carbonyl)amine at 25°C (390.00 mg, 0.81 mmol) and Pd/C (17.30 mg, 0.16 mmol) in EA The stirred mixture in /THF (5 mL) was treated with H for ₂ h. The mixture was filtered through a pad of celite. Filter out the solids. The filtrate was concentrated in vacuo. Concentration in vacuo yielded racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-amino-1-(tert-butyl) as a pink solid (1H-pyrazol-3-yl)-2-methylcyclopentyl ester (260.00 mg, 92.5%). m/z (ES ⁺ ) [M+H] ⁺ = 347.15; HPLC tR = 0.700 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(1-( tert-butyl )-5-(3-(2,2- di Fluoroethoxy )-1- methyl -1H- pyrazole -5 -methamide )-1H- pyrazol -3- yl )-2- methylcyclopentyl ester

Step 7. Racemize -bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-amino-1-( 3-Butyl)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (250.00 mg, 0.72 mmol), [2213-076] 3-(2,2-difluoroethoxy) To a mixture of -1-methyl-1H-pyrazole-5-carboxylic acid (179.00 mg, 0.87 mmol) and DIEA (933.00 mg, 7.22 mmol) in EA (10 mL) was added T ₃ P (3.67 g, 50% Wt, 5.77 mmol). The mixture was stirred at 25°C for 12 hours. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 40% to 70% in 20 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(1-(tert-butyl)-5-) as a yellow solid (3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-methylcyclopentyl Esters (350.00 mg, 90.7%). m/z (ES ⁺ ) [M+H] ⁺ = 535.30; HPLC tR = 0.892 min. Racemic - bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2 -difluoroethoxy )-1- methyl ( 1H- pyrazole -5- methamide )-1H- pyrazol -3- yl )-2- methylcyclopentyl ester

Step 8. Charge racemic-bicyclo[1.1.1]pentan-1-ylcarbamic acid (1S,2R,4S)-4-(1-(tert-butyl)-5 into the round bottom flask -(3-(2,2-difluoroethoxy)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-methylcyclopentan ester (320.00 mg, 0.60 mmol), FA (4 mL) and stir bar, then evacuated and purged with nitrogen three times, and the solution was stirred at 80°C for 2 hours. Concentrate in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 40% to 70% in 20 min; detector, UV 254 nm, in vacuum Concentration produces a yellow oily substance, racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoro) Ethoxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (220.00 mg, 76.8%). m/z (ES ⁺ ) [M+H] ⁺ = 479.60; HPLC tR = 0.650 min. Bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2 -difluoroethoxy )-1 - methyl- 1H- pyrazole -5- methamide )-1H- pyrazol -5- yl )-2 -methylcyclopentyl ester bicyclo [1.1.1] pentan -1- ylcarbamate rel-(1S ,2R,4S)-4-(3-(3-(2,2 -difluoroethoxy )-1- methyl -1H- pyrazole -5- methamide )-1H- pyrazole -5 -yl )-2- methylcyclopentyl ester

Step 9. Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy) -1-Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (220 mg, 0.46 mmol) was prepared by palmar HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate :20 mL/min; Gradient: 70% B to 70% B in 8 minutes; Wavelength: 220/254 nm; RT1(min): 3.71; RT2(min): 6.13; Sample solvent: EtOH:DCM=1:1 --HPLC; injection volume: 0.5 mL; number of runs: 6) Purification. Lyophilization gave bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1R,2S,4R)-4-(3-(3-(2,2-difluoroethyl)) as a white amorphous solid. Oxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)-2-methylcyclopentyl ester (73.4 mg, 66.7%). m/z (ES ⁺ ) [M+H] ⁺ =479.20; HPLC tR = 1.352 min. ¹ H NMR (400 MHz, DMSO-d6) 12.21 (s, 1H), 10.70 (s, 1H), 7.74 (s, 1H), 6.64 (s, 1H), 6.53 - 6.19 (m, 2H), 4.93 ( s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.12 (s, 1H), 2.43 (s, 1H), 2.34 (s, 1H), 2.12 (s , 2H), 1.90 (s, 6H), 1.66 (s, 1H), 1.48 (s, 1H), 0.96 (s, 3H).

Racemic-bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4S)-4-(5-(3-(2,2-difluoroethoxy)-1- Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-methylcyclopentyl ester (220 mg, 0.46 mmol) was analyzed by preparative HPLC (tube Column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH ₃ -MeOH)--HPLC, mobile phase B: EtOH:DCM=1:1--HPLC; flow rate: 20 mL /min; Gradient: 70% B to 70% B in 8 minutes; Wavelength: 220/254 nm; RT1(min): 3.71; RT2(min): 6.13; Sample solvent: EtOH:DCM=1:1--HPLC ;Injection volume: 0.5 mL; Number of runs: 6) Purification. Lyophilization gave bicyclo[1.1.1]pentan-1-ylcarbamate rel-(1S,2R,4S)-4-(3-(3-(2,2-difluoroethyl)) as a white amorphous solid. Oxy)-1-methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)-2-methylcyclopentyl ester (65.8 mg, 59.8%). m/z (ES ⁺ ) [M+H] ⁺ =479.25; HPLC tR = 1.362 min. ¹ H NMR (400 MHz, DMSO-d6) 12.21 (s, 1H), 10.70 (s, 1H), 7.74 (s, 1H), 6.64 (s, 1H), 6.51 - 6.17 (m, 2H), 4.93 ( s, 1H), 4.37 (td, J = 14.9, 3.5 Hz, 2H), 3.95 (s, 3H), 3.12 (s, 1H), 2.45 (s, 1H), 2.34 (s, 1H), 2.12 (s , 2H), 1.90 (s, 6H), 1.67 (s, 1H), 1.46 (s, 1H), 0.96 (s, 3H). Example 18 (1- Methylcyclopropyl ) carbamic acid rel-(1R,2R,4S)-2- fluoro -4-(3-(2-(3- methylisoethazol -5- yl ) ethyl ) Amino )-1H- pyrazol -5- yl ) cyclopentyl ester (1- methylcyclopropyl ) carbamate rel-(1S,2S,4R)-2- fluoro -4-(3-( 2-(3- Methylisoethazol -5- yl ) acetyl )-1H- pyrazol -5- yl ) cyclopentyl ester Racemic- (1R,3S,4S)-3- fluoro -4- hydroxycyclopentane -1- carboxylic acid ethyl ester

Step 1. Charge racemic-(1R,3R,5S)-6-oxabicyclo[3.1.0]hexane-3-carboxylic acid ethyl ester (27.00 g, 0.17 mol) and Et into a round-bottomed flask. ₃ N-3HF (200 mL) and a stir bar was added, then evacuated and purged with nitrogen three times, and the mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This yielded racemic -(1R,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylic acid ethyl ester (26.70 g, crude) as an orange oil. m/z (ES ⁺ ) [M+H] ⁺ = 177.10; HPLC tR = 0.786 min. Racemic- (1R,3S,4S)-3-(( tert-butyldiphenylsilyl ) oxy )-4- fluorocyclopentane -1- carboxylic acid ethyl ester

Step 2. Racemize -(1R,3S,4S)-3-fluoro-4-hydroxycyclopentane-1-carboxylic acid ethyl ester (26.70 g, 152.00 mmol) and 1- at 0°C under nitrogen atmosphere. To a mixture of methylimidazole (16.00 g, 197.00 mmol) in DCM (300 mL) was added dropwise tert-butylchlorodiphenylsilane (50.00 g, 182.00 mmol) in 20 mL DCM. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with DCM (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography (100 g column; elution with PE/EA (ratio: 10/1)). Concentration in vacuo yielded racemic-(1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentane-1-carboxylic acid as a white solid Ethyl ester (27.35 g, 43.5%). m/z (ES ⁺ ) [M+H] ⁺ = 415.25; HPLC tR = 1.544 min. Racemic- 3-((1R,3S,4S)-3-(( tert-butyldiphenylsilyl ) oxy )-4- fluorocyclopentyl )-3- pendantoxypropionitrile

Step 3. To a mixture of CH ₃ CN (5.42 g, 131.90 mmol) in THF (300 mL) was added dropwise n-butyllithium (412 mL, 164.9 mmol) at -78°C under nitrogen atmosphere. The mixture was stirred at -78°C for 1 h, followed by the addition of racemic-(1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentane -Ethyl 1-formate (27.35 g, 65.97 mmol). The mixture was stirred at 78 °C for 4 h. The solution was diluted with water, then adjusted to pH 6~7 with 1M HCl, and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. This yields crude racemic-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl) as an orange oil. -3-Pendantoxypropionitrile (31.47 g, crude product). m/z (ES ⁺ ) [M+H] ⁺ = 410.00; HPLC tR = 1.398 min. Racemic -1-( tert-butyl )-3-((1R,3S,4S)-3-(( tert-butyldiphenylsilyl ) oxy )-4- fluorocyclopentyl ) -1H- pyrazole- 5- amine racemic -1-( tert-butyl )-3-((1S,3S,4S)-3-(( tert-butyldiphenylsilyl ) oxy) )-4- fluorocyclopentyl )-1H- pyrazole -5- amine

Step 4. Charge racemic-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl into the round bottom flask )-3-Penyloxypropionitrile (31.47 g, 76.83 mmol), tert-butylhydrazine hydrochloride (32.55 g, 261.20 mmol), DIPEA (47.67 g, 368.80 mmol), IPA (320 mL) and stirring rod , then evacuated and purged with nitrogen three times, and the mixture was stirred at 80 °C for 12 h. The reaction was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo yields racemic-1-(tert-butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)) as a colorless oil. Oxy)-4-fluorocyclopentyl)-1H-pyrazole-5-amine and racemic-1-(tert-butyl)-3-((1S,3S,4S)-3-((th A mixture of tributyldiphenylsilyloxy)-4-fluorocyclopentyl)-1H-pyrazole-5-amine (26.00 g, 71%). m/z (ES ⁺ ) [M+H] ⁺ = 480.40; HPLC tR = 1.186 min, 1.208 min. Racemic -N-(1-( tert-butyl )-3-((1R,3S,4S)-3-(( tert-butyldiphenylsilyl ) oxy )-4- fluorocyclic Pentyl )-1H- pyrazol -5- yl )-2-(3- methylisoethazol -5- yl ) acetamide racemic -N-(1-( tert-butyl )-3- ((1S,3S,4S)-3-(( tert-butyldiphenylsilyl ) oxy )-4- fluorocyclopentyl )-1H- pyrazol -5- yl )-2-(3 -Methylisoethazol - 5- yl ) acetamide

Step 5. Racemise-1-(tert-butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluoro Cyclopentyl)-1H-pyrazole-5-amine and racemic-1-(tert-butyl)-3-((1S,3S, 4S)-3-((tert-butyldiphenylmethyl) To a solution of silyl)oxy)-4-fluorocyclopentyl)-1H-pyrazole-5-amine (2.00 g, 4.00 mmol) in EA (20 mL) was added 2-(3-methyl Isoethazol-5-yl)acetic acid (0.60 g, 5.00 mmol) and DIEA (5.00 g, 40.00 mmol). Then T ₃ P (20.00 g, 50% Wt, 30.00 mmol) was added dropwise under nitrogen atmosphere at 0°C. The mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (120 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 50% to 100% gradient in 20 min; detector, UV 254 nm. Concentration in vacuo gave a yellow solid, racemic -N-(1-(tert-butyl)-3-((1R,3S,4S)-3-((tert-butyldiphenylsilyl) )oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoethazol-5-yl)acetamide and racemic-N-(1 -(tert-Butyl)-3-((1S,3S,4S)-3-((tert-Butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyrazole A mixture of -5-yl)-2-(3-methylisoethazol-5-yl)acetamide (1.20 g, 50%). m/z (ES ⁺ ) [M+H] ⁺ = 603.40; HPLC tR = 1.482 min. Racemic -N-(1-( tert-butyl )-3-((1R,3S,4S)-3- fluoro -4- hydroxycyclopentyl )-1H- pyrazol -5- yl )-2 -(3- Methylisoethazol -5- yl ) acetamide

Step 6. Charge racemic-N-(1-(tert-butyl)-3-((1R,3S, 4S)-3-((tert-butyldiphenylmethane) into the round bottom flask base)oxy)-4-fluorocyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoethazol-5-yl)acetamide and racemic-N-( 1-(tert-butyl)-3-((1S,3S,4S)-3-((tert-butyldiphenylsilyl)oxy)-4-fluorocyclopentyl)-1H-pyra A mixture of acetamide (1.15 g, 1.95 mmol), THF (12 mL) and stirring rod, then evacuated and purged with nitrogen Scan three times. TBAF-3H ₂ O (2.72 g, 9.77 mmol) was added and the solution was stirred at 50°C for 1 hour. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with 17 x 30 mL saturated brine, then the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 50% in 20 min; detector, UV 254 nm, in vacuum Concentrated. The residue was purified by preparative TLC (PE/EA; ratio: 2/1) to give racemic -N-(1-(tert-butyl)-3-((1R,3S, 4S)-3-Fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoethazol-5-yl)acetamide (0.32 g, 45.0%) . m/z (ES ⁺ ) [M+H] ⁺ = 365.25; HPLC tR = 0.836 min. Racemic - carbonic acid (1S,2S,4R)-4-(1-( tert-butyl )-5-(2-(3- methylisoethazol -5- yl ) acetamide )-1H -pyrazol -3- yl )-2- fluorocyclopentyl ester (4 - nitrophenyl ) ester

Step 7. Racemize -N-(1-(tert-butyl)-3-((1R,3S, 4S)-3-fluoro-4-hydroxycyclopentyl) at 0°C under nitrogen atmosphere -1H-pyrazol-5-yl)-2-(3-methylisoethazol-5-yl)acetamide (300 mg, 0.82 mmol), Py (195 mg, 2.47 mmol) and DMAP (20 mg To a mixture of , 0.16 mmol) in DCM (3 mL) was added portionwise 4-nitrophenyl chloroformate (332 mg, 1.65 mmol). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 70% in 20 min; detector, UV 254 nm, in vacuum Concentration yielded racemic-carbonic acid (1S,2S,4R)-4-(1-(tert-butyl)-5-(2-(3-methylisoethazol-5-yl)ethyl) as a white solid Amido)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (4-nitrophenyl) ester (380 mg, 87.2%). m/z (ES ⁺ ) [M+H] ⁺ = 530.45; HPLC tR = 0.958 min. Racemic- (1- methylcyclopropyl ) carbamic acid (1S,2S,4R)-4-(1-( tert-butyl )-5-(2-(3- methylisoethazole- ) 5- yl ) acetyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 8. Charge racemic-carbonic acid (1S, 2S, 4R)-4-(1-(tert-butyl)-5-(2-(3-methylisoethazole-5)) into the round-bottomed flask. -Acetamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (4-nitrophenyl) ester (370 mg, 0.70 mmol), 1-methylcyclopropyl- 1-amine hydrochloride (150 mg, 1.40 mmol), DIEA (452 mg, 3.49 mmol) and DMAP (8 mg, 0.07 mmol), THF (4 mL) and stir bar, then evacuated and purged with nitrogen three times. The solution was stirred at 25 °C for 2 h. The reaction mixture was diluted with _H2O (15 mL), and the aqueous phase was extracted three times with EA (30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 60% in 15 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-(1-methylcyclopropyl)carbamic acid (1S,2S,4R)-4-(1-(tert-butyl)-5-(2-) as a white solid (3-Methylisoethazol-5-yl)acetyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (260 mg, 80.6%). m/z (ES ⁺ ) [M+H] ⁺ = 462.45; HPLC tR = 0.858 min. Racemic- (1- methylcyclopropyl ) carbamic acid (1S,2S,4R)-2- fluoro -4-(5-(2-(3- methylisoethyl ) -5- yl ) ethyl amide )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 9. Charge racemic-(1-methylcyclopropyl)carbamic acid (1S,2S,4R)-4-(1-(tert-butyl)-5-(2) into the round-bottomed flask. -(3-Methylisoethazol-5-yl)acetyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (240 mg, 0.52 mmol), FA (3 mL) and stirring rod, then evacuated and purged with nitrogen three times, and the solution was stirred at 80°C for 2 h. Concentrate in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 70% in 15 min; detector, UV 254 nm. Concentration in vacuo yielded racemic-(1-methylcyclopropyl)carbamic acid (1S,2S,4R)-2-fluoro-4-(5-(2-(3-methyl)) as a white solid Isoethazol-5-yl)acetyl)-1H-pyrazol-3-yl)cyclopentyl ester (120 mg, 56.9%). m/z (ES ⁺ ) [M+H] ⁺ = 406.40; HPLC tR = 0.742 min. (1- Methylcyclopropyl ) carbamate rel-(1R,2R,4S)-2- fluoro -4-(3-(2-(3- methylisoethazol -5- yl ) acetamide ) ( 1H- pyrazol -5- yl ) cyclopentyl ester (1- methylcyclopropyl ) carbamic acid rel-(1S,2S,4R)-2- fluoro -4-(3-(2- (3- Methylisoethazol -5- yl ) acetyl )-1H- pyrazol -5- yl ) cyclopentyl ester

Step 10. Combine racemic-(1-methylcyclopropyl)carbamic acid (1S,2S,4R)-2-fluoro-4-(5-(2-(3-methylisoethyl)-5 -ethyl)acetyl)-1H-pyrazol-3-yl)cyclopentyl ester (60 mg, 0.15 mmol) by palm preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm ; Mobile phase A: Hex (0.2% DEA)--HPLC, mobile phase B: EtOH: DCM=1:1--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 18 minutes; Wavelength: 220/254 nm; RT1(min): 10.03; RT2(min): 14.82; Sample solvent: EtOH: DCM=1:1--HPLC; Injection volume: 1.4 mL; Number of runs: 4) Purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid rel-(1R,2R,4S)-2-fluoro-4-(3-(2-(3-methyliso㗁)) as a white amorphous solid Azol-5-yl)acetyl)-1H-pyrazol-5-yl)cyclopentyl ester (44.4 mg, 74%). m/z (ES ⁺ ) [M+H] ⁺ = 406.15; HPLC tR = 0.862 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.65 (s, 1H), 7.56 (s, 1H), 6.26 (d, 2H), 5.15 - 4.91 (m, 2H), 3.82 (s, 2H), 2.58 (dd, 1H), 2.20 (s, 4H), 1.97 (s, 1H), 1.87 (s, 1H), 1.24 (s, 4H), 0.61 (s, 2H), 0.48 ( d, 2H).

