CDK inhibitors and methods of use thereof

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 385,905, filed on December 2, 2022, U.S. Provisional Application No. 63 / 578,835, filed on August 25, 2023, and U.S. Provisional Application No. 63 / 590,346, filed on October 13, 2023, the entire contents of each of which are hereby incorporated by reference. Background Art

[0003] Mammalian cyclin-dependent kinases (CDKs) are a family of serine / threonine kinases that are regulated by direct binding to specific cell cycle proteins. CDKs are mainly divided into two groups based on their cellular functions: cell cycle regulators (CDK1, CDK2, CDK4, and CDK6) and gene transcription regulators (CDK7, CDK8, CDK9, CDK11, CDK12, and CDK13). Other CDKs (CDK3, CDK5, CDK10, CDK14, CDK16, CDK18, and CDK20) have been discovered more recently, but little is known about their biological functions (Malumbres, M. et al., Nat Rev Cancer 2009; Chou J. et al., Cancer Discov 2020).

[0004] The role of CDKs as gatekeepers at each stage of cell cycle progression is well established. Cell division after quiescence is initiated by mitogenic stimuli, which signal through the MAPK pathway to upregulate cyclin D, which binds to and activates CDK4 / 6. The activated CDK4 / 6-cyclin D complex directly monophosphorylates and partially inhibits retinoblastoma protein (RB), thereby releasing the E2F transcription factor to initiate the gene expression program necessary for DNA replication. Cyclin E is one of the E2F target genes, which forms a complex and activates CDK2 to further hyperphosphorylate RB and completely release E2F. The activity of the CDK2-cyclin A complex mediates the final stage of DNA replication, while the CDK1-cyclin B and CDK1-cyclin A complexes regulate the mitotic stage involving the separation of sister chromosomes into two daughter cells (Malumbres, M. et al., Nat Rev Cancer 2009; Fassl A. et al., Science 2022).

[0005] Significant genetic evidence suggests that CDK4 / 6-cyclin D may be involved in cancer development and progression. Indeed, the cyclin D (CCND1) gene is frequently amplified and overexpressed in a variety of tumor types, including breast cancer (Sanchez-Vega F. et al., Cell 2018). The role of CDK4 / 6-cyclin D in breast tumorigenesis was confirmed using in vivo genetic models, showing that cyclin D overexpression is sufficient to induce breast tumors in mice (Wang TC et al., Nature 1994). Conversely, genetic ablation of cyclin D or CDK4 abolished breast tumorigenesis driven by well-established oncogenes such as RAS and HER2 in mice (Yu Q. et al., Nature 2001; Yu Q. et al., Cancer Cell 2006).

[0006] Interestingly, a subgroup of breast cancers characterized by luminal gene expression and hormone receptor positivity (HR+) was found in preclinical studies to be exclusively CDK4-cyclin D dependent (Finn RS et al., Brest Cancer Res 2009). Summary of the Invention

[0007] In some embodiments, the present disclosure encompasses the recognition that there is a need to develop CDK selective inhibitor compounds, such as CDK4 selective inhibitor compounds, and methods of using these compounds to treat cancer and other disorders.

[0008] In some embodiments, the present disclosure provides compounds of Formula I':

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy X Each of L, Q, and Z is as defined in the embodiments and classes and subclasses herein.

[0011] In some embodiments, the present disclosure provides compounds of Formula I:

[0012]

[0013] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy X Each of , Q and Z is as defined in the embodiments and classes and subclasses herein.

[0014] In some embodiments, the present disclosure provides a compound of Formula IA or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the present disclosure provides compounds of Formula II, III, and IV; or pharmaceutically acceptable salts thereof.

[0016] In some embodiments, the present disclosure provides compounds of Formula II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU, and II-VV; or pharmaceutically acceptable salts thereof.

[0017] In some embodiments, the present disclosure provides compounds of Formula II-A1, II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, and II-Q1; or pharmaceutically acceptable salts thereof.

[0018] In some embodiments, the present disclosure provides compounds of Formula II-A2, II B2, II-C2, II-D2, II-E2, II-F2, II-G2, and II-H2; or pharmaceutically acceptable salts thereof.

[0019] In some embodiments, the present disclosure provides compounds of Formula V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII; or pharmaceutically acceptable salts thereof.

[0020] In some embodiments, the present disclosure provides compounds of Formula XXIII, XXIV, XXV, XXVI, and XXVII; or pharmaceutically acceptable salts thereof.

[0021] In some embodiments, the present disclosure provides compounds of Formula XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, and XXXIX; or pharmaceutically acceptable salts thereof.

[0022] In some embodiments, the present disclosure provides compounds of Formula XL, XLI, XLII, and XLIII; or pharmaceutically acceptable salts thereof.

[0023] In some embodiments, the present disclosure provides compounds of Formula XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LII, LIII, LIV, and LV; or pharmaceutically acceptable salts thereof.

[0024] In some embodiments, the present disclosure provides compounds of Formula LVI, LVII, LVIII, and LIX; or pharmaceutically acceptable salts thereof.

[0025] In some embodiments, the present disclosure provides compounds of Formula LX, LXI, LXII, LXIII, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, and LXXI; or pharmaceutically acceptable salts thereof.

[0026] In some embodiments, the present disclosure provides compounds of Formula LXXII, LXXIII, LXXIV, and LXXV; or pharmaceutically acceptable salts thereof.

[0027] In some embodiments, the present disclosure provides compounds of Formula LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, LXXXI, LXXXII, LXXXIII, LXXXIV, LXXXV, LXXXVI, and LXXXVII; or pharmaceutically acceptable salts thereof.

[0028] In some embodiments, the present disclosure provides compounds of Formula LXXXVIII, LXXXIX, XC, and XCI; or pharmaceutically acceptable salts thereof.

[0029] 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 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, such as Formula IA, II, III, IV, II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-V, II- I-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU, II-VV, II-A 1. II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, II-Q1, II-A2, II B2, II-C2, II-D2, II-E2, II-F2, II-G2, II-H2, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI , XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or diluent thereof.

[0030] In some embodiments, the present disclosure provides a method of treating a CDK4-mediated disorder comprising administering to a patient in need thereof a compound of Formula I' or a composition comprising said compound. In some embodiments, the present disclosure provides a method of treating a CDK4-mediated disorder comprising administering to a patient in need thereof a compound of Formula I' or a composition comprising said compound.In some embodiments, the present disclosure provides methods of treating a CDK4-mediated disorder comprising administering to a patient in need thereof a compound of the present disclosure, e.g., Formula IA, II, III, IV, II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU, II-VV, I I-A1, II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, II-Q1, II-A2, II B2, II-C2, II-D2, II-E2, II-F2, II-G2, II-H2, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI , XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX XL, XLI, XLII, XLIII XLIV, XLV, XLVI, XLVII, Compounds of LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, LXXXI, LXXXII, LXXXIII, LXXXIV, LXXXV, LXXXVI, LXXXVII, LXXXVIII, LXXXIX, XC or XCI, or compositions containing said compounds.In some embodiments, the present disclosure provides methods of treating a CDK4-mediated disorder comprising administering to a patient in need thereof a compound of the present disclosure, eg, a compound of Formula IA, or a composition comprising the compound.

[0031] In some embodiments, the present disclosure provides a method for providing a compound of formula I' or a synthetic intermediate thereof. In some embodiments, the present disclosure provides a method for providing a compound of formula I or a synthetic intermediate thereof. In some embodiments, the present disclosure provides a method for providing a compound of the present disclosure, such as formula IA, II, III, IV, II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU, II-VV, II-A 1. II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, II-Q1, II-A2, II B2, II-C2, II-D2, II-E2, II-F2, II-G2, II-H2, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI , XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX XL, XLI, XLII, XLIIIXLIV, XLV, XLVI, XLVII, LIX, LX, LXI, LXII, LXIII, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, LXXI, LXXII, LXXIII, LXXIV, LXXV Compounds of LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, LXXXI, LXXXII, LXXXIII, LXXXIV, LXXXV, LXXXVI, LXXXVII, LXXXVIII, LXXXIX, XC or XCI, or their synthetic intermediates.

[0032] In some embodiments, the present disclosure provides a method for providing a pharmaceutical composition comprising a compound of Formula I'. In some embodiments, the present disclosure provides a method for providing a pharmaceutical composition comprising a compound of Formula I.In some embodiments, the present disclosure provides methods for providing pharmaceutical compositions comprising compounds of the present disclosure, such as those of Formula IA, II, III, IV, II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-V, II-W, II-X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-V, II- I-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU, II-VV, I I-A1, II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, II-Q1, II-A2, II B2, II-C2, II-D2, II-E2, II-F2, II-G2, II-H2, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI , XXII, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX XL, XLI, XLII, XLIII XLIV, XLV, XLVI, XLVII, Compounds of LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, LXXXI, LXXXII, LXXXIII, LXXXIV, LXXXV, LXXXVI, LXXXVII, LXXXVIII, LXXXIX, XC or XCI. DETAILED DESCRIPTION

[0033] 1. General Description of Certain Embodiments

[0034] The compounds and pharmaceutical compositions provided herein can be used as inhibitors of CDK4. In some embodiments, the present disclosure provides compounds of Formula I':

[0035]

[0036] or a pharmaceutically acceptable salt thereof, wherein:

[0037] Q is for L 1 ;

[0038] Z is H, halogen or Cy B ;

[0039] L is a covalent bond or a divalent C 1-3 An aliphatic group in which one carbon is optionally replaced by -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)-, -S(O)2-, C 3-6 is replaced by a cycloalkylene or a 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 3-6 Each of the cycloalkylene and 3-6 membered heterocycloalkylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution;

[0040] Cy A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m times A replace;

[0041] CyB is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace;

[0042] Cy X is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated, partially unsaturated or aromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-15 membered saturated, partially unsaturated or aromatic tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur;

[0043] Among them, Cy X L that appeared by u 2 -X 0 replace;

[0044] X 0 is hydrogen, halogen, oxo, CN or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X 0 R appears p times X replace;

[0045] Y is N or CH;

[0046] Each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being qA The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and R X Being q X The number of R 3 Replace; or

[0047] Two occurrences of R A , two occurrences of R B , two occurrences of R X , two Xs appear 0 、X appears 0 and the appearance of R A or the appearance of R A and the appearance of R X Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace;

[0048] L 1 and L 2 Each of is independently a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution;

[0049] Each occurrence of R L Independently R 1 or R2 , and is replaced by t occurrences of R 3 replace;

[0050] Each occurrence of R 1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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 -P(O)R2;

[0051] Each occurrence of R 2 Independently C 1-7 Aliphatic group; -OC 1-7 Aliphatic group; C 1-4 haloalkyl; 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 monocyclic 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;

[0052] Each occurrence of R 3 and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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;

[0053] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a saturated or partially unsaturated 3-7 membered heterocyclic ring 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, or:

[0054] The two R groups on the same nitrogen are taken together with their intervening atoms to 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

[0055] m, n, p, q A ,q B ,q X Each of r, t and u is independently 0, 1, 2, 3 or 4.

[0056] The compounds and pharmaceutical compositions provided herein can be used as inhibitors of CDK4. In some embodiments, the present disclosure provides compounds of Formula I:

[0057]

[0058] or a pharmaceutically acceptable salt thereof, wherein:

[0059] Q is for L 1 ;

[0060] Z is H or Cy B ;

[0061] Cy A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m timesA replace;

[0062] Cy B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace;

[0063] Cy X yes in represents a bond to Q, and Indicates that Cy A Key;

[0064] X is N or CL 2 -X 0 ;

[0065] X 0 is hydrogen, halogen or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X 0 R appears p times X replace;

[0066] Y is N or CH;

[0067] Each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being q A The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and RX Being q X The number of R 3 Replace; or

[0068] Two occurrences of R A , two occurrences of R B , two occurrences of R X or the appearance of R A and the appearance of R X Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace;

[0069] L 1 and L 2 Each of is independently a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution;

[0070] Each occurrence of R L Independently R 1 or R 2 , and is replaced by t occurrences of R 3 replace;

[0071] Each occurrence of R 1is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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;

[0072] Each occurrence of R 2 Independently C 1-7 Aliphatic group; -OC 1-7 Aliphatic group; C 1-4 haloalkyl; 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 monocyclic 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;

[0073] Each occurrence of R 3 and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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;

[0074] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a saturated or partially unsaturated 3-7 membered heterocyclic ring 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, or:

[0075] The two R groups on the same nitrogen are taken together with their intervening atoms to 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

[0076] m, n, p, q A ,q B ,q X Each of r, r and t is independently 0, 1, 2, 3 or 4.

[0077] 2. Compounds and Definitions

[0078] The compounds described herein include those generally described herein and are further described by the categories, subclasses and species disclosed herein. As used herein, unless otherwise indicated, the following definitions will apply. For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. In addition, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999 and "March's Advanced Organic Chemistry", 5th edition, editors: Smith, MB and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference. Chemical name, common name and chemical structure can be used interchangeably to describe the same structure. If both chemical structure and chemical name are used to refer to a chemical compound, and there is ambiguity between the structure and the name, the structure shall prevail.

[0079] As used herein, the term "aliphatic" or "aliphatic group" means a straight chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle" or "alicyclic group") that is fully saturated or contains one or more unsaturated units but is not aromatic, which 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 yet other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in yet other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In some embodiments, an "alicyclic group" (or "carbocycle") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more unsaturated units, but is not aromatic, which has a single point of attachment to the rest of the molecule. The carbocycle may be a bridged bicyclic ring or a fused ring in some cases, for example, an ortho-fused carbocycle, a spiro-fused carbocycle, etc. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hetero groups thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0080] As used herein, unless otherwise indicated, the term "alkyl" refers to a monovalent aliphatic hydrocarbon group having a straight chain, branched chain, monocyclic or polycyclic portion, or a combination thereof, wherein the group is optionally substituted on one or more carbons of the straight chain, branched chain, monocyclic or polycyclic portion, or a combination thereof, with one or more substituents on each carbon, wherein the one or more substituents are independently C1-C 10 Alkyl. 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.

