CDK inhibitors and methods of use thereof

Abstract

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

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 149,095, filed February 12, 2021, U.S. Provisional Application No. 63 / 166,638, filed March 26, 2021, U.S. Provisional Application No. 63 / 192,627, filed May 25, 2021, U.S. Provisional Application No. 63 / 250,473, filed September 30, 2021, and U.S. Provisional Application No. 63 / 292,337, filed December 21, 2021, each of which is incorporated by reference herein in its entirety. [Background technology]

[0002] Cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases regulated by direct binding to cyclins. The first CDKs discovered (CDK1, CDK2, CDK4, and CDK6) bind to their cognate cyclins at specific cell cycle stages, activating their kinase activity and promoting cell cycle progression (Malumbres M. Genome Biology 2014). Related CDK family members (CDK7, CDK8, CDK9, CDK12, and CDK13) are involved in other biological functions, such as transcriptional regulation (Chou J., et al. Cancer Discovery 2020). The cell cycle is initiated following a growth stimulus that signals for the expression of cyclin D, binding to CDK4 / 6, and activation of the kinase. The activated CDK4 / 6-cyclin D complex monophosphorylates the tumor suppressor retinoblastoma protein (RB), initiating the expression of cyclin E and the formation of an activated 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 duplicated DNA within the mother cell, completing cell division and forming two new daughter cells (Otto, T., and Sicinski, P. Nat Rev Cancer 2017).

[0003] Because sustained cell proliferation is a hallmark of cancer, alterations in pathways controlling cell cycle progression are often associated with cancer. Indeed, CCNE1 (the gene encoding cyclin E1 protein) is one of the most frequently amplified genes in various cancers, including ovarian, endometrial, gastric, cervical, bladder, esophageal, lung, and breast cancers (Sanchez-Vega F., et al. Cell 2018; Cerami E., et al. Cancer Discovery 2012). Amplified CCNE1, which causes overexpression of cyclin E1 protein, is thought to be an oncogenic driver of these tumors by increasing CDK2 cyclin E activity. Notably, tumor cells with amplified or overexpressed CCNE1 are dependent on CDK2 activity, thereby providing a rationale for targeting CDK2 in this genetically defined patient population (McDonald ER, et al. Cell 2017; Au-Yeung G., et al. Clin Cancer Research 2016). Furthermore, CDK2 activation through amplification and overexpression of cyclin E1 is a common mechanism of resistance to several approved targeted therapies (e.g., CDK4 / 6 and HER2 modulators), thus supporting the combination of CDK2 targeting with other validated drivers in cancer (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 also significant hematopoietic and gastrointestinal toxicity, likely due to inhibition of CDK1 (Otto, T., and Sicinski, P., Nat. Review Cancer 2017; Kumar, KS, et al. Blood 2015; Shapiro GI, et al. Clin Cancer Research 2001). Although CDK2 activity may not be critical for normal cellular function, CDK1 activity is essential in all cells, particularly in highly proliferating cells of the intestinal and hematopoietic systems (Berthet C., et al. Current Biology 2003; Jayapal SR, et al. Haematologica 2015; Santamaria D., et al. Nature 2007; Lu S., et al. Tox Sciences 2020). [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Malumbres M.Genome Biology 2014 [Non-patent document 2] Chou J.,et al.Cancer Discovery 2020 [Non-patent document 3] Otto, T., and Sicinski, P. Nat Rev Cancer 2017 [Non-patent document 4] Sanchez-Vega F.,et al.Cell 2018;Cerami E.,et al.Cancer Discovery 2012 [Non-Patent Document 5] McDonald ER,et al Cell 2017;Au-Yeung G.,et al.Clin Cancer Research 2016 [Non-patent document 6] Turner NC,et al.J Clin Oncology 2019 [Non-Patent Document 7] Herrera-Abreu MT,et al.Cancer Research 2016 [Non-patent document 8] Scaltriti M., et al.PNAS 201 [Non-Patent Document 9] Otto, T., and Sicinski, P., Nat.Review Cancer 2017 [Non-Patent Document 10] Kumar, KS, et al. Blood 2015 [Non-Patent Document 11] Shapiro GI, et al.Clin Cancer Research 2001 [Non-Patent Document 12] Berthet C.,et al.Current Biology 2003 [Non-Patent Document 13] Jayapal SR,et al.Haematologica 2015 [Non-Patent Document 14] Santamaria D.,et al.Nature 2007;Lu S.,et al.Tox Sciences 2020 Summary of the Invention [Means for solving the problem]

[0005] In some embodiments, the present disclosure encompasses the recognition that there is a need for CDK-selective inhibitor compounds, e.g., CDK2-selective inhibitor compounds, and methods for treating cancer and other disorders using these compounds.

[0006] In some embodiments, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy B , Q, W, and Z are as defined in the embodiments and classes and subclasses herein).

[0007] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy B , Cy C , Q, and P are as defined in the embodiments and classes and subclasses herein).

[0008] In some embodiments, the present disclosure provides a compound of formula II, III, IV, V, VI, VII, VIII, or IX: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy B , Cy C , Q, P, W, X, Y, R Z , R B , and n are as defined in the embodiments and classes and subclasses herein).

[0009] In some embodiments, the present disclosure describes formulas Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII- c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII- a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII -b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, or XXV-c compounds: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy C , Q, Z, W, X, Y, and R Z each as defined in the embodiments and classes and subclasses herein).

[0010] In some embodiments, the present disclosure provides a compound of XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy C, X, Y, and R Z each as defined in the embodiments, classes and subclasses herein).

[0011] In some embodiments, the present disclosure provides a pharmaceutical composition 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 a pharmaceutical composition comprising a compound of the present disclosure, e.g., a compound of Formula II, III, IV, V, VI, VII, VIII, IX, Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII-b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, XXV-c, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent. In some embodiments, the disclosure provides a pharmaceutical composition comprising a compound of the disclosure, e.g., a compound of Formula IA, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent.

[0012] In some embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder, comprising administering to a patient in need thereof a compound of Formula I, or a composition comprising the compound. In some embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder, the method comprising administering to a patient in need thereof a compound of the present disclosure, e.g., Formula II, III, IV, V, VI, VII, VIII, IX, Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, XXV-c, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c, or a composition comprising the compound, to a patient in need thereof. In some embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder, comprising administering a compound of the present disclosure, e.g., a compound of Formula IA, or a composition comprising the compound, to a patient in need thereof.

[0013] In some embodiments, the disclosure provides a process for providing a compound of Formula I or a synthetic intermediate thereof. In some embodiments, the disclosure provides a process for providing a compound of the disclosure, e.g., a compound of Formula II, III, IV, V, VI, VII, VIII, IX, Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a, XIX-b, XI

[0013] In some embodiments, the present disclosure provides a process for providing a compound of formula X-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII-b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, XXV-c, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c, or a synthetic intermediate thereof. In some embodiments, the present disclosure provides a process for providing a compound of the present disclosure, e.g., a compound of formula IA, or a synthetic intermediate thereof.

[0014] In some embodiments, the disclosure provides a process for providing a pharmaceutical composition comprising a compound of Formula I. In some embodiments, the disclosure provides a process for providing a pharmaceutical composition comprising a compound of the disclosure, for example, Formula II, III, IV, V, VI, VII, VIII, IX, Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII-c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, XVIII-c, XIX-a, XIX-b, In some embodiments, the present disclosure provides a process for providing a pharmaceutical composition comprising a compound of Formula XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII-b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, XXV-c, XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c. In some embodiments, the present disclosure provides a process for providing a pharmaceutical composition comprising a compound of the present disclosure, e.g., a compound of Formula IA. DETAILED DESCRIPTION OF THE INVENTION

[0015] 1. Overview of Specific Embodiments The compounds and pharmaceutical compositions thereof provided herein are useful as inhibitors of CDK2. In some embodiments, the present disclosure provides compounds of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q is L 1 and Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R Ais replaced by m occurrences of Cy B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A and Z, plus R B is replaced by n occurrences of Z is hydrogen or L 2 -R Z and R Z is hydrogen or C 1-8 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is hydrogen or Cy C and Cy C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C is replaced by p occurrences of R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by RC is R 3 q C is replaced by occurrences of R A Two occurrences of R B Two occurrences of R C Two occurrences of R A One occurrence of and R L One occurrence of, or R C One occurrence of and R L together with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is 3 is replaced by r occurrences of L 1 and L 2 each of which is independently a covalent bond, or C 1-5 A saturated or unsaturated, linear or branched hydrocarbon chain, in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, and said C 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 is optionally substituted with one occurrence of aliphatic; R L Each occurrence of is independently R 1 or R 2 and R 3 is replaced by t occurrences of R 1 each occurrence is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; R 2 Each occurrence of is independently 1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m, n, p, q A , q B , q C , r, and t are independently 0, 1, 2, 3, or 4).

[0016] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q is L 1 and Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R A is replaced by m occurrences of Cy Bis a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A In addition to P, R B is replaced by n occurrences of P is hydrogen or -L 2 -R P and R P is R, Cy C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C is replaced by p occurrences of R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by R C is R 3 q C is replaced by occurrences of R A Two occurrences of R B Two occurrences of R C Two occurrences of R A One occurrence of and R L One occurrence of, or R C One occurrence of and R Ltogether with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is 3 is replaced by r occurrences of L 1 and L 2 each of which is independently a covalent bond, or C 1-5 A saturated or unsaturated, linear or branched hydrocarbon chain, in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, and said C 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 is optionally substituted with one occurrence of aliphatic; R L Each occurrence of is independently R 1 or R 2 and R 3 is replaced by t occurrences of R 1each occurrence is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; R 2 Each occurrence of is independently 1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m, n, p, q A , q B , q C , r, and t are independently 0, 1, 2, 3, or 4).

[0017] In some embodiments, the present disclosure provides a compound of formula II, III, IV, V, VI, VII, VIII, or IX: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q is L 1 and Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R A is replaced by m occurrences of Cy B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A and P or X plus R Bis replaced by n occurrences of X is O, NR X , and S; Y, O, NR Y , and S; R X and R Y each occurrence of is independently R, R Z is hydrogen or C 1-8 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; P is hydrogen or -L 2 -R P and R P is R, W is hydrogen or Cy C and Cy C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C is replaced by p occurrences of R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by R C is R 3 q C is replaced by occurrences of R A Two occurrences of R B Two occurrences of R C Two occurrences of R A One occurrence of and R L One occurrence of, or R C One occurrence of and R L together with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is 3 is replaced by r occurrences of L 1 and L 2 each of which is independently a covalent bond, or C 1-5 A saturated or unsaturated, linear or branched hydrocarbon chain, in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, and said C 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 is optionally substituted with one occurrence of aliphatic; R L Each occurrence of is independently R 1 or R 2 and R 3 is replaced by t occurrences of R 1each occurrence is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; R 2 Each occurrence of is independently 1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m, n, p, q A , q B , q C , r, and t are independently 0, 1, 2, 3, or 4).

[0018] In some embodiments, the present disclosure describes formulas Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII- c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII- a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII -b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, or XXV-c compounds: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy C , Q, Z, W, X, Y, and R Z each as defined in the embodiments and classes and subclasses herein).

[0019] In some embodiments, the present disclosure provides a compound of XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy C , X, Y, and R Z each as defined in the embodiments, classes and subclasses herein).

[0020] 2. Compounds and Definitions Compounds described herein include those described generally herein and further exemplified by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. In this disclosure, chemical elements are defined as defined in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Further, general principles of organic chemistry are identified in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5 thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference. Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. When a compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure takes precedence.

[0021] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted, or unsubstituted hydrocarbon chain that is fully saturated or contains one or more units of unsaturation, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic (also referred to herein as "carbocyclic" or "alicyclic"), and has a single point of attachment to the rest of the molecule. Unless otherwise specified, an aliphatic group contains 1-6 aliphatic carbon atoms. In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In still other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in still other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, "alicyclic" (or "carbocyclic") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. Carbocycles may, under certain circumstances, be bridged bicyclic or fused rings, e.g., ortho-fused carbocycles, spiro-fused carbocycles, etc. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups, and hybrids thereof, e.g., (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0022] The term "alkyl," as used herein, unless otherwise indicated, refers to a monovalent aliphatic hydrocarbon radical having straight-chain, branched-chain, monocyclic, or polycyclic moieties, or combinations thereof, which radical is optionally substituted on one or more carbons of the straight-chain, branched-chain, monocyclic, or polycyclic moiety, or combinations thereof, with one or more substituents for each carbon, wherein the one or more substituents are independently selected from the group consisting of C1 to C6. 10 Examples of "alkyl" groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0023] The term "lower alkyl" refers to C 1-4 Examples of lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0024] The term "lower haloalkyl" refers to a C alkyl group substituted with one or more halogen atoms. 1-4 refers to a straight or branched alkyl group.

[0025] The term "heteroatom" refers to oxygen, sulfur, nitrogen, phosphorus, or silicon (any oxidized form of nitrogen, sulfur, phosphorus, or silicon, the quaternized form of any basic nitrogen, or a substitutable nitrogen of a heterocycle, e.g., N (such as 3,4-dihydro-2H-pyrrolyl), NH (such as pyrrolidinyl), or NR + (such as N-substituted pyrrolidinyl) means one or more of the following:

[0026] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0027] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n-, where n is a positive integer, preferably 1 to 6, 1 to 4, 1 to 3, 1 to 2, or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0028] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0029] The term "halogen" means F, Cl, Br, or I.

[0030] 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 in the system is aromatic and each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the compounds described herein, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. It will be understood that an "aryl" group can include carbon and heteroatom ring members.

[0031] Unless otherwise defined, the term "heteroaryl" or "heteroaromatic," as used herein, refers to a monocyclic aromatic 5- or 6-membered ring containing one or more heteroatoms, e.g., 1 to 4 heteroatoms, e.g., nitrogen, oxygen, and sulfur, or an 8- to 10-membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring of the polycyclic ring system is aromatic and the point of attachment of the polycyclic ring system is through a ring atom on the aromatic ring. Heteroaryl rings may be attached to adjacent radicals through carbon or nitrogen. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, pyrrole, thiazole, oxazole, isothiazole, isoxazole, imidazole, pyrazole, triazole, pyridine, pyrimidine, indole, and the like. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a heteroaryl ring when its point of attachment is through the benzo ring, e.g., [ka]

[0032] The terms "heterocyclyl" or "heterocyclic group," unless otherwise defined, refer to a saturated or partially unsaturated 3- to 10-membered monocyclic or 7- to 14-membered polycyclic ring system containing bridged or fused rings (e.g., ortho-fused or spiro-fused bicyclic rings) and containing 1 to 4 heteroatoms, such as nitrogen, oxygen, and sulfur. The heterocyclyl ring may be attached to the adjacent radical through a carbon or nitrogen.

[0033] The term "partially unsaturated" with respect to a ring, unless otherwise defined, refers to a monocyclic ring or a constituent ring within a polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, wherein the constituent ring contains at least one degree of unsaturation in addition to that provided in the ring itself but is not aromatic. Examples of partially unsaturated rings include, but are not limited to, 3,4-dihydro-2H-pyran, 3-pyrroline, 2-thiazoline, etc. When a partially unsaturated ring is part of a polycyclic ring system, the other constituent rings of the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the attachment point of the polycyclic ring system is on the partially unsaturated constituent ring. For example, unless otherwise defined, 1,2,3,4-tetrahydroquinoline is a partially unsaturated ring when its attachment point is through the piperidino ring, such as: [ka] .

[0034] The term "saturated" with respect to a ring, unless otherwise defined, refers to a 3- to 10-membered monocyclic ring or a 7- to 14-membered polycyclic (e.g., bicyclic, tricyclic, etc.) ring system, where the monocyclic ring or the constituent ring that is the point of attachment to the polycyclic ring system does not contain any further degree of 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. When a saturated ring is part of a polycyclic ring system, the other constituent rings of the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment of the polycyclic ring system is on the saturated constituent ring. For example, unless otherwise defined, 2-azaspiro[3.4]oct-6-ene is a saturated ring when its point of attachment is through the azetidino ring, e.g., [ka] .

[0035] As used herein, the terms "alkylene," "arylene," "cycloalkylene," "heteroarylene," "heterocycloalkylene," and other similar terms with the suffix "-ylene" refer to a divalent linked version of the group that the suffix modifies. For example, "alkylene" is a divalent alkyl group that connects the groups to which it is attached.

[0036] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or a valence bond connecting two bridgeheads, and a "bridgehead" is any skeletal atom of the ring system that is connected to three or more skeletal atoms (excluding hydrogen). In some embodiments, bridged bicyclic groups have 7 to 12 ring members and 0 to 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include the groups shown below, in which 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 described for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Examples of bridged bicyclic groups include: [ka] .

[0037] As described herein, the compounds described herein may contain "optionally substituted" moieties. In general, the term "substituted," whether preceded by the term "optionally," means that one or more hydrogens of a given moiety have been replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and if multiple positions in any given structure can be substituted with multiple substituents selected from a given group, the substituents may be the same or different at all positions. Combinations of substituents envisioned in this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to a compound that is substantially unchanged when subjected to conditions that allow for its production, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein.

[0038] Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently: halogen; -(CH) 0-4 R°;-(CH2) 0-4 OR°;-O(CH2) 0-4 R°, -O-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 CH(OR°)2;-(CH2) 0-4 SR°;-(CH2) 0~4 Ph, (which may be substituted by R°); —(CH2) 0-4 O(CH2) 0-1 Ph (which may be substituted with R°); -CH=CHPh (which may be substituted with R°); -(CH2) 0-4 O(CH2) 0-1 -pyridyl (which may be substituted by R°); -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R°)2;-(CH2) 0-4 N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2) 0-4 N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2) 0-4N(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°;-(CH2) 0-4 C(O)R°;-C(S)R°;-(CH2) 0-4 C(O)OR°;-(CH2) 0-4 C(O)SR°;-(CH2) 0-4 C(O)OSiR°3;-(CH2) 0-4 OC(O)R°;-OC(O)(CH2) 0-4 SR°;-SC(S)SR°;-(CH2) 0-4 SC(O)R°;-(CH2) 0-4 C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°, -(CH2) 0-4 OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2) 0-4 SSR°;-(CH2) 0-4 S(O)2R°;-(CH2) 0-4 S(O)2OR°;-(CH2) 0-4 OS(O)2R°;-S(O)2NR°2;-(CH2) 0-4 S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-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 linear or branched alkylene)ON(R°)2; or -(C 1-4 linear or branched alkylene)C(O)ON(R°), where each R° may be substituted as defined below and is independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, -CH2- (a 5- to 6-membered heteroaryl ring), or a 3- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent occurrences of R° together with the intervening atom(s) form a 3- to 12-membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0039] Suitable monovalent substituents on R° (or a ring formed by taking two independent occurrences of R° together with the intervening atoms) are independently halogen, —(CH2), 0-2 R ● ,-(Halo R ● ), -(CH2) 0-2 OH, -(CH2) 0-2 OR ● , -(CH2) 0-2 CH(OR ● )2;-O(HaloR ● ), -CN, -N3, -(CH2) 0-2 C(O)R ● , -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR ● , -(CH2) 0-2 SR ● , -(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR ● , -(CH2) 0-2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3. -C(O)SR ● 、 -(C 1-4 Linear or branched alkylene)C(O)OR ● , or -SSR ● and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 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 a saturated carbon atom of R° include ═O and ═S.

[0040] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * , -O(C(R * 2)) 2-3 O-, or -S(C(R * 2)) 2-3 S- is mentioned, R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Preferred divalent substituents attached to adjacent substitutable carbons of an "optionally substituted" group include -O(CR * 2) 2-3 O- and R * Each independent occurrence of may be hydrogen, C, which may be substituted as defined below. 1-6 It is selected from aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0041] R * Suitable substituents on the aliphatic group include halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ●, -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 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.

[0042] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -R † , -NR † 2. -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CHC(O)R † , -S(O)2R † , -S(O)NR † 2. -C(S)NR † 2. -C(NH)NR † 2, or -N(R † )S(O)2R † are listed, and each R † are independently hydrogen, C which may be substituted as defined below 1-6 an aliphatic, 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, regardless of the above definitions, R † two independent occurrences of together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0043] R † Suitable substituents on the aliphatic groups are independently halogen, -R ● ,-(Halo R ● ), -OH, -OR ● , -O(HaloR● ), -CN, -C(O)OH, -C(O)OR ● , -NH2, -NHR ● , -NR ● 2, or -NO2, and each R ● is unsubstituted or, if preceded by "halo", is substituted only with one or more halogens, and independently, C 1-4 Aliphatic, -CH2Ph, -O(CH2) 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.

[0044] As used herein, the term "isomer" refers to compounds that have the same chemical formula but different structural or optical configurations. As used herein, the term "stereoisomer" refers to and includes isomeric molecules that have the same molecular formula but differ in the location of atoms and / or functional groups in space. All stereoisomers of the compounds of the present invention (e.g., stereoisomers that may exist due to asymmetric carbon atoms on various substituents), including enantiomeric and diastereomeric forms, are considered within the scope of the present disclosure. Thus, unless otherwise indicated, single stereochemical isomers of the compounds as well as mixtures of enantiomeric, diastereomeric, and geometric (or conformational) isomers are within the scope of the present disclosure.

[0045] 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. Tautomers are understood to encompass valence tautomers and proton tautomers (also known as proton tautomers). Valence tautomers include interconversions via rearrangement of some of the bonding electrons. Proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Unless otherwise stated, all tautomers of the compounds described herein are within the scope of this disclosure.

[0046] The term "isotopic substitution" as used herein refers to replacing an atom with its isotope. The term "isotope" as used herein refers to an atom having the same atomic number as the atom that predominates in nature, but having a mass number (number of neutrons) different from the mass number of the atom that predominates in nature. A compound having isotopic substitution is understood to refer to a compound in which at least one atom contained therein is replaced with an isotope. Atoms that can be replaced with isotopes include, but are not limited to, hydrogen, carbon, and oxygen. Examples of isotopes of hydrogen atoms include: 2 H (also represented as D) and 3 H. Examples of carbon isotopes include: 13 C and 14 C. Examples of isotopes of the oxygen atom include: 18 0 is an integer from 0 to 10. Unless otherwise specified, all isotopic substitutions of the compounds described herein are within the scope of the present disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents according to the present disclosure.

[0047] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. Exemplary pharmaceutically acceptable salts are found, for example, in Berge, et al. (J. Pharm. Sci. 1977, 66(1), 1; and Gould, P.L., Int. J. Pharmaceutics 1986, 33, 201-217; each of which is incorporated herein by reference in its entirety.

[0048] 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 amino groups formed 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 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, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, and 2-hydroxy-ethanesulfonate. Examples of salts include lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, and valerate.

[0049] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0050] Pharmaceutically acceptable salts are also intended to encompass hemi-salts in which the ratio of compound to acid is 2:1, respectively. Exemplary hemi-salts are salts 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. Other exemplary hemi-salts are salts derived from diprotic mineral acids, such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemi-maleate, hemifumarate, and hemi-succinate.

[0051] As used herein, the term "about" is used herein to mean approximately, in the region of, around, or within a range thereof. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the stated numerical values. In general, the term "about" is used herein to modify a numerical value above or below the stated numerical value by a variance of 20 percent above or below (high or low).

[0052] As used herein, an "effective amount," "sufficient amount," or "therapeutically effective amount" is an amount of a compound that, when administered to a subject or population suffering from or susceptible to a disease, disorder, and / or condition according to a therapeutic regimen, is sufficient to treat the disease, disorder, and / or condition (e.g., to produce a beneficial or desired result, including a clinical result). Thus, an effective amount can be sufficient, for example, to reduce or ameliorate the severity and / or duration of an affliction associated with CDK2 signaling, or one or more symptoms thereof, prevent the progression of a condition or symptom associated with an affliction associated with CDK2 signaling, or enhance or otherwise improve the prophylactic or therapeutic effect(s) of another therapy. An effective amount also includes an amount of a compound that avoids or substantially reduces undesirable side effects.

[0053] As used herein and as well understood in the art, "treatment" refers to an approach for obtaining 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, whether detectable or undetectable, reduction in the severity of the disease or affliction, stabilization (i.e., not worsening) of the disease or affliction state, prevention of the spread of the disease or affliction, delay or slowing of the progression of the disease or affliction, improvement or alleviation of the disease or affliction state, and remission (partial or total). "Treatment" may also mean prolonging survival compared to expected survival in the absence of 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 (e.g., taking into account a history of the symptoms and / or taking into account genetic or other susceptibility factors). Treatment may also be continued after the symptoms have been cured, e.g., to prevent or delay recurrence.