Racemic-(1-methylcyclopropyl)carbamic acid (1S,2S,4R)-2-fluoro-4-(5-(2-(3-methylisoethyl)-5-yl) Acetyl)-1H-pyrazol-3-yl)cyclopentyl ester (60 mg, 0.15 mmol) was analyzed by preparative HPLC (column: CHIRALPAK IG, 2*25 cm, 5 μm; mobile phase A: Hex (0.2% DEA)--HPLC, mobile phase B: EtOH: DCM=1:1--HPLC; flow rate: 20 mL/min; gradient: 50% B to 50% B in 18 minutes; wavelength: 220 /254 nm; RT1(min): 10.03; RT2(min): 14.82; Sample solvent: EtOH: DCM=1:1--HPLC; Injection volume: 1.4 mL; Number of runs: 4) Purification. Lyophilized to obtain (1-methylcyclopropyl)carbamic acid rel-(1S,2S,4R)-2-fluoro-4-(3-(2-(3-methyliso㗁)) as a white amorphous solid Azol-5-yl)acetyl)-1H-pyrazol-5-yl)cyclopentyl ester (44.5 mg, 74%). m/z (ES ⁺ ) [M+H] ⁺ = 406.15; HPLC tR = 0.852 min. ¹ H NMR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.64 (s, 1H), 7.56 (s, 1H), 6.26 (d, 2H), 5.21 - 4.91 (m, 2H), 3.82 (s, 2H), 2.63 - 2.55 (m, 1H), 2.20 (s, 4H), 1.96 (s, 1H), 1.57 (s, 1H), 1.24 (s, 4H), 0.61 (s, 2H), 0.48 (d, 2H). Example 19 Bicyclo [1.1.1] pentan -1- ylcarbamic acid (1S,2R,4R)-2- fluoro -4-(3-((8-( hexahydropyra - 1- yl ) imidazolate ) [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(5-((8- bromoimidazo [1,2-c] pyrimidin -5- yl ) amino )-1-( tert-butyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 1. Add bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H- at 0°C To a solution of pyrazol-3-yl)-2-fluorocyclopentyl ester (500 mg, 1.43 mmol) in DMF (5 mL) was added NaH (285 mg, 60% Wt, 7.13 mmol) portionwise. The mixture was stirred under _N2 atmosphere for 0.5 h. A solution of 8-bromo-5-chloroimidazo[1,2-c]pyrimidine (431 mg, 1.85 mmol) in DMF was added at 0 °C and the mixture was warmed to 25 °C and stirred for 1 h. The reaction was quenched with water and extracted three times with EA. The combined organic layers were washed with brine and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 60% gradient in 10 min; detector, UV 254 nm, resulting in a white color Solid bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-((8-bromoimidazo[1,2-c]pyrimidin-5-yl) Amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (320 mg, 586 μmol, 41.0%). Product was observed by LCMS (RT = 0.797 min), m/z [M+H] ⁺ = 546.15. Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(1-( tert-butyl )-5-((8-( hexahydropyranoyl) -1 - yl ) imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 2. To bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-((8-bromoimidazo[1,2-c]pyrimidine-5- (150 mg, 274 μmol) in NMP (2.5 mL) Add hexahydropyridine (201 mg, 2.33 mmol). The reaction was stirred at 100°C for 0.5 hours. Water was added to the reaction and extracted three times with EA. The combined organic layers were washed with brine and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeOH in water (NH ₄ HCO ₃ ), 100% gradient in 10 min; detector, UV 254 nm , obtaining bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(1-(tert-butyl)-5-((8-(hexahydro)) as a pink solid Pyramide-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (50 mg, 91 μmol, 33%). Product observed by LCMS (RT = 0.646 min), m/z [M+H] ⁺ = 552.20. Bicyclo [1.1.1] pentan -1- ylcarbamic acid (1S,2R,4R)-2- fluoro -4-(3-((8-( hexahydropyra - 1- yl ) imidazo [1 ,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester

Step 3. Prepare bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(1-(tertiary butyl)-5-( (8-(Hexahydropyrazol-1-yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester ( 50 mg, 90 μmol) in FA (2 mL) was stirred for 2 h. The residue was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 0%-100% in 15 min; detector, UV 254 nm, to obtain Crude product. The crude product was purified by preparative HPLC using the following conditions: (column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH4HCO3) + 0.05% NH ₃ . H ₂ O, mobile phase B: 20 mm NaOH+10% ACN; flow rate: 60 mL/min; gradient: 12% B to 38% B in 7 minutes; wavelength: 254 nm/220 nm; RT1(min): 6.63) . Lyophilized to obtain bicyclo[1.1.1]pentan-1-ylcarbamic acid (1S,2R,4R)-2-fluoro-4-(3-((8-(hexahydropyramide-1)) as a pink solid -yl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (3 mg, 6 μmol, 8%, 96.4% purity). Product was observed by LCMS (RT = 0.778 min), m/z [M+H]+ = 496.45. ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.15 (s, 1H), 9.68 (s, 1H), 8.29 (s, 1H), 8.01 (s, 1H), 7.50 (s, 1H), 7.08 (s , 1H), 6.52 (s, 1H), 5.06 (d, J = 55.0 Hz, 1H), 4.87 (s, 1H), 3.20 (d, J = 5.3 Hz, 5H), 2.87 (t, J = 4.8 Hz , 4H), 2.43-2.29 (m, 4H), 1.93 (s, 8H). Example 20 Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-2- fluoro -4-(3-((2-( hexahydropyra - 1- carbonyl ) imidazo [1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester 5- Chloroimidazo [1,2-c] pyrimidine -2- carboxylic acid

Step 1. Charge a round bottom flask with 5-chloroimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (380 mg, 1.68 mmol) in DCE (20 mL) and trimethyl hydroxide Tin (3.05 g, 16.8 mmol) and a stirring rod, and the solution was stirred at 80 °C under _N2 atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was filtered and the filter cake was washed with DCM (50 ml). The filtrate was concentrated under reduced pressure. The crude product was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 10% to 40% gradient in 10 min; detector, UV 254 nm. Concentration in vacuo yielded 5-chloroimidazo[1,2-c]pyrimidine-2-carboxylic acid as a white solid (170 mg, 0.71 mmol, 42%, 83% purity). Complete conversion to product was observed by LCMS (RT = 0.392 min), m/z [M+H] ⁺ = 198.05. 4-(5- Chloroimidazo [1,2-c] pyrimidine -2- carbonyl ) hexahydropyra - 1- carboxylic acid tert-butyl ester

Step 2. Add 5-chloroimidazo[1,2-c]pyrimidine-2-carboxylic acid (240 mg, 1.21 mmol), DIEA (785 mg, 6.07 mmol) and hexahydropyridine at 0°C under _N2 atmosphere. To a stirred solution of 𠯤-1-tert-butylcarboxylate (204 mg, 1.09 mmol) in EA (30 mL) was added dropwise T ₃ P (2.32 g, 50% Wt in EA, 3.64 mmol). The resulting mixture was stirred at 20 °C under _N2 atmosphere for 1 h. The reaction mixture was diluted with _H2O (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative TLC (EA:PE~1:3) to obtain 4-(5-chloroimidazo[1,2-c]pyrimidine-2-carbonyl)hexahydropyramide- as a white solid 1-tert-Butylcarboxylate (250 mg, 0.57 mmol, 47%, 83% purity). Complete conversion to product was observed by LCMS (RT = 0.689 min), m/z [M+H] ⁺ = 366.10. 4-(5-((3-((1R,3S,4R)-3-( bicyclo [1.1.1] pent - 1-ylaminomethyl ) oxy )-4- fluorocyclopentyl )-1-( tert-butyl )-1H- pyrazol -5- yl ) amino ) imidazo [1,2-c] pyrimidine -2- carbonyl ) hexahydropyridine - 1- carboxylic acid tert-butyl ester

Step 3. Add bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-amino-1-(tert-butyl) at 0°C under _N atmosphere To a stirred solution of 4A-MS in DMF (10 mL) was added NaH (88 mg, 60 % Wt, 2.20 mmol), and the resulting mixture was stirred at 0 °C under _N2 atmosphere for 10 min. Then tert-butyl 4-(5-chloroimidazo[1,2-c]pyrimidine-2-carbonyl)hexahydropyra-1-carboxylate (268 mg, 733 μmol) was added portionwise, and the resulting mixture was dissolved in 0 °C and stir for 1 hour under _N2 atmosphere. The reaction was then monitored by LCMS. The resulting mixture was quenched with 20 mL of saturated _NH4Cl . The resulting mixture was extracted with EA (3×50 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (EA:PE~1:1) to obtain 4-(5-((3-((1R,3S,4R)-3-((bicyclo[1.1)) as a white solid .1]pent-1-ylaminoformyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[ 1,2-c]pyrimidine-2-carbonyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (120 mg, 177 μmol, 24.1%). Complete conversion to product was observed by LCMS (RT = 1.104 min), m/z [M+H] ⁺ = 680.40. Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-2- fluoro -4-(3-((2-( hexahydropyra - 1- carbonyl ) imidazo [1 ,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl ) cyclopentyl ester

Step 4. Add 4-(5-((3-((1R,3S,4R)) _- 3-((bicyclo[1.1.1]pentan-1-ylaminomethyl acyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[1,2-c]pyrimidine-2-carbonyl ) A solution of tert-butyl hexahydropyramide-1-carboxylate (140 mg, 206 μmol) in HCOOH (140 mL) was stirred for 1.5 h. The reaction was monitored by LCMS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: 20 mm NaOH+10% ACN; flow rate: 60 mL/min; gradient: 15% B to 38% B in 7 min; wavelength: 220 nm; RT1(min): 7.6 ;Number of runs: 4. This yields bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-2-fluoro-4-(3-((2-(hexahydropyramide)) as a white amorphous solid 1-Carbonyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)cyclopentyl ester (9.4 mg, 17 μmol, 8.5%, 97.1% purity) . Complete conversion to product was observed by LCMS (RT = 1.016 min), m/z [M+H] ⁺ = 524.25. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.31 (s, 1H), 10.28 (s, 1H), 8.70 (s, 1H), 8.06 (s, 1H), 7.68 (s, 1H), 6.96 ( s, 1H), 6.49 (s, 1H), 5.07 (d, J = 55.2 Hz, 1H), 4.85 (d, J = 22.5 Hz, 1H), 4.00 (s, 2H), 3.56 (s, 2H), 3.23 (d, J = 21.1 Hz, 2H), 2.74 (s, 4H), 2.37 (s, 3H), 1.93 (s, 8H). Example 21 Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(3-((2-( azetidin -1- ylmethyl ) imidazo [ 1,2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl )-2- fluorocyclopentyl ester 7- Chloro -5- hydroxyimidazo [1,2-c] pyrimidine -2- carboxylic acid ethyl ester

Step 1. Charge a round bottom flask with 2,6-dichloropyrimidin-4-amine (20 g, 0.12 mol) and ethyl 3-bromo-2-oxypropionate in AcOH (250 mL) (60 g, 75% Wt, 0.23 mol) and a stirring rod, and the solution was stirred at 120°C for 3 hours. The mixture was concentrated in vacuo. The mixture was adjusted to pH 6-7 with _NaHCO3 (aq.), and the aqueous phase was extracted three times with DCM (200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residual product was purified by silica gel chromatography (eluted with DCM/MeOH (ratio: 20/1)). Concentration in vacuo gave 7-chloro-5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (12.8 g, 32 mmol, 26%, 60% purity) as a yellow solid. Complete conversion to product was observed by LCMS (RT = 0.456 min), m/z [M+H] ⁺ = 242.05. 5- Hydroxyimidazo [1,2-c] pyrimidine -2- carboxylic acid ethyl ester

Step 2. To a solution of ethyl 7-chloro-5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate (10 g, 41 mmol) in MeOH (150 mL) under nitrogen atmosphere was added /C (10%, 1.2 g). The mixture was hydrogenated under a hydrogen atmosphere at room temperature for 1 h, filtered through a pad of celite and concentrated under reduced pressure to obtain ethyl 5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylate as a white solid. Ester (6.8 g, 26 mmol, 63%, 80% purity). Complete conversion to product was observed by LCMS (RT = 0.595 min), m/z [M+H] ⁺ = 208.05. 5- Chloroimidazo [1,2-c] pyrimidine -2- carboxylic acid ethyl ester

Step 3. Put 5-hydroxyimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (1 g, 5 mmol), POCl ₃ (20 mL) and stirring rod into the round bottom flask, and add DIEA (10 mL). The resulting solution was then stirred at 100°C under _N2 atmosphere for 16 hours. The mixture was concentrated under reduced pressure. The reaction mixture was diluted with DCM (20 mL), the solution was added dropwise to saturated _NaHCO3 and the pH value was adjusted to approximately 9, and the aqueous phase was extracted three times with DCM (3*50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, 0% to 50% gradient in 18 min; detector, UV 254 nm, resulting in a brown color 5-Chloroimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester as a solid (300 mg, 1.33 mmol, 30%). Complete conversion to product was observed by LCMS (RT = 0.632 min), m/z [M+H] ⁺ = 226.00. 5-((3-((1R,3S,4R)-3-(( bicyclo [1.1.1] pent -1- ylaminomethyl ) oxy )-4- fluorocyclopentyl )-1 -( tert-Butyl )-1H- pyrazol -5- yl ) amino ) imidazo [1,2-c] pyrimidine -2- carboxylic acid ethyl ester

Step 4. Add 5-chloroimidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester (110 mg, 488 μmol) and bicyclo[1.1.1]pentan-1 at 20°C under _N2 atmosphere. -ylcarbamic acid (1S,2R,4R)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (171 mg , 488 μmol) in dioxane (3.5 mL) were added potassium acetate (144 mg, 1.46 mmol), xantphos (113 mg, 195 μmol) and Pd ₂ (dba) ₃ (89.3 mg, 97.5 μmol). The resulting mixture was stirred at 80 °C under _N2 atmosphere for 1 h. The reaction was monitored by LCMS. The resulting mixture was diluted with 10 ml _H2O . The resulting mixture was extracted with DCM (3×10 ml). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC using the following conditions (EA/PE=1:1) to obtain 5-((3-((1R,3S,4R)-3-((bicyclo[1.1)) as a white solid .1]pent-1-ylaminoformyl)oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[ 1,2-c]pyrimidine-2-carboxylic acid ethyl ester (130 mg, 0.22 mmol, 44%, 90% purity). Complete conversion to product was observed by LCMS (RT = 1.156 min), m/z [M+H] ⁺ = 540.25. Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(1-( tert-butyl )-5-((2- formyl imidazo [1,2 -c] pyrimidin -5- yl ) amino )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 5. Add 5-((3-((1R,3S,4R)-3-((bicyclo _[ 1.1.1]pentan-1-ylaminoformyl) )oxy)-4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)amino)imidazo[1,2-c]pyrimidine-2-carboxylic acid ethyl ester A stirred solution of DIBAL-H (200 mg, 371 μmol) in THF (10 mL) (2.22 mL, 1 M in hexane, 2.22 mmol) was added to the reaction mixture. The resulting mixture was stirred at -60 °C under _N2 atmosphere for 0.25 h. The reaction was monitored by LCMS. The resulting mixture was quenched with 20 ml _H2O . The resulting mixture was extracted with DCM (3×20 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC (DCM/MeOH=15:1) to obtain bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-( as a white solid 1-(tert-butyl)-5-((2-formylimidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)-2-fluoro Cyclopentyl ester (110 mg, 0.18 mmol, 50%, 83% purity). Complete conversion to product was observed by LCMS (RT = 0.760 min), m/z [M+H] ⁺ = 496.30. Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(5-((2-( azetidin -1- ylmethyl ) imidazo [1, 2-c] pyrimidin -5- yl ) amino )-1-( tert-butyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 6. Stir bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(1-(tert-butyl)-5- at 0°C under _N atmosphere ((2-Methodyl imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (100 mg, 202 μmol) Solution in DCM (5 mL). 1,3-Propyleneimine (46.1 mg, 807 μmol) in DCM (1 mL) was added dropwise and the resulting mixture was stirred at 0 °C under _N atmosphere for an additional 10 min. Sodium triacetyloxyborohydride (85.5 mg, 404 μmol) was added to the above mixture, and the resulting mixture was stirred at 0°C under _N2 atmosphere for another 0.5 h, and the reaction was monitored by LCMS. The resulting mixture was quenched with 20 ml of saturated _NH4Cl . The resulting mixture was extracted with DCM (3×10 mL). The combined organic layers were washed with brine (1×10 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative TLC using the following conditions (DCM/MeOH=10:1) to obtain bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)- as a white solid 4-(5-((2-(azetidin-1-ylmethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1-(tert-butyl)- 1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (50 mg, 86 μmol, 43%, 92.8% purity). Complete conversion to product was observed by LCMS (RT = 0.736 min), m/z [M+H] ⁺ = 537.40. Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2R,4R)-4-(3-((2-( azetidin -1- ylmethyl ) imidazo [1, 2-c] pyrimidin -5- yl ) amino )-1H- pyrazol -5- yl )-2- fluorocyclopentyl ester

Step 7. Charge a resealable reaction vial with bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R,4R)-4-(5-((( 2-(azetidin-1-ylmethyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1-(tert-butyl)-1H-pyrazole-3- (10 mg, 19 μmol) and a stirring rod, and the mixture was stirred at 100°C under nitrogen atmosphere for 5 h. 50 mg of this crude product was run in parallel. The reaction mixture was concentrated in vacuo, and the residue was purified by preparative HPLC using the following conditions: column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: water (10 mmol/L NH ₄ HCO ₃ +0.05% NH ₃ H ₂ O), mobile phase B: 20 mm NaOH+10% ACN; flow rate: 60 mL/min; gradient: 20% B to 40% B in 7 min; wavelength: 220 nm ; RT1(min): 7.55; Number of runs: 2. This produces bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2R, 4R)-4-(3-((2-(azetidin-1-yl)) as a white amorphous solid Methyl)imidazo[1,2-c]pyrimidin-5-yl)amino)-1H-pyrazol-5-yl)-2-fluorocyclopentyl ester (2.0 mg, 4.1 μmol, 22%, 98.4 % purity). Complete conversion to product was observed by LCMS (RT = 1.467 min), m/z [M+H] ⁺ = 481.20. ¹ H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 10.17 (s, 1H), 8.17 (s, 1H), 8.10 (s, 1H),7.62 (s, 1H), 6.86 (s , 1H), 6.66 (s, 1H), 5.25 - 4.95 (d, 1H), 5.00 (s, 1H), 3.59 (s, 2H), 3.23 (s, 3H), 2.42 (s, 2H), 2.00 ( s, 13H). Example 22 Isopropylcarbamic acid (1R, 2R, 3R)-2- fluoro -3-(3-(3-( methoxymethyl )-1- methyl -1H- pyrazole -5- carboxylic acid) Amino )-1H- pyrazol -5- yl ) cyclopentyl ester isopropylcarbamic acid (1S,2S,3S)-2- fluoro -3-(3-(3-( methoxymethyl )) -1- Methyl -1H- pyrazole -5- methamide )-1H- pyrazol -5- yl ) cyclopentyl ester Racemic- (1R,2S)-2- hydroxycyclopentane -1- carboxylic acid ethyl ester

Step 1. To a solution of ₂ -pendantoxycyclopentane-1-carboxylic acid ethyl ester (40 g, 0.26 mol) in MeOH (1000 mL) was added portionwise NaBH ₄ (11 g, 0.28 mol). The reaction was stirred at 0°C for 1 hour. TLC showed the reaction was complete. The mixture was quenched with acetone (40 mL), saturated _NH4Cl (600 mL) was added and extracted with MTBE (3*800 mL). The combined organic layers were washed with brine (2×300 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (300-400, PE/EA=20/1~10/1) to obtain racemic -(1R,2S)-2-hydroxy ring as a yellow oil. Pentane-1-carboxylic acid ethyl ester (20.5 g, 130 mmol, 51%). m/z (ES ⁺ ) [M+H] ⁺ = 159.05; HPLC tR = 0.667 min. ¹ H NMR (400 MHz, chloroform-d) 4.47 - 4.40 (m, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.92 (s, 1H), 2.68 (ddd, J = 9.9, 8.7, 4.3 Hz, 1H), 2.09 - 1.86 (m, 3H), 1.85 - 1.72 (m, 2H), 1.71 - 1.56 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H). Racemic- (1R,2S)-2-((( methylthio ) thiocarbonyl ) oxy ) cyclopentane -1- carboxylic acid ethyl ester