[0081] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0082] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0083] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + (as in N-substituted pyrrolidinyl)).

[0084] As used herein, the term "unsaturated" means that a moiety has one or more units of unsaturation.

[0085] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein 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 chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0086] The term "alkenylene" refers to a divalent alkenyl group. Substituted alkenylene chains are polymethylene groups containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0087] The term "halogen" means F, Cl, Br or I.

[0088] The term "aryl" used alone or as part of a larger moiety refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3 to 7 ring members. The term "aryl" can 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, anthracenyl, and the like, which may carry one or more substituents. It will be appreciated that an "aryl" group may contain carbon and heteroatom ring members.

[0089] Unless otherwise defined, the term "heteroaryl" or "heteroaromatic" as used herein refers to a monocyclic aromatic 5-6 membered ring containing one or more heteroatoms (e.g., one to four heteroatoms such as nitrogen, oxygen and sulfur), or an 8-10 membered polycyclic ring system containing one or more heteroatoms, wherein at least one ring in the polycyclic ring system is aromatic and the point of attachment of the polycyclic ring system is through ring atoms on the aromatic ring. A heteroaryl ring may be attached to an adjacent group 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, if the point of attachment of 1,2,3,4-tetrahydroquinoline is through a benzo ring, then it is a heteroaryl ring, for example:

[0090]

[0091] Unless otherwise defined, the term "heterocyclyl" or "heterocyclic group" refers to a saturated or partially unsaturated 3-10 membered monocyclic or 7-14 membered polycyclic ring system, including bridged or fused rings (e.g., ortho-fused bicyclic or spiro-fused bicyclic rings), which ring system includes one to four heteroatoms such as nitrogen, oxygen, phosphorus and sulfur. The heterocyclyl ring can be attached to the adjacent group through carbon or nitrogen.

[0092] Unless otherwise defined, the term "partially unsaturated" in the context of a ring 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 the unsaturation provided by 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, and the like. Where a partially unsaturated ring is part of a polycyclic ring system, the other constituent rings in the polycyclic ring system may be saturated, partially unsaturated, or aromatic, but the point of attachment 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 if its point of attachment is through the piperidino ring, e.g.:

[0093]

[0094] Unless otherwise defined, the term "saturated" refers to a 3-10 yuan monocyclic ring or a 7-14 yuan polycyclic (such as a bicyclic, tricyclic, etc.) ring system in the context of a ring, wherein the monocyclic ring or the constituent ring as the connection point of the polycyclic ring system does not contain other unsaturation except the unsaturation provided by the ring itself. The example of a monocyclic saturated ring includes but is not limited to azetidine, oxetane, cyclohexane, etc. In the case where a saturated ring is a part of a polycyclic ring system, other constituent rings in the polycyclic ring system can be saturated, partially unsaturated or aromatic, but the connection point of the polycyclic ring system is on a saturated constituent ring. For example, unless otherwise defined, if the connection point of 2-azaspiro [3.4] oct-6-ene is through an azetidine sub-ring, it is a saturated ring, such as:

[0095]

[0096] As used herein, the terms "alkylene," "arylene," "cycloalkylene," "heteroarylene," "heterocycloalkylene," and other similar terms with the suffix "-ylene" refer to the divalent bonded form of the radical that the suffix modifies. For example, "alkylene" is a divalent alkyl radical that is linked to the radical to which it is attached.

[0097] As used herein, the term "bridged bicyclic" refers to any bicyclic ring system with at least one bridge, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated. As defined by IUPAC, a "bridge" is a non-branched chain or atom or valence bond connecting multiple atoms of two bridgeheads, wherein a "bridgehead" is any skeleton atom bonded to three or more skeleton atoms (excluding hydrogen) of a ring system. In some embodiments, the bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. This type of bridged bicyclic group is well known in the art and includes those groups shown below, wherein each group is connected to the rest of the molecule on any substitutable carbon or nitrogen atom. Unless otherwise indicated, the bridged bicyclic group is optionally substituted by one or more substituents as shown for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of the bridged bicyclic group is optionally substituted. Exemplary bridged bicyclics include:

[0098]

[0099] As described herein, the compounds described herein may contain "optionally substituted" moieties. In general, the term "substituted," whether or not preceded by the term "optionally," means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituents at each position may be the same or different. The combinations of substituents contemplated by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. As used herein, the term "stable" refers to compounds that do not substantially change when subjected to conditions that allow for production, detection, and in certain embodiments, recovery, purification, and use for one or more purposes disclosed herein.

[0100] Suitable monovalent substituents on the substitutable carbon atoms of an "optionally substituted" group are independently halogen; -(CH2) 0– 4R o ; –(CH2) 0–4 OR o ;-O(CH2) 0-4 R o 、–O–(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 CH(OR o )2;–(CH2) 0–4 SR o ; can be R o Substituted –(CH2) 0–4 Ph; can be R oSubstituted –(CH2) 0–4 O(CH2) 0–1 Ph; can be R o Substituted –CH=CHPh; can be R o Substituted –(CH2) 0–4 O(CH2) 0–1 -pyridyl; –NO2; –CN; –N3; -(CH2) 0–4 N(R o )2;–(CH2) 0–4 N(R o )C(O)R o ;–N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;–(CH2) 0–4 N(R o )C(O)OR o ;–N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; –(CH2) 0–4 C(O)R o ;–C(S)R o ; –(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 C(O)SR o ; -(CH2) 0–4 C(O)OSiR o 3;–(CH2) 0–4 OC(O)R o ;–OC(O)(CH2) 0– 4SR o ;–SC(S)SR o ; –(CH2) 0–4 SC(O)R o ; –(CH2) 0–4 C(O)NR o 2;–C(S)NR o 2;–C(S)SR o;–SC(S)SR o 、-(CH2) 0–4 OC(O)NR o 2;-C(O)N(OR o )R o ;–C(O)C(O)R o ;–C(O)CH2C(O)R o ;–C(NOR o )R o ; -(CH2) 0– 4SSR o ; –(CH2) 0–4 S(O)2R o ; –(CH2) 0–4 S(O)2OR o ; –(CH2) 0–4 OS(O)2R o ;–S(O)2NR o 2; -(CH2) 0–4 S(O)R o ;-N(R o )S(O)2NR o 2;–N(R o )S(O)2R o ;–N(OR o )R o ;–C(NH)NR o 2;–P(O)(OR o )R o ;-P(O)R o 2;-OP(O)R o 2;–OP(O)(OR o )2;–SiR o 3;–(C 1–4 linear or branched alkylene)O–N(R o )2; or –(C 1–4 linear or branched alkylene) C(O)O–N(R o )2, where each R o may be substituted as defined below and are independently hydrogen, C 1–6 Aliphatic groups, –CH2Ph, –O(CH2) 0–1 Ph, -CH2-(5-6 membered heteroaryl ring) or a 3-6 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 oTogether with their intervening atoms they form a 3-12 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.

[0101] R o (or through two independent occurrences of R o Suitable monovalent substituents on the ring formed by taking together with their intervening atoms are independently halogen, –(CH2) 0–2 R ● 、–(halogenated R ● ),–(CH2) 0–2 OH, –(CH2) 0–2 OR ● 、–(CH2) 0–2 CH(OR ● )2;-O(halogenated R ● ), –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 · , where each R ● is unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and is independently selected from C 1–4 Aliphatic groups, –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. o Suitable divalent substituents on a saturated carbon atom of include =0 and =S.

[0102] Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =0, =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–, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1–6 An aliphatic group or an unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents attached to the ortho-substitutable carbon of an "optionally substituted" group include: -O(CR * 2) 2–3 O–, where each independent occurrence of R * is selected from hydrogen, C which may be substituted as defined below 1–6 aliphatic or an unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0103] R * Suitable substituents on the aliphatic group include halogen, –R ● 、-(halogenated R ● ),-OH, –OR ● 、–O(halogenated R ● ), –CN, –C(O)OH, –C(O)OR · , –NH2, –NHR · ,–NR · 2 or –NO2, where each R · is unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and is independently C 1–4 Aliphatic groups, –CH2Ph, –O(CH2) 0– 1Ph or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0104] Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include or Each of these are independently hydrogen, C 1–6aliphatic, unsubstituted -OPh, or a 5-6 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definitions, two independent occurrences of Together with their intervening atoms they 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.

[0105] Suitable substituents on the aliphatic group are independently halogen, -R · 、-(halogenated R · ),–OH,–OR · 、–O(halogenated R · ), –CN, –C(O)OH, –C(O)OR ● , –NH2, –NHR ● ,–NR ● 2 or -NO2, where each R ● is unsubstituted or, when preceded by "halo", substituted only by one or more halogens, and is independently C 1–4 Aliphatic groups, –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.

[0106] As used herein, the term "isomer" refers to compounds having the same chemical formula but different structural or optical configurations. As used herein, the term "stereoisomer" refers to and includes isomeric molecules having the same molecular formula but different positioning of atoms and / or functional groups in space. All stereoisomers of the compounds of the present invention (e.g., those that may exist due to asymmetric carbons on various substituents), including enantiomeric and diastereomeric forms, are encompassed within the scope of this disclosure. Therefore, single stereochemical isomers of the compounds of the present invention, as well as mixtures of enantiomers, diastereomers, and geometric (or conformational) isomers, are within the scope of this disclosure.

[0107] As used herein, the term "tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another. It is understood that tautomers encompass valence tautomers and proton tautomers (also known as prototropic tautomers). Valence tautomers include interconversions that occur by reorganization of some bonding electrons. Proton tautomers include interconversions that occur via migration of protons, such as keto-enol and imine-enamine isomerizations. Unless otherwise indicated, all tautomers of the compounds described herein are within the scope of this disclosure.

[0108] As used herein, the term "isotopic substitution" refers to the replacement of an atom by its isotope. As used herein, the term "isotope" refers to an atom having the same atomic number as the atom predominant in nature, but having a different mass number (number of neutrons) than the mass number of the atom predominant in nature. It is understood that a compound having isotopic substitution refers to a compound in which at least one atom is replaced by its isotope. Atoms that can be replaced by their isotopes include, but are not limited to, hydrogen, carbon, and oxygen. Examples of isotopes of hydrogen atoms include 2 H (also denoted as D) and 3 H. Examples of isotopes of carbon atoms include 13 C and 14 C. Examples of isotopes of oxygen atoms include 18 Unless otherwise stated, 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, probes in biological assays, or therapeutic agents according to the present disclosure.

[0109] As used herein, the term "pharmaceutically acceptable salts" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and 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, PL, Int. J. Pharmaceutics 1986, 33, 201-217; (each of which is hereby incorporated by reference in its entirety).

[0110] 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 include salts of amino groups formed with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid) or with organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid) or salts formed by other methods employed 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, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, 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, valerate, and the like.

[0111] Salts derived from appropriate bases include alkali metal salts, alkaline earth metal salts, ammonium salts and N + (C 1–4 Representative alkali metal or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, and the like. Further pharmaceutically acceptable salts include (where appropriate) non-toxic ammonium, quaternary ammonium, and amine cation salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0112] Pharmaceutically acceptable salts are also intended to encompass hemi-salts, wherein the ratio of compound:acid is respectively 2:1. Exemplary hemi-salts include those derived from acids comprising 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 include those derived from diprotic mineral acids such as sulfuric acid. Exemplary preferred hemi-salts include, but are not limited to, hemimaleate, hemifumarate, and hemisuccinate.

[0113] As used herein, the term "about" is used herein to mean approximately, roughly, roughly, or roughly. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values ​​set forth. Generally, the term "about" is used herein to modify a numerical value above and below the stated value by a variation of 20% (higher or lower) above or below the stated value.

[0114] As used herein, an "effective amount," "sufficient amount," or "therapeutically effective amount" is an amount of a compound that, when administered according to a therapeutic dosing regimen to a subject or population suffering from or susceptible to a disease, disorder, and / or condition, is sufficient to treat (e.g., achieve beneficial or desired results, including clinical results) the disease, disorder, and / or condition. Thus, an effective amount can be sufficient, for example, to reduce or lessen the severity and / or duration of a disorder associated with CDK4 signaling or one or more symptoms thereof, to prevent the progression of a condition or symptom associated with a disorder associated with CDK4 signaling, or to enhance or otherwise improve the prophylactic or therapeutic effect of another therapy. An effective amount also includes an amount of a compound that avoids or significantly reduces adverse side effects.

[0115] As used herein and as fully understood in the art, "treatment" is a method for obtaining beneficial or desired results (including clinical results). Beneficial or desired clinical results may include, but are not limited to, alleviating or improving one or more symptoms or conditions, reducing the degree of the disease or illness, stabilizing (i.e., not worsening) the state of the disease or illness, preventing the spread of the disease or illness, delaying or slowing the progress of the disease or illness, improving or alleviating the disease or illness state, and alleviating (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean extending the survival period compared to the expected survival period under untreated conditions. In some embodiments, treatment may be implemented after one or more symptoms have occurred. In other embodiments, treatment may be implemented in the absence of symptoms. For example, treatment may be implemented to susceptible individuals before the onset of symptoms (e.g., according to symptom history and / or according to genetic or other susceptible factors). Treatment may also be continued after the symptoms have subsided, for example to prevent or delay their recurrence.

[0116] The phrase "in need thereof" refers to situations where relief of symptomatic or asymptomatic manifestations of a condition associated with CDK4 signaling activity is desired, or which may otherwise be alleviated by the compounds and / or compositions of the present disclosure.