[0054] The phrase "in need thereof" refers to a need for symptomatic or asymptomatic relief from a condition associated with CDK2 signaling activity or that may otherwise be alleviated with the compounds and / or compositions of the present disclosure.

[0055] 3. Description of Exemplary Embodiments In some embodiments, the present disclosure provides a compound of formula IA: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q is L 1 and Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R A is replaced by m occurrences of Cy B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A and Z, plus R B is replaced by n occurrences of Z is hydrogen or L 2 -R Z and R Z is hydrogen or C 1-8 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; W is hydrogen or Cy C and Cy C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C is replaced by p occurrences of R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by R C is R 3 qC is replaced by occurrences of R A Two occurrences of R B Two occurrences of R C Two occurrences of R A One occurrence of and R L One occurrence of, or R C One occurrence of and R L together with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is 3 is replaced by r occurrences of L 1 and L 2 each of which is independently a covalent bond, or C 1-5 A saturated or unsaturated, linear or branched hydrocarbon chain, in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, and said C 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 is optionally substituted with one occurrence of aliphatic; R L Each occurrence of is independently R 1 or R 2 and R 3 is replaced by t occurrences of R 1each occurrence is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; R 2 Each occurrence of is independently 1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m, n, p, q A , q B , q C , q Z , r, and t are independently 0, 1, 2, 3, or 4).

[0056] As noted above, in some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q is L 1 and Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R A is replaced by m occurrences of Cy B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A In addition to P, R Bis replaced by n occurrences of P is hydrogen or -L 2 -R P and R P is R, Cy C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C is replaced by p occurrences of R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by R C is R 3 q C is replaced by occurrences of R A Two occurrences of R B Two occurrences of R C Two occurrences of R A One occurrence of and R L One occurrence of, or R C One occurrence of and R L together with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is 3 is replaced by r occurrences of L 1 and L 2 each of which is independently a covalent bond, or C 1-5A saturated or unsaturated, linear or branched hydrocarbon chain, in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, and said C 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 is optionally substituted with one occurrence of aliphatic; R L Each occurrence of is independently R 1 or R 2 and R 3 is replaced by t occurrences of R 1 each occurrence is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; R 2 Each occurrence of is independently 1-7aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m, n, p, q A , q B , q C , r, and t are independently 0, 1, 2, 3, or 4).

[0057] As noted above, in some embodiments, the present disclosure provides a compound of formula II, III, IV, V, VI, or VII: [ka] or a pharmaceutically acceptable salt thereof, wherein: Q is L 1 and Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R A is replaced by m occurrences of Cy B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A and P or X plus R B is replaced by n occurrences of X is O, NR X , and S; Y, O, NR Y , and S; R X and R Y each occurrence of is independently R, R Z is hydrogen or C 1-8an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; P is hydrogen or -L 2 -R P and R P is R, W is hydrogen or Cy C and Cy C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C is replaced by p occurrences of R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by R C is R 3 q C is replaced by occurrences of R A Two occurrences of R B Two occurrences of R C Two occurrences of R A One occurrence of and R L One occurrence of, or R C One occurrence of and R Ltogether with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and the ring is 3 is replaced by r occurrences of L 1 and L 2 each of which is independently a covalent bond, or C 1-5 A saturated or unsaturated, linear or branched hydrocarbon chain, in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-, and said C 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 is optionally substituted with one occurrence of aliphatic; R L Each occurrence of is independently R 1 or R 2 and R 3 is replaced by t occurrences of R 1each occurrence is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R; R 2 Each occurrence of is independently 1-7 aliphatic; phenyl; a 5-6 membered monocyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6 an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or two R groups on the same nitrogen, together with their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; m, n, p, q A , q B , q C , r, and t are independently 0, 1, 2, 3, or 4).

[0058] In some embodiments, the present disclosure describes formulas Xa, Xb, Xc, XI-a, XI-b, XI-c, XII-a, XII-b, XII-c, XIII-a, XIII-b, XIII- c, XIV-a, XIV-b, XIV-c, XV-a, XV-b, XV-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII- a, XVIII-b, XVIII-c, XIX-a, XIX-b, XIX-c, XX-a, XX-b, XX-c, XXI-a, XXI-b, XXI-c, XXII-a, XXII -b, XXII-c, XXIII-a, XXIII-b, XXIII-c, XXIV-a, XXIV-b, XXIV-c, XXV-a, XXV-b, or XXV-c compounds: [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof, wherein Cy A , Cy C , Q, Z, W, X, Y, and R Z each as defined in the embodiments and classes and subclasses herein).

[0059] In some embodiments of Formula VIII, IX, Xa, Xb, Xc, XII-a, XII-b, XII-c, XIV-a, XIV-b, XIV-c, XVI-a, XVI-b, XVI-c, XIX-a, XIX-b, XIX-c, XXI-a, XXI-b, or XXI-c, W is selected from the group consisting of Cy C is.

[0060] In some embodiments of formula Xa, Xb, Xc, XI-a, XI-b, XI-c, XVI-a, XVI-b, XVI-c, XVII-a, XVII-b, XVII-c, XVIII-a, XVIII-b, or XVIII-c, Z is L 2 -R Z and R Z is hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; L 2 is as defined in the embodiments, classes, and subclasses herein.

[0061] formulas XII-a, In some embodiments, R Z is hydrogen or C 1-6 An optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0062] In some embodiments, the present disclosure provides a compound of XXVI-a, XXVI-b, XXVI-c, XXVII-a, XXVII-b, XXVII-c, XXVIII-a, XXVIII-b, or XXVIII-c: [ka] or a pharmaceutically acceptable salt thereof, wherein Cy C , X, Y, and R Z each as defined in the embodiments, classes and subclasses herein).

[0063] Generally, as defined above, Cy A is a 5- to 6-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy A Q and Cy B In addition, R A In some embodiments, Cy is substituted with m occurrences of A teeth, [ka] and [ka] represents a covalent bond to Q, [ka] Cy B In some embodiments, Cy represents a covalent bond to A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A teeth, [ka] In some embodiments, Cy A is selected from the group shown in the compounds of Table 1.

[0064] Generally, as defined above, Cy B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A In addition to P, R B In some embodiments of any of Formulas II, III, IV, V, VI, and VII, Cy is substituted with n occurrences of Bis a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A and P or X plus R B In some embodiments of Formula IA, Cy is substituted with n occurrences of B is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenylene; or a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy B Cy A and Z, plus R B has been replaced by n occurrences of

[0065] In some embodiments, Cy B is a 3- to 7-membered saturated or partially unsaturated monocyclic carbocyclic ring. B is a saturated or partially unsaturated 3- to 14-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy B is phenylene. In some embodiments, Cy B is a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] In some embodiments, Cy B is a 3- to 7-membered saturated carbocyclic ring. B is a cyclopropylene ring. In some embodiments, Cy B is a cyclobutylene ring. In some embodiments, Cy B is a cyclopentylene ring. In some embodiments, Cy Bis a cyclohexylene ring. In some embodiments, Cy B is a cycloheptylene ring.

[0067] In some embodiments, Cy B teeth, [ka] and [ka] Cy A represents a covalent bond to [ka] represents a covalent bond to P, X, or Z. In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, CyB teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] is.

[0068] Cy B In some embodiments, Cy A , and P, X or Z are in a trans relationship. B In some embodiments, Cy A and P, X, or Z are in a cis relationship. For example, Cy shown in the compounds of Table 1 B See group.

[0069] In some embodiments, Cy B is a 5-8 membered saturated or partially unsaturated bridged bicyclic or fused carbocyclic ring. B is a 5-8 membered saturated bridged bicyclic or fused carbocyclic ring. B is a 6- to 7-membered saturated bridged bicyclic or fused carbocyclic ring. B teeth, [ka] and [ka] Cy A represents a covalent bond to [ka] represents a covalent bond to P, X, or Z. In some embodiments, CyB teeth, [ka] In some embodiments, Cy B teeth, [ka] is.

[0070] In some embodiments, Cy B is a 3- to 7-membered partially unsaturated carbocyclic ring. B is a 5-6 membered partially unsaturated carbocyclic ring. B teeth, [ka] In some embodiments, Cy B teeth, [ka] is.

[0071] In some embodiments, Cy B is a saturated or partially unsaturated 3- to 7-membered heterocycle having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B is a saturated 3-7 membered monocyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B is a saturated 4- to 7-membered monocyclic heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0072] In some embodiments, Cy B teeth, [ka] and [ka] Cy A represents a covalent bond to [ka] represents a covalent bond to P, X, or Z.

[0073] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] is.

[0074] In some embodiments, Cy B is a 5- to 14-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B is a 9-membered heteroarylene having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B teeth, [ka] is selected from.

[0075] In some embodiments, Cy B is a saturated 6-10 membered bridged bicyclic or fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B is a saturated 6-10 membered bridged bicyclic or fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. B is a saturated 6-10 membered bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy B is a saturated 7-8 membered bridged bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0076] In some embodiments, Cy B is a saturated or partially unsaturated 6- to 10-membered spiro-fused heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, Cy B is a saturated or partially unsaturated 6- to 9-membered spiro-fused heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0077] In some embodiments, Cy B teeth, [ka] and [ka] Cy A represents a covalent bond to [ka] represents a covalent bond to P, X, or Z. In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] In some embodiments, Cy B teeth, [ka] is.

[0078] In some embodiments, Cy B is selected from the group shown in the compounds of Table 1.

[0079] Generally, as defined above, P is hydrogen or -L 2 -R P and L2 and R P and each of the groups is as defined in the embodiments, classes, and subclasses herein. In some embodiments, P is hydrogen. In some embodiments, P is -L 2 -R P In some embodiments, P is -OR P , -NHR P , -SR P , -NHC(O)NHR P , -OC(O)NHR P , and -NHC(O)OR P is.

[0080] In some embodiments, P is -XC(O)YR P where X, Y, and R P and each of the following is as defined in the embodiments, classes, and subclasses herein. In some embodiments, each P is selected from the groups shown in the compounds of Table 1.

[0081] Generally, as defined above, Z is hydrogen or -L 2 -R Z and L 2 and R Z and each of the following is as defined in the embodiments, classes, and subclasses herein. In some embodiments, Z is hydrogen. In some embodiments, Z is -L 2 -R Z In some embodiments, Z is -OR Z , -NHR Z , -SR Z , -NHC(O)NHR Z , -OC(O)NHR Z , and -NHC(O)OR Z In some embodiments, each Z is selected from the groups shown in the compounds of Table 1.

[0082] Generally, as defined above, R P is R, where R is as defined in the embodiments and classes and subclasses herein. In some embodiments, R Pis hydrogen or C 1-6 R is an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. P is hydrogen. In some embodiments, R P is an arbitrarily substituted C 1-6 In some such embodiments, R P is an arbitrarily substituted C 1-4 In some embodiments, R P is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -CH2CH(CH3)2, -C(CH3)3, [ka] In some embodiments, R P is C optionally substituted with -R° or -OR° 1-6 In some embodiments, R P teeth, [ka] In some embodiments, R P teeth, [ka] and R° is —OR° or —N(R°). In some embodiments, R P teeth, [ka] In some embodiments, R P teeth, [ka] In some embodiments, RP teeth, [ka] is.

[0083] In some embodiments, R P is an optionally substituted saturated or partially unsaturated 3- to 7-membered carbocyclic ring. In some embodiments, R P is an optionally substituted saturated 3-membered carbocyclic ring. In some such embodiments, R P teeth, [ka] In some such embodiments, R° is optionally substituted with halogen.

[0084] In some embodiments, R P is an optionally substituted phenyl ring. In some embodiments, R P 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 P is an optionally substituted 4-membered saturated heterocycle having one heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, R P teeth, [ka] In some such embodiments, R P teeth, [ka] is.

[0085] In some embodiments, R P is an optionally substituted 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R Pis an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R P teeth, [ka] In some such embodiments, R P teeth, [ka] is.

[0086] In some embodiments, R P is an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R P teeth, [ka] is.

[0087] In some embodiments, R P is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R P is an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R P is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R P is selected from optionally substituted isothiazolyl, pyridinyl, or pyridazinyl. In some such embodiments, R P teeth, [ka] is.

[0088] In some embodiments, R P is selected from the group shown in the compounds of Table 1.

[0089] Generally, as defined above, R Z is hydrogen or C 1-8 An optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0090] In some embodiments, R Z is hydrogen or C 1-6 R is an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Z is hydrogen. In some embodiments, R Z is an arbitrarily substituted C 1-6 In some such embodiments, R Z is an arbitrarily substituted C 1-4 In some embodiments, R Z is -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -CH2CH(CH3)2, -C(CH3)3, [ka] In some embodiments, R Z is C optionally substituted with -R° or -OR° 1-6 In some embodiments, R Z teeth, [ka] In some embodiments, R Z teeth, [ka] and R° is —OR° or —N(R°). In some embodiments, R Z teeth, [ka] In some embodiments, R Z teeth, [ka] In some embodiments, R Z teeth, [ka] is.

[0091] In some embodiments, R Z is an optionally substituted saturated or partially unsaturated 3- to 7-membered carbocyclic ring. In some embodiments, R Z is an optionally substituted saturated 3-membered carbocyclic ring. In some such embodiments, R Z teeth, [ka] In some such embodiments, R° is optionally substituted with halogen.

[0092] In some embodiments, R Z is an optionally substituted phenyl ring. In some embodiments, R Z 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 Z is an optionally substituted 4-membered saturated heterocycle having one heteroatom selected from nitrogen, oxygen, and sulfur. In some such embodiments, RZ teeth, [ka] In some such embodiments, R Z teeth, [ka] is.

[0093] In some embodiments, R Z is an optionally substituted 5-6 membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R Z is an optionally substituted 5-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R Z teeth, [ka] In some such embodiments, R Z teeth, [ka] is.

[0094] In some embodiments, R Z is an optionally substituted 6-membered saturated or partially unsaturated heterocycle having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some such embodiments, R Z teeth, [ka] is.

[0095] In some embodiments, R Z is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RZ is an optionally substituted 5-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R Z is an optionally substituted 6-membered heteroaryl ring having 1-2 nitrogen atoms. In some embodiments, R Z is selected from optionally substituted isothiazolyl, pyridinyl, or pyridazinyl. In some such embodiments, R Z teeth, [ka] is.

[0096] In some embodiments, R Z is C 1-8 An optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0097] In some embodiments, R Z is an arbitrarily substituted C 1-8 In some embodiments, R Z is an optionally substituted saturated or partially unsaturated 3- to 14-membered carbocyclic ring. In some embodiments, R Z is an optionally substituted 3-10 membered saturated or partially unsaturated heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R Z is an optionally substituted 5-14 membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R Z is an optionally substituted 10-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, RZ is an optionally substituted 10-membered heteroaryl ring having 1 to 4 nitrogen heteroatoms. In some embodiments, R Z is an optionally substituted 10-membered heteroaryl ring having three nitrogen heteroatoms. In some embodiments, R Z is a pyrido[3,4-d]pyridazine.

[0098] In some embodiments, R Z is selected from the group shown in the compounds of Table 1.

[0099] Generally, as defined above, L 2 is a covalent bond, or C 1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 One occurrence of aliphatic is optionally substituted.

[0100] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 is C 1-4A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 In some embodiments, L is optionally substituted with one occurrence of aliphatic. 2 is -CH-. In some embodiments, L 2 is -CH2O-.

[0101] In some embodiments, L 2 is —O—, —NH—, —S—, —NHC(O)NH—, —N(CH)C(O)NH—, —OC(O)NH—, —OC(O)N(CH)—, —NHC(O)O—, —CHC(O)NH—, —CHOC(O)NH—, —C(O)NH—, and —C(O)O—. In some embodiments, L 2 is -O-, -NH-, -S-, -NHC(O)NH-, -N(CH3)C(O)NH-, -OC(O)NH-, -OC(O)N(CH3)-, -NHC(O)O-, -CH2C(O)NH-, -N HC(O)CH2-, -CH2OC(O)NH-, -C(O)NH-, -NHC(O)-, -C(O)O-, -OC(O)-, -NHS(O)2-, -NHS(O)2NH-, and -OC(O)N( i In some embodiments, L 2is —O—. In some embodiments, L 2 is —NH—. In some embodiments, L 2 is -S-. In some embodiments, L 2 is —NHC(O)NH—. In some embodiments, L 2 is —N(CH)C(O)NH—. In some embodiments, L 2 is —OC(O)NH—. In some embodiments, L 2 is —NHC(O)O—. In some embodiments, L 2 is —CHC(O)NH—. In some embodiments, L 2 is —CHOC(O)NH—. In some embodiments, L 2 is —C(O)NH—. In some embodiments, L 2 is —NHC(O)—. In some embodiments, L 2 is —C(O)O—. In some embodiments, L 2 is -OC(O)-. In some embodiments, L 2 is —NHC(O)CH—. In some embodiments, L 2 is -NHS(O)-. In some embodiments, L 2 is —NHS(O)NH—. In some embodiments, L 2 is -OC(O)N( i In some embodiments, L 2 is a covalent bond, -CH2-, -NH-, -O-, -NHC(O)NH-, [ka] and [ka] Cy B represents a covalent bond to [ka] is R P or RZ In some embodiments, L 2 teeth, [ka] and [ka] Cy B represents a covalent bond to [ka] is R P or R Z In some embodiments, L 2 teeth, [ka] and [ka] Cy B represents a covalent bond to [ka] is R P or R Z represents a covalent bond to

[0102] In some embodiments, L 2 is -XC(O)Y-, where X and Y are as defined in the embodiments, classes, and subclasses herein. In some embodiments, X is -O-. In some embodiments, X is -NR X 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 -NR YIn some embodiments, Y is -NH-. In some embodiments, Y is -N(CH3)-. In some embodiments, Y is -S-.

[0103] In some embodiments, each L 2 is selected from the group shown in the compounds of Table 1.

[0104] Generally, as defined above, Q is 1 and L 1 is as defined in the embodiments and classes and subclasses herein. In some embodiments, Q is -NH-, [ka] and [ka] Cy A represents a covalent bond to [ka] Cy C or represents a covalent bond to W. In some embodiments, Q is -NH-. In some embodiments, Q is -O-. In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is [ka] In some embodiments, Q is -NHC(O)NH-. In some embodiments, Q is [ka] is.

[0105] In some embodiments, Q is selected from the groups shown in the compounds of Table 1.

[0106] Generally, as defined above, L 1 is a covalent bond, or C 1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -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)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 One occurrence of aliphatic is optionally substituted.

[0107] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 is C 1-4 A divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of the chain are optionally and independently -CH(R L )-, -C(R L )2-, C 3-6 Cycloalkylene, 3- to 6-membered heterocycloalkylene, 5- to 6-membered heteroarylene, -NH-, -N(R L )-, -NHC(O)-, -N(R L )C(O)-, -C(O)NH-, -C(O)N(RL )-, -NHS(O)2-, -N(R L )S(O)2-, -S(O)2NH-, -S(O)2N(R L )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, or -S(O)2-; 3-6 Each of cycloalkylene, 3- to 6-membered heterocycloalkylene, and 5- to 6-membered heteroarylene is R 1 or C 1-6 One occurrence of aliphatic is optionally substituted.

[0108] In some embodiments, L 1 is -NH-, [ka] and [ka] Cy A represents a covalent bond to [ka] Cy C or represents a covalent bond to W. In some embodiments, L 1 is —NH—. In some embodiments, L 1 is —O—. In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] In some embodiments, L 1 teeth, [ka] is.

[0109] In some embodiments, L 1 is selected from the group shown in the compounds of Table 1.

[0110] Generally, as defined above, R L Each occurrence of is independently R 1 or R 2 and R 3 In some embodiments, R L is R 1 In some embodiments, R L is R 2 is.

[0111] Generally, as defined above, R A , R B , and R C Each occurrence of is independently R 1 or R 2 and R A is R 3 q A occurrences and is replaced by R B is R 3 q B occurrences and is replaced by R C is R 3 q C In some embodiments, R A is R 1 In some embodiments, R B is R 1In some embodiments, R C is R 1 In some embodiments, R A is R 2 In some embodiments, R B is R 2 In some embodiments, R C is R 2 is.

[0112] Generally, as defined above, R 1 Each occurrence of (e.g., R A R 1 Group, R B R 1 group, or R C R 1 groups) are independently oxo, halogen, -CN, -NO, -OR, -SR, -NR, -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -C(O)R, -C(O)OR, -C(O)NR, -C(NR)NR, -C(O)N(R)OR, -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, or -N(R)S(O)R. In some embodiments, R 1 is oxo. In some embodiments, each R 1 are independently halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, or -N(R)S(O)2R.

[0113] In some embodiments, R 1 is halogen, —CN, or —NO. In some embodiments, R1 is -OR, -SR, or -NR2. In some embodiments, R 1 is —S(O)R, —S(O)NR, —S(O)R, —S(O)NR, —C(O)R, —C(O)OR, —C(O)NR, —C(NR)NR, or —C(O)N(R)OR. In some embodiments, R 1 is —S(O)R, —S(O)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, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, or -N(R)S(O)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, -N(H)C(NH)NR, -N(H)S(O)NR, -N(H)S(O)R, or -N(H)S(O)R. In some embodiments, R A is halogen. In some embodiments, R B is halogen. In some embodiments, R B is —C≡N. In some embodiments, R C is —S(O)R. In some embodiments, R C is —S(O)2CH3. In some embodiments, R C is -OR. In some embodiments, R C is —OCH. In some embodiments, R C is oxo. 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.

[0114] Generally, as defined above, R 2 Each occurrence of (e.g., R A R 2 Group, R B R 2 group, or R C R 2 groups) are independently C 1-7 aliphatic; phenyl; 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; a 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 a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is C 1-7 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; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or 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 2 is phenyl. In some embodiments, R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R 2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R2 is a 3- to 7-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R 2 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, R 2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0115] In some embodiments, R A is C 1-7 In some such embodiments, R A is -CH3. In some embodiments, R A is -C(CH3)3.

[0116] In some embodiments, R B is C 1-7 In some such embodiments, R B is -CH3. In some embodiments, R B are -CH3, -CH2CH3, -CH(CH3)2, [ka] In some embodiments, R B is R 3 C replaced with 1-7 In some embodiments, R B is R 3 C replaced with 1-7 It is aliphatic and R 3 is -OR. In some embodiments, R B is R 3 C replaced with 1-2 It is aliphatic and R 3 is -OR. In some embodiments, R B is —CHOH. In some embodiments, R B is oxo. In some embodiments, R Bis -OR and R is C 1-6 In some embodiments, R B is -OCH3.

[0117] In some embodiments, R C is C 1-7 In some such embodiments, R C is —CH or —C(CH). In some embodiments, R C -CHC(CH). In some embodiments, R C is R 3 C replaced with 1-7 In some embodiments, R C is R 3 C replaced with 1-7 It is aliphatic and R 3 is -OR. In some embodiments, R C is R 3 C replaced with 1-2 It is aliphatic and R 3 is -OR. In some embodiments, R C is —CH2OCH3. In some embodiments, R C teeth, [ka] In some embodiments, R C is —N(H)C(O)CH. In some embodiments, R C is —C(O)OR. In some embodiments, R C is -C(O)OR and R is C 1-6 In some embodiments, R C is —C(O)OCH2CH3. In some embodiments, R C is R 3 C replaced with 1-7 It is aliphatic and R 3 is halogen. In some embodiments, R C is R 3 C replaced with 1-7 It is aliphatic and R3 is fluorine. In some embodiments, R C is -CF3. In some embodiments, R C is oxo. In some embodiments, R C is R 3 In some embodiments, R is -OR substituted with C is R 3 is -OR substituted with C 1-6 It is aliphatic and R 3 is -OR. In some embodiments, R C is —OCHCHOH. In some embodiments, R C is R 3 C replaced with 1-7 It is aliphatic and R 3 is -OR. In some embodiments, R C is R 3 C replaced with 1-7 It is aliphatic and R 3 is -OR. In some embodiments, R C is R 3 C replaced with 1-7 It is aliphatic and R 3 is -OR, and R is C optionally substituted with halogen. 1-6 It is aliphatic.