Step 2. Racemic-(1R,2S)-2-hydroxycyclopentane-1-carboxylic acid ethyl ester (20.5 g, 130 mmol) in anhydrous DMSO at room temperature under _N for about 5 min. DBU (11 g, 73 mmol) was added and the reaction was stirred at room temperature for 1 h. CS ₂ (34 g, 0.45 mol) was added to the above reaction, and the reaction was stirred at room temperature for another 1.5 h. Mel (0.02 kg, 0.1 mol) was then added to the above mixture over 20 min. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water (400 ml) and extracted with DCM (3*300 ml). The combined organic layers were washed with brine (3×100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (330 g, PE/EA=0~10%, 30 min) to obtain racemic -(1R,2S)-2-(((( Methylthio)thiocarbonyl)oxy)cyclopentane-1-carboxylic acid ethyl ester (8 g, 0.03 mol, 20%). m/z (ES ⁺ ) [M+H] ⁺ = 249.05; HPLC tR = 0.892 min. ¹ H NMR (400 MHz, chloroform-d) 6.15 (td, J = 5.3, 2.8 Hz, 1H), 4.24 - 4.04 (m, 2H), 3.04 (ddd, J = 9.9, 8.3, 5.7 Hz, 1H), 2.50 (s, 3H), 2.31 - 2.16 (m, 1H), 2.14 - 1.85 (m, 4H), 1.78 - 1.61 (m, 1H), 1.23 (t, J = 7.1 Hz, 3H). Cyclopent -2- ene -1- carboxylic acid ethyl ester

Step 3. Charge racemic-(1R,2S)-2-(((methylthio)thiocarbonyl)oxy)cyclopentane-1-carboxylic acid ethyl ester (26 g, 0.10) into a round-bottomed flask. mol) and a stirring rod, and then the reaction mixture was stirred at 190°C for 3 hours to obtain ethyl cyclopent-2-ene-1-carboxylate (14 g, 0.10 mol, 95%) as a yellow oil. m/z (ES ⁺ ) [M+H] ⁺ = 141.10; HPLC tR = 0.892 min. Racemic- (2R,3S)-2,3- dihydroxycyclopentane -1- carboxylic acid ethyl ester

Step 4. To a solution of cyclopent-2-ene-1-carboxylic acid ethyl ester (5 g, 0.04 mol) in THF (40 mL) and acetone (40 mL) at 0 °C under _N2 was added NMO ( 8 g, 0.07 mol) and K ₂ OsO ₄ (0.1 g, 0.4 mmol) in H ₂ O (5 mL). The reaction was stirred at 25°C for 5 hours. TLC showed the reaction was complete. The mixture was quenched with 10% _Na2SO3 (10 mL) and saturated _NH4Cl (10 mL) and extracted with _DCM . The combined organic layers were washed with brine and dried over _{anhydrous Na2SO4} . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (flash, PE/EA~50% to 100% in 20 min) to obtain racemic -(2R,3S)-2,3-bis as a yellow oil. Hydroxycyclopentane-1-carboxylic acid ethyl ester (3.8 g, 22 mmol, 60%). m/z (ES ⁺ ) [M+H] ⁺ = 175.15; HPLC tR = 0.385 min. Racemic- (3aR,6aS)-2,2- dimethyltetrahydro -4H- cyclopenta [d][1,3] dioxole -4- carboxylate ethyl ester

Step 5. To a solution of racemic-(2R,3S)-2,3-dihydroxycyclopentane-1-carboxylic acid ethyl ester (3.8 g, 22 mmol) in acetone (50 mL) was added 2,2 -Dimethoxypropane (23 g, 0.22 mol), stir at 25°C for 5 min. TsOH (0.41 g, 2.2 mmol) was then added to the mixture, and the mixture was stirred at 25°C for 1 hour. The mixture was quenched with _NaHCO3 (10 ml) and the aqueous phase was extracted three times with EA. The combined organic layers were dried over _Na2SO4 , filtered, and concentrated in vacuo _. The crude product was purified by silica gel chromatography (eluted with PE/EA~10/1). Concentration in vacuo yields racemic -(3aR,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxola as a yellow oil Ethyl en-4-carboxylate (3.2 g, 15 mmol, 68%). m/z (ES ⁺ ) [M+H] ⁺ = 215.05; HPLC tR = 0.742 min. Racemic -3-((3aR,6aS)-2,2- dimethyltetrahydro -4H- cyclopenta [d][1,3] dioxol -4- yl )-3 -Pendant oxypropionitrile

Step 6. To a solution of MeCN (6.1 g, 7.8 mL, 0.15 mol) in THF (40 mL) was added dropwise n-BuLi (18 mL, 45 mmol) at -78 °C under _N2 atmosphere. The reaction mixture was stirred at -78°C for 1.5 hours. Racemic-(3aR,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxole-4-carboxylate is then added dropwise. (3.2 g, 15 mmol) in THF (8 mL) and the mixture was stirred for an additional 1 h. The reaction was quenched with _NH4Cl (10 mL) and extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 , and concentrated under _vacuum to give racemic-3-((3aR,6aS)-2,2-dimethyl as a yellow oil Tetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-3-pentoxypropionitrile (2 g, 0.01 mol, 60%). m/z (ES ⁺ ) [M+H] ⁺ = 210.10; HPLC tR = 0.598 min. Racemic -1-( tert-butyl )-3-((3aR,4S,6aS)-2,2 -dimethyltetrahydro -4H- cyclopenta [d][1,3] m-dioxy Heterocyclopenten -4- yl )-1H- pyrazole -5- amine racemic -1-( tert-butyl )-3-((3aS,4S,6aR)-2,2- dimethyltetrakis Hydrogen -4H- cyclopenta [d][1,3] dioxol -4- yl )-1H- pyrazole -5- amine

Step 7. Charge a round bottom flask with racemic-3-((3aR, 6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][ in iPOH (15 mL) 1,3]dioxol-4-yl)-3-side oxypropionitrile (3.2 g, 15 mmol), DIEA (9.9 g, 76 mmol) and t-BuNHNH ₂ ^. HCl (13 g , 0.11 mol) and a stirring rod, stir the solution at 80°C for 16 hours. The resulting mixture was concentrated in vacuo and extracted with DCM. The combined organic extracts _were washed with brine, dried over anhydrous _Na2SO4 , and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 15 min; detector, UV 254 nm, resulting in off-white color Solid racemic-1-(tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3] Dioxol-4-yl)-1H-pyrazol-5-amine (2 g, 4 mmol, 30%, 56% purity) and racemic-1-(tert-butyl)-3- ((3aS,4S,6aR)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazole- 5-amine (250 mg, 0.66 mmol, 4.3%, 74% purity). Isomer 1: m/z (ES ⁺ ) [M+H] ⁺ = 280.20; HPLC tR = 0.743 min. Isomer 2: m/z (ES ⁺ ) [M+H] ⁺ = 280.20; HPLC tR = 0.777 min.

Isomer 1: 1H NMR (400 MHz, chloroform- d ) 5.60 (s, 1H), 4.65 (dt, J = 33.8, 5.4 Hz, 2H), 3.46 (s, 2H), 2.79 (dt, J = 12.9 , 5.2 Hz, 1H), 1.96 - 1.74 (m, 4H), 1.61 (s, 9H), 1.50 (s, 3H), 1.30 (s, 3H).

Isomer 2: ¹ H NMR (400 MHz, chloroform- d ) 5.34 (d, J = 1.2 Hz, 1H), 4.85 - 4.78 (m, 1H), 4.70 (t, J = 5.4 Hz, 1H), 3.52 (s, 2H), 3.21 - 3.15 (m, 1H), 2.18 - 2.05 (m, 1H), 1.92 - 1.70 (m, 3H), 1.59 (s, 9H), 1.47 (s, 3H), 1.32 (s , 3H). Racemic -N-(1-( tert-butyl )-3-((3aR,4S,6aS)-2,2- dimethyltetrahydro -4H- cyclopenta [d][1,3] Dioxol -4- yl )-1H- pyrazol -5- yl )-3-( methoxymethyl )-1- methyl -1H- pyrazole -5- carboxamide

Step 8. Racemize -1-(tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3 ]dioxol-4-yl)-1H-pyrazole-5-amine (2 g, 7 mmol) and 3-(methoxymethyl)-1-methyl-1H-pyrazole- To a solution of 5-formic acid (1 g, 8 mmol) in EA (45 mL) was added DIEA (5 g, 6 mL, 0.04 mol) and stirred at 0 °C. Then T3P (0.01 kg, 50% Wt, 0.02 mol) was added to the mixture, and the mixture was stirred at 80°C for 16 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted three times with EA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 15 min; detector, UV 254 nm, obtaining off-white color Solid racemic-N-(1-(tert-butyl)-3-((3aR,4S,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1, 3]dioxol-4-yl)-1H-pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide (1.6 g, 3.2 mmol, 40%, 86% purity). m/z (ES ⁺ ) [M+H] ⁺ = 432.20; HPLC tR = 0.763 min. Racemic -N-(1-( tert-butyl )-3-((1S,2R,3S)-2,3- dihydroxycyclopentyl )-1H- pyrazol -5- yl )-3- ( Methoxymethyl )-1- methyl -1H- pyrazole -5- methamide

Step 9. Charge a round bottom flask with racemic-N-(1-(tert-butyl)-3-((3aR,4S) in aqueous HCl solution (15 mL, 1 molar concentration, 15 mmol) ,6aS)-2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-4-yl)-1H-pyrazol-5-yl)- 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (1.6 g, 3.7 mmol) and a stirring rod, stir the solution at 25°C for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 40% gradient in 10 min; detector, UV 254 nm, obtaining a white color Solid racemic-N-(1-(tert-butyl)-3-((1S,2R,3S)-2,3-dihydroxycyclopentyl)-1H-pyrazol-5-yl)- 3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (1.2 g, 3.0 mmol, 81%, 98.3% purity). m/z (ES ⁺ ) [M+H] ⁺ = 392.10; HPLC tR = 0.642 min. Racemic -N-(3-((1S,2R,3S)-3-( benzyloxy )-2- hydroxycyclopentyl )-1-( tert-butyl )-1H- pyrazole -5- methyl )-3-( methoxymethyl )-1- methyl -1H- pyrazole -5- carboxamide

Step 10. Racemize -N-(1-(tert-butyl)-3-((1S,2R,3S)-2,3-dihydroxycyclopentyl)-1H-pyrazole at 25°C To a solution of -5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (900 mg, 2.30 mmol) in toluene (10 mL) was added Bu ₂ SnO (630 mg, 2.53 mmol) and the mixture was stirred at 120°C for 3 hours. Then CsF (384 mg, 2.53 mmol) and benzyl bromide (433 mg, 2.53 mmol) were added to the mixture, and the mixture was stirred at 120°C for 1 hour. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm, resulting in a white color Solid racemic-N-(3-((1S,2R,3S)-3-(benzyloxy)-2-hydroxycyclopentyl)-1-(tert-butyl)-1H-pyrazole- 5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (600 mg, 1.01 mmol, 43.8%, 80.9% purity). m/z (ES ⁺ ) [M+H] ⁺ = 482.50; HPLC tR = 1.093 min. Racemic -N-(3-((1S,2S,3S)-3-( benzyloxy )-2- fluorocyclopentyl )-1-( tert-butyl )-1H- pyrazole -5- methyl )-3-( methoxymethyl )-1- methyl -1H- pyrazole -5- carboxamide

Step 11. Racemize -N-(3-((1S,2R,3S)-3-(benzyloxy)-2-hydroxycyclopentyl)-1-(tert-butyl) at 0°C -1H-pyrazole-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (600 mg, 1.25 mmol) in DCM (48 mL) BAST (2.76 g, 12.5 mmol) was added to the solution. The mixture was then stirred at 0°C for 1 hour. The reaction was quenched with saturated _NaHCO3 (aq), and the mixture was extracted with DCM (3×20 mL). The combined organic extracts _were washed with brine, dried over anhydrous _Na2SO4 , and concentrated in vacuo. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm., to obtain a Yellow oil racemic -N-(3-((1S,2S,3S)-3-(benzyloxy)-2-fluorocyclopentyl)-1-(tert-butyl)-1H- Pyrazol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (200 mg, 100 μmol, 8.03%, 24.2% purity). m/z (ES ⁺ ) [M+H] ⁺ = 484.30; HPLC tR = 1.243 min. Racemic -N-(1-( tert-butyl )-3-((1S,2S,3S)-2- fluoro -3- hydroxycyclopentyl )-1H- pyrazol -5- yl )-3 -( methoxymethyl )-1- methyl -1H- pyrazole -5- methamide

Step 12. Racemize -N-(3-((1S,2S,3S)-3-(benzyloxy)-2-fluorocyclopentyl)-1-(tert-butyl) under nitrogen atmosphere -1H-pyrazole-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (200 mg, 414 μmol) and NH ₃ ^. H ₂ O To a solution of MeOH (5 mL) was added Pd/C (440 mg). The mixture was hydrogenated under hydrogen atmosphere at room temperature for 16 hours, filtered through a pad of celite and concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 60% gradient in 10 min; detector, UV 254 nm, resulting in a white color Solid racemic-N-(1-(tert-butyl)-3-((1S,2S,3S)-2-fluoro-3-hydroxycyclopentyl)-1H-pyrazol-5-yl) -3-(Methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (40 mg, 0.10 mmol, 24%, 98.8% purity). m/z (ES ⁺ ) [M+H] ⁺ = 394.20; HPLC tR = 0.621 min. Racemic - carbonic acid (1S,2S,3S)-3-(1-( tert-butyl )-5-(3-( methoxymethyl )-1- methyl -1H- pyrazole -5- Formamide )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester (4- nitrophenyl ) ester

Step 13. Racemize -N-(1-(tert-butyl)-3-((1S,2S,3S)-2-fluoro-3-hydroxycyclopentyl)-1H-pyridine at 0°C Azol-5-yl)-3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxamide (35 mg, 89 μmol), Py (21 mg, 0.27 mmol) and DMAP To a stirred solution in DCM (3 mL) was added 4-nitrophenyl chloroformate (22 mg, 0.11 mmol). The reaction was stirred at 25°C for 3 hours. The reaction mixture was diluted with water, and the aqueous phase was extracted three times with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to obtain racemic-carbonic acid (1S, 2S, 3S)-3-(1-(third Butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-fluorocyclopenta (4-nitrophenyl) ester (45 mg, 49 μmol, 55%, 61% purity). m/z (ES ⁺ ) [M+H] ⁺ = 559.20; HPLC tR = 1.218 min. Racemic - isopropylcarbamic acid (1S,2S,3S)-3-(1-( tert-butyl )-5-(3-( methoxymethyl )-1- methyl -1H- Pyrazole -5- methamide )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 14. Racemize -carbonic acid (1S,2S,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)-1-methyl-1H-pyridine) Azole-5-carboxamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl (4-nitrophenyl) ester (40 mg, 72 μmol) in THF (2 mL) Propan-2-amine (13 mg, 0.21 mmol) and DIEA (46 mg, 0.36 mmol) were added to the stirring solution. The reaction was stirred at 25°C for 1 hour. The mixture was concentrated and purified by reverse phase flash chromatography using the following conditions: column, C18 silica; mobile phase, MeCN in water, gradient 20% to 70% in 10 min; detector, UV 220 nm. Concentration in vacuo yields racemic-isopropylcarbamic acid (1S,2S,3S)-3-(1-(tert-butyl)-5-(3-(methoxymethyl)) as an off-white solid )-1-Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (25 mg, 46 μmol, 65%, 88.8% purity ). m/z (ES ⁺ ) [M+H] ⁺ = 479.25; HPLC tR = 0.741 min. Racemic - isopropylcarbamic acid (1S,2S,3S)-2- fluoro -3-(5-(3-( methoxymethyl )-1- methyl -1H- pyrazole -5- Formamide )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 15. Charge a round bottom flask with racemic-isopropylcarbamic acid (1S,2S,3S)-3-(1-(tert-butyl)-5- in FA (2 mL) (3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (20 mg, 42 μmol) and a stirring rod, stir the solution at 80°C for 1 hour. The resulting mixture was concentrated under vacuum to obtain racemic-isopropylcarbamic acid (1S,2S,3S)-2-fluoro-3-(5-(3-(methoxymethyl)) as a white solid -1-Methyl-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)cyclopentyl ester (15 mg, 34 μmol, 80%, 94.7% purity). m/z (ES ⁺ ) [M+H] ⁺ = 423.30; HPLC tR = 0.688 min. Isopropylcarbamic acid (1R,2R,3R)-2- fluoro -3-(3-(3-( methoxymethyl )-1- methyl -1H- pyrazole -5- methamide) )-1H- pyrazol -5- yl ) cyclopentyl ester isopropylcarbamate (1S,2S,3S)-2- fluoro -3-(3-(3-( methoxymethyl )-1 -Methyl -1H- pyrazole -5- methamide )-1H- pyrazol - 5- yl ) cyclopentyl ester

Step 16. The obtained crude material was subjected to preparative HPLC by hand (column: CHIRALPAK IC, 2*25 cm, 5 μm; mobile phase A: Hex (0.5% 2M NH ₃ -MeOH), flow rate: 20 mL/min ;Gradient; 40% B to 40% B in 12 minutes; Wavelength: 220/254 nm; RT1(min): 4.55; RT2(min): 8.59; Sample solvent: EtOH: DCM=1: 1; Sample concentration: mg /mL; injection volume: 1.7 mL; number of runs: 1) Purification. Lyophilized to obtain isopropylcarbamate rel-(1R,2R,3R)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-) as a white solid Pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester (6.2 mg, 13 μmol, 31%, 90.0% purity) and isopropylcarbamate rel as a white solid -(1S,2S,3S)-2-Fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide)-1H-pyra Azol-5-yl)cyclopentyl ester (5.1 mg, 12 μmol, 28%).

Isopropylcarbamic acid Rel-(1R,2R,3R)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid) Amino)-1H-pyrazol-5-yl)cyclopentyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 423.20; HPLC tR = 1.287 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.44 (s, 1H), 10.79 (s, 1H), 7.30 - 7.04 (m, 2H), 6.54 (s, 1H), 5.09 - 4.84 (m, 2H) , 4.34 (s, 2H), 4.05 (s, 3H), 3.59 (q, J = 6.8 Hz, 1H), 3.44 (s, 1H), 3.27 (s, 3H), 2.17 (s, 2H), 1.88 ( d, J = 11.2 Hz, 1H), 1.68 (s, 1H), 1.05 (d, J = 6.6 Hz, 6H).

Isopropylcarbamic acid Rel-(1S,2S,3S)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid) Amino)-1H-pyrazol-5-yl)cyclopentyl ester: m/z (ES ⁺ ) [M+H] ⁺ = 423.20; HPLC tR = 1.270 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.44 (s, 1H), 10.79 (s, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 6.54 (s, 1H ), 5.03 (dd, J = 15.8, 7.3 Hz, 2H), 4.87 (s, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.59 (dq, J = 13.4, 6.6 Hz, 1H) , 3.27 (s, 3H), 2.19 (d, J = 16.9 Hz, 2H), 1.95 - 1.80 (m, 1H), 1.72 (d, J = 29.6 Hz, 1H), 1.05 (d, J = 6.5 Hz, 6H).