[0117] 3. Description of Exemplary Embodiments

[0118] In some embodiments, the present disclosure provides compounds of Formula I:

[0119]

[0120] or a pharmaceutically acceptable salt thereof, wherein:

[0121] Q is for L 1 ;

[0122] Z is H or Cy B ;

[0123] Cy Ais phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m times A replace;

[0124] Cy B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace;

[0125] Cy X yes in represents a bond to Q, and Indicates that Cy A Key;

[0126] X is N or CL 2 -X 0 ;

[0127] X 0 is hydrogen, halogen or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X0 R appears p times X replace;

[0128] Y is N or CH;

[0129] Each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being q A The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and R X Being q X The number of R 3 Replace; or

[0130] Two occurrences of R A , two occurrences of R B , two occurrences of R X or the appearance of R A and the appearance of R X Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace;

[0131] L 1 and L 2 Each of is independently a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution;

[0132] Each occurrence of R L Independently R 1 or R 2 , and is replaced by t occurrences of R 3 replace;

[0133] Each occurrence of R 1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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;

[0134] Each occurrence of R 2 Independently C 1-7 Aliphatic group; -OC 1-7 Aliphatic group; C 1-4 haloalkyl; 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 monocyclic 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;

[0135] Each occurrence of R 3and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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;

[0136] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a saturated or partially unsaturated 3-7 membered heterocyclic ring 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, or:

[0137] The two R groups on the same nitrogen are taken together with their intervening atoms to 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

[0138] m, n, p, q A ,q B ,q X Each of r, r and t is independently 0, 1, 2, 3 or 4.

[0139] In some embodiments, the present disclosure provides compounds of Formula IA:

[0140]

[0141] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy B Each of Q, X, and Y is as defined in the embodiments and classes and subclasses herein.

[0142] In some embodiments, the present disclosure provides compounds of Formula II, III, and IV:

[0143]

[0144] or a pharmaceutically acceptable salt thereof, wherein Cy A 、Cy B , Q, X 0 Each of and Y is as defined in the embodiments and classes and subclasses herein.

[0145] In some embodiments, the disclosure provides formulas II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X, II-Y, Compounds of II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU and II-VV:

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154] or a pharmaceutically acceptable salt thereof, wherein Cy B , Q, X 0 , Y, R A Each of and m is as defined in the embodiments and classes and subclasses herein.

[0155] In some embodiments, the present disclosure provides compounds of Formula II-A1, II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, and II-Q1:

[0156]

[0157]

[0158] or a pharmaceutically acceptable salt thereof, wherein Cy A , Q, X 0 , Y, R B Each of and n is as defined in the embodiments and classes and subclasses herein.

[0159] In some embodiments, the present disclosure provides compounds of Formula II-A2, II B2, II-C2, II-D2, II-E2, II-F2, II-G2, and II-H2:

[0160]

[0161] or a pharmaceutically acceptable salt thereof, wherein Cy A , Q, X 0 , Y, R B and R 3 Each of which is as defined in the embodiments and classes and subclasses herein.

[0162] In some embodiments, the present disclosure provides compounds of Formulas V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, and XXII:

[0163]

[0164]

[0165]

[0166] or a pharmaceutically acceptable salt thereof, wherein Q, X 0 , Y, R A 、R B 、R 3 Each of m, m, and n is as defined in the embodiments and classes and subclasses herein.

[0167] In some embodiments, the present disclosure provides compounds of Formula XXIII, XXIV, XXV, XXVI, and XXVII:

[0168]

[0169] or a pharmaceutically acceptable salt thereof, wherein Cy B , Q, X 0 , Y, RA 、R 3 and q A Each of which is as defined in the embodiments and classes and subclasses herein.

[0170] In some embodiments, the present disclosure provides compounds of Formula XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, and XXXIX:

[0171]

[0172]

[0173] or a pharmaceutically acceptable salt thereof, wherein Q, X 0 , Y, R A 、R B 、R 3 Each of and n is as defined in the embodiments and classes and subclasses herein.

[0174] In some embodiments, the present disclosure provides compounds of Formula XL, XLI, XLII, and XLIII:

[0175]

[0176] or a pharmaceutically acceptable salt thereof, wherein Cy B , Q, X 0 , Y, R A 、R 3 and q A Each of which is as defined in the embodiments and classes and subclasses herein.

[0177] In some embodiments, the present disclosure provides compounds of Formula XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LII, LIII, LIV, and LV:

[0178]

[0179]

[0180]

[0181] or a pharmaceutically acceptable salt thereof, wherein Q, X 0 , Y, R A 、R B 、R 3 Each of and n is as defined in the embodiments and classes and subclasses herein.

[0182] In some embodiments, the present disclosure provides compounds of Formula LVI, LVII, LVIII, and LIX:

[0183]

[0184] or a pharmaceutically acceptable salt thereof, wherein Cy B , Q, X 0 , Y, R A 、R 3 and q A Each of which is as defined in the embodiments and classes and subclasses herein.

[0185] In some embodiments, the present disclosure provides compounds of Formula LX, LXI, LXII, LXIII, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, and LXXI:

[0186]

[0187]

[0188] or a pharmaceutically acceptable salt thereof, wherein Q, X 0 , Y, R A 、R B 、R 3 Each of and n is as defined in the embodiments and classes and subclasses herein.

[0189] In some embodiments, the present disclosure provides compounds of Formula LXXII, LXXIII, LXXIV, and LXXV:

[0190]

[0191] or a pharmaceutically acceptable salt thereof, wherein Cy B , Q, X 0 , Y, R A 、R 3 and q A Each of which is as defined in the embodiments and classes and subclasses herein.

[0192] In some embodiments, the present disclosure provides compounds of Formula LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, LXXXI, LXXXII, LXXXIII, LXXXIV, LXXXV, LXXXVI, and LXXXVII:

[0193]

[0194]

[0195]

[0196] or a pharmaceutically acceptable salt thereof, wherein Q, X 0 , Y, R A 、R B 、R 3 Each of and n is as defined in the embodiments and classes and subclasses herein.

[0197] In some embodiments, the present disclosure provides compounds of Formula LXXXVIII, LXXXIX, XC, and XCI:

[0198]

[0199] or a pharmaceutically acceptable salt thereof, wherein Cy B , Q, X 0 , Y, R A 、R 3 and q A Each of which is as defined in the embodiments and classes and subclasses herein.

[0200] As generally defined above, Cy A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-11 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m times A replace.

[0201] In some embodiments, Cy A In some embodiments, Cy A yes

[0202] In some embodiments, Cy A is a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy A R appears m times A In some embodiments, Cy Ais a 3-8 membered monocyclic saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy A R appears m times A In some embodiments, Cy A In some embodiments, Cy A In some embodiments, Cy A In some embodiments, Cy A Is a cyclohexyl ring. In some embodiments, Cy A In some embodiments, Cy A It is a cyclooctyl ring.

[0203] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0204] In some embodiments, Cy A is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A In some embodiments, Cy A is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A In some embodiments, Cy A is a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A replace.

[0205] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0206] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0207] In some embodiments, Cy A is an 8-11 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A In some embodiments, Cy A is an 8-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A In some embodiments, Cy A is a 9-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A In some embodiments, Cy A is a 10-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein CyA R appears m times A In some embodiments, Cy A is an 11-membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A R appears m times A replace.

[0208] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, CyA yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0209] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0210] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0211] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0212] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0213] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0214] In some embodiments, Cy Ais an 8-11 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy A At least 2 occurrences of R A Substituted, wherein the 2 occurrences of R A Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0215] In some embodiments, Cy A yes Two of the R A Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0216] In some embodiments, Cy A yes Two of the R A Together with their intervening atoms, they form a 4-8 membered saturated ring, wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0217] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0218] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0219] In some embodiments, Cy A yes Two of the R A Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0220] In some embodiments, Cy A yes Two of the R A Together with their intervening atoms, they form a 4-8 membered saturated ring, wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0221] In some embodiments, Cy A yes In some embodiments, Cy A yes

[0222] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, CyA yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0223] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0224] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0225] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0226] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0227] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0228] In some embodiments, Cy A is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 3-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 4-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 7-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is an 8-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur.

[0229] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0230] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0231] In some embodiments, Cy A is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 7-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is an 8-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is a 9-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. Ais a 10-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. A is an 11-membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur.

[0232] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0233] In some embodiments, Cy A is a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur. A is a 10-14 membered aromatic or partially unsaturated tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A is a 10-14 membered partially unsaturated tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0234] In some embodiments, Cy A is a 10-membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A is an 11-membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A is a 12-membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A is a 13-membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A is a 14-membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0235] In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, CyA yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes In some embodiments, Cy A yes

[0236] In some embodiments, Cy A yes

[0237] In some embodiments, Cy A is selected from the groups shown in the compounds in Table 1.

[0238] In some embodiments, two occurrences of R A Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0239] In some embodiments, two occurrences of R B Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0240] In some embodiments, two occurrences of R X Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0241] In some embodiments, two occurrences of X 0 Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0242] In some embodiments, the occurrence of X 0 and the appearance of R ATogether with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0243] In some embodiments, the occurrence of R A and the appearance of R X Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0244] In some embodiments, L is a covalent bond or a divalent C 1-3 An aliphatic group in which one carbon is optionally replaced by -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)-, -S(O)2-, C 3-6 is replaced by a cycloalkylene or a 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 3-6 Each of the cycloalkylene and 3-6 membered heterocycloalkylene is optionally replaced by one occurrence of R 1 or C 1-6 Aliphatic substitution.

[0245] In some embodiments, L is a covalent bond. In some embodiments, L is ethynylene. In some embodiments, L is C 1-3 An aliphatic group wherein one carbon is optionally replaced by -C(O)-. In some embodiments, L is C 1-3 An aliphatic group wherein one carbon is optionally replaced by -O-. In some embodiments, L is C 1-3 An aliphatic group wherein one carbon is optionally replaced by -NH-. In some embodiments, L is C 1-3 In some embodiments, L is -NH-. In some embodiments, L is -N(R L )-. In some embodiments, L is -NHC(O)-. In some embodiments, L is -N(R L)C(O)-. In some embodiments, L is -C(O)NH-. In some embodiments, L is -C(O)N(R L )-. In some embodiments, L is -NHS(O)2-. In some embodiments, L is -N(R L )S(O)2-. In some embodiments, L is -S(O)2NH-. In some embodiments, L is -S(O)2N(R L )-. In some embodiments, L is -O-. In some embodiments, L is -C(O)-. In some embodiments, L is -OC(O)-. In some embodiments, L is -C(O)O-. In some embodiments, L is -S-. In some embodiments, L is -S(O)-. In some embodiments, L is -S(O)2-. In some embodiments, L is optionally replaced by one occurrence of R 1 or C 1-6 Aliphatic substituted C 3-6 In some embodiments, L is optionally replaced by one occurrence of R 1 or C 1-6 Aliphatic-substituted 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0246] In some embodiments, Cy B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace.

[0247] In some embodiments, Cy B is R that appears n times B Substituted phenyl.

[0248] In some embodiments, Cy B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by nB replace.

[0249] In some embodiments, Cy B is a 5-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0250] In some embodiments, Cy B is a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0251] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0252] In some embodiments, Cy B is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B replace.

[0253] In some embodiments, Cy B yes

[0254] In some embodiments, Cy B is a 3-8 membered saturated carbocyclic ring, wherein Cy B R appears by n B In some embodiments, Cy B is a 3-7 membered saturated carbocyclic ring, wherein Cy B R appears by n B In some embodiments, Cy B is a 4-7 membered saturated carbocyclic ring, wherein Cy B R appears by n B In some embodiments, Cy B is a 5-7 membered saturated carbocyclic ring, wherein Cy B R appears by n B In some embodiments, Cy B is a 5-6 membered saturated carbocyclic ring, wherein Cy B R appears by n B In some embodiments, Cy B Is a 4-6 membered saturated carbocyclic ring, wherein Cy B R appears by n B replace.

[0255] In some embodiments, Cy B In some embodiments, Cy B In some embodiments, Cy B In some embodiments, Cy B Is a cyclohexyl ring. In some embodiments, Cy B In some embodiments, Cy B It is a cyclooctyl ring.

[0256] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0257] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0258] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0259] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0260] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy Byes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0261] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0262] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0263] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0264] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0265] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0266] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0267] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0268] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0269] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0270] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0271] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0272] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0273] In some embodiments, Cy B is a 3-8 membered saturated or partially unsaturated carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B is a 3-7 membered saturated or partially unsaturated carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B is a 4-7 membered saturated or partially unsaturated carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R BTogether with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B is a 5-7 membered saturated or partially unsaturated carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B is a 5-6 membered saturated or partially unsaturated carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B is a 4-6 membered saturated or partially unsaturated carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0274] In some embodiments, Cy B is a 3-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0275] In some embodiments, Cy B yes Two of the R BTogether with their intervening atoms, they form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0276] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated ring, wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0277] In some embodiments, Cy B is a 4-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0278] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0279] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated ring, wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0280] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0281] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated ring, wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0282] In some embodiments, Cy B is a 5-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0283] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0284] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B yes In some embodiments, Cy B yes

[0285] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 5-6 membered aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B yes In some embodiments, Cy B yes

[0286] In some embodiments, Cy B is a 6-membered saturated or partially unsaturated monocyclic carbocyclic ring, wherein Cy B At least 2 occurrences of R B Substituted wherein the two occurrences of R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0287] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace.

[0288] In some embodiments, Cy B yes Two of the R B Together with their intervening atoms, they form a 5-6 membered aromatic ring, wherein the ring is surrounded by r occurrences of R 3 In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0289] 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 6-7 membered saturated bridged bicyclic or fused carbocyclic ring. B It is a 7-8 membered saturated bridged bicyclic or fused carbocyclic ring.