[0118] Generally, as defined above, R 3 each occurrence independently represents oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)OR, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6is an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocycle having 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. In some embodiments, R 3 is oxo. In some embodiments, R 3 is halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)NR2, -C(NR)NR2, -C(O)N(R)O R, -OC(O)R, -OC(O)NR2, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR2, -N(R)C(NR)NR2, -N(R)S(O)2NR2, -N(R)S(O)R, -N(R)S(O)2R, or C 1-6 is an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocycle having 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. In some embodiments, R 3 is halogen, —CN, or —NO. In some embodiments, R 3 is -OR, -SR, or -NR2. In some embodiments, R 3 is -S(O)R, -S(O)NR, -S(O)R, -S(O)NR, -S(O)F, -OS(O)F, -C(O)R, -C(O)OR, -C(O)NR, -C(NR)NR, or -C(O)N(R)OR. In some embodiments, R 3 is -S(O)R, -S(O)N(H)R, -S(O)R, -S(O)N(H)R, -S(O)F, -OS(O)F, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)NR, or -C(O)N(H)OR. In some embodiments, R 3is -OC(O)R, -OC(O)NR, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(NR)R, -N(R)C(O)NR, -N(R)C(NR)NR, -N(R)S(O)NR, -N(R)S(O)R, or -N(R)S(O)R. In some embodiments, R 3 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, -N(H)C(NH)NR, -N(H)S(O)NR, -N(H)S(O)R, or -N(H)S(O)R. In some embodiments, R 3 is C 1-6 R is an optionally substituted group selected from aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocycle having 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. 3 is an arbitrarily substituted C 1-6 In some embodiments, R 3 is optionally substituted phenyl. In some embodiments, R 3 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 3 is an optionally substituted 5-6 membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0119] Generally, as defined above, W is hydrogen or Cy. C In some embodiments, W is hydrogen. In some embodiments, W is Cy C is.

[0120] Generally, as defined above, Cy Cis a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy C In addition to Q, R C In some embodiments, Cy is substituted with p occurrences of C is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring. C is a saturated or partially unsaturated 3- to 7-membered monocyclic carbocyclic ring. C is cyclopropyl.

[0121] In some embodiments, Cy C is a saturated or partially unsaturated 3- to 14-membered heterocycle having 1 to 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 having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0122] In some embodiments, Cy C is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur. C is a 5-membered heteroaryl ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. C is a 5-membered heteroaryl ring having 1-2 heteroatoms selected from nitrogen, oxygen, and sulfur. C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] is.

[0123] In some embodiments, Cy C is a 6-membered heteroaryl ring having 1 to 3 nitrogen atoms. In some embodiments, Cy C is pyridyl. In some embodiments, Cy C is pyrimidinyl. In some embodiments, Cy C is pyridazinyl. In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] is.

[0124] In some embodiments, Cy C is a 9-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. C is a 9-10 membered heteroaryl having 1-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. C is a 9-10 membered heteroaryl having 2-4 nitrogen atoms. C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] In some embodiments, Cy C teeth, [ka] is.

[0125] Generally, as defined above, each R is independently hydrogen or C 1-6 an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 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 their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is hydrogen. In some embodiments, R is C 1-6 An optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 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 their intervening atoms, form a 4- to 7-membered saturated, partially unsaturated, or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted C 1-6In some embodiments, R is an optionally substituted saturated or partially unsaturated 3- to 7-membered carbocyclic ring. In some embodiments, R is an optionally substituted phenyl. In some embodiments, R is an optionally substituted 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, R is an optionally substituted 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0126] 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 by the compounds in Table 1.

[0127] 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 by the compounds in Table 1.

[0128] 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 by the compounds in Table 1.

[0129] In general, as defined above, q A is 0, 1, 2, 3, or 4. In some embodiments, q A is 0. In some embodiments, q Ais 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 by the compounds in Table 1.

[0130] In general, as defined above, q B is 0, 1, 2, 3, or 4. In some embodiments, q B is 0. In some embodiments, q B is 1. In some embodiments, q B is 2. In some embodiments, q B is 3. In some embodiments, q B is 4. In some embodiments, q B is 0 or 1. In some embodiments, q B is 0, 1, or 2. In some embodiments, q B is 0, 1, 2, or 3. In some embodiments, q B is 1 or 2. In some embodiments, q B is 1, 2, or 3. In some embodiments, q Bis 1, 2, 3, or 4. In some embodiments, q B is 2 or 3. In some embodiments, q B is 2, 3, or 4. In some embodiments, q B is 3 or 4. In some embodiments, q B is selected from the values ​​represented by the compounds in Table 1.

[0131] In general, as defined above, q C is 0, 1, 2, 3, or 4. In some embodiments, q C is 0. In some embodiments, q C is 1. In some embodiments, q C is 2. In some embodiments, q C is 3. In some embodiments, q C is 4. In some embodiments, q C is 0 or 1. In some embodiments, q C is 0, 1, or 2. In some embodiments, q C is 0, 1, 2, or 3. In some embodiments, q C is 1 or 2. In some embodiments, q C is 1, 2, or 3. In some embodiments, q C is 1, 2, 3, or 4. In some embodiments, q C is 2 or 3. In some embodiments, q C is 2, 3, or 4. In some embodiments, q C is 3 or 4. In some embodiments, q C is selected from the values ​​represented by the compounds in Table 1.

[0132] 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 by the compounds in Table 1.

[0133] As generally defined above, t is 0, 1, 2, 3, or 4. In some embodiments, t is 0. 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 by the compounds in Table 1.

[0134] 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 a compound selected from those shown in Table 1 below, or a pharmaceutically acceptable salt, stereoisomer, or mixtures of stereoisomers thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1 below, or a pharmaceutically acceptable salt thereof. In some embodiments, the present disclosure provides a compound set forth in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

Table 1-45

Table 1-46

Table 1-47

Table 1-48

Table 1-49

Table 1-50

Table 1-51

Table 1-52

Table 1-53

Table 1-54

Table 1-55

Table 1-56

Table 1-57

Table 1-58

Table 1-59

Table 1-60

Table 1-61

Table 1-62

Table 1-63

Table 1-64

Table 1-65

Table 1-66

Table 1-67

Table 1-68

Table 1-69

Table 1-70

Table 1-71

Table 1-72

Table 1-73

Table 1-74

Table 1-75

Table 1-76

Table 1-77

Table 1-79

Table 1-80

Table 1-81

Table 1-82

Table 1-83

Table 1-84

Table 1-85

Table 1-86

Table 1-87

Table 1-88

Table 1-89

Table 1-90

Table 1-91

Table 1-92

Table 1-93

Table 1-94

Table 1-95

Table 1-96

Table 1-97

Table 1-98

Table 1-99

Table 1-100

Table 1-101

Table 1-102

Table 1-103

Table 1-104

Table 1-105

Table 1-106

Table 1-107

Table 1-108

Table 1-109

Table 1-110

Table 1-111

Table 1-112

Table 1-113

Table 1-114

[0135] In the chemical structures in Table 1 above, if a stereocenter is indicated with a dashed or wedge-shaped bond and labeled "abs" (or unlabeled), the compound is essentially a single isomer at that stereocenter (rather than an equimolar mixture), and the absolute stereochemistry is as shown in the chemical structure. (See, e.g., the structure in Example 5.) If a stereocenter is indicated with a dashed or wedge-shaped bond and further labeled "or1" or "or2," the compound is a single isomer at that stereocenter, but the absolute stereochemistry of that stereocenter has not been determined. (See, e.g., the structure in Example 27.) If a stereocenter is indicated with a dashed or wedge-shaped bond and further labeled "and1" or "&1," the compound is a mixture of two isomers at that stereocenter: the structure as depicted and an isomer in which the stereocenter has the opposite configuration. (See, e.g., the structure in Example 3.)

[0136] Certain compounds shown in Table 1 above exist in solution at room temperature as non-interconverting atropisomers via the biaryl bond. When one of the atoms in the biaryl bond is labeled "or1," this means that the compound exists in solution at room temperature as non-interconverting atropisomers and that the compound is essentially a single atropisomer (rather than an equimolar mixture).

[0137] In some embodiments, the present disclosure provides a compound of Table 1 above, wherein the compound has a biochemical CDK2 caliper IC of "A." 50In some embodiments, the present disclosure provides a compound of Table 1 above, wherein the compound has a biochemical CDK2 caliper IC of "A" or "B." 50 In some embodiments, the disclosure provides a compound of Table 1 above, wherein the compound has a biochemical CDK2 caliper IC of "A" or "B" or "C." 50 is shown as having

[0138] In some embodiments, the present disclosure provides a compound from Table 1 above, wherein the compound has a Cell nanoBRET IC of "A." 50 In some embodiments, the present disclosure provides a compound of Table 1 above, wherein the compound has a Cell nanoBRET IC of "A" or "B." 50 In some embodiments, the disclosure provides a compound from Table 1 above, wherein the compound has a Cell nanoBRET IC of "A" or "B" or "C." 50 is shown as having

[0139] 4. General Method of Providing the Compounds The compounds described herein may generally be prepared or isolated by synthetic and / or semi-synthetic methods known to those skilled in the art for similar compounds, and by methods detailed in the Examples herein.

[0140] 5. Uses, Formulations, and Administration Pharmaceutically acceptable compositions According to another embodiment, the present disclosure provides a composition comprising a compound described herein or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the present disclosure provides a pharmaceutical composition 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 a mutant thereof in a biological sample or a patient. In certain embodiments, the amount of compound in the compositions described herein is effective to measurably inhibit CDK2 protein kinase or a mutant thereof in a biological sample or a patient. In certain embodiments, the compositions described herein are formulated for administration to a patient in need of such a composition. In some embodiments, the compositions described herein are formulated for oral administration to a patient.

[0141] As used herein, the terms "subject" and "patient" refer to an animal (i.e., a member of the animal kingdom), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, a mouse, a rat, a cat, a monkey, a dog, a horse, or a pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, a rat, a cat, a monkey, a dog, a horse, or a pig.

[0142] 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 being formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, 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, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0143] "Pharmaceutically acceptable derivative" means any non-toxic salt, ester, salt of an ester, or other derivative of a compound described herein that, upon administration to a recipient, is capable of providing, directly or indirectly, a compound described herein, or an inhibitory active metabolite or residue thereof.

[0144] As used herein, an "inhibitorily active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of CDK2 protein kinase or a mutant thereof.

[0145] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0146] The sterile injectable form of the compositions described herein may be an aqueous or oily suspension. These 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 non-toxic parenterally acceptable diluent or solvent, such as a 1,3-butanediol solution. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally used as solvents or suspending media.

[0147] For this purpose, any mild, fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injections, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0148] The pharmaceutically acceptable compositions described herein can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions.For tablets for oral use, commonly used carriers include lactose and cornstarch.Usually, lubricants such as magnesium stearate are also added.For oral administration in capsule form, useful diluents include lactose and dried cornstarch.When aqueous suspensions for oral use are required, the active ingredient is combined with emulsifying and suspending agents.If necessary, certain sweeteners, flavoring agents, or coloring agents can also be added.

[0149] Alternatively, the pharmaceutically acceptable compositions described herein can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and therefore melts in the rectum or vagina to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0150] The pharmaceutically acceptable compositions described herein may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0151] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0152] For topical application, the provided pharmaceutically acceptable composition can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds described herein include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, the provided pharmaceutically acceptable composition can be formulated into 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.

[0153] For intraocular use, the provided pharmaceutically acceptable compositions can be formulated as a micronized suspension in isotonic, pH-adjusted, sterile saline, or, preferably, as a solution in isotonic, pH-adjusted, sterile saline, either with or without a preservative, such as benzylalkonium chloride. Alternatively, for intraocular use, the pharmaceutically acceptable compositions can be formulated into an ointment, such as petrolatum.

[0154] The pharmaceutically acceptable compositions described herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline using benzyl alcohol or other suitable preservatives, absorption enhancers which enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0155] Preferably, the pharmaceutically acceptable compositions described herein are formulated for oral administration. Such formulations can be administered with or without food. In some embodiments, the pharmaceutically acceptable compositions described herein are administered without food. In other embodiments, the pharmaceutically acceptable compositions described herein are administered with food.

[0156] The amount of the compounds described herein that can be combined with a carrier material to produce a single dosage form will vary depending on the patient being treated and the particular mode of administration. Preferably, the provided compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0157] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the particular compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, drug combination, as well as the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in a composition will also depend on the particular compound in the composition.

[0158] The precise dose to be employed in the compositions will also depend on the route of administration and should be decided according to the judgment of the practitioner and each subject's circumstances. In certain embodiments of the present disclosure, suitable dose ranges for oral administration of the compounds of the present disclosure are generally from about 1 mg / day to about 1000 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 800 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 500 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 250 mg / day. In some embodiments, the oral dose is from about 1 mg / day to about 100 mg / day. In some embodiments, the oral dose is from about 5 mg / day to about 50 mg / day. In some embodiments, the oral dose is about 5 mg / day. In some embodiments, the oral dose is about 10 mg / day. In some embodiments, the oral dose is about 20 mg / day. In some embodiments, the oral dose is about 30 mg / day. In some embodiments, the oral dose is about 40 mg / day. In some embodiments, the oral dose is about 50 mg / day. In some embodiments, the oral dose is about 60 mg / day. In some embodiments, the oral dose is about 70 mg / day. In some embodiments, the oral dose is about 100 mg / day. It will be recognized that any of the dosage amounts set forth herein may constitute an upper or lower dosage range and may also be combined with any other dosage amount to form a dosage range inclusive of the upper and lower limits.

[0159] In some embodiments, a pharmaceutically acceptable composition comprises a provided compound and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90% by weight, about 0.01 to about 80% by weight, about 0.01 to about 70% by weight, about 0.01 to about 60% by weight, about 0.01 to about 50% by weight, about 0.01 to about 40% by weight, about 0.01 to about 30% by weight, about 0.01 to about 20% by weight, about 0.01 to about 2.0% by weight, about 0.01 to about 1% by weight, about 0.05 to about 0.5% by weight, about 1 to about 30% by weight, or about 1 to about 20% by weight. The composition can be formulated as a solution, suspension, ointment, capsule, or the like. The pharmaceutical composition can be prepared as an aqueous solution and may contain additional components, such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity-adjusting ingredients, etc.

[0160] 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.

[0161] Examples of pharmaceutically acceptable carriers may include, for example, water or saline, polymers such as polyethylene glycol, carbohydrates and their derivatives, 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, etc. Pharmaceutical carriers may also be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliary agents, stabilizers, thickeners, lubricants, and colorants may be used. Other examples of suitable pharmaceutical carriers can be found, for example, in Remington's: The Science and Practice of Pharmacy, 22nd Ed. (Allen, Loyd V., Jr ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5 th Ed.(Alexander T.Florence,Juergen Siepmann,CRC Press(2009));Handbook of Pharmaceutical Excipients,7 th Ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E. eds., Pharmaceutical Press (2012)), each of which is incorporated herein by reference in its entirety.

[0162] As used herein, pharmaceutically acceptable carriers can be selected from a variety of organic or inorganic materials used in pharmaceutical formulations and incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, bulking agents, glidants, solubilizers, stabilizers, suspending agents, isotonicity agents, vehicles, and thickeners. Pharmaceutical additives, such as antioxidants, flavoring agents, coloring agents, flavor enhancers, preservatives, and sweeteners, can also be added. Examples of acceptable pharmaceutical carriers include, among others, carboxymethylcellulose, crystalline cellulose, glycerin, 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 federal or state regulatory authorities or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, more specifically, in humans.

[0163] Surfactants, such as 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, glycerol, sorbitol, or polyoxyethylenated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic derivatives, such as methacrylates; anionic surfactants, such as alkali stearates, in particular sodium stearate, potassium stearate, or ammonium stearate; calcium stearate or triethanolamine stearate; alkyl sulfates, in particular sodium lauryl sulfate and sodium cetyl sulfate; sodium dodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids, in particular those derived from coconut oil; cationic surfactants, such as those of the formula N + R'R''R'''R''''Y - wherein the R radicals are the same or different optionally hydroxylated hydrocarbon radicals, and Y- is an anion of a strong acid, such as a halide, sulfate, and sulfonate anion; cetyltrimethylammonium bromide is one cationic surfactant that can be used), + Amine salts of R'R''R''' (where the R radicals are the same or different, optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is one of the cationic surfactants that can be used), nonionic surfactants, such as, optionally, polyoxyethylenated esters of sorbitan, in particular polysorbate 80, or polyoxyethylenated alkyl ethers; polyethylene glycol stearates, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0164] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, nonfat dry milk, glycerol, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, and the like. The composition, if desired, can also contain wetting or emulsifying agents, or pH buffering agents.

[0165] 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.Such examples include carbohydrates such as lactose or sucrose, anhydrous dibasic calcium phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearates, silicon dioxide, talc, sodium starch glycolate, acacia, flavoring agents, preservatives, buffers, disintegrants, and coloring agents.Oral administration compositions may contain one or more optional agents that provide pharmaceutically palatable preparations, such as sweeteners such as fructose, aspartame, or saccharin; flavoring agents such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives.

[0166] Uses of the 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.

[0167] The compounds or compositions of the present disclosure may be useful in applications that 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 tumorigenesis 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). Evidence suggests that CDK2 is functionally linked to the hyperproliferation of multiple cancer cells and is a potential therapeutic target for cancer treatment (Chohan, Curr Med Chem 2015). CDK2 plays a role in the oncogenic transformation of breast epithelial cells. Suppression of CDK2 activity can effectively inhibit the proliferation of human breast cancer cells (Ali, Cancer Res 2009). Activated CDK2, in the form of a cyclin D1 / CDK2 fusion protein, induces tumors containing invasive components that exhibit several characteristics in common with 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 well with the degree of cyclin D1 overexpression. The role of cyclin E and its associated kinase CDK2 in ovarian cancer has been studied by screening primary, metastatic, recurrent, and benign ovarian tumors. Using gene amplification, it was shown that cyclin E was amplified in 21% of the analyzed cases, and CDK2 was amplified in 6.4%. Furthermore, cyclin E RNA was overexpressed in 29.5% of ovarian tumors tested, and CDK2 was overexpressed in 6.5%. Cyclin E and CDK2 were overexpressed primarily in primary ovarian cancers (32% and 10%, respectively) compared with metastatic and recurrent disease (Marone, Int J Cancer 1998). CDK2 expression has been found to be significantly elevated in glioma tumors, particularly glioblastoma multiforme (GBM), and is functionally required for GBM cell proliferation and tumorigenesis (Wang, Transl Oncol 2016). CDK2 expression is significantly enriched in GBM tumors and confirmed to be functionally required for tumor growth both in vitro and in vivo. Furthermore, high CDK2 expression has been associated with poor prognosis in GBM patients. Radioresistance is a major factor in poor clinical prognosis and tumor recurrence in GBM patients. CDK2 has been found to be one of the most upregulated kinase-encoding genes in GBM after radiation treatment. CDK2-dependent radioresistance is dependent on GBM tumorigenesis and recurrence after therapeutic treatment (ibid.). Increased CDK2 expression levels have been observed in human cholangiocarcinoma tissues, and apoptosis-related protein 1-dependent inhibition of CDK2 induced cell cycle arrest and suppressed tumor growth (Zheng, Oncol Rep 2016). Overexpression of CDK2 in oral squamous cell carcinoma (SCC) may increase pRB phosphorylation, allowing cancer cells to transition more rapidly to the S phase. In a clinicopathological study of oral SCC, the incidence of CDK2 expression was higher in poorly differentiated lesions and correlated with the pattern of tumor invasion, lymph node metastasis, and survival rate. Changes in CDK2 expression correlated with the progression of oral cancer (Mihara, Jpn J Cancer Res 2001). CDK2 expression was significantly correlated with lymph node involvement, tumor differentiation, pattern of tumor invasion, and shortened survival time. Therefore, increased CDK2 expression is a contributing factor to the progression of oral cancer and a negative predictive marker for patient prognosis (ibid.). CDK2 has been shown to play a role in the cell proliferation of non-small cell lung cancer (Kawana, Am J Pathol 1998). CDK2 has also been shown to play a role in the cell proliferation of prostate cancer (Flores, Endocrinology 2010). The activity of the compounds described herein as inhibitors of CDK kinases, such as CDK2, or mutants thereof, can be assayed in vitro, in vivo, or in cell lines. In vitro assays include assays that determine inhibition of either the phosphorylation activity and / or subsequent functional consequences, or the ATPase activity, of activated CDK2 or its mutants. An alternative in vitro assay quantifies the ability of inhibitors to bind to CDK2. Inhibitor binding can be measured by radiolabeling the inhibitor prior to binding, isolating the inhibitor / CDK2 complex, and measuring the amount of bound radiolabel. Alternatively, inhibitor binding can be determined by performing a competition experiment in which new inhibitors are incubated with CDK2 bound to a known radioligand. Representative in vitro and in vivo assays useful for assaying CDK2 inhibitors include those described and disclosed in the patents and scientific publications cited herein. Detailed conditions for assaying the compounds described herein as inhibitors of CDK2 or mutants thereof are described in the Examples below.

[0168] Treatment of the problem The provided compounds are inhibitors of CDK2 and are therefore useful for treating one or more disorders associated with the activity of CDK2 or its mutants. Accordingly, in certain embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or any of the above-described pharmaceutically acceptable compositions. In certain embodiments, the present disclosure provides a method of treating a CDK2-mediated disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition thereof.

[0169] As used herein, the term "CDK2-mediated" disorder, disease, and / or condition means any disease or other deleterious condition in which CDK2 or a mutant thereof is 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 a mutant thereof is known to play a role. Such CDK2-mediated disorders include, but are not limited to, proliferative disorders (e.g., cancer).

[0170] In some embodiments, the present disclosure provides methods for treating one or more disorders, wherein the disorders are selected from a proliferative disorder and a craniosynostosis syndrome, the methods comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of any of the foregoing, to a patient in need thereof. In some embodiments, the present disclosure provides methods for treating one or more disorders, wherein the disorders are selected from a proliferative disorder and a craniosynostosis syndrome, the methods comprising administering a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof, to a patient in need thereof.

[0171] 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 disorders associated with aberrant signaling within those pathways. In some embodiments, the disorder is associated with cyclin E, cyclin E1, or retinoblastoma protein (RB) signaling.

[0172] In some embodiments, the method of treatment includes: i) identifying a subject in need of such treatment; (ii) providing a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering the provided compound in a therapeutically effective amount to treat, inhibit, and / or prevent a disease state or condition in the subject in need of such treatment.

[0173] In some embodiments, the method of treatment includes: i) identifying a subject in need of such treatment; (ii) providing a composition comprising a disclosed compound, or a pharmaceutically acceptable salt thereof; and (iii) administering the composition in a therapeutically effective amount to treat, inhibit, and / or prevent a disease state or condition in the subject in need of such treatment.

[0174] Another aspect of the present disclosure provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or any of the pharmaceutical compositions described above, for use in treating 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 any of the pharmaceutical compositions described above, for treating a disorder described herein. Similarly, the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating a disorder described herein.

[0175] Proliferative disorders 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.

[0176] 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.

[0177] In some embodiments, the disorder 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. In some embodiments, the bladder cancer is urothelial carcinoma. In some embodiments, the liver cancer is hepatocellular carcinoma. In some embodiments, the lung cancer is lung 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.

[0178] In some embodiments, the proliferative disorder is associated with deregulation of CDK2 or cyclin E. In some embodiments, the deregulation of CDK2 is overexpression of CDK2 or cyclin E. In some embodiments, the 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, the deregulation of CDK2 and cyclin E is overexpression of CDK2 and cyclin E.

[0179] In some embodiments, the proliferative disorder is associated with one or more activating mutations in CDK2. In some embodiments, the activating mutations in CDK2 are mutations in one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutations in CDK2 are mutations in the intracellular kinase domain.

[0180] Route of administration and dosage form The compounds and compositions may be administered in accordance with the methods described herein using any amount and any route of administration effective for treating or reducing the severity of a disorder (e.g., a proliferative disorder or craniosynostosis syndrome). The exact amount required will vary from subject to subject, depending on the subject's species, age, and general condition, the severity of the infection, the particular drug, its mode of administration, and the like. The compounds described herein are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. As used herein, the phrase "unit dosage form" refers to a physically discrete unit of drug appropriate for the patient to be treated. However, it will be understood that the total daily frequency of use of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of sound medical judgment. The specific effective dosage level for a particular patient or organism will vary depending on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the particular compound used; the particular composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the particular compound used; the duration of treatment; drugs used in combination with or concurrently with the particular compound used; and similar factors well known in the medical arts.