Additional compounds prepared according to the method of Example 22 are shown in Table 9 below. Table 9. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] Bicyclo[1.1.1]pentan-1-ylcarbamate(1S,2S,3S)-2-fluoro-3-(3-(1-methyl-3-((2,2,2-trifluoro Ethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-5-yl)cyclopentyl ester (400 MHz, DMSO-d6) δ 12.44 (s, 1H), 10.83 (s, 1H), 7.98 (s, 1H), 7.18 (s, 1H), 6.54 (s, 1H), 4.93 (d, J = 53.9 Hz, 2H), 4.60 (s, 2H), 4.13-4.02 (m, 5H), 3.44-3.35 (m, 1H), 2.36 (s, 1H), 2.17 (s, 2H), 1.92 (s, 7H ), 1.68 (s, 1H). 515.25 Isopropylcarbamic acid ((1R,2S,3S)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide) (yl)-1H-pyrazol-5-yl)cyclopentyl ester (400 MHz, DMSO-d6) 12.44 (s, 1H), 10.80 (s, 1H), 7.21 (d, J = 7.8 Hz, 1H), 7.13 (s, 1H), 6.54 (d, J = 2.1 Hz, 1H), 5.11 - 4.95 (m, 2H), 4.92 (t, J = 5.3 Hz, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.64 - 3.56 (m, 1H), 3.44 (s , 1H), 3.27 (s, 2H), 2.25 - 2.12 (m, 2H), 1.79 - 1.66 (m, 2H), 1.05 (d, J = 6.8 Hz, 6H). 423.15 Example 23 Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2S,4R)-4-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester ( synthetic intermediate ) (3-((1R,3r,5S)-6- oxabicyclo [3.1.0] hex -3- yl )-1-( tert-butyl )-1H- pyrazol -5- yl ) amine Benzyl formate

Step 1. To (1-(tert-butyl)-3-(cyclopent-3-en-1-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (70.0 g) at 25°C To a solution of , 206 mmol, 1.00 eq ) in MeOH (1.40 L) was added NaHCO ₃ (52.0 g, 619 mmol, 24.1 mL, 3.00 eq ). Then m-CPBA (89.0 g, 412 mmol, 80% purity, 2.00 eq ) was added portionwise to the mixture at 0°C. The mixture was stirred at 25°C for 12 hr. HPLC showed that starting material (Rt = 3.177 min) remained and a peak was detected (Rt = 2.631 min). The reaction mixture was poured into _H2O (2.00 L) and extracted with ethyl acetate (1.00 L*3). Wash the organic phase with saturated NaHCO ₃ aqueous solution (1.50 L * 3), saturated sodium sulfite solution (2.00 L), brine (2.00 L), and dry over anhydrous Na ₂ SO ₄ . The organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5: 1 to 3: 1, petroleum ether: ethyl acetate = 1: 1, R _f = 0.47, I ₂ ). The fractions were concentrated in vacuo to give a residue (50.0 g). The residue was further analyzed by SFC (neutral conditions: column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm); mobile phase: [NEU TRI-IPA]; B%: 35%-35%, 4.0 min ) separation. The eluate was concentrated under vacuum to obtain (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(No. Tributyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (11.8 g, 31.0 mmol, 93.2% purity, 15.0% yield). HPLC: Product: Rt = 2.631 min, 6.89% purity at 220 nm. LCMS: Product: Rt = 0.593 min, m/z = 356.3 [M+H] ⁺ HPLC: Product: Rt = 2.637 min, 93.2% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 9.02 (s, 1H), 7.38 - 7.33 (m, 5H), 5.85 (s, 1H), 5.11 (s, 2H), 3.49 (s, 2H) , 3.23 - 3.21 (m, 1H), 2.13 - 2.02 (m, 4H), 1.46 (s, 9H). (1-( tert-Butyl )-3-((1R,3S,4S)-3- fluoro -4- hydroxycyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 2. To a solution of (S, S, S, S)-dimeric (salen) Co (II) complex (1.07 g, 844 μmol, 0.05 eq ) in MTBE (60.0 mL) at 25 °C Add DBN (167 mg, 1.35 mmol, 161.3 uL, 0.08 eq ), add (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-( 3-Butyl)-1H-pyrazol-5-yl)benzylcarbamate (6.00 g, 16.9 mmol, 1.00 eq ), benzyl fluoride (4.19 g, 33.8 mmol, 2.00 eq ) and 1,1, 1,3,3,3-hexafluoropropan-2-ol (11.4 g, 67.5 mmol, 4.00 eq ), followed by 2-hydroperoxy-2-methyl-propane (5 M, 338 uL, 0.10 eq) ), and the mixture was stirred at 25°C for 12 hr. TLC (petroleum ether:ethyl acetate = 1:1) showed (3-((1R,3r,5S)-6-oxabicyclo[3.1.0]hex-3-yl)-1-(tert-butyl) Benzyl)-1H-pyrazol-5-yl)carbamate (R _f = 0.60) was consumed and a new major spot was detected (R _f = 0.30). The mixture was poured into saturated aqueous _NaHCO3 solution (100 mL) and extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with brine (100 mL * 2), dried over _Na2SO4 , filtered and concentrated in _vacuo . The crude product was purified by silica gel chromatography (petroleum ether: ethyl acetate = 10:1 to 5:1, petroleum ether: ethyl acetate = 1:1, R _f = 0.30) to obtain a yellow oily substance ( 1-(tert-Butyl)-3-((1R,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (5.30 g, 14.1 mmol, 83.6% yield). 1H- imidazole -1- carboxylic acid (1S,2S,4R)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 3. To (1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl To a solution of the ester (2.20 g, 5.86 mmol, 1.00 eq ) in THF (44.0 mL) was added CDI (3.80 g, 23.44 mmol, 4.00 eq ). The mixture was stirred at 25°C for 2 hr. LCMS shows that (1-(tert-butyl)-3-((1R,3S,4S)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester has The desired MS is consumed and detected (Rt = 0.531 min). The reaction mixture was poured into _H2O (50.0 mL) and the aqueous phase was extracted with ethyl acetate (40.0 mL*2). The combined organic phases were washed with brine (60.0 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum to obtain 1H-imidazole-1-carboxylic acid (1S,2S,4R)- as a brown oil. 4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (3.50 g, crude product) . LCMS: Product: Rt = 0.531 min, m/z = 470.2 [M+H] ⁺ . (3-((1R,3S,4S)-3-(( bicyclo [1.1.1] pentan -1- ylaminoformyl ) oxy )-4- fluorocyclopentyl )-1-( th Tributyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 4. Add 1H-imidazole-1-carboxylic acid (1S,2S,4R)-4-(5-((benzyloxy)carbonyl)amino)-1-(tert-butyl)- at 25°C. 1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (3.5 g, 7.45 mmol, 1.00 eq ) and bicyclo[1.1.1]pentan-1-amine hydrochloride (8.92 g, 74.6 mmol, To a solution of 10.0 eq , HCl) in 2-Me-THF (35.0 mL) was added TEA (11.3 g, 112 mmol, 15.6 mL, 15.0 eq ). The mixture was heated to 60°C and stirred at 60°C for 12 hr. LCMS showed complete consumption of starting material and the expected mass was detected (Rt = 0.601 min). The reaction mixture was poured into _H2O (50.0 mL) and the aqueous phase was extracted with ethyl acetate (40.0 mL*2). _The combined organic phases were washed with brine (60.0 mL), dried over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give crude product. The residue was purified by silica gel chromatography (petroleum ether: ethyl acetate = 5:1 to 3:1, petroleum ether: ethyl acetate = 2:1, R _f = 0.40). The fractions were concentrated under vacuum to obtain (3-((1R,3S,4S)-3-((bicyclo[1.1.1]pentan-1-ylaminoformyl)oxy) as a white solid) Benzyl -4-fluorocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1.50 g, 3.10 mmol, 52.8% yield over two steps). LCMS: Product: Rt = 0.601 min, m/z = 485.3 (M+H) ^{+ 1} H NMR: (400 MHz, DMSO- d ₆ ) δ 9.11 (s, 1H), 7.96 (s, 1H), 7.53 - 7.24 (m, 5H), 5.98 (s, 1H), 5.11 (s, 2H), 5.09 - 4.88 (m, 2H), 3.29 - 3.16 (m, 1H), 2.39 - 2.28 (m, 1H), 2.25 - 2.10 (m, 1H), 1.99 (s, 7H), 1.71 - 1.55 (m, 1H), 1.48 (s, 9H). Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2S,4R)-4-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl )- 2- fluorocyclopentyl ester

Step 5. Add (3-((1R,3S,4S)-3-((bicyclo[ _1.1.1 ]pent-1-ylaminoformyl)oxy)-4-fluorocyclic Benzyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1.30 g, 2.68 mmol, 1.00 eq ) in THF (13.0 mL) and EtOAc (13.0 mL) Pd/C (130 mg, 10% purity) was added to the solution. The suspension was degassed under vacuum and purged three times with _H2 . The mixture was stirred under _H2 (50 psi) at 25°C for 3 hr. TLC (petroleum ether:ethyl acetate=2:1, _I2 ) indicated complete consumption of starting material ( _Rf =0.45) and the formation of a new spot ( _Rf =0.30). The mixture was filtered and concentrated under reduced pressure to give the product. The crude product was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm * 10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 32%-62%, 10 min) For purification, the eluate was concentrated in vacuo to remove ACN. The residual aqueous solution was freeze-dried to obtain bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2S,4R)-4-(5-amino-1-(tert-butyl)) as a yellow solid -1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (701.82 mg, 1.99 mmol, 74.6% yield, 99.3% purity). LCMS: Product: Rt = 0.432 min, m/z = 351.2 (M+H) ⁺ ; HPLC: Product: Rt = 1.739 min, 99.3% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 7.93 (s, 1H), 5.23 (s, 1H), 5.04 - 4.92 (m, 2H), 4.75 (s, 2H), 3.10 - 3.08 (m, 1H), 2.36 - 2.34 (m, 2H), 2.10 - 2.07 (m, 1H), 1.91 (s, 7H), 1.57 - 1.56 (m, 1H), 1.48 (s, 9H). Example 24 Bicyclo [1.1.1] pentan -1- ylcarbamate (1R,2R,4S)-4-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester ( synthetic intermediate ) (1-( tert-Butyl )-3-((1S,3R,4R)-3- fluoro -4- hydroxycyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 1. To a solution of (R, R, R, R)-dimeric (salen) Co(II) complex (801 mg, 633 μmol, 0.050 eq ) in MTBE (80.0 mL) at 25 °C Add DBN (126 mg, 1.01 mmol, 121 μL, 0.08 eq ), add (4-((1R,3r,5S)-6-oxabicyclo[3.1.0]hexan-3-yl)-1-( Benzyl tert-butyl)-1H-pyrrol-2-yl)carbamate (4.50 g, 12.7 mmol, 1.00 eq ), benzyl fluoride (3.14 g, 25.3 mmol, 2.00 eq ) and 1, 1, 1 , 3, 3, 3-hexafluoropropan-2-ol (8.51 g, 50.6 mmol, 4.00 eq ), followed by 2-hydroperoxy-2-methyl-propane (5 M, 253 μL) at 25°C , 0.100 eq ), and the mixture was stirred at 25°C for 12 hr. LCMS showed that the starting material was consumed and the expected MS was detected (Rt = 0.706 min). The mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 5:1 to 4:1, petroleum ether: ethyl acetate = 2:1, R _f = 0.50). (1-(tert-butyl)-3-((1S,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl)amine was obtained as a yellow oily substance Benzyl formate (3.57 g, 8.70 mmol, 68.7% yield, 91.5% purity). LCMS: Product: Rt = 0.706 min, m/z = 376.2 [M+H] ⁺ HPLC: Product: Rt = 2.619 min, 91.5% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 9.13 - 9.06 (m, 1H), 7.39 - 7.34 (m, 5H), 5.96 (s, 1H), 5.18 (d, J = 4.8 Hz, 1H) , 5.12 (s, 2H), 4.92 - 4.77 (m, 1H ), 4.16 - 4.09 (m, 1H ), 3.18 - 3.11 (m, 1H), 2.36 - 2.34 (m, 1H), 2.09 - 1.99 (m, 2H), 1.57 - 1.51 (m, 1H), 1.48 (s, 9H). 1H- imidazole -1- carboxylic acid (1R,2R,4S)-4-(5-((( benzyloxy ) carbonyl ) amino )-1-( tert-butyl )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 2. To (1-(tert-butyl)-3-((1S,3R,4R)-3-fluoro-4-hydroxycyclopentyl)-1H-pyrazol-5-yl) at 25°C To a solution of benzyl carbamate (1.40 g, 3.54 mmol, 94.9% purity, 1.00 eq ) in THF (26.0 mL) was added CDI (2.30 g, 14.2 mmol, 4.00 eq ), and the mixture was stirred at 25°C for 4 hr. LCMS showed that the starting material was consumed and the expected MS was detected (Rt = 0.717 min). The reaction mixture was poured into water (20.0 mL) and extracted with ethyl acetate (15.0 mL*2), the organic phase was washed with brine (20.0 mL) and dried over _Na2SO4 and concentrated in vacuo _. (1R,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl was obtained as a yellow oily substance )-2-fluorocyclic 1H-imidazole-1-carboxylic acid pentyl ester (1.66 g, crude product). The crude product was used in the next step without purification. LCMS: Product: Rt = 0.717 min, m/z = 470.2 (M+H) ⁺ . (3-((1S,3R,4R)-3-(( bicyclo [1.1.1] pentan -1- ylaminoformyl ) oxy )-4- fluorocyclopentyl )-1-( th Tributyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 3. Add 1H-imidazole-1-carboxylic acid (1R,2R,4S)-4-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)- at 25°C. To a solution of 1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (1.66 g, 3.54 mmol, crude purity, 1.00 eq ) in 2-Me-THF (16.0 mL) was added TEA (5.37 g, 53.0 mmol, 7.38 mL, 15.0 eq ) and bicyclo[1.1.1]pentan-1-amine hydrochloride (4.23 g, 35.4 mmol, 10.0 eq , HCl), the mixture was heated to 60°C and stirred at 60°C 12 hours. LCMS showed that the starting material was consumed and the expected MS was detected (Rt = 0.825 min). The mixture was cooled to 25°C, diluted with water (10.0 mL), extracted with ethyl acetate (10.0 mL * 2), the combined organic layers were washed with brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was Concentrate. The residue was purified by column chromatography (SiO ₂ , petroleum ether: ethyl acetate = 100: 22 to 100: 25, petroleum ether: ethyl acetate = 2: 1, R _f = 0.38). Obtained as a white solid (3-((1S,3R,4R)-3-((bicyclo[1.1.1]pent-1-ylaminomethyl)oxy)-4-fluorocyclopentyl) -Benzyl 1-(tert-butyl)-1H-pyrazol-5-yl)carbamate (1.25 g, 2.51 mmol, 70.9% yield, 97.2% purity). LCMS: Product: Rt = 0.825 min, m/z = 485.3 (M+H) ⁺ . HPLC: Product: Rt = 3.326 min, 97.2% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 9.14 - 9.08 (m, 1H), 7.96 (br d, J = 1.6 Hz, 1H), 7.37 - 7.33 (m, 5H), 5.98 (s, 1H ), 5.11 (s, 2H), 5.08 - 4.95 (m, 2H ), 3.25 - 3.20 (m, 1H), 2.36 - 2.33 (m, 1H), 2.24 - 2.15 (m, 1H ), 2.00 - 1.82 (m , 7H), 1.64 - 1.60 (m, 1H), 1.47 (s, 9H). Bicyclo [1.1.1] pentan -1- ylcarbamate (1R,2R,4S)-4-(5- amino -1-( tert-butyl )-1H- pyrazol -3- yl )- 2- fluorocyclopentyl ester

Step 4. To (3-((1S,3R,4R)-3-((bicyclo[1.1.1]pent-1-ylaminoformyl)oxy)-4-fluoro under _N2 atmosphere Cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (1.35 g, 2.79 mmol, 1.00 eq ) in ethyl acetate (13.0 mL), THF (13.0 mL) was added Pd/C (250 mg, 10% purity, 1.00 eq ). The suspension was degassed and purged 3 times with _H2 . The mixture was stirred under _H2 (50 Psi) at 25°C for 3 hr. LCMS showed that the starting material was consumed and the expected MS was detected (Rt = 0.883 min). The reaction mixture was filtered directly and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge C18 150*50 mm* 10 μm; mobile phase: [water (NH ₄ HCO ₃ )-ACN]; B%: 32%-62%, 10 min) For purification, the eluate was concentrated to remove most of the ACN and lyophilized. Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazole- was obtained as a yellow solid) 3-yl)-2-fluorocyclopentyl ester (736 mg, 2.09 mmol, 75.4% yield, 99.5% purity). LCMS: Product: Rt = 0.883 min, m/z = 351.3 (M+H) ⁺ . HPLC: Product: Rt = 1.698 min, 99.5% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 7.94 (br s, 1H), 5.23 (s, 1H), 5.04 - 4.92 (m, 2H), 4.76 (s, 2H), 3.09 (br d; J = 7.20 Hz, 1H), 2.45 - 2.42 (m, 1H ), 2.36 - 2.33 (m, 1H), 2.10 - 2.07 (m, 1H), 1.91 (br s, 7H ), 1.64 - 1.56 (m, 1H ), 1.48 (s, 9H). Example 25 Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2S,4R)-2- fluoro -4-(5-(1- methyl -3-(( trifluoromethoxy )) Methyl )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) cyclopentyl ester Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2S,4R)-4-(1-( tert-butyl )-5-(1- methyl -3-(( trifluoromethyl) Oxy ) methyl )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 1. Add bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2S,4R)-4-(5-amino-1-(tert-butyl)-1H- at 25℃ To a solution of pyrazol-3-yl)-2-fluorocyclopentyl ester (80.0 mg, 228 μmol, 1.00 eq) in EtOAc (0.80 mL) was added 1-methyl-3-((trifluoromethoxy )Methyl)-1H-pyrazole-5-carboxylic acid (56.3 mg, 251 μmol, 1.10 eq) and DIEA (73.8 mg, 571 μmol, 99.4 μL, 2.50 eq). _T3P (602 mg, 946 μmol, 563 μL, 50.0% purity, 4.15 eq) was then added dropwise at 0°C. The mixture was heated to 70°C and stirred at 70°C for 12 hr. TLC (petroleum ether:ethyl acetate=1:1) showed consumption of starting material (R _f = 0.40) and the formation of a new major spot (R _f = 0.60). The reaction mixture was cooled to 25°C, then poured into ice water (10.0 mL), and extracted with ethyl acetate (10.0 mL * 2). The combined organic layers were washed with saturated aqueous NaHCO ₃ (10.0 mL), brine (10.0 mL), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a residue. Bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2S,4R)-4-(1-(tert-butyl)-5-(1-methyl-) was obtained as a yellow oily substance 3-((trifluoromethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (100 mg, 166 μmol ,Crude). LCMS: Product: RT = 0.591 min, m/z = 557.3 (M+H) ⁺ . Bicyclo [1.1.1] pentan -1- ylcarbamate (1S,2S,4R)-2- fluoro -4-(5-(1- methyl -3-(( trifluoromethoxy ) methyl) )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 2. Prepare bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2S,4R)-4-(1-(tert-butyl)-5-(1-methyl) at 25°C -3-((trifluoromethoxy)methyl)-1H-pyrazole-5-methamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (80.0 mg, 144 μmol, 1.00 eq) was dissolved in formic acid (0.80 mL). The mixture was heated to 65°C and stirred at 65°C for 10 hr. LCMS showed starting material consumed and expected MS detected (RT = 0.525 min). The reaction mixture was poured into _H2O (10.0 mL) and the aqueous phase was extracted with ethyl acetate (10.0 mL*2). The combined organic phases were washed with saturated aqueous NaHCO ₃ (10 mL * 2) and water (10 mL * 2), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude product. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; gradient: 42%-72% B, over 10 min), The eluate was concentrated in vacuo to remove ACN. The residual aqueous solution was freeze-dried to obtain the product. Bicyclo[1.1.1]pentan-1-ylcarbamate (1S,2S,4R)-2-fluoro-4-(5-(1-methyl-3-((trifluoromethyl)) was obtained as a white solid Oxy)methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)cyclopentyl ester (13.55 mg, 26.2 μmol, 18.2% yield, 96.7% purity). LCMS: Product: RT = 0.525 min, m/z = 501.2 (M+H) ⁺ HPLC: Product: RT = 2.913 min, 96.7% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO- d ₆ ) δ 12.3 (s, 1H) 10.9 (s, 1H) 8.05 - 7.92 (m, 1H) 7.28 (s, 1H) 6.53 - 6.38 (m, 1H) 5.17 - 4.96 (m, 4H) 4.09 (s, 3H) 2.70 - 2.53 (m, 2H) 2.37 (s, 1H) 2.34 - 2.18 (m, 1H) 1.92 (s, 7H) 1.71 - 1.56 (m, 1H). Example 26 Bicyclo [1.1.1] pentan -1- ylcarbamate (1R,2R,4S)-2- fluoro- 4-(5-(1- methyl -3-(( trifluoromethoxy )) Methyl )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) cyclopentyl ester Bicyclo [1.1.1] pentan -1- ylcarbamate (1R,2R,4S)-4-(1-( tert-butyl )-5-(1- methyl -3-(( trifluoromethyl) Oxy ) methyl )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl )-2- fluorocyclopentyl ester