[0290] In some embodiments, Cy B is a 5-8 membered saturated or partially unsaturated fused carbocyclic ring. B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0291] In some embodiments, Cy B is a 5-8 membered saturated or partially unsaturated bridged carbocyclic ring. B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0292] In some embodiments, Cy B is a 5-8 membered saturated or partially unsaturated spiro-fused carbocyclic ring. B is a 5-8 membered saturated spiro-fused carbocyclic ring. In some embodiments, Cy B is a 6-7 membered saturated spiro-fused carbocyclic ring. In some embodiments, Cy B is a 7-8 membered saturated spiro-fused carbocyclic ring. In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0293] In some embodiments, Cy B is a 3-7 membered partially unsaturated monocyclic carbocyclic ring. B is a 5-6 membered partially unsaturated monocyclic carbocyclic ring. B yes In some embodiments, Cy B yes

[0294] In some embodiments, Cy B is a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. B is a saturated 3-7 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur. B is a saturated 4-7 membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur.

[0295] In some embodiments, Cy B is a 4-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. B is a 4-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen and oxygen. B yes In some embodiments, Cy B yes In some embodiments, CyB yes In some embodiments, Cy B yes

[0296] In some embodiments, Cy B is a 5-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0297] In some embodiments, Cy B is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. B is a 6-membered monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen and oxygen. B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0298] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, CyB yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0299] In some embodiments, Cy B yes

[0300] In some embodiments, Cy B is a saturated or partially unsaturated 7-10 membered bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy B R appears by n B replace.

[0301] In some embodiments, Cy B is a saturated or partially unsaturated 7-10 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B is a saturated or partially unsaturated 7-8 membered bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy B R appears by n B replace.

[0302] In some embodiments, Cy B is a saturated 7-10 membered bridged bicyclic or fused heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B is a saturated 7-10 membered bridged bicyclic or fused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B is a saturated 7-10 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B is a saturated 7-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein Cy B R appears by n B replace.

[0303] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0304] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0305] In some embodiments, Cy B yes In some embodiments, Cy B yes

[0306] In some embodiments, Cy B yes

[0307] In some embodiments, Cy B yes In some embodiments, Cy B yes

[0308] In some embodiments, Cy B is a saturated or partially unsaturated 7-10 membered spirofused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy B R appears by n B In some embodiments, Cy B is a saturated or partially unsaturated 7-9 membered spirofused heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy B R appears by n B replace.

[0309] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0310] In some embodiments, Cy B yes In some embodiments, Cy B yes In some embodiments, Cy B yes

[0311] In some embodiments, Cy B is selected from the groups shown in the compounds in Table 1.

[0312] In some embodiments, Cy X is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-15 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; wherein Cy X L that appeared by u 2 -X 0 replace.

[0313] In some embodiments, Cy X Is phenyl, where Cy X L that appeared by u 2 -X 0 In some embodiments, Cy X is naphthyl, where Cy X L that appeared by u 2 -X 0 In some embodiments, Cy X is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy X L that appeared by u 2 -X 0 In some embodiments, Cy X is an 8-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy X L that appeared by u 2 -X 0 In some embodiments, Cy X is a 7-12 membered saturated, partially unsaturated or aromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy X L that appeared by u 2 -X0 In some embodiments, Cy X is a 10-15 membered saturated, partially unsaturated or aromatic tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy X L that appeared by u 2 -X 0 replace.

[0314] In some embodiments, Cy X is a 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy X L that appeared by u 2 -X 0 In some embodiments, Cy X is a 13-15 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur, wherein Cy X L that appeared by u 2 -X 0 replace.

[0315] In some embodiments, Cy X yes in represents a bond to Q, and Indicates that Cy A In some embodiments, Cy X yes In some embodiments, Cy X yes In some embodiments, Cy X yes In some embodiments, Cy X yes In some embodiments, Cy X yes In some embodiments, Cy X yes In some embodiments, Cy X yes In some embodiments, Cy X yes

[0316] In some embodiments, Cy X yes in represents a bond to Q, and Indicates that Cy A In some embodiments, Cy X yes in represents a bond to Q, and Indicates that Cy A In some embodiments, Cy X yes in represents a bond to Q, and Indicates that Cy A In some embodiments, Cy X yes in Indicates that Cy A In some embodiments, Cy X yes in represents a bond to Q, and Indicates that Cy A key.

[0317] In some embodiments, Cy X is selected from the groups shown in the compounds in Table 1.

[0318] As generally defined above, X is N or CL 2 -X 0 In some embodiments, X is N. In some embodiments, X is CL 2 -X 0 In some embodiments, X (ie, CL 2 -X 0 In some embodiments, X (ie, CL 2 -X 0 In some embodiments, X (ie, CL 2 -X 0 In some embodiments, X (ie, CL 2 -X 0 In some embodiments, X (ie, CL 2 -X 0 Together) is C-CF3.

[0319] In some embodiments, X is selected from the groups shown in the compounds in Table 1.

[0320] In some embodiments, X 0 is hydrogen, halogen, oxo, CN or a group selected from the following: C 1-8aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X 0 R appears p times X replace

[0321] In some embodiments, X 0 is hydrogen, halogen or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X 0 R appears p times X replace.

[0322] In some embodiments, X 0 In some embodiments, X 0 In some embodiments, X 0 is R that appears p times X Substituted C 1-8 In some embodiments, X 0 is R that appears p times X In some embodiments, X 0 is R that appears p times X In some embodiments, X 0 is a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is separated by p occurrences of R X In some embodiments, X 0 is a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is separated by p occurrences of R X replace.

[0323] In some embodiments, X 0 Is Cl. In some embodiments, X 0 It's F.

[0324] In some embodiments, X 0 is selected from the groups shown in the compounds in Table 1.

[0325] As generally defined above, Y is N or CH. In some embodiments, Y is N. In some embodiments, Y is CH.

[0326] In some embodiments, Y is selected from the groups shown in the compounds in Table 1.

[0327] As generally defined above, Q is L 1 , where L 1 As defined in the embodiments and classes and subclasses herein.

[0328] In some embodiments, Q is a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, -NH-, -N(R L )- or -O- substitution.

[0329] In some embodiments, Q is -NH-, in Indicates that Cy X covalent bonds, and Indicates that Cy B In some embodiments, Q is -NH-, in Indicates that Cy X covalent bonds, and Indicates that Cy B In some embodiments, Q is -NH-, in Indicates that Cy X covalent bonds, and represents a covalent bond to Z.

[0330] In some embodiments, Q is -NH-, In some embodiments, Q is -NH-. In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is

[0331] In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is In some embodiments, Q is

[0332] In some embodiments, Q is selected from the groups shown in the compounds in Table 1.

[0333] In some embodiments, Z is halogen, Cy B Or H. In some embodiments, Z is Cy B Or H. In some embodiments, Z is Cy B , where Cy B In some embodiments, Z is H.

[0334] In some embodiments, -QZ (i.e., Q and Z taken together) is

[0335] In some embodiments, -QZ (i.e., Q and Z taken together) is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is In some embodiments, -QZ is

[0336] In some embodiments, Z is selected from the groups shown in the compounds in Table 1.

[0337] As generally defined above, L 1 Is a covalent bond or C 1-5A saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 Aliphatic substitution.

[0338] In some embodiments, L 1 is a covalent bond. In some embodiments, L 1 It is C 1-6 A divalent saturated or unsaturated linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C1-6 Aliphatic substitution.

[0339] In some embodiments, L 1 Is a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, -NH-, -N(R L )- or -O- substitution.

[0340] In some embodiments, L 1 Yes -NH-, in Indicates that Cy X covalent bonds, and Indicates that Cy B Or a covalent bond of Z.

[0341] In some embodiments, L 1 In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0342] In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes In some embodiments, L 1 yes

[0343] In some embodiments, L 1 is selected from the groups shown in the compounds in Table 1.

[0344] As generally defined above, L2 Is a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 Aliphatic substitution.

[0345] In some embodiments, L 2 is a covalent bond. In some embodiments, L 2 It is C 1-4 A divalent saturated or unsaturated linear or branched hydrocarbon chain, wherein one or two methylene units of the chain are optionally and independently replaced by: -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 In some embodiments, L 2 It is -CH2-.

[0346] In some embodiments, each L 2 is selected from the groups shown in the compounds in Table 1.

[0347] As generally defined above, each occurrence of R L Independently R 1 or R 2 , and is replaced by t occurrences of R 3 In some embodiments, R L It is R 1 In some embodiments, R L It is R 2 .

[0348] As generally defined above, each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being q A The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and R C Being q X The number of R 3 In some embodiments, R A It is R 1 In some embodiments, R B It is R 1 In some embodiments, R X It is R 1 In some embodiments, R A It is R 2 In some embodiments, R B It is R 2 In some embodiments, R X It is R 2 .

[0349] In some embodiments, each occurrence of R 1 (For example, R A R 1 Group, R B R 1 Group or R XR 1 wherein the alkyl radicals (groups) are 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, -N(R)S(O)2R, or -P(O)R2.

[0350] In some embodiments, each occurrence of R 1 (For example, R A R 1 Group, R B R 1 Group or R X R 1 wherein the alkyl radicals (groups) are 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.

[0351] In some embodiments, R 1 In some embodiments, each R 1 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.

[0352] In some embodiments, R 1is halogen, -CN or -NO2. In some embodiments, R 1 Is -OR, -SR or -NR2. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R A In some embodiments, R B In some embodiments, R B It is -CN.

[0353] As generally defined above, each occurrence of R 2 (For example, R A R 2 Group, R B R 2 Group or R X R 2 Group) is independently C 1-7 Aliphatic group; -OC 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 monocyclic 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.

[0354] In some embodiments, R 2 It is C 1-7 In some embodiments, R 2 Yes-OC 1-7 In some embodiments, R 2 It is C 1-4 In some embodiments, R 2 In some embodiments, R 2 is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. 2 is a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring. 2 is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 2 is a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0355] In some embodiments, R A It is C 1-7 In some embodiments, R A In some embodiments, R A is F. In some embodiments, R A Is Cl. In some embodiments, R A is -C(CH3)2OH. In some embodiments, R A is -CH3. In some embodiments, R A In some embodiments, R A In some embodiments, R A is -C(CH3)3. In some such embodiments, R A is -CF3. In some such embodiments, R A It is –CHF2.

[0356] In some embodiments, R A is a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. A is a 4-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.A is a 5-6 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. A is a 5-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A is a 6-membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0357] In some embodiments, R A yes In some embodiments, R A yes In some embodiments, R A yes In some embodiments, R A yes In some embodiments, R A yes In some embodiments, R A yes In some embodiments, R A yes

[0358] In some embodiments, R A In some embodiments, R A It is -N(CH3)2.

[0359] In some embodiments, each R A is selected from the groups shown in the compounds in Table 1.

[0360] In some embodiments, R B It is C 1-7 In some embodiments, R B In some embodiments, R B is F. In some embodiments, R B In some such embodiments, R B is -CH3. In some embodiments, R B Selected from -CH3, -CH2CH3, -CH(CH3)2, In some embodiments, R B Is R 3 Substituted C 1-7 In some embodiments, R B Is R 3 Substituted C 1-7 aliphatic group, where R 3is -OR. In some embodiments, R B Is R 3 Substituted C 1-2 aliphatic group, where R 3 is -OR. In some embodiments, R B is -CH2OH. In some embodiments, R B In some embodiments, R B is –OR, where R is C 1-6 In some embodiments, R B is -OCH3. In some embodiments, R B In some embodiments, R B It is -CN.

[0361] In some embodiments, R B It is -OH.

[0362] In some embodiments, each R B is selected from the groups shown in the compounds in Table 1.

[0363] In some embodiments, R X It is C 1-7 In some embodiments, R X In some embodiments, R X is F. In some embodiments, R X In some such embodiments, R X is -CH3 or -C(CH3)3. In some embodiments, R X is -CH2C(CH3)3. In some embodiments, R X Is R 3 Substituted C 1-7 In some embodiments, R X Is R 3 Substituted C 1-7 aliphatic group, where R 3 is -OR. In some embodiments, R X Is R 3 Substituted C 1-2 aliphatic group, where R 3 is -OR. In some embodiments, R X is -CH2OCH3. In some embodiments, R X yes In some embodiments, R X is -N(H)C(O)CH3. In some embodiments, R X is -C(O)OR. In some embodiments, RX is -C(O)OR, where R is C 1-6 In some embodiments, R X is -C(O)OCH2CH3. In some embodiments, R X Is R 3 Substituted C 1-7 aliphatic group, where R 3 In some embodiments, R X Is R 3 Substituted C 1-7 aliphatic group, where R 3 In some embodiments, R X In some embodiments, R X In some embodiments, R X Is R 3 In some embodiments, R X Is R 3 Substituted –OR, where R is C 1-6 aliphatic group, and R 3 is -OR. In some embodiments, R X It is -OCH2CH2OH.

[0364] In some embodiments, each R X is selected from the groups shown in the compounds in Table 1.

[0365] As generally defined above, each occurrence of R 3 and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0366] In some embodiments, R 3 In some embodiments, R3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 In some embodiments, R 3 is -S(O)2R. In some embodiments, R 3 is -S(O)2NR2. In some embodiments, R 3 is -S(O)R. In some embodiments, R 3 is -S(O)NR2. In some embodiments R 3 is -S(O)2F. In some embodiments R 3 is -OS(O)2F. In some embodiments R 3 is -C(O)R. In some embodiments, R 3 is -C(O)OR. In some embodiments, R 3 is -C(O)NR2. In some embodiments, R 3 is -C(NR)NR2. In some embodiments, R 3 is -C(O)N(R)OR. In some embodiments, R 3 is -OC(O)R. In some embodiments, R 3 is -OC(O)NR2. In some embodiments, R 3 is -N(R)C(O)OR. In some embodiments, R 3 is -N(R)C(O)R. In some embodiments, R 3 is -N(R)C(NR)R. In some embodiments, R 3 is -N(R)C(O)NR2. In some embodiments, R 3 is -N(R)C(NR)NR2. In some embodiments, R 3 is -N(R)S(O)2NR2. In some embodiments, R 3 is -N(R)S(O)R. In some embodiments, R 3 is -N(R)S(O)2R. In some embodiments, R 3 is an optionally substituted C 1-6 In some embodiments, R 3 is an optionally substituted phenyl. In some embodiments, R 3is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. 3 is an optionally substituted 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0367] In some embodiments, each R 3 and -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, -N(R)S(O)R, or an optionally substituted group selected from: C 1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0368] In some embodiments, each R 3 are independently halogen, -CN or -NO2.