[0181] The pharmaceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (by powder, ointment, or drops), bucally, orally or as a nasal spray, etc. In certain embodiments, the compounds described herein can be administered orally or parenterally, one or more times daily, to achieve the desired therapeutic effect, at dosage levels of from about 0.01 mg / kg of subject body weight per day to about 50 mg / kg of subject body weight per day, preferably from about 1 mg / kg of subject body weight per day to about 25 mg / kg of subject body weight per day.

[0182] 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 contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and aromatic agents.

[0183] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, bland, fixed oils, including synthetic monoglycerides or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectables.

[0184] Injectable preparations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0185] To prolong the effect of the compounds described herein, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be accomplished by using a suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its rate of dissolution, which may in turn depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved 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. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0186] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound described herein with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository wax, which is solid at ambient temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity releasing the active compound.

[0187] The solid dosage form for oral administration includes capsule, tablet, pill, powder and granule.In such solid dosage form, active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier, for example, sodium citrate or dicalcium phosphate, and / or a) filler or extender, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binder, for example, carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidinone, sucrose and acacia, c) moisturizer, for example, glycerol, d) disintegrant, for example, agar, calcium carbonate, Potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarders such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, 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.

[0188] Solid compositions of a similar type can 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 such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They may optionally contain opacifying agents, and can also be of a composition that releases the active ingredient(s) alone or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can 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.

[0189] The active compound may also be in microencapsulated form with one or more excipients, as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose, or starch. As is common practice, such dosage forms may also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium tearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also contain buffering agents. They may optionally contain opacifying agents, and may be of a composition that releases the active ingredient(s) alone or preferentially in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0190] 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 necessary preservatives or buffers. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of this disclosure. Additionally, this disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound 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.

[0191] Dosage and regimen According to the methods of the present disclosure, a compound of the present disclosure is administered to a subject in a therapeutically effective amount, e.g., to reduce or ameliorate symptoms of the subject's disorder, which amount is readily determined by one of ordinary skill in the art based on known procedures, including analysis of titration curves established in vivo and the methods and assays disclosed herein.

[0192] In some embodiments, the methods include administering a therapeutically effective dosage of a compound of the present disclosure. In some embodiments, the therapeutically effective dosage 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, 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 recognized that any of the dosage amounts set forth herein may constitute an upper or lower dosage range and may also be combined with any other dosage amount to form a dosage range inclusive of the upper and lower limits.

[0193] In some embodiments, the therapeutically effective dosage is in the range of about 0.1 mg to about 10 mg / kg body weight, about 0.1 mg to about 6 mg / kg body weight, about 0.1 mg to about 4 mg / kg body weight, or about 0.1 mg to about 2 mg / kg body weight.

[0194] In some embodiments, the therapeutically effective dosage is in the range of 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, 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, about 20 to 40 mg, about 40 to 150 mg, about 40 to 120 mg, or about 40 to 80 mg.

[0195] In some embodiments, the methods involve a single dose or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the methods involve administering to a subject in need thereof once daily, twice daily, three times daily, or four times daily 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 involve chronic administration. In still other embodiments, the methods involve administration over weeks, months, years, or decades. In still other embodiments, the methods involve administration over weeks. In still other embodiments, the methods involve administration over months. In still other embodiments, the methods involve administration over years. In still other embodiments, the methods involve administration over decades.

[0196] The dosage administered may vary depending on known factors, such as the pharmacodynamic properties 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; the nature and extent of the symptoms; the type of concurrent treatment, the frequency of treatment, and the desired effect; and excretion rate, all of which can be readily determined and used by one skilled in the art to adjust or titrate the dosage and / or administration regimen.

[0197] Protein kinase inhibition According to one embodiment, the present disclosure relates to a method of inhibiting protein kinase activity in a biological sample, the method comprising contacting the biological sample with a compound described herein or a composition comprising the compound.

[0198] 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, the method comprising contacting the biological sample with a compound described herein or a composition comprising said compound. In certain embodiments, the present disclosure relates to a method of reversibly inhibiting the activity of CDK2 or a mutant thereof in a biological sample, the method comprising contacting the biological sample with a compound described herein or a composition comprising said compound.

[0199] In another embodiment, the present disclosure provides a method for selectively inhibiting CDK2 over one or more of CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have greater than 5-fold selectivity over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have greater than 10-fold selectivity over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have greater than 50-fold selectivity over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have greater than 100-fold selectivity over CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have greater than 200-fold selectivity over CDK1, CDK4, CDK5, CDK6, and CDK9.

[0200] As used herein, the term "biological sample" includes, but is not limited to, a cell culture or extract thereof; a biopsy or extract thereof obtained from a mammal; and blood, saliva, urine, feces, semen, tears, or other bodily fluids or extracts thereof.

[0201] Inhibition of CDK2 (or a variant thereof) activity in a biological sample is useful for a variety of purposes known to those skilled in the art, including, but not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0202] Another embodiment of the present disclosure relates to a method of inhibiting protein kinase activity in a patient, the method comprising administering to the patient a compound described herein, or a composition comprising said compound.

[0203] According to another embodiment, the present disclosure relates to a method of inhibiting the activity of CDK2 or a mutant thereof in a patient, the method comprising administering to the patient a compound described herein or a composition comprising the compound. According to certain embodiments, the present disclosure relates to a method of reversibly inhibiting the activity of one or more CDK2 or mutants thereof in a patient, the method comprising administering to the patient a compound described herein or a composition comprising the compound.

[0204] According to another embodiment, the present disclosure relates to a method 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 composition thereof. Such disorders are described in detail herein. In some embodiments, the present disclosure relates to a method 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 composition thereof, wherein the compound reversibly inhibits CDK2 or a mutant thereof.

[0205] According to another embodiment, the present disclosure provides a method of inhibiting signaling activity of CDK2 or a mutant thereof in a subject, the method comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition thereof to a subject in need thereof. In some embodiments, the present disclosure provides a method of inhibiting CDK2 signaling activity in a subject, the method comprising administering a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable composition thereof to a subject in need thereof.

[0206] In some embodiments, the present disclosure relates to a method 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 composition thereof, wherein the compound reversibly inhibits CDK2 or a mutant thereof.

[0207] The compounds described herein can be incorporated into drugs that catalyze the destruction of CDK2, thereby inhibiting CDK2 function. For example, the compounds can be incorporated into proteolysis-targeting chimeras (PROTACs). PROTACs are bifunctional molecules, with one portion capable of binding to an E3 ubiquitin ligase and the other portion capable of binding to a target protein for degradation by cellular protein quality control mechanisms. Once the target protein is recruited to a specific E3 ligase, it is tagged for destruction (i.e., ubiquitination) and then degraded by the proteasome. Any E3 ligase can be used. The portion of the PROTAC that binds to the E3 ligase is linked to the portion of the PROTAC that binds to the target protein via a linker consisting of a variable chain of atoms. Thus, when CDK2 is recruited to the E3 ligase, the CDK2 protein is destroyed. The variable chain of atoms can include, for example, a ring, heteroatoms, and / or repeating polymer units. It can be rigid or flexible. It can be attached to the two moieties described above using standard techniques in the field of organic synthesis.

[0208] Combination therapy Depending on the particular disorder, condition, or disease to be treated, additional therapeutic agents that are normally administered to treat that condition may be administered in combination with the compounds and compositions described herein. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease, or condition, being treated."

[0209] Thus, in certain embodiments, methods of treatment include administering a compound or composition described herein in combination with one or more additional therapeutic agents, hi certain other embodiments, methods of treatment include administering a compound or composition described herein as the sole therapeutic agent.

[0210] In some embodiments, the one or more additional therapeutic agents are selected from antibodies, antibody-drug conjugates, kinase inhibitors, immunomodulatory agents, and histone deacetylase inhibitors. In some embodiments, the one or more additional therapeutic agents are selected from the following agents, or pharmaceutically acceptable salts thereof: BCR-ABL inhibitors: e.g., imatinib, inilotinib, nilotinib, dasatinib, bosutinib, ponatinib, bafetinib, danusertib, saracatinib, PF03814735; ALK inhibitors (see, e.g., Dardaei et al., 2018, Nat Med.; 24(4):512-517): e.g., crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entresinib, lorlatinib; BRAF inhibitors (see, e.g., Prahallad et al., 2015, Cell Rep. 12, 1978-1985): e.g., vemurafenib, dabrafenib; FGFR inhibitors: e.g., infigratinib, dovitinib, erdafitinib, BLU-554, AZD4547; FLT3 inhibitors: e.g., sunitinib, midostaurin, tanutinib, sorafenib, 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): e.g., trametinib, cobimetinib, binimetinib, selumetinib; ERK inhibitors: e.g., ulixertinib, MK-8353, LY-3214996; VEGF receptor inhibitors: e.g., bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide, sorafenib; tyrosine kinase inhibitors: e.g., e.g., Epidermal growth factor receptor (EGFR) inhibitors: gefitinib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors: e.g., trastuzumab, neratinib, lapatinib, lapatinib; MET inhibitors: e.g., crizotinib, cabozantinib; CD20 antibodies: e.g., rituximab, tositumomab, ofatumumab;DNA synthesis inhibitors: e.g., capecitabine, gemcitabine, nelarabine, hydroxycarbamide; antitumor agents: e.g., oxaliplatin, cisplatin; HER dimerization inhibitors: e.g., pertuzumab; human granulocyte colony-stimulating factor (G-CSF) modulators: e.g., filgrastim; immunomodulators: e.g., afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: e.g., dacetuzumab; pro-apoptotic receptor agonists (PARA): e.g., dulanermin; heat shock protein (HSP) inhibitors : for example, tanespimycin (17-allylamino-17-desmethoxygeldanamycin); hedgehog antagonists: for example, vismodegib; proteasome inhibitors: for example, bortezomib; PI3K inhibitors: for example, pictilisib, dactolisib, bupalisib, taselisib, idelalisib, duvelisib, umbralisib; phospholipase A2 inhibitors: for example, anagrelide; BCL-2 inhibitors: for example, venetoclax; aromatase inhibitors: exemestane, letrozole, anastrozole, faslodex, tamoxifen; Topoisomerase I inhibitors: for example, irinotecan, topotecan; topoisomerase II inhibitors: for example, etoposide, teniposide; mTOR inhibitors: for example, temsirolimus, ridaforimus, everolimus, sirolimus; osteoclast bone resorption inhibitors: for example, zoledronic acid; CD33 antibody-drug conjugates: for example, gemtuzumab ozogamicin; CD22 antibody-drug conjugates: for example, inotuzumab ozogamicin; CD20 antibody-drug conjugates: for example, ibritumomab tiuxetan; somatosteine ​​analogs: for example, octotreat Otides; interleukin-11 (IL-11): for example, oprelvekin; synthetic erythropoietin: for example, darbepoetin alfa; receptor activator of nuclear factor kappa B (RANK) inhibitors: for example, denosumab; thrombopoietin mimetic peptides: for example, romiplostim; cell growth stimulators: for example, palifermin; anti-insulin-like growth factor 1 receptor (IGF-1R) antibodies: for example, figitumumab; anti-CS1 antibodies: for example, elotuzumab; CD52 antibodies: for example, alemtuzumab; CTLA-4 inhibitors: for example, tremelimumab, ipilimumab;PD1 inhibitors: e.g., nivolumab, pembrolizumab; immunoadhesins: e.g., pidilizumab, AMP-224; PDL1 inhibitors: e.g., MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C, or MDX-1105; LAG-3 inhibitors: e.g., BMS-986016; GITR agonists: GITR fusion proteins and anti-GITR antibodies; histone deacetylase inhibitors (HDIs): e.g., boninostat; anti-CTLA4 antibodies: e.g., alkylating agents: for example, temozolomide, dactinomycin, melphalan, altretamine carmustine, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretamine, ifosfamide, procarbazine, mechlorethamine, mustine and mechloroethamine, streptozocin, thiotepa; biological response modifiers: for example, bacillus Calmette-Guerin, denileukin diftitox; antitumor anticancer agents: for example, cefotaxime ... Biologics: e.g., doxorubicin, bleomycin, daunorubicin, daunorubicin liposome, mitoxantrone, epirubicin, idarubicin, mitomycin C; antimicrotubule agents: e.g., estramustine; cathepsin K inhibitors: e.g., odanacatib; epothilone analogs: e.g., ixabepilone; TpoR agonists: e.g., eltrombopag; antimitotic agents: e.g., docetaxel; adrenal steroid inhibitors: e.g., aminoglutethimide; antiandrogens: e.g., nilutamide; androgen receptor inhibitors Medications: for example, enzalutamide, abiraterone acetate, orteronel, galeterone, and ceviteronel, bicalutamide, flutamide; androgens: for example, fluoxymesterone; CDK1 inhibitors: for example, alvocidib, palbociclib, ribociclib, trilaciclib, abemaciclib; gonadotropin-releasing hormone (GnRH) receptor agonists: for example, leuprolide or leuprolide acetate; taxane antitumor agents: for example, cabazitaxel, larotaxel; 5-HT1a receptor agonists: for example, zaliproden;HPV vaccines: for example, Cervarix® sold by GlaxoSmithKline, Gardasil® sold by Merck; iron chelators: for example, deferasirox; antimetabolites: for example, claribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, cytarabine liposomal, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, pentostatin; bisphosphonates: for example, pamidronate; demethylating agents: for example, 5-azacytidine, decitabine; antitumor plant alkaloids: for example, paclitaxel protein-bound; vinblastine, vincristine, vinorelbine, paclitaxel; retinoids: for example, alitretinoin, tretinoin, isotretinoin, bexarotene; glucocorticosteroids: Cytokines: e.g., interleukin-2, interleukin-11 (opplebekin), interferon alpha (IFN-α); estrogen receptor downregulators: fulvestrant; antiestrogens: e.g., tamoxifen, toremifene; selective estrogen receptor modulators (SERMs): e.g., raloxifene; luteinizing hormone-releasing hormone (LHRH) agonists: e.g., goserelin; progesterones: e.g., megestrol; cytotoxic agents: arsenic trioxide, asparaginase (L-asparaginase, also known as erwinia L-asparaginase); anti-nausea drugs: e.g., NK-1 receptor antagonists (e.g., casopitant); cytoprotective agents: e.g., 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, CD137, CD40, and LAG3. Immunotherapeutic agents that may act as immune checkpoint inhibitors useful in the methods of the present disclosure include, but are not limited to, inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFR beta.

[0211] In some embodiments, the one or more additional therapeutic agents are selected from the following agents: anti-CDK2 antibodies; cytotoxic agents; estrogen receptor targeted therapy or other endocrine therapy, immune checkpoint inhibitors, other CDK inhibitors, receptor tyrosine 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 references therein).

[0212] The structures of active compounds identified by code number, generic name, or trade name can be obtained from the current edition of the standard reference "The Merck Index," or from databases such as international patents (e.g., IMS World Publications).

[0213] The compounds described herein can also be used in combination with known therapeutic processes, 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 insufficient sensitivity to radiation therapy.

[0214] The compounds described herein can be administered alone or in combination with one or more other therapeutic compounds, possible combination therapy in the form of a fixed combination, or the administration of the compounds described herein, where one or more other therapeutic compounds are administered alternately or independently, or in the form of a fixed combination and one or more other therapeutic compounds. The compounds described herein can be administered in combination with, or in addition to, chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination thereof, particularly for tumor treatment. Long-term treatment is possible, as well as adjuvant therapy in conjunction with other treatment strategies, as described above. Other possible treatments include therapy to maintain the patient's condition after tumor regression, or even chemopreventive therapy, for example, for at-risk patients.

[0215] These additional agents can be administered separately from the compound-containing compositions provided as part of a multiple dose regimen. Alternatively, these agents can be part of a single dosage form, mixed together with the compounds described herein in a single composition. When administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a certain period of each other, usually within 5 hours of each other.

[0216] As used herein, the terms "combination," "combined," and related terms refer to simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, a compound described herein can be administered simultaneously with another therapeutic agent, or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present disclosure provides single unit dosage forms comprising a compound described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0217] The amounts of both the compounds described herein and the additional therapeutic agent (in compositions containing such additional therapeutic agents) that may be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. Preferably, the compositions described herein should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the compounds described herein can be administered.

[0218] In those compositions that include an additional therapeutic agent, the additional therapeutic agent and the compound described herein may act synergistically. Thus, the amount of additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, the additional therapeutic agent can be administered in a dosage of 0.01 to 1,000 μg / kg body weight / day.

[0219] The amount of additional therapeutic agent present in the compositions described herein will not exceed the amount that would normally be administered in a composition comprising that agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the invention will be in the range of about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0220] The compounds described herein or pharmaceutical compositions thereof can also be incorporated into compositions for coating implantable medical devices, such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents are used to overcome restenosis (re-narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of thrombus formation or platelet activation. These undesirable effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition containing a kinase inhibitor. The present disclosure also contemplates implantable devices coated with the compounds described herein.

[0221] Any of the compounds and / or compositions of the present disclosure may be provided in a kit comprising the compound and / or composition. Thus, in some embodiments, the compounds and / or compositions of the present disclosure are provided in a kit.

[0222] The present disclosure is further illustrated by the following non-limiting examples. [Example]

[0223] To facilitate a more complete understanding of the present disclosure, examples are provided herein. The following examples serve to illustrate exemplary 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 merely illustrative.

[0224] As shown in the examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. While the general methods illustrate the synthesis of specific compounds described herein, it will be understood that the following general methods, and other methods known to those of skill in the art, can be applied to other classes and subclasses and species of each of these compounds, as described herein. Additional compounds described herein were prepared in substantially similar manner to those herein in the examples and methods known to those of skill in the art.

[0225] In the description of synthetic methods set forth below, it should be understood that all reaction conditions (e.g., reaction solvents, atmospheres, temperatures, durations, and work-up procedures) are selected from standard conditions for the reaction unless otherwise indicated. In the general scheme, those skilled in the art of organic synthesis will understand that the functional groups present on various portions of the molecule must be compatible with the proposed reagents and reactions. Substituents that are incompatible with the reaction conditions will be apparent to those skilled in the art, and therefore alternative methods (e.g., use of protecting groups or alternative reactions) are indicated. Starting materials in the examples are commercially available or readily prepared from known materials by standard methods.

[0226] At least some of the compounds identified herein as "intermediates" are contemplated as compounds of the present disclosure.

[0227] Example 1 N-(1-methylcyclopropyl)-2-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetamide [ka] Methyl (Z)-3-(2-(tert-butoxy)-2-oxoethylidene)cyclopentane-1-carboxylate [ka] Step 1: To a mixture of tert-butyl 2-(diethoxyphosphoryl)acetate (35 g, 0.14 mol) in THF (100 mL) was added dropwise LiHMDS (140 mL, 0.14 mol) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 0 °C for 1 h, and then methyl 3-oxocyclopentane-1-carboxylate (10 g, 70 mmol) was added. The mixture was stirred at 25 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL), and the aqueous phase was extracted three times with ethyl acetate (100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by silica gel chromatography (20 g column; eluted with PE / EA; 8 / 1). Concentration in vacuo gave methyl (Z)-3-(2-(tert-butoxy)-2-oxoethylidene)cyclopentane-1-carboxylate (4.8 g, 28%) as a colorless oil. m / z (ES + ) [M+H] + = 241.10; HPLC tR = 1.227 min.

[0228] Methyl 3-(2-(tert-butoxy)-2-oxoethyl)cyclopentane-1-carboxylate [ka] Step 2: A stirred mixture of methyl (Z)-3-(2-(tert-butoxy)-2-oxoethylidene)cyclopentane-1-carboxylate (4.8 g, 20 mmol) and Pd / C (0.43 g, 4.0 mmol) in MeOH (50 mL) was treated with H2 at 25 °C for 2 h. The mixture was filtered through a Celite pad. The filtrate was concentrated in vacuo. Concentration in vacuo afforded methyl 3-(2-(tert-butoxy)-2-oxoethyl)cyclopentane-1-carboxylate (4.1 g, 85%) as a colorless oil. m / z (ES + ) [M+Na] + = 265.15; HPLC tR = 1.243 min.

[0229] tert-Butyl 2-(3-(2-cyanoacetyl)cyclopentyl)acetate [ka] Step 3: To a mixture of CHCN (1.4 g, 34 mmol) and methyl 3-(2-(tert-butoxy)-2-oxoethyl)cyclopentane-1-carboxylate (4.1 g, 17 mmol) in THF (40 mL) was added LiHMDS (25 mL, 25 mmol) dropwise at −78° C. under a nitrogen atmosphere. The mixture was gradually warmed to room temperature and stirred at room temperature for an additional 2 h. The reaction mixture was quenched with HO (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. tert-Butyl 2-(3-(2-cyanoacetyl)cyclopentyl)acetate (1.6 g, 38%) was isolated as a colorless oil. m / z (ES + ) [M+H] + = 252.10; HPLC tR = 0.982 min.

[0230] tert-Butyl 2-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)acetate [ka] Step 4: To a mixture of tert-butylhydrazine (0.88 g, 9.9 mmol) in EtOH (5 mL) was added NaOH (0.40 g, 9.9 mmol) in portions at 25 °C under a nitrogen atmosphere. After the mixture was stirred at 25 °C for 1 h, tert-butyl 2-(3-(2-cyanoacetyl)cyclopentyl)acetate (2.5 g, 9.9 mmol) was added. The mixture was stirred at 50 °C for 3 h. The reaction mixture was diluted with HO (50 mL) and 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 15 min; detector, UV 220 nm). Concentration in vacuo gave tert-butyl 2-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)acetate (2 g, 60%) as a colorless oil. m / z (ES + ) [M+H] + = 322.30; HPLC tR = 0.985 min.

[0231] tert-Butyl 2-(3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl)acetate [ka] Step 5: A round-bottom flask was charged with tert-butyl 2-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)acetate (2 g, 6 mmol), 2-(3-methylisoxazol-5-yl)acetic acid (1 g, 7 mmol), HATU (4 g, 9 mmol), DIEA (2 g, 0.02 mol), and DCM (20 mL). The solution was stirred at 25 °C for 1 h. The reaction mixture was diluted with HO (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 crude material obtained was purified by silica gel chromatography (eluted with DCM / MeOH = 20 / 1). Concentration in vacuo afforded tert-butyl 2-(3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl)acetate (800 mg, 30%) as a colorless oil. m / z (ES + ) [M+H] + = 445.35; HPLC tR = 1.243 min.

[0232] 2-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetic acid [ka] Step 6: A stirred mixture of tert-butyl 2-(3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl acetate (844 mg, 1.90 mmol) in FA (8 mL) was treated with N at 75 °C for 12 h. The resulting crude material was purified on C18 (acetonitrile / water). Lyophilization afforded 2-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetic acid (600 mg, 95.1%) as a yellow oil. m / z (ES + ) [M+H] + = 333.20; HPLC tR = 0.302 min.

[0233] N-(1-methylcyclopropyl)-2-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetamide [ka] Step 7: A resealable reaction vial was charged with 2-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetic acid (600 mg, 1.81 mmol), 1-methylcyclopropan-1-amine (642 mg, 9.03 mmol), HOBt (415 mg, 2.71 mmol), EDC (692 mg, 3.61 mmol), and a stir bar, then degassed and purged with nitrogen three times. DCM (10 mL) was added, and the mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with HO (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 crude material obtained was purified by silica gel chromatography (1 g column; eluted with DCM / MeOH; 20 / 1). Concentration in vacuo afforded N-(1-methylcyclopropyl)-2-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetamide (187 mg, 26.9%) as a colorless oil. m / z (ES + ) [M+H] + = 386.35; HPLC tR = 0.778 min.