Step 1. To bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2R,4S)-4-(5-amino-1-(tert-butyl)-1H-pyrazole-3 To a solution of -yl)-2-fluorocyclopentyl ester (80.0 mg, 228.29 μmol, 1.00 eq) in EtOAc (1.00 mL) was added 1-methyl-3-((trifluoromethoxy)methyl) -1H-Pyrazole-5-carboxylic acid (56.29 mg, 251.12 μmol, 1.10 eq), DIEA (73.76 mg, 570.73 μmol, 99.41 μL, 2.50 eq). Then T ₃ P (830 mg, 1.30 mmol, 776.43 μL, 50% purity, 5.71 eq) was added at 0°C. The mixture was heated to 67°C and stirred at 67°C for 12 hr. TLC (petroleum ether:ethyl acetate=2:1) indicated consumption of starting material (R _f = 0.40) and formation of a new major spot (R _f = 0.60). The reaction mixture was cooled to 25°C, then poured into ice water (5.00 mL), and extracted with ethyl acetate (5.00 mL * 2). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution (5.00 mL * 4), brine (5.00 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The reactants were used in the next step without purification. Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2R,4S)-4-(1-(tert-butyl)-5-(1-methyl-3-) was obtained as a yellow solid ((Trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (90.0 mg, 121.28 μmol, 53.13 % yield, 75% purity). LCMS: Product: RT = 0.586 min, m/z = 557.4 (M+H) ⁺ . Bicyclo [1.1.1] pentan -1- ylcarbamate (1R,2R,4S)-2- fluoro -4-(5-(1- methyl -3-(( trifluoromethoxy ) methyl) )-1H- pyrazole -5- methamide )-1H- pyrazol -3- yl ) cyclopentyl ester

Step 2. Combine bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2R,4S)-4-(1-(tert-butyl)-5-(1-methyl-3-( (Trifluoromethoxy)methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)-2-fluorocyclopentyl ester (80.0 mg, 143.74 μmol, 1.00 eq ) in formic acid (1.00 mL) was degassed and purged 3 times with _N2 , then the mixture was stirred at 65°C under _N2 atmosphere for 10 hr. LCMS showed 4.9% starting material remaining and expected MS detected (RT = 0.531 min). The reaction mixture was cooled to 25°C, then poured into water (10.0 mL) and extracted with ethyl acetate (10.0 mL * 2). The combined organic layers were washed with saturated aqueous NaHCO ₃ solution (10.0 mL * 4), brine (10.0 mL * 2), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by reversed-phase HPLC (column: Phenomenex luna C18 150*25 mm* 10 μm; mobile phase: [water (FA)-ACN]; gradient: 46%-73% B, over 9 min), Adjust the pH to 7-8 with saturated _NaHCO solution, concentrate to remove most of the ACN, and extract with ethyl acetate (10.0 mL * 2). _The combined organic layers were washed with brine (10.0 mL * 2), dried over _Na2SO4 , filtered, concentrated and lyophilized to give the product. Bicyclo[1.1.1]pentan-1-ylcarbamate (1R,2R,4S)-2-fluoro-4-(5-(1-methyl-3-((trifluoromethyl)) was obtained as a white solid Oxy)methyl)-1H-pyrazole-5-carboxamide)-1H-pyrazol-3-yl)cyclopentyl ester (18.0 mg, 35.39 μmol, 24.6% yield, 98.4% purity). LCMS: Product: RT = 0.531 min, m/z = 501.2 (M+H) ⁺ ; LCMS: Product: RT = 0.587 min, m/z = 501.2 (M+H) ⁺ . HPLC: Product: RT = 2.768 min, 98.4% purity at 220 nm. ¹ H NMR: (400 MHz, DMSO) δ 12.32 (br d, J = 1.6 Hz, 1H), 10.87 (s, 1H), 7.99 -7.98 (m, 1H), 7.28 (s, 1H), 6.47 (br s, 1H), 5.10 - 4.98 (m, 4H), 4.09 (s, 3H), 2.65 - 2.58 (m, 2H), 2.38 - 2.35 (m, 2H), 1.95 - 1.88 (m, 7H), 1.67 - 1.60 (m, 1H). Example 27 (2R, 3R, 4R)-3,4- dihydroxytetrahydrofuran- 2- carboxylic acid methyl ester ( synthetic intermediate ) (3aR,7S,7aS)-2,2- dimethyltetrahydro -4H-[1,3] dioxolo [4,5-c] pyran -6,7- diol

Step 1. Prepare (3S,4R,5R)-tetrahydro-2H-pyran-2,3,4,5-tetraol (150 g, 999 mmol, 1.00 eq) and 2 at 20 °C under _N , to a solution of 2-dimethoxypropane (312 g, 3.00 mol, 367 mL, 3.00 eq) in DMF (150 mL) was added TsOH·H ₂ O (1.90 g, 9.99 mmol, 0.01 eq). The mixture was stirred at 18 - 20°C for 12 hr. The mixture was then heated to 32°C and stirred at 32°C for 5 hr. TLC (petroleum ether/ethyl acetate = 0/1, PMA) showed consumption of starting material (R _f = 0.15) and the formation of several spots (R _f = 0.34, 0.44, 0.72, 0.90). The reaction mixture was concentrated in vacuo to remove DMF and 2,2-dimethoxypropane. The mixture was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 50/1 to 0/1, petroleum ether/ethyl acetate = 0/1, R _f = 0.34 and 0.44) to obtain a colorless oil. (3aR,7S,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c]pyran-6,7-di Alcohol (72.0 g, 379 mmol). ^1H NMR: (400 MHz, DMSO _-d6 ) . δ 6.59 - 5.79 (m, 1H), 5.38 - 4.87 (m, 1H), 4.85 - 4.42 (m, 1H), 4.21 - 4.09 (m, 1H), 4.02 - 3.87 (m, 2H), 3.69 - 3.64 ( m, 1H), 3.55 - 3.37 (m, 1H), 1.39 - 1.35 (m, 3H), 1.25 - 1.19 (m, 3H). (3aR,7S,7aS)-7- Hydroxy -2,2- dimethyltetrahydro -6H-[1,3] dioxolo [4,5-c] pyran -6- one

Step 2. Add (3aR,7S,7aS)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5-c] at 15 - 25℃ To a mixture of pyran-6,7-diol (53.0 g, 279 mmol, 1.00 eq) and Na ₂ CO ₃ (44.3 g, 418 mmol, 1.50 eq) in DCM (300 mL) was added Br ₂ (66.8 g , 418 mmol, 21.5 mL, 1.50 eq). The mixture was stirred at -25°C for 3 hr. TLC (petroleum ether/ethyl acetate = 1/1, PMA) showed that most of the starting material (R _f = 0.30) was consumed and one major spot formed (R _f = 0.50). The mixture was filtered and _the filtrate was washed with saturated _{aqueous Na2S2O3} (0.50 M, 500 mL) and brine (300 mL). The organic layer was dried _{over Na2SO4} and concentrated to give a residue (60.0 g crude). The crude residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 10/1 to 0/1, petroleum ether/ethyl acetate = 1/1, R _f = 0.50) to obtain (3aR) as a white solid ,7S,7aS)-7-hydroxy-2,2-dimethyltetrahydro-6H-[1,3]dioxolo[4,5-c]pyran-6-one (35.0 g, 186 mmol). ¹ H NMR: (400 MHz, CDCl ₃ ) δ 4.59 (dd, J = 5.2, 11.2 Hz, 1H), 4.55 - 4.47 (m, 1H), 4.46 - 4.41 (m, 1H), 4.40 - 4.34 (m, 1H), 4.13 (dd, J = 8.0, 11.2 Hz, 1H), 3.50 (br s, 1H), 1.52 (s, 3H), 1.38 (s, 3H). Trifluoromethanesulfonate (3aR,7S,7aR)-2,2- dimethyl -6- side oxytetrahydro- 4H-[1,3] dioxolo [4,5-c ] pyran -7- yl ester

Step 3. Add (3aR,7S,7aS)-7-hydroxy-2,2-dimethyltetrahydro-6H-[1,3]dioxa under _N2 at -20℃~-30℃ To a solution of cyclopenta[4,5-c]pyran-6-one (35.0 g, 186 mmol, 1.00 eq) in DCM (525 mL) was added pyridine (58.9 g, 744 mmol, 60.1 mL, 4.00 eq) and Tf ₂ O (105 g, 372 mmol, 61.4 mL, 2.00 eq). The mixture was stirred at -20°C ~ -30°C for 2 hr. TLC (petroleum ether/ethyl acetate = 1/1, PMA) indicated complete consumption of starting material (R _f = 0.50) and the formation of a new spot (R _f = 0.70). The mixture was poured into brine (600 mL) and separated. The organic layer was washed with brine (500 mL). The organic layer was dried over _Na2SO4 , filtered and concentrated to give a residue _. Obtained as yellow solid triflate (3aR, 7S, 7aR)-2,2-dimethyl-6-side oxytetrahydro-4H-[1,3]dioxolo[ 4,5-c]pyran-7-yl ester (59.6 g, crude), which was used in the next step without further purification. (2R,3R,4R)-3,4- Dihydroxytetrahydrofuran -2- carboxylic acid methyl ester

Step 4. Trifluoromethanesulfonate (3aR,7S,7aR)-2,2-dimethyl-6-side oxytetrahydro-4H-[1,3]dioxolo[4 A mixture of ,5-c]pyran-7-yl ester (59.6 g, 186 mmol, 1.00 eq) in HCl/MeOH (595 mL, 1% purity, 12.8 eq) was stirred at 25°C for 2 hr. Then HCl (2 M, 46.5 mL, 0.50 eq) was added to the mixture at 25°C. After heating to 70°C, the mixture was stirred at 70°C for 3 hr. TLC (petroleum ether/ethyl acetate = 1/1, PMA) indicated complete consumption of the starting material (R _f = 0.70) and the formation of a new major spot (R _f = 0.10). The reaction mixture was concentrated in vacuo to remove MeOH and _H2O . Add NaHCO ₃ solid to the residue to adjust pH = 7 ~ 8. The mixture was filtered and the filtrate was concentrated. The residue was purified twice by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 0/1, petroleum ether/ethyl acetate = 1/1, R _f = 0.10) to obtain (2R,3R,4R)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester (32.0 g, 197 mmol) was a colorless oil. HRMS-TOF: m/z = 163.0601 (M+H) ⁺ . ^1H NMR: (400 MHz, DMSO _-d6 ) . δ 5.29 (d, J = 6.0 Hz, 1H), 4.99 (d, J = 4.4 Hz, 1H), 4.13 - 4.09 (m, 1H), 4.08 - 4.00 (m, 2H), 3.93 (dd, J = 4.4 , 9.0 Hz, 1H), 3.65 (s, 3H), 3.64 - 3.59 (m, 1H). Example 28 1-( tert-butyl )-3-((2S,3R,4R)-4-(( tert-butyldimethylsilyl ) oxy )-3- fluorotetrahydrofuran -2- yl ) -1H- pyrazole -5- amine ( synthetic intermediate ) 1-( tert-butyl )-3-((2S,3S,4S)-3-(( tert-butyldimethylsilyl ) oxy (base )-4- fluorotetrahydrofuran -2- yl )-1H- pyrazole -5- amine ( synthetic intermediate ) (2R,3R,4R)-4-( benzoyloxy )-3- hydroxytetrahydrofuran -2- carboxylic acid methyl ester (2R,3R,4R)-3-( benzoyloxy )-4- Hydroxytetrahydrofuran -2- carboxylic acid methyl ester

Step 1. To a solution of (2R,3R,4R)-3,4-dihydroxytetrahydrofuran-2-carboxylic acid methyl ester (10 g, 61.68 mmol, 1 eq.) in pyridine (100 mL) at 0°C Add BzCl (3.47 g, 24.67 mmol, 2.86 mL, 0.4 eq.). The mixture was stirred at -25 °C for 16 h. The mixture was diluted with water (300 mL) and extracted with EtOAc (300 mL * 3). The combined organic layers were washed with 1 M HCl (500 mL*2) and 500 mL NaCl aqueous solution, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (PE/EtOAc = 1/0 to 1/1, TLC: PE/EtOAc = 1/1, Rf = 0.50) to obtain (2R, 3R, 3R, 4R)-4-(benzoyloxy)-3-hydroxytetrahydrofuran-2-carboxylic acid methyl ester and (2R,3R,4R)-3-(benzoyloxy)-4-hydroxytetrahydrofuran-2 - Mixture of methyl formate (4.2 g, 62.31% yield, 97.44% purity). LC-MS (ESI ⁺ ) m/z : 267.2 (M+H) ⁺ . (2S,3S,4R)-4-( benzoyloxy )-3- fluorotetrahydrofuran -2- carboxylic acid methyl ester (2R,3S,4S)-3-( benzoyloxy )-4- Fluorotetrahydrofuran -2- carboxylic acid methyl ester

Step 2. Add (2R,3R,4R)-4-(benzyloxy)-3-hydroxytetrahydrofuran-2-carboxylic acid methyl ester and (2R,3R,4R)-3-(benzene) at 0°C. To a solution of formyloxy)-4-hydroxytetrahydrofuran-2-carboxylic acid methyl ester (4.2 g, 15.77 mmol, 1 eq.) in DCM (50 mL) was added DAST (10.17 g, 63.10 mmol, 8.34 mL, 4 eq.). The mixture was stirred at -25 °C for 2 h. DAST (5.09 g, 31.55 mmol, 4.17 mL, 2 eq.) was added to the mixture at 0 °C, and the mixture was stirred at 25 °C for 14 h. The mixture was slowly quenched by saturated _Na2CO3 (200 mL), then extracted with DCM (300 mL _* 3). The combined organic layers were washed with aqueous NaCl solution (300 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced _pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 10/1 to 1/1) to obtain (2S, 3S, 4R)-4-(benzyl) as a colorless oil. Methyl acyloxy)-3-fluorotetrahydrofuran-2-carboxylate and (2R,3S,4S)-3-(benzoyloxy)-4-fluorotetrahydrofuran-2-carboxylate (2.8 g, 10.37 mmol, 65.74% yield, 99.34% purity). LC-MS (ESI ⁺ ) m/z : 269.2 (M+H) ⁺ . (2S,3S,4R)-3- fluoro - 4- hydroxytetrahydrofuran -2- carboxylic acid (2R,3S,4S)-4- fluoro -3- hydroxytetrahydrofuran - 2- carboxylic acid

Step 3. To (2S,3S,4R)-4-(benzyloxy)-3-fluorotetrahydrofuran-2-carboxylic acid methyl ester and (2R,3S,4S)-3-(benzyloxy) To a solution of methyl)-4-fluorotetrahydrofuran-2-carboxylate (2.4 g, 8.95 mmol, 1 eq.) in THF (20 mL) and H ₂ O (5 mL) was added LiOH·H ₂ O (1.88 g, 44.74 mmol, 5 eq.). The mixture was stirred at -20 °C for 16 h. The mixture was diluted with water (50 mL), then adjusted to pH=3 by HCl (1 M), and the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with NaCl aqueous solution (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain (2S, 3S, 4R)-3-fluoro-4-hydroxy as a white solid. Tetrahydrofuran-2-carboxylic acid and (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylic acid (1.95 g, crude) were used directly in the next step without further purification. (2S,3S,4R)-3- Fluoro - 4-hydroxytetrahydrofuran -2- carboxylic acid methyl ester (2R,3S,4S)-4- fluoro -3- hydroxytetrahydrofuran -2- carboxylic acid methyl ester

Step 4. Add (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2-carboxylic acid and (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylic acid (1.4 g, 9.33 To a solution of mmol, 1 eq.) in MeOH (15 mL) was added H ₂ SO ₄ (457.38 mg, 4.66 mmol, 248.58 μL, 0.5 eq.). The mixture was stirred at 65 °C for 3 h. The mixture was diluted with water (50 mL), then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with NaCl aqueous solution (50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain (2S, 3S, 4R)-3-fluoro-4 as a colorless oil. -Hydroxytetrahydrofuran-2-carboxylic acid methyl ester and (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylic acid methyl ester (1.2 g, crude product), which were used directly in the next step without further purification. steps. (2S,3R,4R)-4-(( tert-butyldimethylsilyl ) oxy )-3- fluorotetrahydrofuran -2- carboxylic acid methyl ester (2R,3S,4S)-3-((( th) Tributyldimethylsilyloxy )-4- fluorotetrahydrofuran - 2- carboxylic acid methyl ester

Step 5. To (2S,3S,4R)-3-fluoro-4-hydroxytetrahydrofuran-2-carboxylic acid methyl ester and (2R,3S,4S)-4-fluoro-3-hydroxytetrahydrofuran-2-carboxylic acid methyl ester ( To a solution of 1.2 g, 7.31 mmol, 1 eq.) in DMF (12 mL), DMAP (44.66 mg, 365.56 μmol, 0.05 eq.) and imidazole (995.46 mg, 14.62 mmol, 2 eq.) were added, followed by Tributyldimethylsilyl chloride (2.20 g, 14.62 mmol, 1.80 mL, 2 eq.) was added to the mixture. The mixture was stirred at -20 °C for 16 h. The mixture was diluted with water (50 mL), then the mixture was extracted with EtOAc (50 mL * 3). The combined organic layers were washed with _aqueous NaCl solution (50 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EtOAc = 1/0 to 20/1, TLC (PMA): PE/EtOAc = 10/1, Rf = 0.48) to obtain a colorless oil. (2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-carboxylic acid methyl ester and (2R,3S,4S)-3-( (tert-Butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-carboxylic acid methyl ester (503 mg, 1.81 mmol, 24.71% yield). 3-((2S,3R,4R)-4-(( tert-butyldimethylsilyl ) oxy )-3- fluorotetrahydrofuran -2- yl )-3- pentanoxypropionitrile 3-( (2R,3S,4S)-3-(( tert-butyldimethylsilyl ) oxy )-4- fluorotetrahydrofuran -2- yl )-3- pentoxypropionitrile

Step 6. Add n-butyllithium (2.5 M, 2.16 mL, 3 eq.) dropwise to THF (5 mL) at -72 °C under _N , followed by MeCN (221.18 mg, 5.39 mmol, 283.57 μL, 3 eq.) was added dropwise to the mixture, and the mixture was stirred at -72°C for 1 h, followed by adding (2S,3R,4R)-4-((third) in THF (2 mL) Butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-carboxylic acid methyl ester and (2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy) Methyl-4-fluorotetrahydrofuran-2-carboxylate (500 mg, 1.80 mmol, 1 eq) was added dropwise to the mixture, and the mixture was stirred at -72 °C under _N2 atmosphere for 1 h. The reaction mixture was quenched by adding saturated NH ₄ Cl (20 mL), followed by extraction with EtOAc (20 mL * 3). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain the crude product 3-((2S,3R,4R)-4-((tert-butyldimethyl) as a yellow solid Silyl)oxy)-3-fluorotetrahydrofuran-2-yl)-3-side oxypropionitrile and 3-((2R,3S,4S)-3-((tert-butyldimethylsilane) (yl)oxy)-4-fluorotetrahydrofuran-2-yl)-3-pendantoxypropionitrile (430 mg, crude), which was used directly in the next step without further purification. 1-( tert-butyl )-3-((2S,3R,4R)-4-(( tert-butyldimethylsilyl ) oxy )-3- fluorotetrahydrofuran -2- yl )-1H -Pyrazole - 5- amine ( synthetic intermediate ) 1-( tert-butyl )-3-((2S,3S,4S)-3-(( tert-butyldimethylsilyl ) oxy ) -4- Fluorotetrahydrofuran -2- yl )-1H- pyrazole -5- amine ( synthetic intermediate )

Step 7. To 3-((2S,3R,4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl)-3-oxypropyl Nitrile and 3-((2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)-4-fluorotetrahydrofuran-2-yl)-3-side oxypropionitrile ( To a solution of 430 mg, 1.50 mmol, 1 eq.) in i -PrOH (5 mL) was added tert-butylhydrazine; hydrochloride (242.37 mg, 1.95 mmol, 1.3 eq.) and DIEA (251.38 mg, 1.95 mmol, 338.79 μL, 1.3 eq.). The mixture was stirred at 80 °C for 3 h. The mixture was diluted with water (10 mL), then the mixture was extracted with EtOAc (10 mL * 3). The combined organic layers were washed with _aqueous NaCl solution (20 mL), dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , PE/EtOAc = 1/0 to 5/1, TLC (KMnO ₄ ): PE/EtOAc = 3/1, R _f = 0.38) to obtain yellow oil. 1-(tert-butyl)-3-((2S,3R, 4R)-4-((tert-butyldimethylsilyl)oxy)-3-fluorotetrahydrofuran-2-yl )-1H-pyrazole-5-amine and 1-(tert-butyl)-3-((2S,3S,4S)-3-((tert-butyldimethylsilyl)oxy)- 4-Fluorotetrahydrofuran-2-yl)-1H-pyrazol-5-amine (180 mg, 432.81 μmol, 28.93% yield, 85.97% purity). LC-MS (ESI ⁺ ) m/z : 358.5 (M+H) ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.73 (d, J = 2.7 Hz, 1H), 5.09 - 4.70 (m, 2H), 4.56 - 4.45 (m, 1H), 4.32 - 3.66 (m, 2H ), 3.50 (br s, 2H), 1.67 - 1.59 (m, 9H), 0.94 - 0.84 (m, 9H), 0.14 - 0.01 (m, 6H).