[0369] In some embodiments, each R 3 are independently -OR, -SR or -NR2.

[0370] In some embodiments, each R 3 is independently -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 or -C(O)N(R)OR.

[0371] In some embodiments, each R 3 are independently -S(O)2R, -S(O)2N(H)R, -S(O)R, -S(O)N(H)R, -S(O)2F, -OS(O)2F, -C(O)R, -C(O)OR, -C(O)N(H)R, -C(NH)NR2 or -C(O)N(H)OR.

[0372] In some embodiments, each R 3are independently 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.

[0373] In some embodiments, each R 3 is independently -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)NR2, -N(H)C(NH)NR2, -N(H)S(O)2NR2, -N(H)S(O)R, or -N(H)S(O)2R.

[0374] In some embodiments, each R 3 is independently an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, phenyl, 3-7 membered saturated or partially unsaturated heterocyclic rings having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, and 5-6 membered heteroaryl rings having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0375] In some embodiments, R 3 It is -CH3.

[0376] In some embodiments, each R 3 is selected from the groups shown in the compounds in Table 1.

[0377] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from: C 1-6 an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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, 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 nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0378] In some embodiments, R is hydrogen. In some embodiments, R is an optionally substituted group selected from the group consisting of: C 1-6aliphatic, a saturated or partially unsaturated 3-7 membered carbocyclic ring, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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, 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 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur in addition to nitrogen. In some embodiments, R is an optionally substituted C 1-6 In some embodiments, R is an optionally substituted saturated or partially unsaturated 3-7 membered carbocyclic ring. In some embodiments, R is an optionally substituted phenyl ring. In some embodiments, R is an optionally substituted 3-7 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 5-6 membered heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0379] In some embodiments, each occurrence of R is independently hydrogen or C 1-6 In some embodiments, each occurrence of R is independently hydrogen or methyl.

[0380] 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 ​​shown for the compounds in Table 1.

[0381] 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 ​​shown for the compounds in Table 1.

[0382] 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 ​​shown for the compounds in Table 1.

[0383] As generally defined above, q A is 0, 1, 2, 3, or 4. In some embodiments, q A is 0. In some embodiments, q A is 1. In some embodiments, q A is 2. In some embodiments, q A is 3. In some embodiments, q A is 4. In some embodiments, q A is 0 or 1. In some embodiments, q A is 0, 1 or 2. In some embodiments, q A is 0, 1, 2, or 3. In some embodiments, q A is 1 or 2. In some embodiments, q A is 1, 2, or 3. In some embodiments, q A is 1, 2, 3, or 4. In some embodiments, q A is 2 or 3. In some embodiments, q A is 2, 3 or 4. In some embodiments, q Ais 3 or 4. In some embodiments, q A The values ​​shown in the compounds in Table 1 were selected.

[0384] As generally 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 B is 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 The values ​​shown in the compounds in Table 1 were selected.

[0385] As generally defined above, q X is 0, 1, 2, 3, or 4. In some embodiments, q X is 0. In some embodiments, q X is 1. In some embodiments, q X is 2. In some embodiments, q X is 3. In some embodiments, q X is 4. In some embodiments, q X is 0 or 1. In some embodiments, q X is 0, 1 or 2. In some embodiments, q X is 0, 1, 2, or 3. In some embodiments, q X is 1 or 2. In some embodiments, q X is 1, 2, or 3. In some embodiments, q X is 1, 2, 3, or 4. In some embodiments, q X is 2 or 3. In some embodiments, q X is 2, 3 or 4. In some embodiments, q Xis 3 or 4. In some embodiments, q X The values ​​shown in the compounds in Table 1 were selected.

[0386] 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 ​​shown for the compounds in Table 1.

[0387] 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 ​​shown for the compounds in Table 1.

[0388] As generally defined above, u is 0, 1, 2, 3, or 4. In some embodiments, u is 0. In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3. In some embodiments, u is 4. In some embodiments, u is 0 or 1. In some embodiments, u is 0, 1, or 2. In some embodiments, u is 0, 1, 2, or 3. In some embodiments, u is 1 or 2. In some embodiments, u is 1, 2, or 3. In some embodiments, u is 1, 2, 3, or 4. In some embodiments, u is 2 or 3. In some embodiments, u is 2, 3, or 4. In some embodiments, u is 3 or 4. In some embodiments, u is selected from the values ​​shown for the compounds in Table 1.

[0389] Examples of compounds described herein include the compounds listed in the tables and examples herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures thereof. In some embodiments, the present disclosure includes compounds selected from those shown in Table 1 below, or pharmaceutically acceptable salts, stereoisomers, or mixtures thereof. In some embodiments, the present disclosure provides compounds given in Table 1 below, or pharmaceutically acceptable salts thereof. In some embodiments, the present disclosure provides compounds given in Table 1 below.

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433]

[0434]

[0435]

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[0776] In the chemical structures in Table 1 above, when a stereocenter is depicted with a dashed line or a wedge-shaped bond and is 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, for example, the structure of compound I-1.) When a stereocenter is depicted with a dashed line or a wedge-shaped bond and is also labeled "or1" or "or2," the compound is a single isomer at that stereocenter, but the absolute stereochemistry at that stereocenter has not yet been determined. (See, for example, the structure of compound I-36.) Similarly, when the compound name contains "rel-," it is a single isomer at the indicated stereocenter, but the absolute stereochemistry at these stereocenters has not yet been determined. When a stereocenter is depicted with a dashed line or a wedge-shaped bond and is also labeled "and1" or "&1," the compound is a mixture of two isomers at that stereocenter: the structure as drawn and an isomer in which the chiral (stereogenic) center has the opposite configuration. (See, for example, the structure of the intermediate in Example 15.)

[0777] Certain compounds shown in Table 1 above exist in solution as non-interconvertible atropisomers across the biaryl bond at room temperature. When one of the atoms of the biaryl bond is labeled "or1," this indicates that the compound exists in solution as a non-interconvertible atropisomer at room temperature and that the compound is essentially a single atropisomer (rather than an equimolar mixture).

[0778] In some embodiments, the present disclosure provides compounds in Table 1 above, wherein the compounds are represented by the biochemical CDK4 Caliper method IC 50 In some embodiments, the present disclosure provides compounds in Table 1 above, wherein the compounds are represented by the biochemical CDK4 Caliper method IC 50 is "A" or "B". In some embodiments, the present disclosure provides compounds in Table 1 above, wherein the compounds are represented by the biochemical CDK4 Caliper method IC 50 is "A" or "B" or "C".

[0779] In some embodiments, the present disclosure provides compounds in Table 1 above, wherein the compounds are represented as Cell NanoBRET IC 50 In some embodiments, the present disclosure provides compounds in Table 1 above, wherein the compounds are represented as Cell Nano BRET IC 50 is "A" or "B". In some embodiments, the present disclosure provides compounds in Table 1 above, wherein the compounds are represented as Cell Nano BRET IC 50 is "A" or "B" or "C".

[0780] 4. General Methods for Providing Compounds of the Invention

[0781] The compounds described herein can generally be prepared or isolated by synthetic and / or semisynthetic methods known to those skilled in the art for similar compounds, as well as by the methods described in detail in the Examples herein.

[0782] 5. Use, preparation and administration

[0783] Pharmaceutically acceptable compositions

[0784] According to another embodiment, the present disclosure provides a composition comprising a compound as 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 as described herein and a pharmaceutically acceptable carrier. The amount of compound in the composition as described herein is such that it can effectively inhibit CDK4 protein kinase or its mutant in a biological sample or patient to a measurable extent. In certain embodiments, the amount of compound in the composition as described herein is such that it can effectively inhibit CDK4 protein kinase or its mutant in a biological sample or patient to a measurable extent. In certain embodiments, the composition as described herein is formulated for administration to a patient in need of such a composition. In some embodiments, the composition as described herein is formulated for oral administration to a patient.

[0785] As used herein, the terms "subject" and "patient" refer to an animal (i.e., a member of the kingdom Animalia), preferably a mammal, and most preferably a human. In some embodiments, the subject is a human, mouse, rat, cat, monkey, dog, horse, or pig. In some embodiments, the subject is a human. In some embodiments, the subject is a mouse, rat, cat, monkey, dog, horse, or pig.

[0786] 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 formulated therewith. 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin.

[0787] "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.

[0788] As used herein, the term "inhibitory active metabolite or residue thereof" means that the metabolite or residue thereof is also an inhibitor of CDK4 protein kinase or a mutant thereof.

[0789] The compositions described herein can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously.

[0790] The sterile injectable forms of the compositions described herein can be aqueous or oily suspensions. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspending media.

[0791] For this purpose, any gentle fixed oil can be used, including synthetic monoglycerides or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) can be used to prepare injections, as can natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). For the purpose of preparation, other conventional surfactants can also be used, such as Tween, Span, and other emulsifiers or bioavailability enhancers commonly used in the preparation of pharmaceutically acceptable solids, liquids or other dosage forms.

[0792] 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. In the case of tablets for oral administration, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dry corn starch. When an oral aqueous suspension is desired, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0793] 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 agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal or vaginal temperature and will therefore melt in the rectum or vagina to release the drug. Such substances include cocoa butter, beeswax, and polyethylene glycol.

[0794] The pharmaceutically acceptable compositions described herein can also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations for each of these areas or organs can be readily prepared.

[0795] Topical application to the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0796] For topical application, the pharmaceutically acceptable composition provided can be formulated into a suitable ointment containing an active component suspended or dissolved in one or more carriers. Carriers for topical application of compounds described herein include, but are not limited to, mineral oil, liquid vaseline, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable composition provided can be formulated into a suitable lotion or cream containing an active component 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.

[0797] For ophthalmic use, the provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably as solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable compositions can be formulated as ointments such as petrolatum.

[0798] 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 solutions in saline using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0799] 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.

[0800] The amount of the compound described herein that can be combined with a carrier material to produce a single dosage form of the composition will vary depending on the patient being treated, the particular mode of administration, and preferably, the provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0801] 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 specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the attending physician and the severity of the specific disease being treated. The amount of the compound described herein in the composition will also depend on the specific compound in the composition.

[0802] The precise dosage to be used in the composition will also depend on the route of administration and should be determined according to the judgment of the practitioner and the circumstances of each subject. In specific embodiments of the present disclosure, suitable dosage ranges for oral administration of a compound 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 appreciated that any dose listed herein may constitute an upper or lower dose range and may be combined with any other dose to constitute a dose range that includes both the upper and lower limits.

[0803] In some embodiments, the pharmaceutically acceptable composition contains a provided compound and / or a pharmaceutically acceptable salt thereof at a concentration ranging from about 0.01 to about 90 wt %, about 0.01 to about 80 wt %, about 0.01 to about 70 wt %, about 0.01 to about 60 wt %, about 0.01 to about 50 wt %, about 0.01 to about 40 wt %, about 0.01 to about 30 wt %, about 0.01 to about 20 wt %, about 0.01 to about 2.0 wt %, about 0.01 to about 1 wt %, about 0.05 to about 0.5 wt %, about 1 to about 30 wt % or about 1 to about 20 wt %. The composition can be formulated as a solution, suspension, ointment or capsule, etc. The pharmaceutical composition can be prepared as an aqueous solution and can contain additional components such as preservatives, buffers, tonicity agents, antioxidants, stabilizers, viscosity adjusting components, etc.

[0804] 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.

[0805] The example of pharmaceutically acceptable carrier can comprise for example water or saline solution, polymer (such as polyethylene glycol), carbohydrate and derivative thereof, oil, fatty acid or alcohol. Non-limiting examples of oil as pharmaceutical carrier comprise oil from petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil etc. Pharmaceutical carrier can also be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silicon dioxide, urea etc. In addition, adjuvant, stabilizing agent, thickening agent, lubricant and coloring agent can be used. Other examples of suitable pharmaceutical carriers are described, for example, in Remington's: The Science and Practice of Pharmacy, 22nd ed. (Allen, Loyd V., Jr., ed., Pharmaceutical Press (2012)); Modern Pharmaceutics, 5th ed. (Alexander T. Florence, Juergen Siepmann, CRC Press (2009)); Handbook of Pharmaceutical Excipients, 7th ed. (Rowe, Raymond C.; Sheskey, Paul J.; Cook, Walter G.; Fenton, Marian E., eds., Pharmaceutical Press (2012)) (each of which is hereby incorporated by reference in its entirety).

[0806] Pharmaceutically acceptable carriers used herein can be selected from various organic or inorganic substances, which can be used as raw materials for pharmaceutical preparations and incorporated as analgesics, buffers, binders, disintegrants, diluents, emulsifiers, excipients, extenders, glidants, solubilizers, stabilizers, suspending agents, tonicity agents, vehicles and tackifiers. Pharmaceutical additives such as antioxidants, aromatics, colorants, flavor enhancers, preservatives and sweeteners can also be added. The example of an acceptable pharmaceutical carrier includes carboxymethyl cellulose, crystalline cellulose, glycerol, gum arabic, lactose, magnesium stearate, methylcellulose, powder, saline, sodium alginate, sucrose, starch, talc and water etc. In some embodiments, the term "pharmaceutically acceptable" means approved by a regulatory agency of a federal or state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeias for use in animals, particularly for humans.