[0234] N-(1-methylcyclopropyl)-2-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetamide [ka] Step 8: N-(1-methylcyclopropyl)-2-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetamide (400 mg, 1.04 mmol) was purified by preparative chiral HPLC (column: CHIRALPAK IG, 2 × 25 cm, 5 µm; mobile phase A: MtBE (0.1% TEA) - HPLC, mobile phase B: IPA:DCM = 1:1; flow rate: 20 mL / min; gradient: 40% B to 40% B in 19 min; wavelength: 220 / 254 nm; RT1 (min): 11.69; RT2 (min): 15.11; sample solvent: IPA:DCM = 1:1; injection volume: 0.3 mL; number of runs: 10). Lyophilization afforded N-(1-methylcyclopropyl)-2-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)acetamide (44 mg, 11%) as a white amorphous solid. m / z (ES + ) [M+H] + = 386.25; HPLC tR = 0.800 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.61 (s, 1H), 7.99 (s, 1H), 6.24 (d, J = 14.6 Hz, 2H), 3.83 (s, 2H), 3.02 (dq, J = 10.7, 8.4 Hz, 1H), 2.20 (s, 4H), 2.10 (dt, J = 13.5, 7.0 Hz, 1H), 2.06 - 1.92 (m, 3H), 1.77 (dq, J = 14.8, 7.7 Hz, 1H), 1.59 (dtd, J = 12.5, 9.3, 6.5 Hz, 1H), 1.31 (dtd, J = 12.9, 9.1, 5.9 Hz, 1H), 1.25 (s, 3H), 1.18 (dt, J = 12.3, 10.5 Hz, 1H), 0.59 - 0.52 (m, 2H), 0.52 - 0.44 (m, 2H).

[0235] Additional compounds prepared according to the method of Example 1 are shown in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0236] Example 2 rel-(1R,4S)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cycloheptyl(1-methylcyclopropyl)carbamate [ka] Methyl 4-((tert-butyldiphenylsilyl)oxy)cycloheptane-1-carboxylate [ka] Step 1: To a mixture of methyl 4-hydroxycycloheptane-1-carboxylate (1 g, 6 mmol) and 1H-imidazole (1 g, 0.02 mol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (2 g, 7 mmol) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 25 °C for 12 h. 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 crude product was purified by silica gel chromatography (eluted with PE / EA (ratio: 10 / 1)). Concentration in vacuo afforded methyl 4-((tert-butyldiphenylsilyl)oxy)cycloheptane-1-carboxylate (2 g, 5 mmol, 80%) as a yellow oil. m / z (ES + ) [M+H]+ = 411.20; HPLC tR = 1.527 min.

[0237] 3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-3-oxopropanenitrile [ka] Step 2: To a solution of methyl 4-((tert-butyldiphenylsilyl)oxy)cycloheptane-1-carboxylate (1.8 g, 4.4 mmol) and acetonitrile (0.36 g, 8.8 mmol) in THF (20 mL) was added lithium bis(trimethylsilyl)amide (0.81 g, 4.8 mmol) dropwise at −78° C. under a nitrogen atmosphere. The mixture was warmed to 25° C. and stirred for 1 h. The mixture was quenched with saturated NH4Cl. 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 crude product was purified by silica gel chromatography eluting with PE / EA (ratio: 30 / 1). Concentration in vacuo gave 3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-3-oxopropanenitrile (1.7 g, 4.1 mmol, 92%) as a yellow oil. m / z (ES + ) [M+H] + = 420.10; HPLC tR = 1.280 min.

[0238] 1-(tert-butyl)-3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-1H-pyrazol-5-amine [ka] Step 3: A round-bottom flask was charged with tert-butylhydrazine hydrochloride (0.76 g, 6.1 mmol), sodium hydroxide (0.24 g, 6.1 mmol), EtOH (18 mL), and a stir bar. The solution was stirred at 25 °C for 1 h. 3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-3-oxopropanenitrile (1.7 g, 4.1 mmol) was added, and the solution was stirred at 50 °C for 6 h. The mixture was quenched 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 70% gradient in 12 min; detector, UV 254 nm) to give 1-(tert-butyl)-3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-1H-pyrazol-5-amine (1.9 g, 3.9 mmol, 96%) as a yellow oil. m / z (ES + ) [M+H] + = 490.50; HPLC tR = 1.305 min.

[0239] N-(1-(tert-butyl)-3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 4: A round-bottom flask was charged with 1-(tert-butyl)-3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-1H-pyrazol-5-amine (1 g, 2 mmol), 2-(3-methylisoxazol-5-yl)acetic acid (0.3 g, 2 mmol), N-ethyl-N-isopropylpropan-2-amine (0.8 g, 6 mmol), EA (12 mL), and a stir bar. T3P (2 g, 50 wt%, 3 mmol) in EA was added, and the solution was stirred at 25 °C for 3 h. 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 80% to 100% gradient in 10 min; detector, UV 254 nm) to give N-(1-(tert-butyl)-3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (1.1 g, 1.8 mmol, 90%) as a yellow oil. m / z (ES + ) [M+H] + = 613.25; HPLC tR = 1.543 min.

[0240] N-(1-(tert-butyl)-3-(4-hydroxycycloheptyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 5: A round-bottom flask was charged with N-(1-(tert-butyl)-3-(4-((tert-butyldiphenylsilyl)oxy)cycloheptyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (1.1 g, 1.8 mmol) and a stir bar. 1N TBAF in THF (12 mL) was added and the solution was stirred at 75° C. for 16 h. The mixture was quenched with water (20 mL) and 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 70% gradient in 15 min; detector, UV 254 nm) to give N-(1-(tert-butyl)-3-(4-hydroxycycloheptyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (450 mg, 1.20 mmol, 67%) as a yellow oil. m / z (ES + ) [M+H] + = 375.15; HPLC tR = 0.860 min.

[0241] 4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cycloheptyl(1-methylcyclopropyl)carbamate [ka] Step 6: A round-bottom flask was charged with N-(1-(tert-butyl)-3-(4-hydroxycycloheptyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (790 mg, 2.11 mmol), 1-isocyanato-1-methylcyclopropane (6.8 mL, 0.62 M in toluene, 4.22 mmol), N-ethyl-N-isopropylpropan-2-amine (818 mg, 6.33 mmol), toluene (10 mL), and a stir bar. The solution was stirred at 110° C. for 20 hours. The mixture was concentrated in vacuo. The residue was purified by reverse-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 220 nm) to give 4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cycloheptyl(1-methylcyclopropyl)carbamate (800 mg, 1.70 mmol, 80.4%) as a yellow oil. m / z (ES + ) [M+H] + = 472.15; HPLC tR = 1.098 min.

[0242] 4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cycloheptyl(1-methylcyclopropyl)carbamate [ka] Step 7: A round-bottom flask was charged with 4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cycloheptyl(1-methylcyclopropyl)carbamate (870 mg, 1.84 mmol) and a stir bar. HCOOH (8 mL) was added, and the solution was stirred at 75 °C for 8 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 70% gradient in 15 min; detector, UV 220 nm) to afford 4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cycloheptyl(1-methylcyclopropyl)carbamate (650 mg, 1.56 mmol, 84.8%) as a yellow amorphous solid. m / z (ES + ) [M+H] + = 416.40; HPLC tR = 0.926 min

[0243] rel-(1R,4S)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cycloheptyl(1-methylcyclopropyl)carbamate [ka] Step 8: 4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cycloheptyl(1-methylcyclopropyl)carbamate (650 mg, 1.56 mmol) was purified by preparative chiral HPLC (Column: CHIRALPAK IF, 2 × 25 cm, 5 µm; Mobile phase A: Hex (0.2% TEA)-HPLC; Mobile phase B: MeOH:DCM = 1:1; Flow rate: 20 mL / min; Gradient: 60% B to 60% B in 21 min; Wavelength: 220 / 254 nm; RT1 (min): 7.33; RT2 (min): 13.51; Sample solvent: MeOH:DCM = 1:1; Injection volume: 0.3 mL; Number of runs: 9). Lyophilization afforded rel-(1R,4S)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cycloheptyl(1-methylcyclopropyl)carbamate (31.1 mg, 74.9 μmol, 4.78%) as a white amorphous solid. m / z (ES + ) [M+H] + = 416.35; HPLC tR = 0.909 min. 1 H NMR (400 MHz, DMSO-d6) δ 12.06 (s, 1H), 10.62 (s, 1H), 7.32 (s, 1H), 6.27 (s, 1H), 6.22 (s, 1H), 4.74 (s, 1H), 3.83 (s, 2H), 2.97-2.66 (m, 1H), 2.21 (s, 3H), 1.94 (d, J = 7.4 Hz, 2H), 1.77 (s, 5H), 1.58 (d, J = 11.2 Hz, 2H), 1.39 (s, 1H), 1.24 (s, 3H), 0.59 (s, 2H), 0.47 (s, 2H).

[0244] Additional compounds prepared according to the method of Example 2 are shown in Table 3 below. [Table 3-1] [Table 3-2]

[0245] Example 3 (1R,3S)-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] [ka] Methyl 3-((tert-butyldiphenylsilyl)oxy)cyclopentane-1-carboxylate [ka] Step 1: To an ice-cold solution of methyl 3-hydroxycyclopentane-1-carboxylate (3.5 g, 24 mmol) and EtN (7.4 g, 10 mL, 73 mmol) in DMF (40 mL) was added TBDPS-Cl (10 g, 36 mmol), and the resulting mixture was stirred at room temperature overnight. The resulting mixture was diluted with EA (100 mL) and washed with brine (3 × 80 mL). The organic layer was dried over NaSO and concentrated in vacuo. The residue was purified by silica gel chromatography (eluted with 0–15% EA in petroleum ether) to give methyl 3-((tert-butyldiphenylsilyl)oxy)cyclopentane-1-carboxylate (8.8 g, 23 mmol, 95%) as a light solid. m / z (ES + ) [M+H] + = 383.15; HPLC tR = 1.425 min. Methyl 3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentane-1-carboxylate [ka]

[0246] Step 2: To a solution of methyl 3-((tert-butyldiphenylsilyl)oxy)cyclopentane-1-carboxylate (8.8 g, 23 mmol) in THF (100 mL) at −78° C. was added LDA solution (13.7 mL, 2 M in THF, 27.6 mmol). The resulting mixture was stirred at −78° C. for 0.5 h, and then MeI (16 g, 0.12 mol) was added to the above mixture at −78° C. After stirring for an additional 1 h, the reaction mixture was allowed to warm to room temperature. The resulting mixture was quenched with NH4Cl (sat. aq. 150 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 0-15% EA in petroleum ether) to give methyl 3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentane-1-carboxylate (8.5 g, 21 mmol, 93%) as a light oil. + ) [M+H] + = 397.20; HPLC tR = 1.507 min.

[0247] 3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-3-oxopropanenitrile [ka] Step 3: To a solution of methyl 3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentane-1-carboxylate (8.5 g, 21 mmol) and MeCN (1.1 g, 26 mmol) in THF (80 mL) was added LiHMDS (21 mL, 1 M in THF, 21 mmol) dropwise, slowly enough to maintain the internal temperature below −60° C. After stirring at −70° C. for 1 h, the reaction was quenched with saturated NH4Cl (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give 3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-3-oxopropanenitrile (8 g, 0.02 mol, 90%) as a light oil. m / z (ES + ) [M+H] + = 406; HPLC tR = 1.507 min.

[0248] 1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-1H-pyrazol-5-amine [ka] Step 4: Sodium hydroxide (0.2 g, 5 mmol) was added in portions to a suspension of tert-butylhydrazine hydrochloride (0.8 g, 6 mmol) in EtOH (0.5 mL) at room temperature and stirred for 1 hour at room temperature. An ethanol solution of 3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-3-oxopropanenitrile (2 g, 5 mmol) was added at room temperature, and the mixture was then heated to 50° C. and stirred overnight. The reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 15 min; detector, UV 220 nm) to give 1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-1H-pyrazol-5-amine (0.95 g, 2.0 mmol, 40%) as a white solid. m / z (ES + ) [M+H] + = 476.40; HPLC tR = 1.287 min.

[0249] N-(1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 5: To a cooled mixture of 1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-1H-pyrazol-5-amine (0.95 g, 2.0 mmol), 2-(3-methylisoxazol-5-yl)acetic acid (0.34 g, 2.4 mmol), and DIEA (0.77 g, 6.0 mmol) in DCM (10 mL), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (3.8 g, 50 wt% solution in ethyl acetate, 6.0 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with saturated aqueous NaCO (10 mL) and extracted with DCM (2 × 10 mL). The organic layer was washed with Na2CO3 (2 × 10 mL), brine (30 mL), and concentrated. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% over 15 min; detector, UV 220 nm). This afforded N-(1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (1.05 g, 1.75 mmol, 88%) as a white solid. m / z (ES + ) [M+H] + = 599.50; HPLC tR = 1.608 min.

[0250] N-(1-(tert-butyl)-3-(3-hydroxy-1-methylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 6: A mixture of N-(1-(tert-butyl)-3-(3-((tert-butyldiphenylsilyl)oxy)-1-methylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (1.05 g, 1.75 mmol) and TBAF (15 mL, 1 M in THF, 15 mmol) was stirred at 75° C. for 6 h. The reaction mixture was cooled to room temperature, diluted with water (10 mL), and extracted with EA (3×150 mL). The combined organic layers were washed with brine (2×100 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 40 min; detector, UV 220 nm) to give N-(1-(tert-butyl)-3-(3-hydroxy-1-methylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (450 mg, 1.25 mmol, 71.2%) as a white solid. m / z (ES + ) [M+H] + = 361.25; HPLC tR = 0.817 min.

[0251] 3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-3-methylcyclopentyl(1-methylcyclopropyl)carbamate [ka] Step 7: To a stirred mixture of N-(1-(tert-butyl)-3-(3-hydroxy-1-methylcyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide (450 mg, 1.25 mmol) and 1-isocyanato-1-methylcyclopropane (0.6 M in toluene) (6 mL, 4 mmol) was added dropwise DIEA (484 mg, 3.75 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by reverse-phase flash to give 3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-3-methylcyclopentyl(1-methylcyclopropyl)carbamate (480 mg, 1.05 mmol, 84.0%) as a pale yellow oil. m / z (ES + ) [M+H] + = 458.40; HPLC tR = 1.170 min.

[0252] 3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] Step 8: A solution of 3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-3-methylcyclopentyl(1-methylcyclopropyl)carbamate (480 mg, 1.05 mmol) in FA (3 mL) was stirred at 70 °C for 4 h. The resulting mixture was concentrated to dryness and purified by reverse-phase flash to give 3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (360 mg, 897 μmol, 85.5%) as a white solid. m / z (ES + ) [M+H] += 402.20; HPLC tR = 0.880 min.

[0253] cis-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate and trans-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] Step 9: 3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (360 mg, 897 μmol) was separated 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 + 0.1% NH3 HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 42% B, 42% B in 8 min; Wavelength: 220 nm; RT1 (min): 6.97 / 7.93; Number of runs: 3) to obtain cis-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H trans-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (60 mg, 0.15 mmol, 17%) as a white solid, and trans-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (220 mg, 548 μmol, 61.1%) as a white solid.

[0254] cis:m / z (ES + ) [M+H] + = 402.35; HPLC tR = 0.854 min.

[0255] trans:m / z (ES+ ) [M+H] + = 402.40; HPLC tR = 0.894 min. (1R,3S)-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] Step 10: cis-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (100 mg, 249 μmol) was purified by preparative chiral HPLC (using the following conditions: column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.2% TEA)-HPLC, mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 70% B to 70% B in 15 min; wavelength: 220 / 254 nm; RT (min): 5.33; sample solvent: EtOH:DCM = 1:1-HPLC; injection volume: 0.9 mL; number of runs: 3). This gave (1R,3S)-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (34 mg, 85 μmol, 34%) as a white amorphous solid. m / z (ES + ) [M+H] + = 402.35; HPLC tR = 0.861 min. 1H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.61 (s, 1H), 7.16 (d, J = 103.7 Hz, 1H), 6.26 (d, J = 28.0 Hz, 2H), 5.05 (s, 1H), 3.83 (s, 2H), 2.20 (s, 3H), 2.18 - 2.04 (m, 2H), 1.99 (s, 1H), 1.85 (d, J = 14.0 Hz, 1H), 1.69 (s, 2H), 1.23 (d, J = 8.9 Hz, 6H), 0.58 (s, 2H), 0.45 (s, 2H).

[0256] (1R,3R)-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] trans-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (220 mg, 548 μmol) was purified by preparative chiral HPLC (using the following conditions: column: CHIRALPAK IH, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.2% TEA)-HPLC, mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 8 min; wavelength: 220 / 254 nm; RT (min): 5.03; sample solvent: EtOH:DCM = 1:1-HPLC; injection volume: 0.4 mL; number of runs: 6). This gave (1R,3R)-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (81.3 mg, 203 μmol, 37.0%) as a white amorphous solid.

[0257] m / z (ES + ) [M+H] += 402.35; HPLC tR = 0.900 min.

[0258] 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.63 (s, 1H), 7.23 (d, J = 88.4 Hz, 1H), 6.26 (d, J = 27.4 Hz, 2H), 5.02 (d, J = 41.5 Hz, 1H), 3.83 (s, 2H), 2.39 - 2.25 (m, 1H), 2.21 (s, 3H), 2.10 - 1.97 (m, 1H), 1.91 (d, J = 6.5 Hz, 1H), 1.72 (d, J = 44.1 Hz, 3H), 1.35 (s, 3H), 1.24 (s, 3H), 0.61 (d, J = 6.1 Hz, 2H), 0.48 (d, J = 5.2 Hz, 2H).

[0259] (1S,3R)-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] cis-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (100 mg, 249 μmol) was purified by preparative chiral HPLC (using the following conditions: column: CHIRALPAK IG, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.2% TEA)-HPLC, mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 70% B to 70% B in 15 min; wavelength: 220 / 254 nm; RT (min): 10.65; sample solvent: EtOH:DCM = 1:1-HPLC; injection volume: 0.9 mL; number of runs: 3). This gave (1S,3R)-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (34 mg, 85 μmol, 34%) as a white amorphous solid.

[0260] m / z (ES + ) [M+H] + = 402.35; HPLC tR = 0.865 min.

[0261] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.62 (s, 1H), 7.29 (s, 1H), 6.26 (d, J = 26.7 Hz, 2H), 5.05 (s, 1H), 3.83 (s, 2H), 2.20 (s, 3H), 2.16 - 2.03 (m, 2H), 1.98 (s, 1H), 1.86 (s, 1H), 1.73 - 1.59 (m, 2H), 1.23 (d, J = 8.7 Hz, 6H), 0.51 (d, J = 49.6 Hz, 4H).

[0262] (1S,3S)-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] trans-3-Methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (220 mg, 548 μmol) was purified by preparative chiral HPLC (using the following conditions: column: CHIRALPAK IH, 2 × 25 cm, 5 μm; mobile phase A: Hex (0.2% TEA)-HPLC; mobile phase B: EtOH:DCM = 1:1-HPLC; flow rate: 20 mL / min; gradient: 30% B to 30% B in 8 min; wavelength: 220 / 254 nm; RT (min): 7.26; sample solvent: EtOH:DCM = 1:1-HPLC; injection volume: 0.4 mL; number of runs: 6). This gave (1S,3S)-3-methyl-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate (86.8 mg, 216 μmol, 39.5%) as a white amorphous solid.

[0263] m / z (ES + ) [M+H] + = 402.35; HPLC tR = 0.898 min.

[0264] 1 H NMR (400 MHz, DMSO-d6) δ 12.12 (s, 1H), 10.63 (s, 1H), 7.34 (s, 1H), 6.26 (d, J = 27.2 Hz, 2H), 5.02 (d, J = 42.9 Hz, 1H), 3.83 (s, 2H), 2.42 - 2.25 (m, 1H), 2.21 (s, 3H), 2.01 (s, 1H), 1.92 (t, J = 9.4 Hz, 1H), 1.72 (d, J = 46.0 Hz, 3H), 1.35 (s, 3H), 1.24 (s, 3H), 0.60 (s, 2H), 0.48 (s, 2H).

[0265] Additional compounds prepared according to the method of Example 3 are shown in Table 4 below. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0266] Example 4 3-Fluoro-4-isopropylpyridazine [ka] 4-(Prop-1-en-2-yl)pyridazin-3(2H)-one [ka] Step 1: A round-bottom flask containing 6-chloropyridazin-3(2H)-one (10 g, 1 Eq, 77 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (23 g, 1.8 Eq, 0.14 mol), potassium carbonate (32 g, 3 Eq, 0.23 mol), dioxane / HO (20 mL), and a stir bar was degassed and purged with nitrogen three times, and Pd(dppf)Cl (2.8 g, 0.05 Eq, 3.8 mmol) was added. The mixture was stirred at 100 °C for 2 h. The solution was concentrated. The crude material was purified by flash chromatography (acetonitrile / water). Lyophilization gave 4-(prop-1-en-2-yl)pyridazin-3-ol (4.0 g, 31%) as a white amorphous solid.

[0267] 4-Isopropylpyridazin-3(2H)-one [ka] Step 2: A round-bottom flask was charged with 4-(prop-1-en-2-yl)pyridazin-3-ol (4 g, 1 eq, 0.03 mol), Pd / C (0.5 g), MeOH (20 mL), and a stir bar, then degassed and purged with hydrogen three times. The mixture was stirred at 25 °C for 2 h. The mixture was filtered, and the filtrate was concentrated to give 4-isopropylpyridazin-3(2H)-one (3.7 g, 91%) as a yellow oil.

[0268] 3-chloro-4-isopropylpyridazine [ka] Step 3: A round-bottom flask was charged with 4-isopropylpyridazin-3-ol (3.7 g, 1 eq, 27 mmol), POCl3 (15 mL), and a stirring bar, and the solution was stirred at 85 °C for 4 h. The reaction mixture was poured into ice water. The solution was extracted three times with EA. The combined organic phases were concentrated. The crude material obtained was purified by flash chromatography (acetonitrile / water). Lyophilization afforded 3-chloro-4-isopropylpyridazine (3.8 g, 24 mmol, 91%) as a black oil.

[0269] 3-Fluoro-4-isopropylpyridazine [ka] Step 4: A solution of 3-chloro-4-isopropylpyridazine (1.9 g, 12.1 mmol, 1 eq), CsF (12.8 g, 84.7 mmol, 7 eq), and 4A molecular sieves (1 g) in DMSO (25 mL) was stirred at 100 °C for 16 h. The solution was filtered. The solution was purified by flash (MeCN / HO) to give 3-fluoro-4-isopropylpyridazine (410 mg, 24%) as a black oil.

[0270] Example 5 4-Cyclopropylisothiazol-3-ol [ka] 3-(benzyloxy)isothiazole [ka] Step 1: To a mixture of isothiazol-3(2H)-one (5 g, 0.05 mol) in DMF (50 mL) was added potassium carbonate (13.66 g, 0.1 mol) and (bromomethyl)benzene (10.09 g, 0.06 mol) in portions at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 4 h. 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 three times with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (10 g column; eluted with PE / EA; ratio: 30 / 1). Concentration in vacuo afforded 3-(benzyloxy)isothiazole (5.5 g, 29 mmol, 60%) as a clear oil.

[0271] 3-(benzyloxy)-4-bromoisothiazole [ka] Step 2: A round-bottom flask was charged with 3-(benzyloxy)isothiazole (5.5 g, 29 mmol), 1-bromopyrrolidine-2,5-dione (5.6 g, 32 mmol), MeCN (60 mL), and a stir bar. The solution was stirred at 25 °C for 2 days. The mixture was quenched 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 crude product was purified by silica gel chromatography (15 g column; eluted with PE / EA; ratio: 50 / 1). Concentration in vacuo afforded 3-(benzyloxy)-4-bromoisothiazole (6 g, 0.02 mol, 80%) as a clear oil.

[0272] 3-(benzyloxy)-4-cyclopropylisothiazole [ka] Step 3: A resealable reaction vial was charged with 3-(benzyloxy)-4-bromoisothiazole (200 mg, 740 μmol), cyclopropylboronic acid (636 mg, 7.40 mmol), PdCl(dppf) (54.2 mg, 74.0 μmol), CsCO (482 mg, 1.48 mmol), 1,4-dioxane / HO (4 mL, 4 / 1), and a stir bar, then degassed and purged with nitrogen three times. The mixture was stirred at 100 °C for 12 h. The 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 20% to 100% in 20 min; detector, UV 254 nm) to give 3-(benzyloxy)-4-cyclopropylisothiazole (130 mg, 562 μmol, 75.9%) as a brown oil.

[0273] 4-Cyclopropylisothiazol-3-ol [ka] Step 4: A round-bottom flask was charged with 3-(benzyloxy)-4-cyclopropylisothiazol (600 mg, 2.59 mmol) and a stir bar. Concentrated HCl (6 mL) was added, and the solution was stirred at 50 °C for 5 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 30% gradient in 10 min; detector, UV 254 nm) to afford 4-cyclopropylisothiazol-3-ol (280 mg, 1.98 mmol, 76.5%) as a yellow amorphous solid.