Additional compounds prepared according to the methods of Example 28 and methods described herein are shown in Table 10 below. Table 10. Additional exemplary compounds compound structure ¹ H NMR MS [M+1] Bicyclo[1.1.1]pentan-1-ylcarbamate (3R,4R,5S)-4-fluoro-5-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d6) 12.61 (s, 1H), 10.86 (s, 1H), 8.23 (s, 1H), 6.67 (d, J = 15.9 Hz, 2H), 5.29-5.00 (m, 3H), 4.80 (q, J = 8.9 Hz, 2H), 4.34 (d, J = 8.2 Hz, 1H), 3.96 (s, 3H), 3.79 (d, J = 10.7 Hz, 1H), 2.40 (s, 1H), 1.95 (s, 6H). 503.35 Bicyclo[1.1.1]pentan-1-ylcarbamate (2S,3S,4S)-4-fluoro-2-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d6) 12.68 (s, 1H), 10.89 (s, 1H), 8.26 (s, 1H), 6.69-6.56 (m, 2H), 5.35-5.16 (m, 2H), 4.89 (s , 1H), 4.80 (q, J = 8.9 Hz, 2H), 4.22 (dd, J = 23.5, 11.7 Hz, 1H), 3.97 (s, 4H), 2.39 (s, 1H), 1.94 (s, 6H) . 503.30 Bicyclo[1.1.1]pentan-1-ylcarbamate (2S,3R,4S)-4-fluoro-2-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d6) 12.68 (s, 1H), 10.90 (s, 1H), 8.25 (s, 1H), 6.64 (d, J = 28.1 Hz, 2H), 5.36-5.14 (m, 2H), 4.86 (d, J = 19.5 Hz, 1H), 4.79 (t, J = 8.9 Hz, 2H), 4.21 (dd, J = 23.1, 11.9 Hz, 1H), 3.97 (s, 4H), 2.39 (s, 1H ), 1.93 (s, 6H). 503.15 Example 29 ( tert-butoxycarbonyl )(1-( tert-butyl )-3-((2R,3R*,4S*)-3- fluoro -4- hydroxytetrahydrofuran -2- yl )-1H- pyra Azol -5- yl ) carbamic acid benzyl ester ( synthetic intermediate ) ( tert-butoxycarbonyl ) (1-( tert-butyl )-3-((2R,3R*,4R*)-3- fluoro -4- Hydroxytetrahydrofuran -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester ( synthetic intermediate ) (1-( tert-butyl )-3-((2S,4R)-4-(( tert-butyldimethylsilyl ) oxy ) tetrahydrofuran -2- yl )-1H- pyrazole -5 -Benzyl carbamate _ _

Step 1. Treat 1-(tert-butyl)-3-((2S, 4R)-4-((tert-butyldimethylsilyl)oxy) with benzyl chloroformate (15.0 mL, 106 mmol) A cold (0 °C) solution of tetrahydrofuran-2-yl)-1H-pyrazol-5-amine (17.8 g, 52.4 mmol) in acetonitrile (124 mL). After the addition was complete, the reaction was warmed to room temperature and stirred for 90 minutes. Sodium bicarbonate (14.1 g, 168 mmol) was added in one portion and the suspension was stirred at room temperature for 67 h. The reaction mixture was poured into half-saturated _NaHCO3 (800 mL) and extracted with ethyl acetate. The organic layer was washed with brine (400 mL). The aqueous phase was back-extracted with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dried under high vacuum over 48 h and used directly in the next step without further analysis. (1-( tert-Butyl )-3-((2S,4R)-4- hydroxytetrahydrofuran -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 2. Under an argon atmosphere, crude (1-(tert-butyl)-3-((2S,4R)-4-((tert-butyldimethylsilyl)oxy)tetrahydrofuran-2 Benzyl-1H-pyrazol-5-yl)carbamate (32.33 g) was diluted with THF (80.0 mL) and cooled to -70°C. A solution of TBAF (105 mL, 105 mmol) in THF (1.0 M) was slowly added while maintaining the internal temperature below -65 °C. After the addition was complete, the dry ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 7 h. The reaction mixture was cooled to 0 °C and poured carefully into a cold stirred mixture of ice and saturated NaHCO ₃ . The material was extracted with ethyl acetate and the organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by flash chromatography on a silica column using 20% to 100% EtOAc in hexane. The desired fractions were concentrated in vacuo to give (1-(tert-butyl)-3-((2S,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazole- as a colorless oil) 5-yl)benzylcarbamate (14.19 g, 75% yield over 2 steps). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.38 (m; 5 H); 6.28 (br s; 1 H); 6.25 (br s; 1 H); 5.67 (d; J = 10.89 Hz; 1 H); 5.20 (s; 2 H); 5.07 (dd; J = 9.11; 1.79 Hz; 1 H); 4.42-4.47 (m; 1 H); 3.94-3.99 (m; 2 H); 2.37-2.44 ( m; 1 H); 2.31 (d; J = 13.68 Hz; 1 H); 1.58 (s; 9 H). ESI-MS (m/z+): 360.2 [M+H] ⁺ . (S)-(1-( tert-butyl )-3-(4- side oxytetrahydrofuran -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 3. Treat (1-(tert-butyl)-3-() with water (0.25 mL, 13.9 mmol) and Dess-Martin Periodinane (24.9 g, 52.9 mmol) at 0°C A solution of (2S,4R)-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (14.2 g, 39.5 mmol) in dichloromethane (250 mL). After 20 min, the ice-water bath was removed and the reaction was allowed to warm to room temperature. After 2 hours, _the orange suspension was cooled back to 0°C and quenched with _a cold saturated solution of 1:1 _NaHCO3 / _Na2S2O3 . The ice-water bath was removed and the mixture was stirred at room temperature for 60 min. The suspension was diluted with DCM, the organic phase separated and washed with saturated _NaHCO3 and brine. The organic layer was dried over _MgSO4 , filtered and concentrated in vacuo. The residue was placed under high vacuum overnight. The crude material was purified by flash chromatography on a silica column (eluting with 10% to 30% ethyl acetate in hexanes). The desired fractions were concentrated in vacuo and the resulting pink wet solid was dried under high vacuum. The solid was further purified by trituration with dichloromethane and hexanes to obtain (S)-(1-(tert-butyl)-3-(4-side oxytetrahydrofuran-2-yl)- as a beige solid) 1H-pyrazol-5-yl)carbamic acid benzyl ester (11.17 g, 79% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.35-7.39 (m; 5 H); 6.32 (s; 1 H); 6.24 (br s; 1 H); 5.30-5.34 (m; 1 H); 5.20 (s; 2 H); 4.09 (d; J = 16.82 Hz; 1 H); 3.94 (d; J = 16.81 Hz; 1 H); 2.91 (dd; J = 17.97; 7.32 Hz; 1 H); 2.76 ( dd; J = 17.95; 7.00 Hz; 1 H); 1.58 (s; 9 H). ESI-MS (m/z+): 358.3 [M+H] ⁺ . (S)-( tert-Butoxycarbonyl )(1-( tert-butyl )-3-(4- side oxytetrahydrofuran -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 4. In a round bottom flask (500 mL), treat (S)-(1-(tert-butyl)-3-(4-oxygen) with triethylamine (6.06 mL, 43.5 mmol) at room temperature (tetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (15.0 g, 42.2 mmol), di-tert-butyl dicarbonate (11.2 g, 50.6 mmol) and 4-dimethyl A mixture of aminopyridine (516 mg, 4.22 mmol) in DCM (150 mL). No significant exotherm occurred (internal temperature remained below 22-23°C). After 90 min, the reaction mixture was poured into saturated NaHCO _solution /water (1:1, 300 mL). Add more DCM (100 mL) for extraction. After separation of the organic phase, the aqueous layer was extracted again with DCM (2×50 mL). The organic layers were combined, washed with brine (100 mL), dried over _MgSO4 , filtered and concentrated in vacuo. The brown oil was dried under high vacuum with gentle heating (<50°C) using a heat gun. The crude oil (20.9 g) was purified by flash chromatography on a _SiO2 column. Select the fraction to obtain (S)-(tert-butoxycarbonyl)(1-(tert-butyl)-3-(4-side oxytetrahydrofuran-2-yl)-1H-pyridine as an oily substance) Azol-5-yl)carbamate benzyl ester. (S)-( tert-butyloxycarbonyl )(1-( tert-butyl )-3-(4-(( tert-butyldimethylsilyl ) oxy) oxy )-2,5- dihydro Furan -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 5. In a round bottom flask (1 L), place (S)-(tert-butoxycarbonyl)(1-(tert-butyl)-3-(4-side oxytetrahydrofuran-2-yl) Benzyl-1H-pyrazol-5-yl)carbamate (19.2 g, 42.1 mmol) was degassed under vacuum (3 cycles, vacuum/argon). Next, DCM (100 mL) was added and the solution was cooled to 0 °C and treated successively with tert-butyl dimethylsilyltrifluoromethanesulfonate (13.0 mL, 55.5 mmol) dropwise after 4-5 min , treat with slowly added triethylamine (7.97 mL, 57.2 mmol) over 5-10 min, keeping the internal temperature below 5°C. After 45 min at 0 °C, the reaction was diluted with heptane (200 ml) and the mixture was quenched with saturated NaHCO ₃ solution/brine (1:1, 200 ml). The organic layer was washed with brine (100 mL), dried over _MgSO4 , filtered and concentrated in vacuo. The crude oil was gently heated with a hot air gun (<50°C) and placed under high vacuum to obtain (S)-(tert-butoxycarbonyl)(1-(tert-butyl) as an oil )-3-(4-((tert-Butyldimethylsilyl)oxy)-2,5-dihydrofuran-2-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester. ¹ H NMR (400 MHz, CDCl3): δ 7.28-7.32 (m; 3 H); 7.20-7.26 (m; 2 H); 6.01 (s; 1 H); 5.74-5.76 (m; 1 H); 5.15 -5.25 (m; 2 H); 4.83 (dq; J = 8.65; 1.93 Hz; 1 H); 4.37-4.49 (m; 2 H); 1.47 (d; J = 7.44 Hz; 9 H); 1.43 (d ;J = 3.41 Hz; 9 H); 0.94 (s; 9 H); 0.19-0.21 (m; 6 H). ESI-MS (m/z+): 572.4 [M+H]+. The crude mixture was carried to the next step without any further purification. ( tert-butoxycarbonyl )(1-( tert-butyl )-3-((2R,3R*)-3- fluoro -4- side-oxytetrahydrofuran -2- yl )-1H- pyrazole -5 -yl ) benzylcarbamate ( tert-butoxycarbonyl )(1-( tert -butyl )-3-((2R,3R*)-3- fluoro -4- side oxytetrahydrofuran -2- yl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 6. In a round bottom flask (1 L), place N-Boc-(S)-(1-(tert-butyl)-3-(4-((tert-butyldimethylsilyl)) Benzyl(oxy)-2,5-dihydrofuran-2-yl)-1H-pyrazol-5-yl)carbamate (16.9 g, 29.6 mmol) in vacuum (3 cycles, vacuum/argon) Degas. Next, anhydrous ACN (250 mL) was added and the solution was cooled to -35°C to -30°C. The yellow solution was treated with SelectFluor (11.0 g, 31.0 mmol) in one portion. After 5 min, the cooling bath was removed and the reaction was slowly warmed to 0 °C over 10-15 min. Then, an ice-water bath was placed and the reaction was stirred at 0°C for 1 h. The reaction mixture was poured into saturated _NH4Cl solution/water/brine (1:1:1, 900 mL), extracted with EtOAc (800 mL), washed with brine (300 mL), dried over _MgSO4 , filtered and Concentrate in vacuo. The residue was further dried under high vacuum. The crude brown oil was passed by flash chromatography on a _SiO2 column, loading a DCM/hexane mixture (1:2) and going from 100% DCM to 5% EtOAc in DCM and to 10% EtOAc in DCM. Purified after elution with EtOAc. TLC (EtOAc/hexane (1:2): Rf (compound 7b) = 0.46; Rf (compound 7a) = 0.24).

Obtained as light yellow oily substance (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R, 3R*)-3-fluoro-4-side oxytetrahydrofuran-2-yl) )-1H-pyrazol-5-yl)carbamic acid benzyl ester (compound 7a) (2.51 g, 18% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.27-7.32 (m; 3 H); 7.20-7.23 (m; 1 H); 7.16-7.18 (m; 1 H); 6.11 (dd; J = 2.40; 1.09 Hz; 1 H); 5.36-5.41 (m; 1 H); 5.11-5.26 (m; 3 H); 4.34 (dd; J = 17.39; 13.97 Hz; 1 H); 4.07-4.12 (m; 1 H) ); 1.46 (d; J = 1.42 Hz; 9 H); 1.42 (d; J = 6.69 Hz; 9 H). ESI-MS (m/z+): 494.3 [M+H ₂ O+H].

Obtained as light yellow oily substance (tert-butoxycarbonyl)(1-(tert-butyl)-3-((2R, 3R*)-3-fluoro-4-side oxytetrahydrofuran-2-yl) )-1H-pyrazol-5-yl)carbamic acid benzyl ester (compound 7b) (5.43 g, 39% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28-7.33 (m; 3 H); 7.19-7.25 (m; 2 H); 6.18 (s; 1 H); 5.33 (dd; J = 9.54; 6.24 Hz ;0.5 H); 5.10-5.24 (m; 3.5 H); 4.11-4.23 (m; 2 H); 1.48 (d; J = 2.55 Hz; 9 H); 1.44 (d; J = 6.75 Hz; 9 H) . ESI-MS (m/z+): 494.3 [M+H ₂ O+H]; 476.3 [M+H]. ( tert-butoxycarbonyl )(1-( tert-butyl )-3-((2R,3R*,4R*)-3- fluoro -4- hydroxytetrahydrofuran -2- yl )-1H - pyrazole- 5- yl ) benzylcarbamate

Step 7. In a flamed dried round bottom flask (250 mL) under an argon atmosphere, (S)-2-methyl-CBS-oxazaborolidine (1.80 g, A solution of 6.49 mmol) in THF (30.0 mL) was cooled to -70 °C and treated with borane-dimethyl sulfide complex (551 uL, 5.81 mmol). The dry ice bath was removed and the reaction mixture was warmed to -30°C. The reaction was immediately cooled back to -70°C. After 15-20 min, a suspension is obtained. Next, N-Boc-(1-(tert-butyl)-3-((2R)-3-fluoro-4-side oxytetrahydrofuran-2-yl)-1H- A solution of benzyl pyrazol-5-yl)carbamate (2.51 g, 5.28 mmol) in THF (30.0 mL) was added dropwise to the first solution while maintaining the internal temperature below -65°C. Rinse the flask with additional THF (3 x 3 mL). The reaction was held at -70°C for 5 min. The dry ice bath was removed and the reaction mixture was warmed to 0°C (at approximately -50°C, a turbid solution was observed). After reaching -5°C to 0°C, an ice-water bath was placed and the reaction was kept at this temperature for 30 min. Next, the reaction was cooled back to -70°C and MeOH (4 mL) was added dropwise to quench the reaction. Replace the dry ice bath with an ice-water bath and heat the reaction mixture to 0°C for 15-20 min. A large number of bubbles were observed. Next, the reaction mixture was poured into a semisaturated _aqueous NaHCO solution (500 mL) and extracted with EtOAc (400 mL). The organic layer was separated and washed with brine (200 mL). The aqueous phase was back-extracted with EtOAc (200 mL). The organic layers were combined, dried over _Na2SO4 , filtered and concentrated in _vacuo . The residue was co-evaporated with heptane and placed under high vacuum. The crude material was purified by flash chromatography on _SiO2 , loading 100% DCM and dissolving from 6% to 50% EtOAc in DCM to afford (tert-butoxycarbonyl) as a colorless oil. (1-(tert-Butyl)-3-((2R,3R*,4R*)-3-fluoro-4-hydroxytetrahydrofuran-2-yl)-1H-pyrazol-5-yl)carbamic acid benzyl Ester (1.59 g, 63% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28-7.33 (m; 3 H); 7.19-7.23 (m; 2 H); 6.16 (s; 1 H); 5.11-5.24 (m; 2.5 H); 5.00-5.06 (m; 1.5 H); 4.46-4.57 (m; 1 H); 4.13-4.18 (m; 1 H); 3.93-3.99 (m; 1 H); 3.79 (ddd; J = 70.04; 10.88; 3.02 Hz; 1 H); 1.48 (d; J = 4.82 Hz; 9 H); 1.42 (d; J = 2.97 Hz; 9 H). ESI-MS (m/z+): 478.3 [M+H] ⁺ .