[0807] It is also suitable to use surfactants in the formulation, for example detergents. Specific examples of surfactants include polyvinyl pyrrolidone, polyvinyl alcohol, copolymers of vinyl acetate and vinyl pyrrolidone, polyethylene glycol, benzyl alcohol, mannitol, glycerol, sorbitol or polyoxyethylated esters of sorbitan; lecithin or sodium carboxymethylcellulose; or acrylic acid derivatives such as methacrylates, anionic surfactants such as alkaline 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 dioctylsulfosuccinate; or fatty acids, in particular fatty acids derived from coconut oil, cationic surfactants such as formula N + R'R”R”'R””Y - A water-soluble quaternary ammonium salt of wherein the R groups are identical or different optionally hydroxylated hydrocarbon groups, and Y - It is an anion of a strong acid, such as a halide ion, sulfate and sulfonate anion; hexadecyltrimethylammonium bromide is one of the cationic surfactants that can be used, with the formula N + Amine salts of R'R"R"', wherein the R groups are identical or different optionally hydroxylated hydrocarbon groups; octadecylamine hydrochloride is one of the cationic surfactants that can be used, nonionic surfactants, such as optionally polyoxyethylated esters of sorbitan, in particular polysorbate 80, or polyoxyethylated alkyl ethers; polyethylene glycol stearate, polyoxyethylated derivatives of castor oil, polyglycerol esters, polyoxyethylated fatty alcohols, polyoxyethylated fatty acids or copolymers of ethylene oxide and propylene oxide, amphoteric surfactants, such as substituted lauryl compounds of betaine.

[0808] Suitable pharmaceutical carriers may also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, polyethylene glycol 300, water, ethanol, polysorbate 20, etc. If necessary, the composition of the present invention may also contain a wetting agent or emulsifier or a pH buffering agent.

[0809] Tablet and capsule formulations may further contain one or more adjuvants, binders, diluents, disintegrants, excipients, fillers or lubricants, each of which is known in the art. Examples of such substances include carbohydrates (such as lactose or sucrose), anhydrous calcium hydrogen phosphate, corn starch, mannitol, xylitol, cellulose or its derivatives, microcrystalline cellulose, gelatin, stearate, silicon dioxide, talc, sodium starch glycolate, gum arabic, flavorings, preservatives, buffers, disintegrants and coloring agents. Oral compositions may contain one or more optional agents, such as sweeteners (such as fructose, aspartame or saccharin); flavorings (such as peppermint, wintergreen oil or cherry oil); coloring agents; and preservatives to provide pharmaceutically palatable preparations.

[0810] Uses of compounds and pharmaceutically acceptable compositions

[0811] The compounds and compositions described herein can generally be used to inhibit kinases or their mutants. In some embodiments, the kinases inhibited by the compounds and compositions described herein are cyclin-dependent kinases (CDKs). In some embodiments, the kinases inhibited by the compounds and compositions described herein are one or more of CDK1, CDK2, CDK4, and CDK6. In some embodiments, the kinases inhibited by the compounds and compositions described herein are CDK4.

[0812] The compounds or compositions disclosed herein can be used in applications that benefit from inhibition of the CDK4 enzyme. For example, the CDK4 inhibitors described herein can generally be used to treat proliferative diseases.

[0813] Cyclin D and its related kinase CDK4 are known to be factors in tumorigenesis and proliferation in a variety of cancer types, including melanoma, upper gastrointestinal cancer, head and neck cancer, breast cancer, lung cancer, and bladder cancer (Cerami E et al., (2012) Cancer Discov 2(5), 401–4; Gao J et al., (2013) Science Signaling 6(269), 11). In breast cancer, cyclin D and CDK4 are associated with poor clinical outcome (Lundgren K et al., (2012) Breast Cancer Res 14(2), R57).

[0814] Studies in transgenic animals have shown that cyclin D1 deficiency strongly and specifically impairs mammary epithelial cell proliferation, suggesting a key role for the CDK4 / 6 pathway in this tissue (Sicinski P et al. (1995) Cell 82(4), 621–30). Furthermore, cyclin D1 and CDK4 are essential for the formation and growth of several murine mammary tumors (Yu Q et al. (2001) Nature 411(6841), 1017–21; Yu Q et al. (2006) Cancer Cell 9(1), 23–32; Jeselsohn R et al. (2010) Cancer Cell 17(1), 65–76). In estrogen receptor-positive human breast cancer cell lines, combined inhibition of CDK4 / 6 and ER (with endocrine therapy) synergistically reduces tumor cell proliferation (Finn RS et al. (2009) Breast Cancer Res 11(5), R77).

[0815] Furthermore, many cancers exhibit amplification of CDK4 (most notably liposarcoma and glioblastoma) (Cerami E et al. (2012) Cancer Discov 2(5), 401–4). Certain genomic translocations and specific gene mutations can also significantly increase cyclin D levels in tumor cells. The resulting increase in CDK4 activity was expected to confer sensitivity to CDK4 inhibitors, and this is indeed the case (Gong X et al. (2017) Cancer Cell 32(6), 761–776e6).

[0816] The activity of the compounds described herein as inhibitors of CDK kinases (e.g., CDK4) or their mutants can be determined in vitro, in vivo, or in a cell line. In vitro assays include determining the inhibition of phosphorylation activity and / or subsequent functional results or activated CDK4 or its mutant ATPase activity. Alternative in vitro assays quantify the ability of inhibitors to bind to CDK4. Inhibitor binding can be measured by radiolabeling the inhibitor before binding, separating the inhibitor / CDK4 complex, and determining the amount of radiolabeled binding. Alternatively, inhibitor binding can be determined by running a competition experiment in which a new inhibitor is incubated with a CDK4 bound to a known radioligand. Representative in vitro and in vivo assays that can be used to measure CDK4 inhibitors include assays described and disclosed in patents and scientific publications described herein. Detailed conditions for determining compounds described herein as inhibitors of CDK4 or its mutants are given in the examples below.

[0817] Treatment of symptoms

[0818] The compounds provided are inhibitors of CDK4 and are therefore useful in treating one or more conditions associated with the activity of CDK4 or its mutants. Thus, in certain embodiments, the present disclosure provides methods for treating a CDK4-mediated condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In certain embodiments, the present disclosure provides methods for treating a CDK4-mediated condition in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0819] As used herein, the term "CDK4-mediated" disorder, disease and / or condition refers to any disease or other deleterious condition in which CDK4 or a mutant thereof is known to play a role. Thus, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which CDK4 or a mutant thereof is known to play a role. Such CDK4-mediated disorders include, but are not limited to, proliferative disorders (e.g., cancer).

[0820] In some embodiments, the present disclosure provides a method for treating one or more conditions, wherein the conditions are selected from proliferative conditions and craniosynostosis syndrome, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition of either of the foregoing. In some embodiments, the present disclosure provides a method for treating one or more conditions, wherein the conditions are selected from proliferative conditions and craniosynostosis syndrome, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present disclosure, or a pharmaceutically acceptable composition thereof.

[0821] In some embodiments, the disorder is associated with CDK4 signaling. CDK4 is known to have multiple upstream and downstream signaling pathways, and inhibition of CDK4 can be used to treat disorders associated with abnormal signaling within these pathways. In some embodiments, the disorder is associated with cyclin D, cyclin D1, or retinoblastoma protein (RB) signaling.

[0822] In some embodiments, the treatment methods include the steps of: 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 a subject in need of such treatment.

[0823] In some embodiments, the treatment methods include the steps of: 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 a subject in need of such treatment.

[0824] Another aspect of the present disclosure provides a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either for use in treating a condition described herein. Another aspect of the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of either for treating a condition described herein. Similarly, the present disclosure provides the use of a compound as defined herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating a condition described herein.

[0825] Proliferative disorders

[0826] 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.

[0827] In some embodiments, the proliferative disorder is breast cancer, prostate cancer, squamous cell lung cancer, 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 bile duct carcinoma, hepatocellular carcinoma, breast cancer, prostate cancer, squamous cell lung cancer, 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, squamous cell lung cancer, gastric cancer, breast cancer, or urothelial carcinoma.

[0828] In some embodiments, the condition is ovarian cancer, endometrial cancer, stomach cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, gastric 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 squamous cell carcinoma of the lung 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.

[0829] In some embodiments, the proliferative disorder is associated with dysregulation of CDK4 or cyclin D. In some embodiments, dysregulation of CDK4 is overexpression of CDK4 or cyclin D. In some embodiments, dysregulation of cyclin D is overexpression of CDK4 or cyclin D. In some embodiments, the proliferative disorder is associated with dysregulation of CDK4 and cyclin D. In some embodiments, dysregulation of CDK4 and cyclin D is overexpression of CDK4 and cyclin D.

[0830] In some embodiments, the proliferative disorder is associated with one or more activating mutations in CDK4. In some embodiments, the activating mutation in CDK4 is a mutation in one or more of the intracellular kinase domain and the extracellular domain. In some embodiments, the activating mutation in CDK4 is a mutation in the intracellular kinase domain.

[0831] Route of administration and dosage form

[0832] According to the methods described herein, the compounds and compositions can be administered in any amount and by any route of administration that is effective in treating a condition (e.g., a proliferative condition or craniosynostosis) or alleviating the severity of the condition. The exact amount required will vary from subject to subject, depending on the type, age, and general condition of the subject, the severity of the infection, the specific agent, its mode of administration, and the like. The compounds described herein are preferably formulated in unit dosage form for ease of administration and consistency of dosage. The expression "unit dosage form" as used herein refers to a physical discrete unit of a medicament suitable for a patient to be treated. However, it will be understood that the total daily dosage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dose level for any particular patient or organism will depend on a variety of factors, including the condition being treated and the severity of the condition; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or concurrently with the specific compound used, and similar factors well known in the medical field.

[0833] The pharmaceutically acceptable compositions described herein can be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powders, ointments, or drops), buccally, as an oral or nasal spray, etc. In certain embodiments, the compounds described herein can be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg, preferably about 1 mg / kg to about 25 mg / kg, of the subject's body weight per day, once or more a day to achieve the desired therapeutic effect.

[0834] 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, the liquid dosage form may also contain inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly 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 include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and fragrances.

[0835] Injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared using suitable dispersants or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in non-toxic parenteral acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution USP and isotonic sodium chloride solution can be used. In addition, conventionally sterile fixed oils are used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are also used to prepare injections.

[0836] The injectable formulations can be sterilized, for example, by filtration through a bacteria-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 prior to use.

[0837] In order to prolong the efficacy of the compounds described herein, it is generally desirable to slow the absorption of the compound from the subcutaneous or intramuscular injection site. This can be achieved by using a suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn may depend on the crystal size and crystal form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oily vehicle. Injectable reservoir forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of compound to polymer and the properties of the specific polymer used, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0838] 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 melts in the rectum or vaginal cavity to release the active compound.

[0839] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier (e.g., sodium citrate or dicalcium phosphate) and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption promoters such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0840] In the soft filling and hard filling gelatin capsules of the excipients such as lactose or milk sugar and high molecular weight polyethylene glycol etc., also similar types of solid compositions can be used as fillers. The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared to have coating and shell, as other coatings known in the field of enteric coating and pharmaceutical preparation. They can optionally contain sunscreen, and can also have such composition, that they only or preferentially release active ingredient in a certain part of intestinal tract, optionally release active ingredient in a delayed manner. The example of operable embedded composition comprises polymeric substance and wax. In the soft filling and hard filling gelatin capsules of the excipients such as lactose or milk sugar and high molecular weight polyethylene glycol etc., also similar types of solid compositions can be used as fillers.

[0841] The active compound can also be in a microencapsulated form together with one or more excipients as described above. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells, such as enteric coatings, controlled release coatings and other coatings known in the art of pharmaceutical formulation. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose or starch. According to conventional practice, such dosage forms can also include other substances other than the inert diluent, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage form can also include a buffer. They can optionally contain opacifiers and can also have a composition such that they release the active ingredient only or preferentially in a certain part of the intestinal tract, optionally releasing the active ingredient in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0842] The dosage form for topical or transdermal administration of the compounds described herein includes ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be needed. Ophthalmic preparations, ear drops and eye drops are also considered to be within the scope of the present disclosure. In addition, the present 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 prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. Rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0843] Dosage and administration schedule

[0844] 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 alleviate or ameliorate the symptoms of a condition in the subject. This amount can be readily determined by a skilled artisan based on known procedures, including analysis of titration curves established in vivo and the methods and assays disclosed herein.

[0845] In some embodiments, the methods comprise administering a therapeutically effective dose of a compound of the present disclosure. In some embodiments, the therapeutically effective dose is at least about 0.0001 mg / kg body weight, at least about 0.001 mg / kg body weight, at least about 0.01 mg / kg body weight, at least about 0.05 mg / kg body weight, at least about 0.1 mg / kg body weight, at least about 0.25 mg / kg body weight, at least about 0.3 mg / kg body weight, at least about 0.5 mg / kg body weight, at least about 0.75 mg / kg body weight, at least about 1 mg / kg body weight, at least about 2 mg / kg body weight, at least about 3 mg / kg body weight, at least about 4 mg / kg body weight, at least about 5 mg / kg body weight, at least about 6 mg / kg body weight, at least about 7 mg / kg body weight, at least about 8 mg / kg body weight, at least about 9 mg / kg body weight, at least about 10 mg / kg body weight, at least about 15 mg / kg body weight, at least about 20 mg / kg body weight.