[0274] Example 6 (1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate and (1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] trans-(1R,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentan-1-ol [ka] Step 1: To a mixture of cyclopentane-1,3-diol (1 g, 0.01 mol) and imidazole (0.8 g, 0.01 mol) in DMF (50 mL) was added TBDPSCl (2 g, 9 mmol) in portions at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with HO (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 material obtained was purified by silica gel chromatography (1 g column; eluted with PE / EA 4 / 1). Concentration in vacuo afforded trans-3-((tert-butyldiphenylsilyl)oxy)cyclopentan-1-ol (262 mg, 8%) as a white solid.

[0275] m / z (ES + ) [M+Na] + = 364.05; HPLC tR = 1.373 min.

[0276] trans-(1R,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl methanesulfonate [ka] Step 2: To a mixture of trans-3-((tert-butyldiphenylsilyl)oxy)cyclopentan-1-ol (120 mg, 352 μmol) and EtN (107 mg, 1.06 mmol) in DCM (3 mL) was added MsCl (63.4 mg, 423 μmol) dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with HO (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, trans-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl methanesulfonate (130 mg, 88.1%), was isolated as a colorless oil.

[0277] m / z (ES + ) [M+H] + = 419.05; HPLC tR = 1.332 min.

[0278] 1-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-3-nitro-1H-1,2,4-triazole [ka] Step 3: To a mixture of 3-nitro-1H-1,2,4-triazole (88 mg, 0.77 mmol) and trans-3-((tert-butyldiphenylsilyl)oxy)cyclopentan-1-ol (0.22 g, 0.64 mmol) in DMF (5 mL) was added CsCO (0.63 g, 1.9 mmol) in portions at 25 °C under a nitrogen atmosphere. The mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with HO (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 material obtained was purified by silica gel chromatography (1 g column; eluted with PE / EA = 4 / 1). Concentration in vacuo gave 1-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-3-nitro-1H-1,2,4-triazole (16 mg, 5.7%) as a colorless oil.

[0279] m / z (ES + ) [M+H] + = 437.30; HPLC tR = 1.468 min.

[0280] 1-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-1,2,4-triazol-3-amine [ka] Step 4: A stirred mixture of 1-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-3-nitro-1H-1,2,4-triazole (745 mg, 1.71 mmol) and Pd / C (182 mg) in THF (1 mL) was treated with H at 25° C. for 2 hours. The solid was filtered off. The filtrate was concentrated in vacuo to give 1-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-1,2,4-triazol-3-amine (625 mg, 90.1%) as a colorless oil.

[0281] m / z (ES + ) [M+H] + = 407.35; HPLC tR = 1.348 min.

[0282] N-(1-((1S,3R)-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-1,2,4-triazol-3-yl)-2-(3-methylisoxazol-5-yl))acetamide [ka] Step 5: To a mixture of 1-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-1,2,4-triazol-3-amine (780 mg, 1.92 mmol), DIEA (744 mg, 5.75 mmol), and 2-(3-methylisoxazol-5-yl)acetic acid (325 mg, 2.30 mmol) in EA (10 mL) was added T3P (1.83 g, 5.75 mmol) dropwise at 0 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 30 min. The reaction mixture was diluted with HO (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 (3 g column; eluted with DCM / MeOH; ratio: 20 / 1). Concentration in vacuo gave N-(1-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-1,2,4-triazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (900 mg, 88.6%) as a yellowish solid.

[0283] m / z (ES + ) [M+H] + = 530.04; HPLC tR = 1.436 min.

[0284] N-(1-((1S,3R)-3-hydroxycyclopentyl)-1H-1,2,4-triazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 6: A resealable reaction vial was charged with N-(1-(cis-3-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-1H-1,2,4-triazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (460 mg, 868 μmol), TBAF (454 mg, 1.74 mmol), THF (5 mL), and a stir bar. The mixture was then degassed and purged with nitrogen three times, and stirred at 70 °C for 2 h. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm). Concentration in vacuo gave N-(1-((cis-3-hydroxycyclopentyl)-1H-1,2,4-triazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (80 mg, 32%) as a colorless oil.

[0285] m / z (ES + ) [M+H] + = 292.15; HPLC tR = 0.743 min.

[0286] (1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] Step 7: A resealable reaction vial was charged with N-(1-(cis-3-hydroxycyclopentyl)-1H-1,2,4-triazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (400 mg, 1.37 mmol), 1-isocyanato-1-methylcyclopropane (533 mg, 5.49 mmol), DIEA (710 mg, 5.49 mmol), toluene (10 mL), and a stir bar. The mixture was then degassed and purged with nitrogen three times, and the mixture was stirred at 110 °C for 12 h. The reaction mixture was diluted with HO (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 material was purified by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm column; mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10% B to 35% B, 35% B in 8 min; wavelength: 220 nm; RT1 (min): 7.32). Lyophilization afforded cis-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate (100 mg, 18.7%) as a white solid.

[0287] (1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate and (1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate [ka] Step 8: cis-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate (150 mg, 386 μmol) was purified by preparative chiral HPLC (column: DZ-CHIRALPAK IG-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: Hex (0.2% IPAmine): (EtOH:DCM = 1:1) = 60:40; flow rate: 1 mL / min; injection volume: 5 μL mL). Lyophilization gave (1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate (38.8 mg, 25.9%) as a white solid.

[0288] m / z (ES + ) [M+H] + = 389.15; HPLC tR = 1.082 min.

[0289] 1 H NMR (400 MHz, DMSO-d6) δ 10.68 (s, 1H), 8.41 (s, 1H), 7.41 (s, 1H), 6.24 (s, 1H), 4.99 (s, 1H), 4.76 - 4.68 (m, 1H), 3.87 (s, 2H), 2.60 - 2.52 (m, 1H), 2.08 (d, J = 24.8 Hz, 3H), 2.03 - 1.89 (m, 4H), 1.81 (s, 1H), 1.23 (s, 2H), 0.59 (s, 2H), 0.47 (s, 2H).

[0290] cis-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate (150 mg, 386 μmol) was purified by preparative chiral HPLC (column: DZ-CHIRALPAK IG-3, 4.6 × 50 mm, 3.0 μm; mobile phase A: Hex (0.2% IPAmine): (EtOH:DCM = 1:1) = 60:40; flow rate: 1 mL / min; injection volume: 5 μL mL). Lyophilization gave (1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-1,2,4-triazol-1-yl)cyclopentyl(1-methylcyclopropyl)carbamate (35.1 mg, 90.4 μmol, 23.4%) as a white solid. m / z (ES + ) [M+H] + = 389.15; HPLC tR = 1.082 min.

[0291] 1 H NMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 8.41 (s, 1H), 7.41 (s, 1H), 6.24 (s, 1H), 4.99 (s, 1H), 4.71 (q, J = 7.6 Hz, 1H), 3.87 (s, 2H), 2.60 - 2.52 (m, 1H), 2.21 (s, 3H), 2.11 (s, 1H), 1.95 (s, 2H), 1.80 (s, 1H), 1.23 (s, 3H), 0.59 (s, 2H), 0.47 (s, 2H).

[0292] Example 7 (1s,4s)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide and (1r,4r)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide [ka] Methyl (1s,4s)-4-(isopropylcarbamoyl)cyclohexane-1-carboxylate [ka] Step 1: To a stirred solution of (1s,4s)-4-(methoxycarbonyl)cyclohexane-1-carboxylic acid (3 g, 0.02 mol) and propan-2-amine (1 g, 0.02 mol) in ethyl acetate (20 mol), DIEA (6 g, 0.05 mol) and T3P (12 g, 50 wt% in ethyl acetate, 0.02 mmol) were added. The reaction was stirred at room temperature for 1 h. LCMS showed the reaction was complete. The mixture was concentrated and recrystallized from PE / EA = 1:8. This gave methyl (1s,4s)-4-(isopropylcarbamoyl)cyclohexane-1-carboxylate (3.24 g, 14.3 mmol, 90%) as a white solid.

[0293] m / z (ES + ) [M+H] + = 228.20; HPLC tR = 0.918 min.

[0294] (1s,4s)-4-(2-cyanoacetyl)-N-isopropylcyclohexane-1-carboxamide [ka] Step 2: To a solution of methyl (1s,4s)-4-(isopropylcarbamoyl)cyclohexane-1-carboxylate (2.2 g, 9.7 mmol) and acetonitrile (0.60 g, 15 mmol) in THF (20 mL) was added LiHMDS (21 mL, 1 M in THF, 21 mmol) dropwise under a nitrogen atmosphere at −78° C. The mixture was warmed to 25° C. and stirred for 4 h. The mixture was quenched with saturated NH4Cl. 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 70% gradient in 15 min; detector, UV 254 nm) to give (1s,4s)-4-(2-cyanoacetyl)-N-isopropylcyclohexane-1-carboxamide (1.75 g, 7.41 mmol, 77%) as an off-white amorphous solid.

[0295] m / z (ES + ) [M+H] + = 237.20; HPLC tR = 0.739 min.

[0296] (1s,4s)-4-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)-N-isopropylcyclohexane-1-carboxamide [ka] Step 3: Sodium hydroxide (439 mg, 11.0 mmol) was added in portions to a suspension of tert-butylhydrazine hydrochloride (1.37 g, 11.0 mmol) in EtOH (14 mL) at room temperature and stirred at room temperature for 1 hour. An ethanolic solution of (1s,4s)-4-(2-cyanoacetyl)-N-isopropylcyclohexane-1-carboxamide (1.73 g, 7.32 mmol) was added at room temperature, and the mixture was then heated to an internal temperature of 50 °C and stirred overnight. The mixture was quenched 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 15 min; detector, UV 254 nm) to give (1s,4s)-4-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)-N-isopropylcyclohexane-1-carboxamide (1.3 g, 4.2 mmol, 58%) as a white amorphous solid.

[0297] m / z (ES + ) [M+H] + = 307.25; HPLC tR = 0.788 min.

[0298] (1s,4s)-4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)-N-isopropylcyclohexane-1-carboxamide [ka] Step 4: To a mixture of (1s,4s)-4-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)-N-isopropylcyclohexane-1-carboxamide (1.4 g, 4.6 mmol), 2-(3-methylisoxazol-5-yl)acetic acid (0.97 g, 6.9 mmol), and DIEA (1.8 g, 2.4 mL, 14 mmol) in EA (15 mL) was added dropwise phosphane-t3 in EA (4.4 g, 50 wt% in EA, 6.9 mmol) at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 2 h. The mixture was quenched 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 reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 80% gradient in 20 min; detector, UV 220 nm) to give (1s,4s)-4-(1-(tert-butyl)-3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)-N-isopropylcyclohexane-1-carboxamide (1.8 g, 4.2 mmol, 92%) as a yellow amorphous solid.

[0299] m / z (ES + ) [M+H] + = 430.45; HPLC tR = 0.955 min.

[0300] (1s,4s)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide [ka] Step 5: A round-bottom flask was charged with (1s,4s)-4-(1-(tert-butyl)-3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)-N-isopropylcyclohexane-1-carboxamide (200 mg, 466 μmol) and a stir bar. HCOOH (3 mL) was added and the solution was stirred at 75° C. for 12 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 60% gradient in 15 min; detector, UV 254 nm) to give (1s,4s)-N-isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide (120 mg, 321 μmol, 69.0%) as a white amorphous solid.

[0301] m / z (ES + ) [M+H] + = 374.10; HPLC tR = 0.646 min.

[0302] (1s,4s)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide and (1r,4r)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide [ka] (1s,4s)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide (120 mg, 321 μmol) was purified by preparative chiral HPLC (Column: CHIRAL ART Amylose-SA, 2 × 25 cm, 5 μm; Mobile phase A: MtBE (0.1% DEA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 21 min; Wavelength: 220 / 254 nm; RT (min): 5.48; Sample solvent: EtOH-HPLC; Injection volume: 1 mL; Number of runs: 4). Lyophilization gave (1s,4s)-N-isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide (64.3 mg, 172 μmol, 53.6%) as a white amorphous solid.

[0303] m / z (ES + ) [M+H] + = 374.10; HPLC tR = 0.658 min.

[0304] 1 H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 10.63 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 6.30 (s, 1H), 6.23 (s, 1H), 3.91-3.72 (m, 3H), 2.82 (s, 1H), 2.20 (s, 4H), 1.93 (d, J = 15.1 Hz, 2H), 1.65 (t, J = 9.0 Hz, 4H), 1.49 (q, J = 6.4, 4.2 Hz, 2H), 1.01 (d, J = 6.6 Hz, 6H).

[0305] [ka] (1r,4r)-N-Isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide (120 mg, 321 μmol) was purified by preparative chiral HPLC (Column: CHIRAL ART Amylose-SA, 2 × 25 cm, 5 μm; Mobile phase A: MtBE (0.1% DEA)-HPLC, Mobile phase B: EtOH-HPLC; Flow rate: 20 mL / min; Gradient: 50% B to 50% B in 21 min; Wavelength: 220 / 254 nm; RT (min): 11.01; Sample solvent: EtOH-HPLC; Injection volume: 1 mL; Number of runs: 4). Lyophilization gave (1r,4r)-N-isopropyl-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexane-1-carboxamide (19.9 mg, 53.3 μmol, 16.6%) as a white amorphous solid.

[0306] m / z (ES + ) [M+H] + = 374.15; HPLC tR = 0.647 min.

[0307] 1 H NMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.61 (s, 1H), 7.58 (d, J = 7.7 Hz, 1H), 6.24 (d, J = 11.9 Hz, 2H), 3.90-3.70 (m, 3H), 2.61-2.52 (m, 1H), 2.20 (s, 3H), 2.07 (tt, J = 11.7, 3.4 Hz, 1H), 1.96 (dd, J = 13.2, 3.5 Hz, 2H), 1.76 (dd, J = 13.5, 3.5 Hz, 2H), 1.46 (qd, J = 12.7, 2.9 Hz, 2H), 1.38-1.22 (m, 2H), 1.03 (d, J = 6.6 Hz, 6H).

[0308] Example 8 (1s,4s)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexyl isopropylcarbamate [ka] Methyl (1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylate [ka] Step 1: To a stirred solution of methyl (1s,4s)-4-hydroxycyclohexane-1-carboxylate (5 g, 0.03 mol) in DMF (25 mL) at 0 °C, imidazole (6 g, 0.09 mol) and TBDPS-Cl (0.01 kg, 0.04 mol) were added. The reaction was stirred at room temperature overnight. The resulting solution was diluted with 30 mL of water and then extracted with ethyl acetate (3 × 40 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether) to afford methyl (1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylate (10.59 g, 26.70 mmol, 80%) as a colorless oil. m / z (ES + ) [M+H] + = 397.30; HPLC tR = 1.595 min.

[0309] 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile [ka] Step 2: To a stirred solution of methyl (1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexane-1-carboxylate (5 g, 0.01 mol) in tetrahydrofuran (15 mL) was added acetonitrile (1.0 g, 25 mmol). To the mixture was added dropwise LiHMDS (25 mL of a 1 M solution in THF, 0.03 mol) under N at −70° C. The reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate (3×40 mL). The organic layers were combined, washed with brine, dried, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate / (5 / 1)) to give 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile (4.6 g, 11 mmol, 90%) as a yellow oil.

[0310] m / z (ES + ) [M+H] + = 406.10 ; HPLC tR = 1.386 min.

[0311] 1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-amine [ka] Step 3: A solution of tert-butylhydrazine hydrochloride (2.1 g, 17 mmol) and NaOH (0.67 g, 17 mmol) in ethanol (25 mL) was stirred for 1 h, then 3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-3-oxopropanenitrile (4.5 g, 11 mmol) was added. The reaction was stirred at 50° C. overnight. The solid was filtered off. The filtrate was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 95% gradient over 10 min; detector, UV 220 nm) to give 1-(tert-butyl)-5-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-3-amine (2.5 g, 5.3 mmol, 47%) as a yellow oil.

[0312] m / z (ES + ) [M+H] + = 476.35; HPLC tR = 1.234 min.

[0313] N-(1-(tert-butyl)-3-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5)-yl)acetamide [ka] Step 4: To a stirred solution of 1-(tert-butyl)-5-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-3-amine (1.9 g, 1 eq, 4.0 mmol) and 2-(3-methylisoxazol-5-yl)acetic acid (0.85 g, 1.5 eq, 6.0 mmol) in ethyl acetate (15 mL), DIEA (1.5 g, 2.1 mL, 3 eq, 12 mmol) and propanephosphonic cyclic anhydride / EA (3.8 g, 50 wt%, 6.0 mmol) were added. The reaction was stirred at room temperature for 2 h. LCMS indicated the reaction was complete. The mixture was concentrated and purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 95% to 100% gradient in 10 min; detector, UV 220 nm). This gave N-(1-(tert-butyl)-5-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (2.043 g, 3.411 mmol, 85%) as a yellow oil.

[0314] m / z (ES + ) [M+H] + = 599.55; HPLC tR = 1.596 min.

[0315] N-(1-(tert-butyl)-3-((1s,4s)-4-hydroxycyclohexyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 5: To a stirred solution of N-(1-(tert-butyl)-5-((1s,4s)-4-((tert-butyldiphenylsilyl)oxy)cyclohexyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (1.9 g, 3.2 mmol) in THF (15 mL) was added 1 M TBAF in THF (19 mL). The reaction was stirred at 75° C. for 18 hours. The resulting mixture was washed with water and extracted with ethyl acetate. The organic layers were combined, dried, and concentrated in vacuo. The mixture was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 19% gradient over 10 min; detector, UV 220 nm) to give N-(1-(tert-butyl)-5-((1s,4s)-4-hydroxycyclohexyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (880 mg, 2.44 mmol, 77%) as a yellow oil.

[0316] m / z (ES + ) [M+H] + = 361.10; HPLC tR = 0.858 min.

[0317] (1s,4s)-4-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclohexyl isopropylcarbamate [ka] Step 6: To a stirred solution of N-(1-(tert-butyl)-5-((1s,4s)-4-hydroxycyclohexyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (650 mg, 1.80 mmol) in toluene (6 mL) was added DIEA (699 mg, 5.41 mmol) and 2-isocyanatopropane (460 mg, 5.41 mmol). The reaction was stirred at 85° C. overnight. The resulting mixture was concentrated and purified by reverse-phase flash chromatography. Purification using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 19% gradient in 10 min; detector, UV 220 nm) gave (1s,4s)-4-(1-(tert-butyl)-3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexyl isopropylcarbamate (368 mg, 826 μmol, 45.8%) as a yellow oil.

[0318] m / z (ES + ) [M+H] + = 446.15; HPLC tR = 1.059 min.

[0319] (1s,4s)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexyl isopropylcarbamate [ka] Step 7: (1s,4s)-4-(1-(tert-butyl)-3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexyl isopropylcarbamate (350 mg, 786 μmol) was dissolved in formic acid (6 mL). The reaction was stirred at 75° C. overnight. The mixture was concentrated and purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 46% gradient in 10 min; detector, UV 220 nm) to afford (1s,4s)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexyl isopropylcarbamate (210 mg, 539 μmol, 68.6%) as a white solid. The solid was purified by preparative HPLC (column: Xselect CSH OBD column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 30% B to 31% B in 7 min, wavelength: 220 nm). Lyophilization afforded (1s,4s)-4-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclohexyl isopropylcarbamate (139.2 mg, 357.4 μmol, 69.6%) as a white amorphous solid.

[0320] m / z (ES + ) [M+H] + = 390.15; HPLC tR = 0.726 min.

[0321] 1 H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 10.65 (s, 1H), 6.94 (d, J = 7.6 Hz, 1H), 6.29 (s, 1H), 6.22 (s, 1H), 4.75 (s, 1H), 3.83 (s, 2H), 3.61-3.55 (m, 1H), 2.67 (s, 1H), 2.20 (s, 3H), 1.78-1.71 (m, 5H), 1.64 (t, J = 14.2 Hz, 3H), 1.04 (d, J = 6.5 Hz, 6H).

[0322] Example 9 N-(5-((1S,3R)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide and N-(5-((1R,3S)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Benzyl (1-(tert-butyl)-3-((1R,3R)-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] Step 1: To an ice-cold solution of benzyl (1-(tert-butyl)-5-(trans-3-hydroxycyclopentyl)-1H-pyrazol-3-yl)carbamate (1 g, 3 mmol), 5,5-dimethylimidazolidine-2,4-dione (0.4 g, 3 mmol), and triphenylphosphine (1 g, 4 mmol) in THF (10 mL) was added DIAD (0.8 g, 4 mmol), and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with EA (100 mL), washed with brine (2 × 80 mL), and dried over NaSO. The organic layer was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 40 min; detector, UV 220 nm) to give benzyl (1-(tert-butyl)-5-(cis-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)carbamate (1.03 g, 2.20 mmol, 80%) as a white solid.

[0323] m / z (ES +) [M+H] + = 468.25; HPLC tR = 1.106 min.

[0324] Benzyl (1-(tert-butyl)-3-((1R,3R)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] Step 2: To a solution of benzyl (1-(tert-butyl)-5-(cis-3-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)carbamate (100 mg, 1.07 mmol) in toluene (5 mL) at 0 °C, a solution of Red-Al (3.09 g, 70 wt% in toluene) was added dropwise slowly enough to maintain the internal temperature below 5 °C. After stirring at room temperature for an additional 5 h, the resulting mixture was quenched with NH4Cl (saturated aqueous solution 150 mL) and extracted with EA (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over Na2SO4, and concentrated in vacuo. This product was combined from five additional similarly prepared batches (each starting from 100 mg) and purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 100% gradient in 15 min; detector, UV 220 nm) to give benzyl (1-(tert-butyl)-5-(cis-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)carbamate (250 mg, 551 μmol, 51.5%) as a white solid.

[0325] m / z (ES + ) [M+H] + = 454.15; HPLC tR = 1.103 min.

[0326] 1-((1R,3R)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)-4,4-dimethylimidazolidin-2-one [ka] Step 3: At room temperature (20-25 °C), a suspension of Pd / C (50%, 77 mg) and benzyl (1-(tert-butyl)-5-(cis-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)carbamate (330 mg, 728 μmol) in 2-propanol (10 mL) was degassed and purged with hydrogen (3 cycles), then stirred under a hydrogen balloon at room temperature for 0.5 h. The suspension was filtered. The filtrate was concentrated in vacuo, and the residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 20 min; detector, UV 220 nm) to give 1-(cis-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)-4,4-dimethylimidazolidin-2-one (180 mg, 563 μmol, 77.4%) as a white solid.

[0327] m / z (ES + ) [M+H] + = 320.25; HPLC tR = 1.093 min.

[0328] N-(1-(tert-butyl)-3-((1S,3R)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 4: To a mixture of 1-(cis-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)-4,4-dimethylimidazolidin-2-one (200 mg, 626 μmol), 2-(3-methylisoxazol-5-yl)acetic acid (97.2 mg, 689 μmol), and DIEA (243 mg, 1.88 mmol) in EA (5 mL) was added dropwise 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (478 mg, 50% wt. in EA, 751 μmol) under a nitrogen atmosphere at 0° C. The mixture was stirred at 25° C. for 1 h. The reaction was quenched with saturated Na2CO3 (10 mL) and extracted with DCM (2 × 10 mL). The organic layer was further washed with Na2CO3 (2 × 10 mL) and brine (30 mL) and concentrated. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 20% to 80% gradient in 20 min; detector, UV 220 nm) to give N-(1-(tert-butyl)-5-(cis-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (230 mg, 520 μmol, 83.0%) as a white amorphous solid.

[0329] m / z (ES + ) [M+H] + = 443.20; HPLC tR = 0.955 min.

[0330] N-(5-((1S,3R)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 5: A solution of N-(1-(tert-butyl)-5-(cis-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (50 mg, 9.02 μmol) in TFA / HO (5 mL, 20:1) was stirred at 90° C. for 0.5 h. The resulting mixture was concentrated to dryness. This product was combined with five additional similarly prepared batches (starting from 50 mg each) and purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, gradient 0% to 100% in 15 min; detector, UV 220 nm) to give N-(5-(cis-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (128 mg, 331 μmol, 73.3%) as a white solid.

[0331] m / z (ES + ) [M+H] + = 387.30; HPLC tR = 0.804 min.