The exemplary compounds shown below were synthesized using the methods of Example 29 and the methods described herein. Bicyclo[1.1.1]pentan-1-ylcarbamate (3S,4R,5S)-4-fluoro-5-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.61 (s, 1H), 10.87 (s, 1H), 8.23 (s, 1H), 6.66 (d, J = 14.0 Hz, 2H), 5.35-4.98 (m, 3H) , 4.80 (q, J = 8.9 Hz, 2H), 4.34 (d, J = 9.0 Hz, 1H), 3.96 (s, 3H), 3.78 (d, J = 10.6 Hz, 1H), 2.40 (s, 1H) , 1.95 (s, 6H). [M+H] = 503.20 Bicyclo[1.1.1]pentan-1-ylcarbamate (3R,4S,5R)-4-fluoro-5-(3-(1-methyl-3-(2,2,2-trifluoroethane) Oxy)-1H-pyrazole-5-carboxamide)-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester (400 MHz, DMSO-d ₆ ) 12.61 (s, 1H), 10.87 (s, 1H), 8.23 (s, 1H), 6.66 (d, J = 14.0 Hz, 2H), 5.35-4.98 (m, 3H) , 4.80 (q, J = 8.9 Hz, 2H), 4.34 (d, J = 9.0 Hz, 1H), 3.96 (s, 3H), 3.78 (d, J = 10.6 Hz, 1H), 2.40 (s, 1H) , 1.95 (s, 6H). [M+H] = 503.2 Isopropylcarbamic acid (3R,4S,5R)-4-fluoro-5-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide) )-1H-pyrazol-5-yl)tetrahydrofuran-3-yl ester ¹ H NMR (CDCl ₃ , 400 MHz): δ 10.38 (1H, br s), 9.51 (1H, s), 6.80 (1H, s), 6.77 (1H, s), 5.29-5.38 (1H, m), 4.82-4.86 (1H, m), 4.47 (2H, s), 4.21 (1H, t, J = 8.3 Hz), 4.15 (3H, s), 3.96-4.01 (1H, m), 3.76-3.84 (1H, m), 3.41 (3H, s), 1.16 (6H, d, J = 6.6 Hz) [M+H] = 425.3 Bicyclo[1.1.1]pentan-1-ylcarbamate (3R,4S,5R)-5-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)-4-fluorotetrahydrofuran-3-yl ester ¹ H NMR (400 MHz, CDCl ₃ ): δ 10.17 (br. s; 1 H); 8.83 (s; 1 H); 6.77 (s; 1 H); 5.95-6.26-6.12 (m; 2 H); 5.30-5.47 (m; 2 H); 5.04-5.28 (m; 2 H); 4.38 (td; J = 13.33; 4.20 Hz; 2 H); 4.22-4.29 (m; 1 H); 4.05 (s; 3 H); 3.98-4.03 (m; 1 H); 2.44 (s; 1 H); 2.05 (s; 6 H). [M+H] = 485.2 Bicyclo[1.1.1]pentan-1-ylcarbamate (3R,4R,5R)-5-(3-(3-(2,2-difluoroethoxy)-1-methyl-1H- Pyrazole-5-methamide)-1H-pyrazol-5-yl)-4-fluorotetrahydrofuran-3-yl ester 1H NMR (400 MHz, CDCl ₃ ): δ 10.21 (br s; 1 H); 8.71 (s; 1 H); 6.76 (s; 1 H); 5.95-6.25 (m; 2 H); 5.12-5.36 ( m; 4 H); 4.39 (td; J = 13.35; 4.17 Hz; 2 H); 4.19 (t; J = 12.43 Hz; 2 H); 4.06 (s; 3 H); 2.41 (s; 1 H); 2.00 (s; 6H). [M+H] = 485.1 Example 30 rel -( tert-butoxycarbonyl )(1-( tert-butyl )-3-((1S,2R,3S)-2- fluoro -3- hydroxycyclopentyl )-1H - pyrazole- 5- yl ) Benzyl carbamate ( synthetic intermediate ) ( Tertiary butoxycarbonyl )(1-( tertiary butyl )-3-(3- side oxycyclopentyl )-1H- pyrazol -5- yl ) carbamic acid benzyl ester

Step 1. In a round bottom flask (500 mL), treat (1-(tert-butyl)-3-(3-pendantoxycyclopentyl) with triethylamine (6.06 mL, 43.5 mmol) at room temperature )-1H-pyrazol-5-yl)carbamic acid benzyl ester (15.0 g, 42.2 mmol), di-tert-butyl dicarbonate (11.2 g, 50.6 mmol) and 4-dimethylaminopyridine (516 mg , 4.22 mmol) in DCM (150 mL). No significant exotherm occurred (internal temperature remained below 22-23°C). After 90 min, the reaction mixture was poured into saturated NaHCO _solution /water (1:1, 300 mL). Add more DCM (100 mL) for extraction. After separation of the organic phase, the aqueous layer was extracted again with DCM (2×50 mL). The organic layers were combined, washed with brine (100 mL), dried over _MgSO4 , filtered and concentrated in vacuo. The brown oil was dried under high vacuum with gentle heating (<50°C) using a heat gun. The crude oil (20.9 g) was subjected to flash chromatography on a SiO ₂ column, loading DCM/hexane (1:5; 240 mL) and starting with 10% EtOAc in hexane (1 L); 30% (1 L) and 50% (1 L) were dissolved and purified. Fraction selection by TLC (25% EtOAc in hexanes: Rf (product) = 0.35) afforded (tert-butoxycarbonyl)(1-(tert-butyl)-3 as a colorless oil -(3-Pendantoxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (20.2 g, 98% yield). ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.28-7.31 (m; 3 H); 7.19-7.23 (m; 2 H); 5.89 (s; 1 H); 5.15-5.23 (m; 2 H); 3.42-3.50 (m; 1 H); 2.57 (dd; J = 18.36; 7.81 Hz; 1 H); 2.46 (ddd; J = 18.42; 8.36; 2.41 Hz; 1 H); 2.31-2.39 (m; 2 H ); 2.17-2.26 (m; 1 H); 2.00-2.09 (m; 1 H); 1.46 (d; J = 0.92 Hz; 9 H); 1.43 (d; J = 2.43 Hz; 9 H). ESI-MS (m/z+): 456.2 [M+H] ⁺ . ( tert-butyloxycarbonyl )(1-( tert-butyl )-3-(3-(( tert -butyldimethylsilyl ) oxy ) cyclopent -2- en- 1- yl ) -1H- pyrazol -5- yl ) carbamate benzyl ester

Step 2. In a round bottom flask (1 L), place N-Boc-(1-(tert-butyl)-3-(3-side oxycyclopentyl)-1H-pyrazol-5-yl) Benzyl carbamate (19.2 g, 42.1 mmol) was degassed under vacuum (3 cycles, vacuum/argon). Next, DCM (100 mL) was added and the solution was cooled to 0 °C and treated successively with tert-butyl dimethylsilyltrifluoromethanesulfonate (13.0 mL, 55.5 mmol) dropwise after 4-5 min , treat with slowly added triethylamine (7.97 mL, 57.2 mmol) over 5-10 min, keeping the internal temperature below 5°C. After 45 min at 0 °C, the reaction was diluted with heptane (200 mL) and the mixture was quenched with saturated NaHCO3 solution/brine (1:1, 200 mL). The organic layer was washed with brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude oil was gently heated with a hot air gun (<50°C) and placed under high vacuum to obtain a mixture of 3a and 3b (24.7 g, ratio 1.7:1) as a yellow oil. ESI-MS (m/z+): 570.4 [M+H] ⁺ . The crude mixture was carried to the next step without any further purification. rel -( tert-butoxycarbonyl )(1-( tert-butyl )-3-((1S,2R)-2- fluoro -3- pendantoxycyclopentyl )-1H- pyrazole -5- Benzyl carbamate ( diastereomer C )

Step 3. In a round bottom flask (1 L), add N-Boc-(1-(tert-butyl)-3-(3-((tert-butyldimethylsilyl)oxy)oxy)cyclo A crude mixture of pent-2-en-1-yl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (24.0 g, 42.1 mmol) was degassed under vacuum (3 cycles, vacuum/argon) . Next, anhydrous ACN (150 mL) was added and the solution was cooled to -35°C to -30°C. The yellow solution was treated with SelectFluor (15.2 g, 43.0 mmol) in one portion. After 5 min, the dry ice bath was removed and the internal temperature was slowly increased to 0 °C over 10 min and maintained at this temperature using an ice water bath. After 30 min after the addition, the reaction mixture was poured into saturated NH ₄ Cl solution/water/brine (1:1:1, 600 mL). The material was extracted with EtOAc (600 mL). The organic phase was separated, washed with brine (200 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was co-evaporated with heptane (2×20-30 mL) and placed under high vacuum overnight. The crude oil (21.8 g) was subjected to flash chromatography on a _SiO2 column, loading a DCM/hexane mixture (1:3) and going from 100% hexane to 10% EtOAc in hexane (2 L), to 20% EtOAc in hexane (3 L), to 30% EtOAc in hexane (1-2 L) and purified. Fractions were selected by TLC. TLC (EtOAc (1:2) in hexanes): three spots: Rf (Asteriomer A) = 0.57; Rf (Asteriomer B) = 0.49; C and D) = 0.39.

Diastereomer A was isolated as pure material (3.26 g, 16% yield), which was a colorless oil that solidified as a white wet solid. 1H NMR (400 MHz, CDCl3): δ 7.30-7.32 (m; 3 H); 7.20-7.22 (m; 2 H); 5.89 (d; J = 2.17 Hz; 1 H); 5.16-5.24 (m; 2 H); 5.04 (ddt; J = 51.50; 13.06; 8.01 Hz; 1 H); 3.59-3.64 (m; 1 H); 2.65-2.68 (m; 2 H); 2.52-2.61 (m; 1 H); 2.30-2.42 (m; 1 H); 1.45 (s; 9 H); 1.44 (d; J = 2.41 Hz; 9 H). ESI-MS (m/z+): 474.2 [M+H].

Diastereomer B was isolated as pure material as a colorless oil (2.52 g, 13% yield). 1H NMR (400 MHz, CDCl3): δ 7.29-7.33 (m; 3 H); 7.20-7.23 (m; 2 H); 6.00 (d; J = 2.51 Hz; 1 H); 5.16-5.24 (m; 2 H); 4.99 (dt; J = 50.54; 10.43 Hz; 1 H); 3.35-3.46 (m; 1 H); 2.32-2.53 (m; 3 H); 2.05-2.14 (m; 1 H); 1.48 ( s; 9 H); 1.44 (d; J = 2.78 Hz; 9 H). ESI-MS (m/z+): 474.2 [M+H].

Diastereomers C and D were isolated as a mixture (6.87 g) and carried to the next step without any further purification. ESI-MS (m/z+): 474.2 [M+H]. rel -( tert-butoxycarbonyl )(1-( tert-butyl )-3-((1S,2R,3S)-2- fluoro -3- hydroxycyclopentyl )-1H- pyrazole -5- Benzyl carbamate _

Step 4. In a flame-dried round bottom flask (250 mL) under an argon atmosphere, (S)-2-methyl-CBS-oxaborolidine (1.48 g, 5.07 mmol) was dissolved in THF (24 mL) was cooled to -70 °C and treated with borane-dimethyl sulfide complex (441 uL, 4.65 mmol). The dry ice bath was removed and the reaction mixture was warmed to -30°C (temperature controlled by thermocouple measurement). The reaction was immediately cooled back to -70°C. After 5-10 min, a solution of diastereomers C and D (2 g, 4.22 mmol) as a mixture in THF (24 mL) was added dropwise to the first solution via cannula over 10-12 min. and keep the internal temperature below -65°C. The reaction was held at -70°C for 5 min. The dry ice bath was removed and the reaction mixture was warmed to 0°C. Place an ice-water bath and keep the reaction at this temperature for 30 min. The reaction was then cooled back to -70°C and MeOH (4 mL) was added dropwise to quench the reaction. Replace the dry ice bath with an ice-water bath and heat the reaction mixture to 0°C for 15-20 min. Next, the reaction mixture was poured into semisaturated _aqueous NaHCO solution (100 mL) and extracted with EtOAc (200 mL). The aqueous phase was back-extracted with EtOAc (50 mL, 2×). The organic layers were combined, washed with _brine , dried over _Na2SO4 , filtered, and concentrated in vacuo. The mixture was purified twice through a 220 g silica gel column using a mixture gradient (0-40%) of EtOAc in hexane to obtain rel-(tert-butoxycarbonyl)(1-(tert-butyl) as a mixture )-3-((1S,2R,3S)-2-fluoro-3-hydroxycyclopentyl)-1H-pyrazol-5-yl)carbamic acid benzyl ester (1.19 g). ESI-MS (m/z+): 476.2 [M+H] ⁺ .

The exemplary compounds shown below were synthesized using the methods of Example 30 and the methods described herein. Isopropylcarbamic acid (1S,2R,3S)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide) )-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, DMSO-d ₆ ) 12.28 (s, 1H), 10.72 (s, 1H), 7.32 - 6.98 (m, 2H), 6.47 (s, 1H), 5.17 - 4.91 (m, 2H) , 4.34 (s, 2H), 4.05 (s, 3H), 3.67 - 3.54 (m, 1H), 3.41 (dd, J = 36.8, 9.6 Hz, 1H), 3.27 (s, 3H), 2.22 - 1.99 (m , 3H), 1.80 (d, J = 10.5 Hz, 1H), 1.05 (d, J = 6.6 Hz, 6H). [M+H] = 423.35 Isopropylcarbamic acid (1R,2S,3R)-2-fluoro-3-(3-(3-(methoxymethyl)-1-methyl-1H-pyrazole-5-methamide) )-1H-pyrazol-5-yl)cyclopentyl ester ¹ H NMR (400 MHz, CDCl ₃ ): δ 9.86 (br s; 1 H); 9.44 (br s; 1 H); 6.77 (s; 1 H); 6.73 (s; 1 H); 4.99-5.18 ( m; 2 H); 4.66-4.74 (m; 1 H); 4.49 (s; 2 H); 4.17 (s; 3 H); 3.77-3.87 (m; 1 H); 3.45 (s; 3 H); 3.15-3.33 (m; 1 H); 2.05-2.26 (m; 3 H); 1.91-2.05 (m; 1 H); 1.16-1.18 (m; 6 H). [M+H] = 423.3 Example 31

Compounds of the present disclosure were tested in the CDK2/Cyclin E fluorescence-based microfluidic mobility shift assay (PerkinElmer).

Active wild-type CDK2/cyclin E complex was purchased from Eurofins (14-475). Compound stocks were prepared in DMSO and serially diluted to 11 concentrations by 3-fold dilution. Transfer 200 nL of compound to individual wells in a 384-well plate (Greiner, 781201), then add 15 uL of 1.3X enzyme and ATP containing 0.13 nM CDK2/Cyclin E and 2660 uM ATP in 1X reaction buffer The reaction buffer contains 10 mM Hepes pH 7.5, 0.01% Brij-35, 10 mM MgCl ₂ , 1 mM EGTA, 0.05% BSA and 2 mM DTT. Compounds were incubated in the presence of CDK2/cyclin E complex and ATP for 30 minutes at room temperature. Start by adding 5 uL of 4× peptide solution containing 6 uM of fluorescently labeled substrate peptide (FL peptide 18 (amino acid sequence 5-FAM-QSPKKG, PerkinElmer, 760362)) in 1× reaction buffer catalytic reaction.

The final reaction components were 0.1 nM CDK2/cyclin E, 2000 μM ATP, 1.5 μM FL peptide 18 and 1% DMSO. The reaction was incubated at room temperature for 20 hours and stopped with 75 uL of stop solution containing 0.5 M EDTA. Samples were analyzed using a LabChip EZ reader (PerkinElmer).

The results of the CDK2 biochemical Caliper analysis are presented in Table 1. Compounds with an IC50 of less than or equal to 100 nM are designated as "A"; compounds with an IC50 of greater than 100 nM but less than or equal to 250 nM are designated as "B"; compounds with an IC50 of greater than 250 nM but less than or equal to 1 μM are designated as "B" Compounds with an IC50 are designated "C"; and compounds with an IC50 greater than 1 μM but less than or equal to 100 μM are designated "D". The absolute values for the exemplary compounds of Table 1 are shown in Tables 11-14. Example 32

Compounds described herein were also tested in the nanoBRET TE intracellular kinase assay. Test compounds were prepared in DMSO stocks. 45 uL of the stock solution was transferred to a 384-well plate (Greiner, 781201) and a 3-fold 11-point dilution was performed. Dilute 293-NB2 cells expressing nanoLuciferase-tagged targets in cell growth medium (DMEM + 10% FBS + 1% Penicillin/Streptomycin medium) and inoculate 40 uL of 7.5E4 cells/mL in a separate in a 384-well cell culture plate and incubate overnight at 37°C/5% CO ₂ /100% humidity. Add 2 uL of 20× Complete NanoBRET K-10 Tracer (Promega NanoBRET) to each well of the cell plate except the control well. Transfer 80 nL of each concentration of compound from the compound plate to the corresponding well in the cell culture plate using an Echo550 liquid handler. Incubate the plate for 2 hours at 37°C/5% _CO2 /100% humidity. Add 20 uL of 3× complete Nano-Glo substrate and ECD NanoLuc inhibitor (Promega NanoBRET) to each well. Chemiluminescence was then read on an EnVision reader (PerkinElmer).

Cell nanoBRET analysis results are presented in Table 1. Compounds with an _IC50 of less than or equal to 100 nM are designated as "A"; compounds with an IC50 of greater than 100 nM but less than or equal to 250 nM are designated as "B"; compounds with an _IC50 of greater than 250 nM but less than or equal to 1 are designated as "B" Compounds with an _IC50 of μM are designated as "C"; and compounds with an IC50 of greater than 1 μM but less than or equal to ₁₀₀ μM are designated as "D". Example 33

Compounds of the present disclosure were tested in a fluorescence-based microfluidic mobility shift assay for CDK1/cyclin B according to the following procedure.

Active wild-type CDK1/cyclin B complex was purchased from Carna Biosciences (04-102). Compound stocks were prepared in DMSO and serially diluted to 11 concentrations by 3-fold dilution. Transfer 200 nL of compound to individual wells in a 384-well plate (Greiner, 781201), then add 15 uL of 1.3X enzyme and ATP containing 0.13 nM CDK1/Cyclin B and 2660 uM ATP in 1X reaction buffer The reaction buffer contains 10 mM Hepes pH 7.5, 0.01% Brij-35, 10 mM MgCl ₂ , 1 mM EGTA, 0.05% BSA and 2 mM DTT. Compounds were incubated in the presence of CDK1/cyclin B complex and ATP for 30 minutes at room temperature. By adding 5 uL of 6 uM fluorescently labeled substrate peptide (FL peptide 29 5-FAM-GGGPATPKKAKKL-CONH2 (amino acid sequence 5-FAM-GGGPATPKKAKKL, PerkinElmer, 760429)) in 1× reaction buffer. 4× peptide solution to initiate the catalytic reaction. The final reaction components were 0.5 nM CDK1/cyclin B, 2000 μM ATP, 1.5 μM FL peptide 29 and 1% DMSO. The reaction was incubated at room temperature for 90 minutes and stopped with 75 uL of stop solution containing 0.5 M EDTA. Samples were analyzed using a LabChip EZ reader (PerkinElmer).

The CDK1 biochemical Caliper assay results were used to calculate the selectivity of CDK2/cyclin E versus CDK1/cyclin B. Selectivity values for the exemplary compounds from Table 1 were calculated as the ratio of CDK1/Cyclin B _IC50 divided by CDK2/Cyclin E _IC50 (from Example 31), as shown in Tables 11, 12, 13 and 14 .