[0014] In some embodiments, the dosage of the present invention may be any of the following: at least about 150mg / kg body weight, at least about 200mg / kg body weight, at least about 250mg / kg body weight, at least about 300mg / kg body weight, at least about 350mg / kg body weight, at least about 400mg / kg body weight, at least about 450mg / kg body weight, at least about 500mg / kg body weight, at least about 550mg / kg body weight, at least about 600mg / kg body weight, at least about 650mg / kg body weight, at least about 700mg / kg body weight, at least about 750mg / kg body weight, at least about 800mg / kg body weight, at least about 900mg / kg body weight or at least about 1000mg / kg body weight. It will be appreciated that any dosage listed herein can constitute upper or lower limit dosage range, and can be combined with any other dosage to constitute the dosage range that comprises upper and lower limit.

[0846] In some embodiments, a therapeutically effective dose 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.

[0847] In some embodiments, the therapeutically effective dose 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.

[0848] In some embodiments, the method comprises a single dose or administration (e.g., as a single injection or deposition). Alternatively, in some embodiments, the method comprises administering to a subject in need once a day, twice a day, three times a day, or four times a day for a period of 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 method comprises long-term administration. In yet other embodiments, the method comprises administering over the course of weeks, months, years, or decades. In still other embodiments, the method comprises administering over the course of weeks. In still other embodiments, the method comprises administering over the course of months. In still other embodiments, the method comprises administering over the course of years. In still other embodiments, the method comprises administering over the course of decades.

[0849] 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 condition and weight of the recipient; the nature and extent of symptoms; the type of concurrent treatment, the frequency of treatment and the desired effect; and the rate of excretion. These are readily determined and can be used by the skilled artisan to adjust or titrate the dosage and / or dosing regimen.

[0850] Inhibition of protein kinases

[0851] According to one embodiment, the present disclosure relates to a method of inhibiting protein kinase activity in a biological sample, comprising the step of contacting the biological sample with a compound described herein or a composition comprising the compound.

[0852] According to another embodiment, the present disclosure relates to a method for inhibiting the activity of CDK4 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound as described herein or a composition comprising the compound. In certain embodiments, the present disclosure relates to a method for reversibly inhibiting the activity of CDK4 or a mutant thereof in a biological sample, comprising the step of contacting the biological sample with a compound as described herein or a composition comprising the compound.

[0853] In another embodiment, the present disclosure provides a method for selectively inhibiting CDK4 relative to one or more of CDK1, CDK2, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have a selectivity of more than 5 times relative to CDK1, CDK2, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have a selectivity of more than 10 times relative to CDK1, CDK4, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have a selectivity of more than 50 times relative to CDK1, CDK2, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have a selectivity of more than 100 times relative to CDK1, CDK2, CDK5, CDK6, and CDK9. In some embodiments, the compounds described herein have a selectivity of more than 200 times relative to CDK1, CDK2, CDK5, CDK6, and CDK9.

[0854] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0855] Inhibiting the activity of CDK4 (or its mutants) in biological samples can be used for a variety of purposes known to those skilled in the art. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological sample storage, and biological assays.

[0856] Another embodiment of the present disclosure is directed to a method of inhibiting protein kinase activity in a patient, comprising the step of administering to the patient a compound described herein or a composition comprising the compound.

[0857] According to another embodiment, the present disclosure relates to a method of inhibiting the activity of CDK4 or a mutant thereof in a patient, comprising the step of administering to the patient a compound as described herein or a composition comprising said compound. According to certain embodiments, the present disclosure relates to a method of reversibly inhibiting the activity of one or more CDK4 or mutants thereof in a patient, comprising the step of administering to the patient a compound as described herein or a composition comprising said compound.

[0858] According to another embodiment, the present disclosure provides a method for treating a condition mediated by CDK4 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound as described herein or a pharmaceutically acceptable composition thereof. Such conditions are described in detail herein. In some embodiments, the present disclosure provides a method for treating a condition mediated by CDK4 or a mutant thereof in a patient in need thereof, comprising administering to the patient a compound as described herein or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits CDK4 or a mutant thereof.

[0859] According to another embodiment, the present disclosure provides a method for inhibiting the signaling activity of CDK4 or a mutant thereof in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable composition thereof. In some embodiments, the present disclosure provides a method for inhibiting the signaling activity of CDK4 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described herein or a pharmaceutically acceptable composition thereof.

[0860] In some embodiments, the present disclosure provides a method of treating a disorder mediated by CDK4 or a mutant thereof in a patient in need thereof, comprising the step of administering to the patient a compound described herein or a pharmaceutically acceptable composition thereof, wherein the compound reversibly inhibits CDK4 or a mutant thereof.

[0861] Compounds described herein can also inhibit CDK4 function by being incorporated into a medicament for catalyzing the destruction of CDK4. For example, the compound can be incorporated into a proteolytic targeting chimera (PROTAC). PROTAC is a bifunctional molecule, a portion of which is capable of engaging an E3 ubiquitin ligase, and another portion has the ability to bind to a target protein intended to be degraded by a cellular protein quality control mechanism. Target protein is recruited to a specific E3 ligase, causing it to be marked for destruction (i.e., ubiquitination) and subsequently degraded by the proteasome. Any E3 ligase can be used. The portion of PROTAC engaging the E3 ligase is connected to the portion of PROTAC engaging the target protein via a linker consisting of a variable atom chain. Therefore, CDK4 is recruited to the E3 ligase, which will result in the destruction of CDK4 protein. The variable atom chain can include, for example, rings, heteroatoms and / or repeating polymer units. It can be rigid or flexible. Standard techniques in the field of organic synthesis can be used to connect it to the above-mentioned two parts.

[0862] Combination therapy

[0863] 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 considered "appropriate for the disease or condition being treated."

[0864] Thus, in certain embodiments, the method of treatment comprises administering a compound or composition as described herein in combination with one or more additional therapeutic agents. In certain other embodiments, the method of treatment comprises administering a compound or composition as described herein as the sole therapeutic agent.

[0865] In some embodiments, the one or more additional therapeutic agents are selected from an antibody, an antibody-drug conjugate, a kinase inhibitor, an immunomodulator, and a histone deacetylase inhibitor. In some embodiments, the one or more additional therapeutic agents are selected from the following agents or pharmaceutically acceptable salts thereof: BCR-ABL inhibitors: for example, imatinib, initinib, nilotinib, dasatinib, bosutinib, ponatinib, bafitinib, danusetib, sacatinib, PF03814735; ALK inhibitors (see Dardaei et al., 2018, Nat Med.; 24(4):512-517): for example, crizotinib, NVP-TAE684, ceritinib, alectinib, brigatinib, entrectinib, lorlatinib; BRAF inhibitors (see Prahallad et al., 2015, Cell Rep. 12, 1978–1985): for example, vemurafenib, dabrafenib; FGFR inhibitors: for example, infigratinib, dovitinib, erdafitinib, BLU-554, AZD 4547; FLT3 inhibitors: such as sunitinib, midostaurin, tanutinib, sorafenib, lestaurinib, quizartinib, and critinib; 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): for example, trametinib, cobimetinib, bemetinib, selumetinib; ERK inhibitors: for example, uritinib, MK-8353, LY-3214996; VEGF receptor inhibitors: for example, bevacizumab, axitinib, aflibercept, brivanib, motesanib, pasireotide, sorafenib; tyrosine kinase inhibitors: for example, erlotinib, linifanib, sunitinib, pazopanib; epidermal growth factor receptor (EGFR) inhibitors: gefitinib, osimertinib, cetuximab, panitumumab; HER2 receptor inhibitors: for example, trastuzumab, Neratinib, Lapatinib, Lapatinib; MET inhibitors: such as crizotinib, cabozantinib; CD20 antibodies: such as rituximab, tositumomab, ofatumumab; DNA synthesis inhibitors: such as capecitabine, gemcitabine, nelarabine, hydroxyurea; anti-tumor agents: such as oxaliplatin, cisplatin; HER dimerization inhibitors: such as pertuzumab; human granulocyte colony-stimulating factor (G-CSF) regulators: such as filgrastim; immunomodulators: such as afutuzumab, lenalidomide, thalidomide, pomalidomide; CD40 inhibitors: such as dacillinamycin; pro-apoptotic receptor agonists (PARA): such as duranamine; heat shock protein (HSP) inhibitors: such as tanespiramycin (17-allylamino-17-demethoxygeldanamycin);Hedgehog antagonists: such as vismodegib; proteasome inhibitors: such as bortezomib; PI3K inhibitors: such as pixitacitabine, daclizumab, buparicitab, taselicib, idelalisib, duvelisib, ulbrisib; phospholipase A2 inhibitors: such as anagrelide; BCL-2 inhibitors: such as venetoclax; aromatase inhibitors: exemestane, letrozole, anastrozole, fulvestrant, tamoxifen; topoisomerase I inhibitors: such as irinotecan and topotecan; topoisomerase II inhibitors: such as etoposide and teniposide; mTOR inhibitors: such as temsirolimus, lidaformolimus, everolimus, sirolimus; osteoclastic bone resorption inhibitors: such as zoledronic acid; CD33 antibody-drug conjugates: such as gemtuzumab ozogamicin; CD 22 Antibody drug conjugates: such as inotuzumab ozogamicin; CD20 antibody drug conjugates: such as ibritumomab tiuxetan; somatostatin analogs: such as octreotide; interleukin-11 (IL-11): such as oprelukin; synthetic erythropoietin: such as darbepoietin alfa; receptor activator of nuclear factor κB (RANK) inhibitors: such as denosumab; thrombopoietin mimetic peptides: such as romiplostim; cell growth stimulators: such as palifermin; anti-insulin-like growth factor-1 receptor (IGF-1R ) antibodies: such as afinitus; anti-CS1 antibodies: such as elotuzumab; CD52 antibodies: such as alemtuzumab; CTLA-4 inhibitors: such as tremelimumab, ipilimumab; PD1 inhibitors: such as nivolumab, pembrolizumab; immunoadhesins: such as pidilizumab, AMP-224; PDL1 inhibitors: such as MSB0010718C; YW243.55.S70, MPDL3280A; MEDI-4736, MSB-0010718C or MDX- 1105; LAG-3 inhibitors: such as BMS-986016; GITR agonists; GITR fusion proteins and anti-GITR antibodies; histone deacetylase inhibitors (HDIs): such as vornistat; anti-CTLA4 antibodies: such as tremelimumab and ipilimumab; alkylating agents: such as temozolomide, dactinomycin, melphalan, altretinoin, bendamustine, busulfan, carboplatin, lomustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, altretinoin, ifosfamide, procarbazine, nitrogen mustard, mustard, streptozotocin, and thiotepa; biological response modifiers: e.g., BCG, denileukin; antitumor antibiotics: e.g., doxorubicin, bleomycin, daunorubicin, liposomal daunorubicin, mitoxantrone, epirubicin, idarubicin, and mitomycin C; antimicrotubule agents: e.g., estramustine; cathepsin K inhibitors: e.g., oxabepilone; epothilone analogs: e.g., ixabepilone; TpoR agonists: e.g., eltrombopag; antimitotic agents: e.g., docetaxel; adrenal steroid inhibitors: e.g., aminoglutethimide;Antiandrogens: such as nilutamide; androgen receptor inhibitors: such as enzalutamide, abiraterone acetate, oteranolol, galactron and severone, bicalutamide, flutamide; androgens: such as fluoxymesterone; CDK1 inhibitors: such as avosidic, palbociclib, ribociclib, tricepsin, abemaciclib; gonadotropin-releasing hormone (GnRH) receptor agonists: such as leuprolide or leuprolide acetate; taxane antineoplastic drugs: such as cabazitaxel, larotaxel; 5-HT1a receptor agonists: such as zaliproden; HPV vaccines: such as those sold by GlaxoSmithKline; Sold by Merck Iron chelators: for example, deferasirox; antimetabolites: for example, cladribine, 5-fluorouracil, 6-thioguanine, pemetrexed, cytarabine, liposomal cytarabine, decitabine, hydroxyurea, fludarabine, floxuridine, cladribine, methotrexate, pentostatin; bisphosphonates: for example, pamidronate; demethylating agents: for example, 5-azacitidine, decitabine; antitumor plant alkaloids: for example, protein-bound paclitaxel; vinblastine, vincristine, vinorelbine, paclitaxel; retinoids: for example, alitretinoin, tretinoin, isotretinoin, bexarotene; glucocorticoids: for example, hydrocortisone, dexamethasone, prednisolone, prednisone, methylprednisolone; cytokines: for example, Such as interleukin-2, interleukin-11 (oprelvekin), alpha interferon α (IFN-α); estrogen receptor downregulator: fulvestrant; antiestrogens: such as tamoxifen, toremifene; selective estrogen receptor modulators (SERMs): such as raloxifene; luteinizing hormone-releasing hormone (LHRH) agonists: such as goserelin; progesterone: such as megestrol acetate; cytotoxic drugs: arsenic trioxide, asparaginase (also known as L-asparaginase, Erwinia L-asparaginase); antiemetics: such as NK-1 receptor antagonists (such as casopitant); cytoprotective agents: such as amifostine, folinic acid; 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 factor 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40, and LAG3. Immunotherapeutic agents that can be used 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, TI M3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, and / or TGFRβ.

[0866] In some embodiments, the one or more additional therapeutic agents are selected from the following agents: anti-CDK4 antibodies; cytotoxic drugs; 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; YK Chae et al., Oncotarget 2017, 8: 16052-16074; L. Formisano et al., Nat. Comm. 2019, 10: 1373-1386; and references cited therein.)

[0867] The structures of the active compounds identified by code numbers, common names or trade names can be taken from the current edition of the standard compendium "The Merck Index" or from databases such as international patents (eg IMS World Publications).