[0332] N-(5-((1S,3R)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 6: cis-N-(5-(3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (128 mg, 331 μmol) was purified by preparative chiral HPLC using the following conditions: Column: CHIRALPAK Purification by IG column, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.2% TEA) HPLC, mobile phase B: EtOH:DCM = 1:1 HPLC; flow rate: 20 mL / min; gradient: 90% B to 90% B in 18 min; wavelength: 220 / 254 nm; RT (min): 5.46; sample solvent: EtOH:DCM = 1:1 HPLC; injection volume: 2.2 mL; number of runs: 2) gave cis-N-(5-(-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (50.5 mg, 131 μmol, 39.5%) as a white amorphous solid.

[0333] m / z (ES + ) [M+H] + = 387.15; HPLC tR = 0.653 min.

[0334] 1 H NMR (400 MHz, DMSO) δ 1.17 (d, J = 2.7 Hz, 6H), 1.63 (dt, J = 18.7, 11.4, 11.4 Hz, 3H), 1.76 (d, J = 9.9 Hz, 1H), 1.91- 2.13 (m, 2H), 2.20 (d, J = 1.4 Hz, 3H), 3.05 (d, J = 9.6 Hz, 3H), 3.83 (s, 2H), 4.22 (q, J = 8.3, 8.3, 8.3 Hz, 1H), 5.97 - 6.51 (m, 3H), 10.65 (s, 1H), 12.14 (s, 1H).

[0335] N-(5-((1R,3S)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 7: cis-N-(5-(3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (128 mg, 331 μmol) was purified by preparative chiral HPLC using the following conditions: Column: CHIRALPAK Purification by IG column, 2 × 25 cm, 5 μm; mobile phase A: hexane (0.2% TEA) HPLC, mobile phase B: EtOH:DCM = 1:1 HPLC; flow rate: 20 mL / min; gradient: 90% B to 90% B in 18 min; wavelength: 220 / 254 nm; RT (min): 8.40; sample solvent: EtOH:DCM = 1:1 HPLC; injection volume: 2.2 mL; number of runs: 2) gave N-(5-((1R,3S)-3-(4,4-dimethyl-2-oxoimidazolidin-1-yl)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (48.2 mg, 125 μmol, 37.7%) as a white amorphous solid.

[0336] m / z (ES + ) [M+H] + = 387.15; HPLC tR = 0.662 min.

[0337] 1H NMR (400 MHz, DMSO-d6) δ 1.17 (d, J = 2.7 Hz, 6H), 1.41- 1.68 (m, 3H), 1.76 (d, J = 9.7 Hz, 1H), 2.02 (dd, J = 18.5, 7.6 Hz, 2H), 2.20 (s, 3H), 3.05 (d, J = 8.9 Hz, 3H), 3.83 (s, 2H), 4.22 (q, J = 8.4, 8.3, 8.3 Hz, 1H), 6.11- 6.58 (m, 3H), 10.65 (s, 1H), 12.14 (s, 1H).

[0338] Example 10 2-(3-methylisoxazol-5-yl)-N-(5-((1S,3R)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide and 2-(3-methylisoxazol-5-yl)-N-(5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide [ka] (1S,3S)-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl methanesulfonate [ka] Step 1: To a mixture of benzyl (1-(tert-butyl)-5-(trans-3-hydroxycyclopentyl)-1H-pyrazol-3-yl)carbamate (250 mg, 699 μmol) and EtN (84.9 mg, 839 μmol) in DCM (10 mL) was added MsCl (303 mg, 2.10 mmol) dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with HO (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 to give trans-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl methanesulfonate (300 mg, 98.5%) as a yellow oil.

[0339] m / z (ES + ) [M+H] + = 436.25; HPLC tR = 1.202 min.

[0340] 3-((1S,3R)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-amine [ka] Step 2: A resealable reaction vial was charged with trans-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl methanesulfonate (300 mg, 689 μmol), 4-bromopyridin-3-ol (144 mg, 827 μmol), K2CO3 (286 mg, 2.07 mmol), DMF (10 mL), and a stir bar. The mixture was then degassed and purged with nitrogen three times, and the mixture was stirred at 80 °C for 3 h. The reaction mixture was diluted with HO (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 preparative TLC (PE / EA; ratio: 4 / 1) to give 5-(cis-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-amine (120 mg, 45.5%) as a yellow oil.

[0341] m / z (ES + ) [M+H] + = 379.20; HPLC tR = 0.810 min.

[0342] N-(3-((1S,3R)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 3: A resealable reaction vial was charged with 5-(cis-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-amine (256 mg, 675 μmol), DIEA (349 mg, 2.70 mmol), and 2-(3-methylisoxazol-5-yl)acetamide (114 mg, 810 μmol) in EA (5 mL), and T3P (644 mg, 2.02 mmol) was added dropwise at 0° C. under a nitrogen atmosphere. The mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with HO (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 preparative TLC (DCM / MeOH; ratio: 20 / 1) to give N-(5-(cis-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (240 mg, 70.8%) as a yellow oil.

[0343] m / z (ES + ) [M+H] + =502.10; HPLC tR =0.747 min.

[0344] N-(1-(tert-butyl)-3-((1S,3R)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-5-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 4: A resealable reaction vial was charged with N-(5-((1S,3R)-3-((4-bromopyridin-3-yl)oxy)cyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (60 mg, 0.12 mmol), prop-1-en-2-ylboronic acid (12 mg, 0.14 mmol), Pd(dppf)Cl (8.7 mg, 12 μmol), KCO (46 mg, 0.36 mmol), dioxane / HO (1 mL), and a stir bar. The mixture was then degassed and purged with nitrogen three times, and the mixture was stirred at 60 °C for 1 h. The reaction mixture was diluted with HO (50 mL), and the aqueous phase was extracted three times with EA (100 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH; ratio: 20 / 1) to give N-(1-(tert-butyl)-5-((1S,3R)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (40 mg, 72%) as an orange oil.

[0345] m / z (ES + ) [M+H] + = 464.25; HPLC tR = 1.100 min.

[0346] 2-(3-Methylisoxazol-5-yl)-N-(5-((1S,3R)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide [ka] Step 5: A resealable reaction vial was charged with N-(1-(tert-butyl)-5-(cis-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (200 mg, 431 μmol), FA (5 mL), and a stir bar, then degassed and purged with nitrogen three times, and the mixture was stirred at 75° C. for 12 h. The resulting crude material was purified by C18 flash (acetonitrile / water / 0.1% formic acid). Concentration in vacuo afforded 2-(3-methylisoxazol-5-yl)-N-(5-(cis-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide (70 mg, 39.8%) as a colorless oil.

[0347] m / z (ES + ) [M+H] + = 408.30; HPLC tR = 0.790 min.

[0348] 2-(3-Methylisoxazol-5-yl)-N-(5-((1S,3R)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide [ka] 2-(3-Methylisoxazol-5-yl)-N-(5-(cis-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide (70 mg, 0.17 mmol) was purified by preparative chiral 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 32 min; Wavelength: 220 / 254 nm; RT1 (min): 15.69; RT2 (min): 25.34; Sample Solvent: EtOH:DCM = 1:1 - HPLC; Injection Volume: 0.8 mL; Number of Runs: 4). Lyophilization afforded 2-(3-methylisoxazol-5-yl)-N-(5-((1S,3R)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide (28.9 mg, 41%) as a white solid.

[0349] m / z (ES + ) [M+H] + = 408.35; HPLC tR = 0.962 min.

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.62 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.29 (s, 1H), 6.22 (s, 1H), 5.27 - 5.20 (m, 2H), 5.05 (s, 1H), 3.83 (s, 2H), 3.18 - 3.07 (m, 1H), 2.66 (dt, J = 14.4, 7.3 Hz, 1H), 2.20 (s, 3H), 2.10 - 1.97 (m, 5H), 1.89 (d, J = 13.4 Hz, 1H), 1.76 (td, J = 14.0, 12.3, 5.3 Hz, 2H).

[0351] 2-(3-Methylisoxazol-5-yl)-N-(5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide [ka] 2-(3-Methylisoxazol-5-yl)-N-(5-(cis-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide (70 mg, 0.17 mmol) was purified by preparative chiral 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 32 min; Wavelength: 220 / 254 nm; RT1 (min): 15.69; RT2 (min): 25.34; Sample Solvent: EtOH:DCM = 1:1 - HPLC; Injection Volume: 0.8 mL; Number of Runs: 4). Lyophilization afforded 2-(3-methylisoxazol-5-yl)-N-(5-((1R,3S)-3-((4-(prop-1-en-2-yl)pyridin-3-yl)oxy)cyclopentyl)-1H-pyrazol-3-yl)acetamide (25.9 mg, 37%) as a white solid.

[0352] m / z (ES + ) [M+H] + = 408.35; HPLC tR = 0.928 min. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (s, 1H), 10.63 (s, 1H), 8.31 (s, 1H), 8.15 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 4.8 Hz, 1H), 6.29 (s, 1H), 6.22 (s, 1H), 5.23 (qd, J = 2.7, 2.0, 1.3 Hz, 2H), 5.06 (d, J = 4.4 Hz, 1H), 3.83 (s, 2H), 3.13 (p, J = 9.2 Hz, 1H), 2.67 (tt, J = 14.3, 7.3 Hz, 1H), 2.20 (s, 3H), 2.10 - 1.97 (m, 5H), 1.89 (d, J = 13.0 Hz, 1H), 1.85 - 1.69 (m, 2H).

[0353] Additional compounds prepared according to the methods of Example 9 or Example 10 are shown in Table 6 below. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] [Table 5-9] [Table 5-10] [Table 5-11] [Table 5-12] [Table 5-13] [Table 5-14] [Table 5-15] [Table 5-16] [Table 5-17] [Table 5-18]

[0354] Example 11 (1R,3S)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate and (1S,3R)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] N-(5-bromo-2-chloropyridin-4-yl)-2-methoxyacetamide [ka] Step 1: To an ice-cold solution of 5-bromo-2-chloropyridin-4-amine (5 g, 1 eq, 24 mmol) in DCM (50 mL) was added TEA (3.6 g, 1.5 eq, 36 mmol) and 2-methoxyacetyl chloride (3.9 g, 1.5 eq, 36 mmol). The mixture was stirred at 20 °C for 16 h. The solvent was removed under reduced pressure, and the residue was dissolved in water (70 mL) and extracted with EtOAc (3 × 50 mL). The combined organic extracts were washed with brine, dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (mobile phase A: water (10 mmol / L NH HCO ), mobile phase B: ACN; flow rate: 60 mL / min, gradient: 45% B to 55% B in 7 min). After evaporation of the solvent, N-(2,5-dichloropyridin-4-yl)-2-methoxyacetamide (1.51 g, 5.4 mmol, 22%) was obtained as a pale yellow solid.

[0355] m / z (ES + ) [M+H] + = 278.85; HPLC tR = 0.997 min.

[0356] N-(5-bromo-2-chloropyridin-4-yl)-2-methoxyethanethioamide [ka] Step 2: To a solution of N-(5-bromo-2-chloropyridin-4-yl)-2-methoxyacetamide (1.33 g, 1 eq, 4.76 mmol) in toluene (20 mL) was added 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiadiphosphetane 2,4-disulfide (1.44 g, 0.75 eq, 3.57 mmol). The mixture was heated at 110° C. under N for 4 h. The reaction mixture was filtered to remove the filter cake, and the filtrate was concentrated in vacuo. The resulting crude material was purified by silica gel chromatography (eluting with a 20:1 mixture of petroleum ether / ethyl acetate) to give 2-(1-benzothiophen-2-yl)-N-(1-{5-[(3S)-1-methylpiperidin-3-yl]pyrimidin-2-yl}-1H-pyrazol-4-yl)acetamide (1.1 g, 4.76 mmol, 78%) as a yellow amorphous solid.

[0357] m / z (ES + ) [M+H] + = 294.90; HPLC tR = 0.727 min.

[0358] 6-chloro-2-(methoxymethyl)thiazolo[5,4-c]pyridine [ka] Step 3: To a solution of N-(5-bromo-2-chloropyridin-4-yl)-2-methoxyethanethioamide (490 mg, 1 eq, 1.66 mmol) in NMP (5 mL) was added NaH (59.7 mg, 0.9 eq, 1.49 mmol). The mixture was heated at 160 °C for 1 h. The reaction mixture was allowed to reach room temperature and poured into ice-cold water, followed by extraction with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by flash (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40B to 50B in 8 min). After evaporation of the solvent, 6-chloro-2-(methoxymethyl)thiazolo[5,4-c]pyridine (240 mg, 1.12 mmol, 67.4%) was obtained as a brown solid.

[0359] m / z (ES + ) [M+H] + = 215.00; HPLC tR = 0.594 min.

[0360] cis-3-(5-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step 4: To a solution of benzyl (1-(tert-butyl)-5-(cis-3-hydroxycyclopentyl)-1H-pyrazol-3-yl)carbamate (5 g, 1 eq, 0.01 mol) in toluene (20 mL) were added 2-isocyanatopropane (6 g, 5 eq, 0.07 mol) and DIEA (5 g, 3 eq, 0.04 mol). The mixture was stirred at 85 °C for 16 h. The mixture was diluted with water, and the aqueous phase was extracted with EA (3 × 40 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material obtained was purified by flash (mobile phase A: water / 0.1% formic acid, mobile phase B: ACN; flow rate: 60 mL / min, gradient: 40B to 50B in 8 min). After evaporation of the solvent, cis-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (4.2 g, 8.9 mmol, 60%) was obtained as a brown amorphous solid.

[0361] m / z (ES + ) [M+H] + = 443.10; HPLC tR = 0.889 min.

[0362] cis-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step 5: To a solution of cis-3-(3-(((benzyloxy)carbonyl)amino)-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (4.2 g, 1 eq, 9.5 mmol) in MeOH (15 mL), nitrogen was bubbled through the reaction mixture three times. Pd / C (0.50 g, 0.5 eq, 4.7 mmol) was then added. After bubbling H2 through the reaction mixture three times, the mixture was stirred with H2 at room temperature for 2 h. The reaction mixture was filtered to remove the filter cake, and the filtrate was concentrated in vacuo. The resulting crude material was purified by flash elution (mobile phase A: water / 0.1% formic acid, mobile phase B: ACN; flow rate: 60 mL / min, gradient: 45 B to 55 B in 6 min). After evaporation of the solvent, cis-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (2.3 g, 7.5 mmol, 79%) was obtained as a brown amorphous oil.

[0363] m / z (ES + ) [M+H] + = 309.15; HPLC tR = 0.691 min.

[0364] cis-3-(1-(tert-butyl)-5-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step 6: 6-Chloro-2-(methoxymethyl)thiazolo[5,4-c]pyridine (234 mg, 1.2 eq, 1.09 mmol), Cs2CO3 (1.18 g, 4 eq, 3.63 mmol), and Xphos (86.4 mg, 0.2 eq, 182 μmol) were added to a solution of cis-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (280 mg, 1 eq, 908 μmol) in DME (4 mL). After bubbling nitrogen through the reaction mixture for 5 min, Pd2dba3 (166 mg, 0.2 eq, 182 μmol) was added. The reaction mixture was heated at 90 °C with vigorous stirring for 3 h. After cooling to room temperature, the mixture was evaporated, extracted with ethyl acetate (3 × 50 mL), dried over Na2SO4, and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water, mobile phase B: ACN; flow rate: 60 mL / min, gradient: 45% B to 55% B in 6 min). After evaporation of the solvent, cis-3-(1-(tert-butyl)-3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (120 mg, 247 μmol, 27.2%) was obtained as a brown oil.

[0365] m / z (ES + ) [M+H] + = 487.10; HPLC tR = 1.029 min.

[0366] (1R,3S)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step 7: A solution of cis-3-(1-(tert-butyl)-3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (101 mg, 1 Eq, 208 μmol) in FA (2 mL) was heated at 70° C. for 45 min. After cooling to room temperature, the mixture was evaporated. The crude residue was purified by preparative HPLC (Column: Sunfire prep C18 column, 30 × 150 mm, 5 μm; Mobile phase A: water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 10% B to 45% B in 7 min); after evaporation of the solvent, cis-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (27 mg, 63 μmol, 30%) was obtained as a yellow solid.

[0367] (1R,3S)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate and (1S,3R)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step 8: cis-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (27 mg, 1 eq, 63 μmol) was purified by chiral HPLC (column: CHIRALPAK Purification by IG column, 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: 80% B to 80% B in 14.5 min; wavelength: 220 / 254 nm; RT1 (min): 9.73; RT2 (min): 12.26; sample solvent: EtOH:DCM = 1:1 HPLC; injection volume: 0.9 mL; lyophilization afforded (1R,3S)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (6 mg, 0.01 mmol, 40%) as a pale yellow amorphous solid.

[0368] m / z (ES + ) [M+H] + = 431.15; HPLC tR = 0.731 min.

[0369] 1 H NMR (400 MHz, chloroform-d) δ 8.77 (s, 1H), 7.77 (s, 1H), 7.28 (s, 1H), 6.02 (s, 1H), 5.24 (s, 1H), 4.86 (s, 2H), 4.70 (s, 1H), 3.83 (s, 1H), 3.60 (s, 3H), 3.22 (t, J = 8.3 Hz, 1H), 2.53 (s, 1H), 2.16 (d, J = 5.5 Hz, 1H), 1.97 (s, 2H), 1.90 (d, J = 10.1 Hz, 2H), 1.28 (s, 1H), 1.18 (dd, J = 6.7, 2.5 Hz, 6H).

[0370] Lyophilization afforded (1S,3R)-3-(3-((2-(methoxymethyl)thiazolo[5,4-c]pyridin-6-yl)amino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (8.4 mg, 20 μmol, 62%) as a pale yellow amorphous solid.

[0371] m / z (ES + ) [M+H] + = 431.10; HPLC tR = 0.724 min.

[0372] 1 H NMR (400 MHz, chloroform-d) δ 8.78 (s, 1H), 7.76 (s, 1H), 7.35 (s, 1H), 6.03 (s, 1H), 5.24 (s, 1H), 4.86 (s, 2H), 4.71 (s, 1H), 3.83 (s, 1H), 3.60 (s, 3H), 3.26-3.18 (m, 1H), 2.54 (s, 1H), 2.18-2.12 (m, 1H), 1.96 (s, 2H), 1.90 (d, J = 9.5 Hz, 2H), 1.28 (s, 1H), 1.18 (dd, J = 6.8, 2.9 Hz, 6H).

[0373] Additional compounds prepared according to the method of Example 11 are shown in Table 7 below. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11]

[0374] Example 12 (1R,3S)-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate and (1S,3R)-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] cis-3-(1-(tert-butyl)-5-(isothiazol-3-ylamino)-1H-pyrazol-3-yl)cyclopentyl isopropylcarbamate [ka] Step 1: 3-Bromoisothiazole (223 mg, 2 eq, 1.36 mmol), cesium carbonate (887 mg, 4 eq, 2.72 mmol), and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (39.4 mg, 0.1 eq, 68.1 μmol) were added to a solution of cis-3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (210 mg, 1 eq, 681 μmol) in dioxane (4 mL). After bubbling nitrogen through the reaction mixture for 5 min, Pd(dba) (62.3 mg, 0.1 eq, 68.1 μmol) was added. The reaction mixture was heated at 110 °C with vigorous stirring for 16 h. After cooling to room temperature, the mixture was evaporated, extracted with ethyl acetate (3 × 40 mL), dried over NaSO, and evaporated in vacuo. The crude residue was purified by flash chromatography (mobile phase A: water (10 mmol / L NHHCO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 45% B to 55% B in 6 min). After evaporation of the solvent, cis-3-(1-(tert-butyl)-3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (102 mg, 261 μmol, 38.3%) was obtained as a pale yellow solid.

[0375] m / z (ES + ) [M+H] + = 392.50; HPLC tR = 0.854 min.

[0376] cis-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step 2: A solution of cis-3-(1-(tert-butyl)-3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (115 mg, 1 Eq, 294 μmol) in FA (2 mL) was heated at 70 °C for 16 h. After cooling to room temperature, the mixture was evaporated. The residue was purified by flash chromatography (mobile phase A: water (10 mmol / L NH4HCO3), mobile phase B: ACN; flow rate: 55 mL / min, gradient: 45% B to 55% B in 7 min). After evaporation of the solvent, cis-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (60 mg, 0.18 mmol, 61%) was obtained as a colorless amorphous solid.

[0377] m / z (ES + ) [M+H] + = 336.25; HPLC tR = 0.921 min.

[0378] (1R,3S)-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate and (1S,3R)-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate [ka] Step 3: cis-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (60 mg, 1 eq, 0.18 mmol) was purified by chiral HPLC (Column: CHIRALPAK IE, 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: 40% B to 40% B in 15 min; Wavelength: 220 / 254 nm; RT1 (min): 8.13; RT2 (min): 11.87; Sample solvent: EtOH:DCM = 1:1 - HPLC; Injection volume: 0.6 mL). Lyophilization gave (1R,3S)-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (18.6 mg, 55.5 μmol, 62%) as a white amorphous solid.

[0379] m / z (ES + ) [M+H] + = 336.05; HPLC tR = 0.676 min.

[0380] 1 H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 4.7 Hz, 1H), 7.51 (s, 1H), 6.87 (d, J = 4.7 Hz, 1H), 6.27 (s, 1H), 5.22 (s, 1H), 4.69 (s, 1H), 3.83 (s, 1H), 3.22 (q, J = 8.1 Hz, 1H), 2.50 (s, 1H), 2.14 (s, 1H), 1.93 (d, J = 22.8 Hz, 4H), 1.17 (t, J = 5.5 Hz, 6H).

[0381] Lyophilization gave (1S,3R)-3-(3-(isothiazol-3-ylamino)-1H-pyrazol-5-yl)cyclopentyl isopropylcarbamate (14.9 mg, 44.4 μmol, 50%) as a white amorphous solid.

[0382] m / z (ES+ ) [M+H] + = 336.05; HPLC tR = 0.675 min.

[0383] 1 H NMR (400 MHz, chloroform-d) δ 8.49 (d, J = 4.8 Hz, 1H), 7.58 (s, 1H), 6.88 (d, J = 4.8 Hz, 1H), 6.29 (s, 1H), 5.22 (s, 1H), 4.71 (s, 1H), 3.83 (s, 1H), 3.21 (t, J = 8.2 Hz, 1H), 2.50 (s, 1H), 2.15 (d, J = 8.6 Hz, 1H), 1.91 (s, 4H), 1.17 (t, J = 5.7 Hz, 6H).

[0384] Example 13 1-Isopropyl-3-((1R,3S)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea and 1-Isopropyl-3-((1S,3R)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea [ka] Benzyl cis-(1-(tert-butyl)-3-(3-(1,3-dioxoisoindolin-2-yl)cyclopentyl)-1H-pyrazol-5-yl)carbamate [ka] Step 1: To a mixture of benzyl cis-(1-(tert-butyl)-5-(3-hydroxycyclopentyl)-1H-pyrazol-3-yl)carbamate (780 mg, 2.18 mmol), PPh3 (743 mg, 2.84 mmol), and isoindoline-1,3-dione (385 mg, 2.62 mmol) in THF (10 mL) was added dropwise DIAD (574 mg, 2.84 mmol) under a nitrogen atmosphere at 0 °C. The mixture was stirred at 0 °C for 1 h. After stirring the mixture at 25 °C for 12 h, the reaction mixture was diluted with HO (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 crude product was purified by silica gel chromatography (2 g column; eluted with PE / EA; ratio: 8 / 1). Concentration in vacuo gave benzyl cis-(1-(tert-butyl)-5-(3-(1,3-dioxoisoindolin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)carbamate (1 g, 90%) as a colorless oil.

[0385] m / z (ES + ) [M+H] + = 487.35; HPLC tR = 1.285 min.

[0386] cis-2-(3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl)isoindoline-1,3-dione [ka] Step 2: A stirred mixture of cis-benzyl (1-(tert-butyl)-5-(3-(1,3-dioxoisoindolin-2-yl)cyclopentyl)-1H-pyrazol-3-yl)carbamate (1 g, 2 mmol) and Pd / C (0.2 g) in THF (10 mL) was treated with H at 25° C. for 2 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 afforded cis-2-(3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)isoindoline-1,3-dione (670 mg, 90%) as a colorless oil.

[0387] m / z (ES + ) [M+H] + = 0.868; HPLC tR = 353.25 min.