The following table shows the potency (CDK2/E IC50) and selectivity (CDK2/E versus CDK1/B) values for exemplary sets of compounds from Table 1 with respect to stereochemistry and fluorine substituent position within each set. different. Surprisingly, the addition of fluorine substituents at specific positions on the cyclopentyl ring and the specific stereochemistry with respect to the cyclopentyl ring confirmed the selectivity of CDK2/cyclin E over CDK1/cyclin B for all cases examined (and the highest selectivity in each group), while advantageously maintaining a low (ie, most potent) CDK2/cyclin E _IC50 value. Without wishing to be bound by theory, it is understood that better selectivity allows for a potentially larger therapeutic window such that off-target effects (eg, toxicity) can be minimized, resulting in better tolerated agents. As described in Tables 11-14 below, for example, compounds exhibiting the highest potency and greatest selectivity are those having structures such as those depicted in Formulas XXVI-c and XXVII-c. Table 11. structure CDK2/E IC50 (µM) Selectivity of CDK2/E over CDK1/B 0.012 196.67 0.058 21.22 3.15 31.75 1.49 25.85 0.022 44.05 0.104 57.12 5.66 17.67 10 10 0.017 100.47 0.01 54.3 Table 12. structure CDK2/E IC50 (µM) Selectivity of CDK2/E over CDK1/B 0.00228 292.98 0.006 23.17 0.127 44.33 0.235 59.45 Table 13. structure CDK2/E IC50 (µM) Selectivity of CDK2/E over CDK1/B 0.00228 292.98 0.003 30..33 0.127 36.22 0.322 68.32 0.011 80.82 Table 14. structure CDK2/E IC50 (µM) Selectivity of CDK2/E over CDK1/B 0.003 252.00 0.015 49.33 0.708 20.54 0.478 114.79 0.003 169.29 0.002 88.50 incorporated by reference

All publications and patents mentioned herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In the event of a conflict, this application, including any definitions, will control. equivalent

Although specific embodiments of the present disclosure have been discussed, the foregoing description is illustrative and not restrictive. Many variations of the present disclosure will become apparent to those skilled in the art upon review of this specification. The full scope of the present disclosure should be determined by reference to the claimed claims, along with the full scope of equivalents thereof, and the specification, along with such changes.

Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, etc. used in the specification and claims are to be understood as being modified in all instances by the term "about." Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and accompanying claims are approximations that may vary depending on the desired properties sought to be obtained by the present disclosure.

Claims (64)

A compound of formula I, I or a pharmaceutically acceptable salt thereof, wherein: Q is L ¹ ; Cy ^A is a 5-6 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^A is replaced by m instances of R ^A in addition to Q and Cy ^B ; Cy ^B is , , or ,in represents the covalent bond with Cy ^A and Represents a covalent bond with ^P ; P is L ² -RP; R ^P is a group selected from the following: C _1-8 aliphatic group, saturated or partially unsaturated 3-14 membered carbocyclic ring, phenyl group, 1-4 3-10 membered saturated or partially unsaturated heterocycles having heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-5-membered heterocyclic rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 14-membered heteroaryl ring; wherein R ^P is substituted by q ^P instances of R ^P1 in addition to L ² ; R ^P1 is R ³ ; Cy ^C is a saturated or partially unsaturated 3-14-membered carbocyclic ring; having 1- 4 saturated or partially unsaturated 3-14 membered heterocycles with heteroatoms independently selected from nitrogen, oxygen and sulfur; phenyl; or 5 with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -14-membered heteroaryl; wherein Cy ^C is substituted by p instances of R ^C in addition to Q; R ^C is L ³ -R ^C1 or L ³ -H; R ^C1 is C _1-4 aliphatic group; benzene radical; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; an 8-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur -10-membered bicyclic heteroaryl ring; 3-7-membered saturated or partially unsaturated carbocyclic ring; 3-7-membered saturated or partially unsaturated monocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur Cyclic heterocycle; or 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^C1 is independently selected from halogen, C _1- 0-4 instances of ₄ haloalkyl, C _1-4 alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of R ^A , R ^B is independently R ¹ or R ² , where R ^A is replaced by q ^A instances of R ³ , R ^B is replaced by q ^B instances of R ³ , or two instances of R ^A , two instances of R ^B , two instances of R ^C , one instance of R ^A and an instance of R ^L , or an instance of R ^C and an instance of R ^L together with intervening atoms form a 4-8 membered saturated, moiety having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Unsaturated or aromatic ring; wherein the ring is substituted by r instances of R ³ ; Each of L ¹ , L ² and L ³ is independently a covalent bond, or C _1-5 saturated or unsaturated, straight chain or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _{3 -6-} cycloalkyl, 3-6-membered heterocycloalkyl, 5-6-membered heteroaryl, -NH-, -N(R ^L )-, -NHC(O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S (O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein each of the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5-6 membered heteroaryl group is deemed to be is substituted by one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² and is substituted by t instances of R ³ ; each instance of R ¹ is independently It is a side oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S (O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC( O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R) C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R or -N(R)S( O) ₂ R; Each instance of R ² is independently a C _1-7 aliphatic group; phenyl; a 5-6 membered monocyclic heterocyclic heterocyclic group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Aryl ring; 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated carbocyclic ring; having 1-2 A 3-7-membered saturated or partially unsaturated monocyclic heterocyclic ring with heteroatoms independently selected from nitrogen, oxygen and sulfur; or a 7-12-membered heterocyclic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur Saturated or partially unsaturated bicyclic heterocycle; Each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, -C(O)R, -C( O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R )C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR) NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or optionally substituted groups selected from the following : C _1-6 aliphatic group, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 independently 5-6 membered heteroaryl rings selected from heteroatoms of nitrogen, oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from: C _1-6 aliphatic, saturated or Partially unsaturated 3-7 membered carbocyclic ring, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 1-4 independently A 5-6 membered heteroaryl ring selected from heteroatoms of nitrogen, oxygen and sulfur, or: Two R groups on the same nitrogen together with intervening atoms form 0-3 independent rings in addition to the nitrogen 4-7 membered saturated, partially unsaturated or heteroaryl rings selected from heteroatoms of nitrogen, oxygen and sulfur; and each of m, n, p, q ^A , q ^B , q ^P , r and t are independently 0, 1, 2, 3, or 4. a compound of formula II or III, , II III or a pharmaceutically acceptable salt thereof, wherein: X is selected from O, NR ^X and S; Y is selected from O, NR ^Y and S; Each instance of R ^X and R ^Y is independently R; Q series L ¹ ; Cy ^B series , , or ,in Represents a _covalent bond ^with 3-10 membered saturated or partially unsaturated heterocyclic rings having heteroatoms of nitrogen, oxygen and sulfur, and 5-14 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein ^{RP , in addition to _} , a saturated or partially unsaturated 3-14-membered heterocyclic ring with heteroatoms of oxygen and sulfur; phenyl; or a 5-14-membered heteroaryl group with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; Wherein Cy ^C, in addition to Q, is also substituted by p instances of ^RC ; ^RC is L ³ -R ^C1 or L ³ -H; R ^C1 is a C _1-4 aliphatic group; phenyl; having 1-4 5-6 membered monocyclic heteroaryl rings with heteroatoms independently selected from nitrogen, oxygen and sulfur; 8-10 membered bicyclic heteroaryls with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur base ring; 3-7 membered saturated or partially unsaturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or having 1 -4 7-12 membered saturated or partially unsaturated bicyclic heterocycles independently selected from nitrogen, oxygen and sulfur heteroatoms; wherein R ^C1 is independently selected from halogen, C _1-4 haloalkyl, C _1- 0-4 instances of ₄ alkoxy and C _1-4 haloalkoxy groups are substituted; each instance of ^RB is independently R ¹ or R ² , wherein ^RB is substituted with q ^B instances of R ³ , or two instances of R ^B , two instances of R ^C , or one instance of R ^C and one instance of R ^L together with intervening atoms form a heterogeneous mixture having 0-4 independently selected from nitrogen, oxygen, and sulfur. A 4-8 membered saturated, partially unsaturated or aromatic ring of atoms; wherein the ring is substituted by r instances of R ³ ; each of L ¹ , L ² and L ³ is independently a covalent bond, or C _1-5 saturated or unsaturated, straight or branched hydrocarbon chains, wherein one or two methylene units of the chain are optionally and independently replaced by the following groups: -CH(R ^L )-, -C (R ^L ) ₂ -, C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group, 5-6 membered heteroaryl group, -NH-, -N(R ^L )-, -NHC( O)-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )-, -NHS(O) ₂ -, -N(R ^L ) S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C(O)-, -OC(O)-, -C( O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, 3-6 membered heterocycloalkyl group and 5-6 membered cycloalkyl group Each of the heteroaryl groups is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group; each instance of R ^L is independently R ¹ or R ² and substituted with t instances of R ³ ; Each instance of R ¹ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O) N(R)OR, -OC(O)R, -OC(O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C( NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O) R or -N(R)S(O) ₂ R; each instance of R ² is independently a C _1-7 aliphatic group; phenyl; having 1-4 residues independently selected from nitrogen, oxygen and sulfur 5-6 membered monocyclic heteroaryl ring of atoms; 8-10 membered bicyclic heteroaryl ring with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; 3-7 membered saturated or partially unsaturated Saturated carbocyclic ring; 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; or 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring of sulfur heteroatom; each instance of R ³ is independently a pendant oxygen group, halogen, -CN, -NO ₂ , -OR, -SR, -NR ₂ , -S(O) ₂ R, -S(O) ₂ NR ₂ , -S(O)R, -S(O)NR ₂ , -S(O) ₂ F, -OS(O) ₂ F, - C(O)R, -C(O)OR, -C(O)NR ₂ , -C(NR)NR ₂ , -C(O)N(R)OR, -OC(O)R, -OC( O)NR ₂ , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR ₂ , -N(R)C(NR)NR ₂ , -N(R)S(O) ₂ NR ₂ , -N(R)S(O)R, -N(R)S(O) ₂ R or selected from The following optionally substituted groups: C _1-6 aliphatic group, phenyl group, 3-7 membered saturated or partially unsaturated heterocycle with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur , and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from the following: C _1-6 aliphatic groups, saturated or partially unsaturated 3-7 membered carbocyclic rings, phenyl groups, 3-7 membered saturated or partially unsaturated heteroatoms with 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. ring, and a 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or: two R groups on the same nitrogen together with the intervening atom form except the nitrogen In addition, there are 4-7 membered saturated, partially unsaturated or heteroaryl rings having 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur; and n, p, q ^B , q ^P , r and t Each of these is independently 0, 1, 2, 3 or 4. Such as the compound of claim 1 or 2, wherein P is selected from -OR ^P , -NHR ^P -, -SR ^P , -NHC(O)NHR ^P , -OC(O)NHR ^P and -NHC(O)OR ^P . The compound of any one of claims 1 to 3, wherein R ^P is an optionally substituted group selected from C _1-6 aliphatic groups and saturated or partially unsaturated 3-7 membered carbocyclic rings. The compound of any one of claims 1 to 4, wherein Cy ^C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. The compound of any one of claims 1 to 5, wherein Q is selected from -NH-, , and ,in represents the covalent bond with Cy ^A and Represents the covalent bond with Cy ^C. The compound of any one of claims 1 to 6, wherein Q is -NH-. The compound of any one of claims 1 and 3 to 7, wherein Cy ^A is a heteroaryl group having 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The compound of any one of claims 1 and 3 to 8, wherein Cy ^A is selected from: , , , , , , , and ,in represents the covalent bond with Q and Represents the covalent bond with Cy ^B. The compound of any one of claims 1 to 9, wherein n is 0, 1, 2, 3 or 4. Such as the compound of claim 1, wherein the compound is of formula XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b or XXVII-c: , XXVI-a , XXVI-b XXVI-c XXVII-a , XXVII-b XXVII-c or its pharmaceutically acceptable salt. Such as the compound of claim 1, wherein the compound is formula XXVI-c: XXVI-c or its pharmaceutically acceptable salt. Such as the compound of claim 1, wherein the compound is formula XXVII-c: XXVII-c or its pharmaceutically acceptable salt. The compound of any one of claims 11 to 13, wherein R ^P is selected from the following groups: phenyl, 3-10 membered saturated with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Or partially unsaturated heterocycles, and 5-14 membered heteroaryl rings with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein R ^P in addition to L ² also undergoes q ^P of R ^P1 instance instead. The compound of any one of claims 11 to 13, wherein R ^P is a C _1-3 aliphatic group substituted by q ^P instances of R ^P1 . The compound of any one of claims 11 to 13, wherein R ^P is -CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH(CH ₃ ) ₂ or -CH ₂ CH(CH ₃ ) ₂ , -C(CH ₃ ) ₃ , or . The compound of any one of claims 11 to 13, wherein R ^P is . The compound of any one of claims 11 to 13 or claim 17, wherein R ^P is , , , , or . The compound of any one of claims 11 to 13, wherein R ^P is a saturated or partially unsaturated 4-14-membered carbocyclic ring substituted by q ^P instances of R ^P1 . Such as the compound of any one of claims 11 to 13 or claim 19, wherein R ^P is a saturated or partially unsaturated 4-membered carbocyclic ring substituted by q ^P instances of R ^P1 . Such as the compound of any one of claims 11 to 13 or claims 19 to 20, wherein R ^P is or . Such as the compound of any one of claims 11 to 13 or claims 19 to 20, wherein R ^P is , , , , , or . The compound of any one of claims 11 to 13, wherein R ^P is a phenyl ring substituted by q ^P instances of R ^P1 . The compound of any one of claims 11 to 13, wherein R ^P is a 3-10 membered saturated group having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted by q ^P instances of R ^P1 Or partially unsaturated heterocycle. The compound of any one of claims 11 to 13 or claim 24, wherein R ^P is a 4-membered saturated heterocycle having 1 heteroatom selected from nitrogen, oxygen and sulfur substituted by q ^P instances of R ^P1 . Such as the compound of any one of claims 11 to 13 or claims 24 to 25, wherein R ^P is , or . The compound of any one of claims 11 to 13, wherein R ^P is a saturated 5-6 member having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted by q ^P instances of R ^P1 Or partially unsaturated heterocycle. A compound as claimed in any one of claims 11 to 13 or 25, wherein R ^P is optionally substituted with q ^P instances of R ^P1 having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Substituted 5-membered saturated or partially unsaturated heterocycle. Such as the compound of any one of claims 11 to 13 or claims 27 to 28, wherein R ^P is , or . A compound as claimed in any one of claims 11 to 13 or 27, wherein R ^P is a 6-membered saturated substituted with q ^P instances of R ^P1 having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. Or partially unsaturated heterocycle. A compound according to any one of claims 11 to 13, 27 or 30, wherein R ^P is . The compound of any one of claims 11 to 13, wherein R ^P is a 5-14 membered heteroatom having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur substituted by q ^P instances of R ^P1 Aryl ring. A compound as claimed in any one of claims 11 to 13 or 32, wherein R ^P is optionally substituted with q ^P instances of R ^P1 having 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Substituted 5-membered heteroaryl ring. The compound of any one of claims 11 to 13 or 32, wherein R ^P is a 6-membered heteroaryl ring having 1-2 nitrogen atoms substituted by q ^P instances of R ^P1 . The compound of any one of claims 11 to 13 or 32, wherein R ^P is selected from isothiazolyl, pyridyl or pyrazyl substituted by q ^P instances of R ^P1 . A compound according to any one of claims 11 to 13 or 32, wherein R ^P is , , , , , , , , , , , , or . The compound of any one of claims 11 to 36, wherein Q is a covalent bond, or C _1-5 saturated or unsaturated, linear or branched hydrocarbon chain, wherein one or two methylene groups in the chain Units are optionally and independently substituted with the following groups: -CH(R ^L )-, -C(R ^L ) ₂ -, C _3-6 cycloalkyl, 3-6 membered heterocycloalkyl, 5- 6-membered heteroaryl, -NH-, -N(R ^L )-, -N(R ^L )C(O)-, -C(O)NH-, -C(O)N(R ^L )- , -NHS(O) ₂ -, -N(R ^L )S(O) ₂ -, -S(O) ₂ NH-, -S(O) ₂ N(R ^L )-, -O-, -C (O)-, -OC(O)-, -C(O)O-, -S-, -S(O)- or -S(O) ₂ -; wherein the C _3-6 cycloalkyl group, Each of the 3-6 membered heterocycloalkyl and the 5-6 membered heteroaryl is optionally substituted with one instance of R ¹ or a C _1-6 aliphatic group. The compound of any one of claims 11 to 37, wherein Q is -O-, -NH-, , ,-NHC(O)NH-, or ,in represents the covalent bond with Cy ^A and Represents the covalent bond with Cy ^C. The compound of any one of claims 11 to 38, wherein Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring; saturated or partially saturated with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Unsaturated 3-14-membered heterocycle; phenyl; or 6-14-membered heteroaryl with 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy ^C in addition to Q also undergoes R ^C replaced by p instances. The compound of any one of claims 11 to 39, wherein Cy ^C is a saturated or partially unsaturated 3-14 membered carbocyclic ring. The compound of any one of claims 11 to 40, wherein Cy ^C is a saturated or partially unsaturated 3-7 membered monocyclic carbocyclic ring. The compound of any one of claims 11 to 41, wherein Cy ^C is cyclopropyl. The compound of any one of claims 11 to 39, wherein Cy ^C is a saturated or partially unsaturated 3-14 membered heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound of any one of claims 11 to 39, wherein Cy ^C is phenyl. The compound of any one of claims 11 to 39, wherein Cy ^C is a 6-14 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound of any one of claims 11 to 38, wherein Cy ^C is a 5-membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen or sulfur. The compound of any one of claims 11 to 38 or 46, wherein Cy ^C is , , , or . The compound of any one of claims 11 to 39 or 45, wherein Cy ^C is a 6-membered heteroaryl ring having 1-3 nitrogen atoms. The compound of any one of claims 11 to 39, 45 or 48, wherein Cy ^C is pyridyl, pyrimidinyl or pyrimidinyl. Such as the compound of any one of claims 11 to 39, 45 or 48 to 49, wherein Cy ^C is , , , , or . The compound of any one of claims 11 to 37 or 43, wherein Cy ^C is a 9-10 membered heteroaryl group having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound of any one of claims 11 to 37, 43 or 49, wherein Cy ^C is a 9-10 membered heteroaryl group having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. The compound of any one of claims 11 to 37, 43 or 49, wherein Cy ^C is a 9-10 membered heteroaryl group having 2-4 nitrogen atoms. The compound of any one of claims 11 to 37, 43 or 49, wherein Cy ^C is , , , , , , , , , , , , , , or . The compound of any one of claims 1 to 52, wherein the compound is selected from those shown in Table 1, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 53 and a pharmaceutically acceptable carrier. A method of inhibiting CDK2 signaling activity in an individual, which includes administering a therapeutically effective amount of a compound as claimed in any one of claims 1 to 53 or a pharmaceutical composition as claimed in claim 54 to an individual in need. A method of treating a CDK2-mediated disorder in an individual, comprising administering a therapeutically effective amount of a compound as claimed in any one of claims 1 to 53 or a pharmaceutical composition as claimed in claim 54 to an individual in need thereof. A method of treating a condition in an individual, wherein the condition is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer , laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer or pancreatic cancer, the method includes administering to an individual in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 55 or Such as the pharmaceutical composition of claim 56. The method of claim 59, wherein the bladder cancer is urothelial cancer. The method of claim 59, wherein the liver cancer is hepatocellular carcinoma. The method of claim 59, wherein the lung cancer is squamous cell carcinoma or non-small cell lung cancer. The method of claim 59, wherein the laryngeal cancer is laryngeal squamous cell carcinoma. The method of claim 59, wherein the skin cancer is melanoma.