[0388] cis-2-(3-(1-(tert-butyl)-5-(pyrimidin-2-ylamino)-1H-pyrazol-3-yl)cyclopentyl)isoindoline-1,3-dione [ka] Step 3: A resealable reaction vial was charged with cis-2-(3-(3-amino-1-(tert-butyl)-1H-pyrazol-5-yl)cyclopentyl)isoindoline-1,3-dione (1.5 g, 4.3 mmol), 2-bromopyrimidine (0.81 g, 5.1 mmol), CsCO (4.2 g, 13 mmol), Pd(dba) (0.39 g, 0.43 mmol), Xantphos (0.49 g, 0.85 mmol), dioxane (20 mL), and a stir bar. The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 110 °C for 1 h. The reaction mixture was diluted with HO (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 (10 g column; eluted with PE / EA; ratio: 2 / 1) and concentrated in vacuo to give cis-2-(3-(1-(tert-butyl)-3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)isoindoline-1,3-dione (1 g, 50%) as an orange solid.

[0389] m / z (ES + ) [M+H] + = 431.25; HPLC tR = 1.127 min.

[0390] cis-N-(3-(3-aminocyclopentyl)-1-(tert-butyl)-1H-pyrazol-5-yl)pyrimidin-2-amine [ka] Step 4: A resealable reaction vial was charged with cis-2-(3-(1-(tert-butyl)-3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)isoindoline-1,3-dione (1 g, 2 mmol), NH2NH2·HO / MeOH (3:1) (4 mL), and a stir bar. The mixture was degassed and purged with nitrogen three times, and the mixture was stirred at 50 °C for 1 h. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient over 20 min; detector, UV 250 nm). Concentration in vacuo afforded cis-N-(5-(3-aminocyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-yl)pyrimidin-2-amine (500 mg, 70%) as a colorless solid.

[0391] m / z (ES + ) [M+H] + = 301.30; HPLC tR = 0.718 min.

[0392] cis-1-(3-(1-(tert-butyl)-5-(pyrimidin-2-ylamino)-1H-pyrazol-3-yl)cyclopentyl)-3-isopropylurea [ka] Step 5: To a mixture of cis-N-(5-(3-aminocyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-yl)pyrimidin-2-amine (560 mg, 1.86 mmol) and DIEA (723 mg, 5.59 mmol) in DCM (5 mL) was added 2-isocyanatopropane (190 mg, 2.24 mmol) dropwise at 25 °C under a nitrogen atmosphere. The mixture was stirred at 25 °C for 2 h. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 15 min; detector, UV 220 nm). Concentration in vacuo gave cis-1-(3-(1-(tert-butyl)-3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropylurea (360 mg, 50.1%) as a white solid.

[0393] m / z (ES + ) [M+H] + = 386.40; HPLC tR = 0.902 min.

[0394] cis-1-Isopropyl-3-(3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea [ka] Step 6: A resealable reaction vial was charged with cis-1-(3-(1-(tert-butyl)-3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)-3-isopropylurea (340 mg, 882 μmol), FA (10 mL), and a stir bar, then degassed and purged with nitrogen three times, and the mixture was stirred at 75° C. for 12 h. The reaction was concentrated in vacuo. The reaction mixture was poured into 10 mL of MeOH. The isolated solid was collected to give cis-1-isopropyl-3-(3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea (220 mg, 75.7%) as a white solid.

[0395] m / z (ES+ ) [M+H] + = 330.30; HPLC tR = 0.735 min.

[0396] 1-Isopropyl-3-((1R,3S)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea [ka] Step 7: The cis-1-isopropyl-3-(3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea (220 mg, 668 μmol) material was purified by preparative chiral HPLC (Column: CHIRALPAK IE, 2 × 25 cm, 5 μm; Mobile Phase A: Hex (0.2% CHCOOH) - HPLC, Mobile Phase B: EtOH:DCM = 1:1 - HPLC; Flow Rate: 20 mL / min; Gradient: 40% B to 40% B in 31 min; Wavelength: 220 / 254 nm; RT (min): 19.81; Sample Solvent: EtOH:DCM = 1:1 - HPLC; Injection Volume: 1.2 mL; Number of Runs: 14). Lyophilization gave 1-isopropyl-3-((1R,3S)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea (64 mg, 0.19 mmol, 29%) as a white solid.

[0397] m / z (ES + ) [M+H] + = 330.20; HPLC tR = 0.615 min.

[0398] 1H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 9.55 (s, 1H), 8.42 (d, J = 4.8 Hz, 2H), 6.76 (t, J = 4.8 Hz, 1H), 6.32 (s, 1H), 5.82 (d, J = 7.6 Hz, 1H), 5.54 (d, J = 7.7 Hz, 1H), 3.96 (p, J = 7.4 Hz, 1H), 3.65 (dp, J = 7.7, 6.4 Hz, 1H), 3.08 - 2.95 (m, 1H), 2.31 (dt, J = 13.6, 7.3 Hz, 1H), 1.94 (dddd, J = 33.7, 15.2, 12.3, 7.4 Hz, 2H), 1.68 (dtd, J = 10.8, 8.8, 8.2, 6.4 Hz, 1H), 1.51 - 1.32 (m, 2H), 1.02 (dd, J = 6.5, 1.0 Hz, 6H).

[0399] 1-Isopropyl-3-((1S,3R)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea [ka] The cis-1-isopropyl-3-(3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea (220 mg, 668 μmol) material was purified by preparative chiral HPLC (CHIRALPAK IE, 2 × 25 cm, 5 μm column; mobile phase A: Hex (0.2% CHCOOH) HPLC, mobile phase B: EtOH:DCM = 1:1 HPLC; flow rate: 20 mL / min; gradient: 40% B to 40% B in 31 min; wavelength: 220 / 254 nm; RT (min): 25.25; sample solvent: EtOH:DCM = 1:1 HPLC; injection volume: 1.2 mL; number of runs: 14). Lyophilization gave 1-isopropyl-3-((1S,3R)-3-(3-(pyrimidin-2-ylamino)-1H-pyrazol-5-yl)cyclopentyl)urea (65.7 mg, 29.9%) as a white solid.

[0400] m / z (ES + ) [M+H] + = 330.15; HPLC tR = 0.615 min.

[0401] 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H), 9.55 (s, 1H), 8.42 (d, J = 4.7 Hz, 2H), 6.76 (t, J = 4.8 Hz, 1H), 6.32 (s, 1H), 5.82 (d, J = 7.5 Hz, 1H), 5.54 (d, J = 7.7 Hz, 1H), 3.96 (h, J = 7.4 Hz, 1H), 3.72 - 3.59 (m, 1H), 3.00 (h, J = 8.6 Hz, 1H), 2.31 (dt, J = 13.4, 7.1 Hz, 1H), 2.04 - 1.83 (m, 2H), 1.68 (dtd, J = 10.9, 8.8, 8.1, 6.4 Hz, 1H), 1.51 - 1.32 (m, 2H), 1.02 (dd, J = 6.5, 1.0 Hz, 6H).

[0402] Additional compounds prepared according to the method of Example 13 are shown in Table 8 below. [Table 7-1] [Table 7-2] [Table 7-3]

[0403] Example 14 N-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide and N-((1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide [ka] cis-N-(3-(1-(tert-butyl)-5-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-3-yl)cyclopentyl)benzamide [ka] Step 1: A round-bottom flask was charged with N-(5-(cis-3-aminocyclopentyl)-1-(tert-butyl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (180 mg, 1 Eq, 374 μmol), DCM (6 mL), TEA (120 mg, 3 Eq, 1.12 mmol), and a stir bar. At 0° C., benzoyl chloride (63.1 mg, 1.2 Eq, 449 μmol) was added, and the solution was stirred at 25° C. for 1 h. The resulting crude material was purified by TLC (DCM / MeOH=10:1). Concentration in vacuo afforded N-(cis-3-(1-(tert-butyl)-3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide (130 mg, 289 μmol, 77.3%) as a yellow amorphous solid.

[0404] m / z (ES + ) [M+H] + = 450.15; HPLC tR = 0.942 min.

[0405] cis-N-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide [ka] Step 2: A round-bottom flask was charged with N-(cis-3-(1-(tert-butyl)-3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide (130 mg, 1 Eq, 289 μmol), FA (3 mL) was added, and the solution was stirred at 75° C. for 16 h. The resulting crude material was purified by flash chromatography (acetonitrile / water). Lyophilization afforded cis-N-(3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide (90 mg, 0.23 mmol, 79%) as a white amorphous solid.

[0406] m / z (ES + ) [M+H] + = 394.10; HPLC tR = 0.517 min.

[0407] N-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide and N-((1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide [ka] Step 3: N-(cis-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide (90 mg, 1 eq, 0.23 mmol) was purified by chiral 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: 60% B to 60% B in 11 min; Wavelength: 220 / 254 nm; RT1 (min): 6.97; RT2 (min): 8.65; Sample solvent: EtOH:DCM = 1:1 - HPLC; Injection volume: 0.3 mL; Number of runs: 6). Lyophilization afforded N-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide (27.5 mg, 0.070 mmol, 30.5%) as a white amorphous solid and N-((1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide (29.6 mg, 0.075 mmol, 32.9%) as a white amorphous solid.

[0408] N-((1R,3S)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide:

[0409] m / z (ES + ) [M+H] + = 394.15; HPLC tR = 1.128 min.

[0410] 1H NMR (400 MHz, DMSO-d6) 12.13 (s, 1H), 10.64 (s, 1H), 8.42 (d, J = 7.6 Hz, 1H), 7.88-7.81 (m, 2H), 7.56-7.48 (m, 1H), 7.48-7.41 (m, 2H), 6.35 (s, 1H), 6.22 (s, 1H), 4.37 (q, J = 7.6 Hz, 1H), 3.83 (s, 2H), 3.13-3.02 (m, 1H), 2.39 (dd, J = 12.9, 7.0 Hz, 1H), 2.20 (s, 3H), 2.02 (t, J = 7.9 Hz, 2H), 1.78-1.69 (m, 2H), 1.69-1.61 (m, 1H).

[0411] N-((1S,3R)-3-(3-(2-(3-methylisoxazol-5-yl)acetamido)-1H-pyrazol-5-yl)cyclopentyl)benzamide:

[0412] m / z (ES + ) [M+H] + = 394.20; HPLC tR = 1.112 min.

[0413] 1 H NMR (400 MHz, DMSO-d6) 12.13 (s, 1H), 10.64 (s, 1H), 8.42 (d, J = 7.4 Hz, 1H), 7.87-7.81 (m, 2H), 7.56-7.49 (m, 1H), 7.49-7.41 (m, 2H), 6.35 (s, 1H), 6.22 (s, 1H), 4.42-4.34 (m, 1H), 3.83 (s, 2H), 3.11-3.02 (m, 1H), 2.39 (dd, J = 13.1, 7.1 Hz, 2H), 2.20 (s, 3H), 2.02 (t, J = 8.0 Hz, 2H), 1.81-1.61 (m, 4H), 1.08 (t, J = 7.2 Hz, 1H).

[0414] Example 15 2-(3-Methylisoxazol-5-yl)-N-(5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)acetamide [ka] 2-(5-Bromo-1H-pyrazol-3-yl)isoindoline-1,3-dione [ka] Step 1: Under a nitrogen atmosphere, a solution of 5-bromo-1H-pyrazol-3-amine (2.5 g, 1 eq, 15 mmol) and isobenzofuran-1,3-dione (2.7 g, 1.2 eq, 19 mmol) in AcOH (25 mL) was added at room temperature. The reaction mixture was stirred at 125 °C for 16 hours. The mixture was cooled to room temperature. The mixture was concentrated, and the residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated under reduced pressure to give 2-(5-bromo-1H-pyrazol-3-yl)isoindoline-1,3-dione (4.4 g, 15 mmol, 98%) as a yellow solid.

[0415] m / z (ES + ) [M+H] + = 291.85; HPLC tR = 0.773 min.

[0416] 2-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)isoindoline-1,3-dione [ka] Step 2: To a solution of 2-(5-bromo-1H-pyrazol-3-yl)isoindoline-1,3-dione (4 g, 0.01 mol) and K2CO3 (6 g, 0.04 mol) in MeCN (30 mL) was added 1-(chloromethyl)-4-methoxybenzene (3 g, 0.02 mol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 16 h. The mixture was cooled to room temperature, filtered, and the filter cake was washed with EA (3 × 250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2 / 1)) to give 2-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (5 g, 0.01 mol, 90%) as an off-white solid.

[0417] m / z (ES + ) [M+H] + = 411.95; HPLC tR = 0.939 min.

[0418] 2-(1-(4-Methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione [ka] Step 3: To a solution of 2-(5-bromo-1-(4-methoxybenzyl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (5 g, 0.01 mol) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (6 g, 0.02 mol) in 1,4-dioxane (20 mL) was added potassium acetate (4 g, 0.04 mol) and PdCl(dppf)-CHCl adduct (1 g, 1 mmol) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 100 °C for 16 h. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with EA (3 × 250 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1 / 1)) to give 2-(1-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (2.6 g, 4.5 mmol, 40%, purity 80%) as an off-white solid.

[0419] m / z (ES + ) [M+H] + = 460.05; HPLC tR = 1.225 min.

[0420] 2-(1-(4-Methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione [ka] Step 4: To a solution of 2-(1-(4-methoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (600 mg, 1.31 mmol) and 7-bromothieno[3,2-d]pyrimidine (281 mg, 1.31 mmol) dissolved in THF (10 mL) was added KPO (831 mg, 3.92 mmol) and Pd XantPhos G3 (111 mg, 131 μmol). The resulting mixture was stirred at 50 °C under a N atmosphere for 1.5 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated in vacuo. The residue was purified by reverse-phase flash chromatography (using the following conditions: column, C18 silica gel; mobile phase, ACN in water, 0% to 100% gradient over 20 min; detector, UV 254 nm) to give 2-(1-(4-methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (190 mg, 406 μmol, 31.1%) as a yellow solid.

[0421] m / z (ES + ) [M+H] + = 468.00; HPLC tR = 1.052 min.

[0422] 1-(4-Methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-amine [ka] Step 5: A solution of 2-(1-(4-methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)isoindoline-1,3-dione (190 mg, 406 μmol) was dissolved in MeOH (2 mL) and N₂H₄·H₂O (6 mL). The resulting mixture was stirred at 50 °C under a nitrogen atmosphere for 2 h. The resulting mixture was concentrated in vacuo. The desired product could be detected by LCMS. The residue was purified by reverse-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 NH₄HCO₃), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 50% B in 8 min; Detector: UV 254 nm). This gave 1-(4-methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-amine (100 mg, 296 μmol, 72.9%) as an orange solid.

[0423] m / z (ES + ) [M+H] + = 338.00; HPLC tR = 0.734 min.

[0424] N-(1-(4-Methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide [ka] Step 6: To a stirred solution of 1-(4-methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-amine (100 mg, 296 μmol), 2-(3-methylisoxazol-5-yl)acetic acid (62.7 mg, 445 μmol), and DIEA (115 mg, 889 μmol) in DCM (3 mL) at room temperature, T3P (283 mg, 889 μmol) was added dropwise. The resulting mixture was stirred at 25° C. under a nitrogen atmosphere for 1 hour. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The mixture was concentrated to give N-(1-(4-methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (120 mg, 261 μmol, 87.9%) as a yellow solid.

[0425] m / z (ES + ) [M+H] + = 461.00; HPLC tR = 0.911 min.

[0426] 2-(3-Methylisoxazol-5-yl)-N-(5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)acetamide [ka] Step 7: To a vial was added N-(1-(4-methoxybenzyl)-5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)-2-(3-methylisoxazol-5-yl)acetamide (110 mg, 239 μmol) and TFA (2 mL) at room temperature. The resulting mixture was further stirred at 80 °C for 1 h. The resulting mixture was concentrated in vacuo. The crude residue was purified 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: 10% B to 35% B, 35% B in 8 min; Wavelength: 220 nm). This gave 2-(3-methylisoxazol-5-yl)-N-(5-(thieno[3,2-d]pyrimidin-7-yl)-1H-pyrazol-3-yl)acetamide (42.6 mg, 125 μmol, 52.4%) as a white solid.

[0427] m / z (ES + ) [M+H] + = 341.05; HPLC tR = 0.975 min.

[0428] 1 H NMR (400 MHz, DMSO-d6) 13.03 (s, 1H), 10.89 (s, 1H), 9.63 (s, 1H), 9.31 (s, 1H), 8.77 (s, 1H), 7.48 (s, 1H), 6.28 (s, 1H), 3.91 (s, 2H), 2.22 (s, 3H).

[0429] Example 16 N-(5-(bicyclo[2.2.1]heptan-1-yl)-1H-pyrazol-3-yl)pyrimidin-2-amine [ka] Methylbicyclo[2.2.1]heptane-1-carboxylate [ka] Step 1: Sulfinyl dichloride (1.31 g, 2.2 eq, 11.0 mmol) was added dropwise to a solution of bicyclo[2.2.1]heptane-1-carboxylic acid (700 mg, 1 eq, 4.99 mmol) in MeOH (16 mL) at 0 °C under a nitrogen atmosphere. The mixture was stirred at 60 °C for 3 h. The solvent was removed under reduced pressure at room temperature to give methyl bicyclo[2.2.1]heptane-1-carboxylate (720 mg, 4.67 mmol, 93.5%) as a white solid. The crude product was used in the next step without further purification.

[0430] m / z (ES + ) [M+H] + = 155.10; HPLC tR = 1.035 min.

[0431] 3-(bicyclo[2.2.1]heptan-1-yl)-3-oxopropanenitrile [ka] Step 2: LiHMDS (1.17 g, 7.00 mL, 1 mol, 1.5 eq, 7.00 mmol) was added to a solution of methyl bicyclo[2.2.1]heptane-1-carboxylate (720 mg, 1 eq, 4.67 mmol) and acetonitrile (383 mg, 2 eq, 9.34 mmol) in THF (16 mL) at −78 °C. The reaction mixture was stirred at −78 °C for 1 h. LCMS showed no SM. The reaction mixture was quenched with saturated NH4Cl (15 mL), and the aqueous phase was extracted three times with DCM (60 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 3-(bicyclo[2.2.1]heptan-1-yl)-3-oxopropanenitrile (730 mg, 4.47 mmol, 95.8%), which was used in the next step without further purification.

[0432] m / z (ES + ) [M+H] + = no mass signal; HPLC tR = 0.976 min.

[0433] 3-(bicyclo[2.2.1]heptan-1-yl)-1-(tert-butyl)-1H-pyrazol-5-amine [ka] Step 3: tert-Butylhydrazine hydrochloride (836 mg, 1.5 eq, 6.71 mmol) and sodium hydroxide (179 mg, 1 eq, 4.47 mmol) were stirred in EtOH (5 mL) for 1 h. The solution was added dropwise to a solution of 3-(bicyclo[2.2.1]heptan-1-yl)-3-oxopropanenitrile (730 mg, 1 eq, 4.47 mmol) in EtOH (8 mL). The solution was stirred at 50 °C for 2 h. The reaction mixture was diluted with saturated NH4Cl (20 mL), and the aqueous phase was extracted three times with DCM (40...

Claims

1. Compound of formula XXVIII-c: 【Chemistry 515】 or a pharma- ceutically acceptable salt thereof, R Ｚ is hydrogen or C １－８ an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 14-membered carbocyclic ring, phenyl, a 3- to 10-membered saturated or partially unsaturated heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 14-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy Ｃ is a saturated or partially unsaturated 3- to 14-membered carbocyclic ring; a saturated or partially unsaturated 3- to 14-membered heterocyclic ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; phenyl; or a 5- to 14-membered heteroaryl having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Cy is Ｃ is R Ｃ is replaced by p occurrences of R Ｃ Each occurrence of is independently R １ Or R ２ and R Ｃ is R ３ Noq Ｃ has been replaced by occurrences of; or R Ｃ two occurrences of together with their intervening atoms form a 4-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which ring is ３ is replaced by r occurrences of R １ Each occurrence of is independently selected from oxo, halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. 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 N.R. ２ , -N(R)S(O)R, or -N(R)S(O) ２ R, R ２ Each occurrence of １－７ aliphatic; phenyl; 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; a 3-7 membered saturated or partially unsaturated carbocycle; a 3-7 membered saturated or partially unsaturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or a 7-12 membered saturated or partially unsaturated bicyclic heterocycle having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, R ３ Each occurrence of is independently selected from oxo, halogen, -CN, -NO ２ , -OR, -SR, -NR ２ , -S(O) ２ R, -S(O) ２ N.R. 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 N.R. ２ , -N(R)S(O)R, -N(R)S(O) ２ R or C １－６ an optionally substituted group selected from aliphatic, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; Each R is independently hydrogen or C １－６ an optionally substituted group selected from an aliphatic, saturated or partially unsaturated 3- to 7-membered carbocyclic ring, phenyl, a 3- to 7-membered saturated or partially unsaturated heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5- to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; or Two R groups on the same nitrogen, together with their intervening atoms, form 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 each of p, q C, and r is independently 0, 1, 2, 3, or 4).

2. R Ｚ But, C １－６ 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, which is an optionally substituted group selected from aliphatic and saturated or partially unsaturated 3- to 7-membered carbocyclic rings.

3. The compound of claim 2, or a pharma- ceutically acceptable salt thereof, wherein R Z is optionally substituted C 1-4 aliphatic.

4. R Z is -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -C(CH 3 ) 2 CN, 【Chemistry 516】 4. The compound of claim 3, wherein:

5. The compound according to claim 2, or a pharma- ceutically acceptable salt thereof, wherein R Z is an optionally substituted saturated or partially unsaturated 3- to 7-membered carbocyclic ring.

6. R Z is 【Chemistry 517】 6. The compound of claim 5, wherein:

7. R Z is 【Chemistry 518】 6. The compound of claim 5, wherein:

8. Cy Ｃ is a 5-6 membered heteroaryl ring having 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, or a pharma- ceutically acceptable salt thereof.

9. The compound of claim 8, or a pharma- ceutically acceptable salt thereof, wherein CyC is a 5-membered heteroaryl ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur.

10. The compound of claim 9, or a pharma- ceutically acceptable salt thereof, wherein CyC is a 5-membered heteroaryl ring having 1 to 2 heteroatoms selected from nitrogen, oxygen, and sulfur.

11. Cy C is 【Chemistry 519】 11. The compound according to any one of claims 1 to 10, wherein:

12. Cy C is 【Chemistry 520】 11. The compound according to any one of claims 1 to 10, wherein:

13. Cy C is 【Chemistry 521】 11. The compound according to any one of claims 1 to 10, wherein:

14. The compound of claim 12, or a pharma- ceutically acceptable salt thereof, wherein R C is C1-7 aliphatic.

15. The compound according to claim 11, or a pharma- ceutically acceptable salt thereof, wherein at least one R C is -CH 3 .

16. The compound according to claim 13, or a pharma- ceutically acceptable salt thereof, wherein R C is -OR.

17. The compound according to claim 13, or a pharma- ceutically acceptable salt thereof, wherein R C is -OR substituted with R 3 .

18. The compound according to claim 17, or a pharma- ceutically acceptable salt thereof, wherein R3 is halogen, --CN, or --NO2.

19. The compound of claim 16 or claim 17, or a pharma- ceutically acceptable salt thereof, wherein R is an optionally substituted C1-6 aliphatic.

20. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein p is 2.

21. The compound according to any one of claims 1 to 20, wherein q C is 2, or a pharma- ceutically acceptable salt thereof.

22. The compound of claim 1, 【Table 19-1】 【Table 19-2】 【Table 19-3】 【Table 19-4】 22. The compound according to any one of claims 1 to 21, or a pharma- ceutically acceptable salt thereof, selected from:

23. 23. A pharmaceutical composition comprising a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

24. A composition or pharmaceutical composition for inhibiting CDK2 signaling activity in a subject, comprising a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23.

25. A composition or pharmaceutical composition for treating a CDK2 mediated disorder in a subject, comprising a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23.

26. A composition or pharmaceutical composition for treating a disorder in a subject, wherein the disorder 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, comprising a compound according to any one of claims 1 to 22 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to claim 23.

27. The composition of claim 26, wherein the bladder cancer is urothelial carcinoma.

28. The composition of claim 26, wherein the liver cancer is hepatocellular carcinoma.

29. 27. The composition of claim 26, wherein the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

30. 27. The composition of claim 26, wherein the laryngeal cancer is laryngeal squamous cell carcinoma.

31. 27. The composition of claim 26, wherein the skin cancer is melanoma.

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