[0868] The compounds described herein can also be used in combination with known treatments, such as administration of hormones or radiation therapy. In certain embodiments, provided compounds are used as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0869] The compounds described herein can be administered alone or in combination with one or more other therapeutic compounds, with possible combination therapies taking the form of fixed combinations, or the administration of the compounds described herein and one or more other therapeutic compounds being staggered or given independently of one another, or a fixed combination and one or more other therapeutic compounds being administered in combination. Furthermore or in addition, the compounds described herein can be administered in conjunction with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these therapies, particularly for the treatment of tumors. As described above, long-term therapy is also feasible in conjunction with adjuvant therapy in the context of other treatment strategies. Other possible treatments include therapies to maintain the patient's status after tumor regression, or even chemopreventive therapy, for example in patients at risk.

[0870] These additional agents can be administered separately from the compositions containing the provided compounds 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. If administered as part of a multiple dose regimen, the two active agents can be administered simultaneously, sequentially, or within a period of time of each other (usually within five hours of each other).

[0871] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present disclosure. For example, a compound described herein can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms, or administered together in a single unit dosage form. Thus, the present disclosure provides a single unit dosage form comprising a compound described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

[0872] The amount of the compound described herein and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier material to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions described herein should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the compound described herein can be administered.

[0873] In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compounds described herein may act synergistically. Thus, the amount of the additional therapeutic agent in such compositions will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such compositions, a dosage of between 0.01 and 1,000 μg / kg body weight / day of the additional therapeutic agent may be administered.

[0874] The amount of additional therapeutic agent present in the compositions described herein will not exceed the amount typically administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions disclosed herein will range from about 50% to 100% of the amount typically present in a composition comprising that agent as the only therapeutically active agent.

[0875] The compounds described herein or their pharmaceutical compositions 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 have been used to overcome restenosis (narrowing of the blood vessel wall after injury). However, patients using stents or other implantable devices are at risk of thrombosis or platelet activation. These adverse effects can be prevented or mitigated by pre-coating the device with a pharmaceutically acceptable composition comprising a kinase inhibitor. The present disclosure also contemplates implantable devices coated with the compounds described herein.

[0876] Any compound and / or composition of the present disclosure may be provided in the form of a kit comprising the compound and / or composition. Thus, in some embodiments, the compound and / or composition of the present disclosure is provided in the form of a kit.

[0877] The present disclosure is further described by the following non-limiting examples.

[0878] Example

[0879] Examples are provided herein to facilitate a more complete understanding of the present disclosure. The following examples are used to illustrate the preparation and implementation of the present disclosure. However, the scope of the present disclosure should not be interpreted as being limited to the specific embodiments disclosed in these examples which are merely illustrative.

[0880] As shown in the following examples, in certain exemplary embodiments, compounds were prepared according to the following general procedures. It will be understood that while the general methods describe the synthesis of certain compounds described herein, the following general methods, as well as other methods known to those of ordinary 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 by methods substantially similar to those described in the examples herein and methods known to those of ordinary skill in the art.

[0881] In the description of the following synthetic method, unless otherwise indicated, it will be understood that all reaction conditions (for example, reaction solvent, atmosphere, temperature, duration and post-processing procedure) are selected from the standard conditions for the reaction, unless otherwise indicated. In a general scheme, it will be understood by those skilled in the art of organic synthesis that the functional group present on each part of the molecule should be compatible with the reagent and reaction suggested. Substituents incompatible with the reaction conditions are apparent to those skilled in the art, and therefore alternative methods (for example, using blocking groups or performing alternative reactions) are indicated. The starting materials of the embodiments are either commercially available or are easy to prepare by known materials using standard methods.

[0882] At least some of the compounds identified herein as "intermediates" are considered to be compounds of the present disclosure.

[0883] 4. List of implementation plans

[0884] The following numbered embodiments, while not limiting, illustrate certain aspects of the present disclosure:

[0885] 1. A compound of formula I:

[0886]

[0887]

[0888] or a pharmaceutically acceptable salt thereof, wherein:

[0889] Q is for L 1 ;

[0890] Z is H or Cy B ;

[0891] Cy Ais phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m times A replace;

[0892] Cy B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace;

[0893] Cy X yes in represents a bond to Q, and Indicates that Cy A Key;

[0894] X is N or CL 2 -X 0 ;

[0895] X 0 is hydrogen, halogen or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X0 R appears p times X replace;

[0896] Y is N or CH;

[0897] Each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being q A The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and R X Being q X The number of R 3 Replace; or

[0898] Two occurrences of R A , two occurrences of R B , two occurrences of R X or the appearance of R A and the appearance of R X Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace;

[0899] L 1 and L 2 Each of is independently a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution;

[0900] Each occurrence of R L Independently R 1 or R 2 , and is replaced by t occurrences of R 3 replace;

[0901] Each occurrence of R 1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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;

[0902] Each occurrence of R 2 Independently C 1-7 Aliphatic group; -OC 1-7 Aliphatic group; C 1-4 haloalkyl; 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 monocyclic 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;

[0903] Each occurrence of R 3and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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;

[0904] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a saturated or partially unsaturated 3-7 membered heterocyclic ring 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, or:

[0905] The two R groups on the same nitrogen are taken together with their intervening atoms to 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

[0906] m, n, p, q A ,q B ,q X Each of r, r and t is independently 0, 1, 2, 3 or 4.

[0907] 2. The compound of embodiment 1, wherein Z is Cy B .

[0908] 3. The compound of embodiment 1, wherein Z is hydrogen.

[0909] 4. The compound of any one of embodiments 1 to 3, wherein Q is a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, -NH-, -N(R L)- or -O- substitution.

[0910] 5. The compound of any one of embodiments 1 to 4, wherein Q is -NH-, in Indicates that Cy X covalent bonds, and represents a covalent bond to Z.

[0911] 6. The compound of embodiment 1, wherein the compound has formula IA:

[0912]

[0913] or a pharmaceutically acceptable salt thereof.

[0914] 7. The compound according to any one of embodiments 1-6, wherein Y is N.

[0915] 8. The compound according to any one of embodiments 1-6, wherein Y is CH.

[0916] 9. The compound of any one of embodiments 1-8, wherein X is -CL 2 -X 0 .

[0917] 10. The compound of any one of embodiments 1-9, wherein L 2 It is a covalent bond.

[0918] 11. The compound of embodiment 1, wherein the compound has formula II, III or IV:

[0919]

[0920] or a pharmaceutically acceptable salt thereof.

[0921] 12. The compound of any one of embodiments 1-11, wherein Cy A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0922] 13. The compound of any one of embodiments 1-11, wherein Cy A yes

[0923] 14. The compound of embodiment 1, wherein the compound has the formula II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II-X. , II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU or II-VV:

[0924]

[0925]

[0926]

[0927]

[0928]

[0929]

[0930]

[0931] or a pharmaceutically acceptable salt thereof.

[0932] 15. The compound of any one of embodiments 1-14, wherein Cy B is a 3-8 membered saturated carbocyclic ring wherein the ring is surrounded by n occurrences of R B replace.

[0933] 16. The compound of any one of embodiments 1-14, wherein Cy B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is surrounded by n occurrences of R B replace.

[0934] 17. The compound of embodiment 1, wherein the compound has formula II-A1, II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1 or II-Q1:

[0935]

[0936]

[0937]

[0938] or a pharmaceutically acceptable salt thereof.

[0939] 18. The compound of embodiment 1, wherein the compound has formula II-A2, II-B2, II-C2, II-D2, II-E2, II-F2, II-G2 or II-H2:

[0940]

[0941]

[0942] or a pharmaceutically acceptable salt thereof.

[0943] 19. The compound of embodiment 1, wherein the compound has formula V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI or XXII:

[0944]

[0945]

[0946]

[0947]

[0948] or a pharmaceutically acceptable salt thereof.

[0949] 20. The compound of any one of embodiments 1-19, wherein X 0 It's a halogen.

[0950] 21. The compound of embodiment 20, wherein X 0 It's Cl.

[0951] 22. The compound of embodiment 20, wherein X 0 It's F.

[0952] 23. The compound according to any one of embodiments 1 to 22, wherein Q is -NH-.

[0953] 24. The compound of any one of embodiments 1-23, wherein at least one occurrence of R BIs oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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.

[0954] 25. The compound of any one of embodiments 1-23, wherein at least one occurrence of R B It is -OH.

[0955] 26. The compound of any one of embodiments 1-25, wherein at least one occurrence of R A Is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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.

[0956] 27. The compound of embodiment 26, wherein at least one occurrence of R A It's a halogen.

[0957] 28. The compound of any one of embodiments 1-25, wherein at least one occurrence of R A It is 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 monocyclic 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.

[0958] 29. The compound of embodiment 28, wherein at least one occurrence of R AIs q A The number of R 3 Substituted C 1-7 Aliphatic group.

[0959] 30. The compound of any one of embodiments 1-29, wherein at least one occurrence of R 3 Is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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, or -N(R)S(O)2R.

[0960] 31. The compound of any one of embodiments 1-30, wherein at least one occurrence of R 3 It's a halogen.

[0961] 32. The compound of any one of embodiments 1-30, wherein at least one occurrence of R 3 It is -S(O)2R, -S(O)2NR2, -C(O)OR or -C(O)NR2.

[0962] 33. The compound of any one of embodiments 1-29, wherein at least one occurrence of R 3 is an optionally substituted C 1-6 Aliphatic group.

[0963] 34. The compound of embodiment 33, wherein at least one occurrence of R 3 It's methyl.

[0964] 35. The compound according to any one of embodiments 1-15, wherein the compound is selected from the compounds shown in Table 1 or pharmaceutically acceptable salts thereof.

[0965] 36. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 35 and a pharmaceutically acceptable carrier.

[0966] 37. A method of inhibiting CDK4 signaling activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-35 or a pharmaceutical composition according to embodiment 36.

[0967] 38. A method of treating a CDK4-mediated disorder in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound according to any one of embodiments 1-35 or a pharmaceutical composition according to embodiment 36.

[0968] 39. A method of treating a condition in a subject, wherein the condition is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer, or pancreatic cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of Embodiments 1-35 or a pharmaceutical composition of Embodiment 36.

[0969] 40. The method of embodiment 39, wherein the bladder cancer is urothelial carcinoma.

[0970] 41. The method of embodiment 39, wherein the liver cancer is hepatocellular carcinoma.

[0971] 42. The method of embodiment 39, wherein the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

[0972] 43. The method of embodiment 39, wherein the laryngeal cancer is laryngeal squamous cell carcinoma.

[0973] 44. The method of embodiment 39, wherein the skin cancer is melanoma.

[0974] Example 1

[0975] (4-(Cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo

[0976] [d] imidazol-6-yl) pyrimidin-2-yl) amino) -2-methylpyridin-3-yl) ketone (Compound I-17)

[0977]

[0978] 5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine

[0979]

[0980] Step 1: 4-Fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (2 g, 1 eq, 6 mmol), Pd(dppf)Cl (0.5 g, 0.1 eq, 0.6 mmol) and KCO (2 g, 2 eq, 0.01 mol) were added to a solution of 4-chloro-5-fluoropyrimidin-2-amine (465 mg, 0.5 eq, 3.15 mmol) in dioxane / HO (10:1, 10 mL) under nitrogen atmosphere. The reaction mixture was heated at 100° C. with vigorous stirring for 3 h and then quenched with water. The precipitated solid was collected by filtration and washed with EtOAc (20 mL) to give 5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (1.4 g, 4.6 mmol, 70%) as a yellow solid. m / z (ES + )[M+H] + =304.20; HPLC tR=0.665min.

[0981] 1-(6-chloro-2-methylnicotinoyl)piperidin-4-one

[0982]

[0983] Step 2: To a solution of 6-chloro-2-methylnicotinic acid (1 g, 1 eq, 6 mmol) in DCM (50 mL) was added piperidin-4-one (0.9 g, 1.5 eq, 9 mmol), DIEA (2 mL, 12 M, 4 eq, 0.02 mol), and HATU (2.2 g, 1 eq, 5.8 mmol). The mixture was stirred at 25°C for 4 hours and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 10% to 70% in 15 minutes; wavelength: 254 nm). The desired fractions were combined and then concentrated in vacuo to give 1-(6-chloro-2-methylnicotinyl)piperidin-4-one (900 mg, 3.56 mmol, 60%) as a colorless liquid. m / z (ES + )[M+H] + =253.15; HPLC tR=0.648min.

[0984] 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylnicotinoyl)piperidin-4-one

[0985]

[0986] Step 3: 5-Fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (401 mg, 1 eq, 1.32 mmol), CsCO (859 mg, 2 eq, 2.64 mmol), Xanphos (140 mg, 0.183 eq, 242 μmol), and Pd(dba) (100 mg, 0.0826 eq, 109 μmol) were added to a solution of 1-(6-chloro-2-methylnicotinoyl)piperidin-4-one (334 mg, 1 eq, 1.32 mmol) in 1,4-dioxane (10 mL) under a nitrogen atmosphere. The reaction mixture was heated at 110° C. with vigorous stirring for 4 h and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 10% to 70% in 15 minutes; wavelength: 254 nm). The desired fractions were combined and then concentrated in vacuo to give 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylnicotinoyl)piperidin-4-one (160 mg, 308 μmol, 23.3%) as a yellow solid. m / z (ES + )[M+H] + =520.45; HPLC tR=0.919min.

[0987] (4-(Cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (Compound I-17)

[0988]

[0989] Step 4: To a solution of 1-(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylnicotinoyl)piperidin-4-one (160 mg, 1 eq, 308 μmol) in DCM (9 mL) was added cyclopropylamine (0.33 g, 0.48 mL, 12 M, 19 eq, 5.8 mmol) at 25° C. and the resulting mixture was stirred at 25° C. for 30 min. Then, sodium borohydride (0.34 g, 30 eq, 9.24 mmol) was added to the mixture and the mixture was stirred at 25° C. for 1.3 h and then concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 50% B, 50% B over 8 minutes; wavelength: 220 nm; tR1 (min): 8.08). The desired fractions were combined and lyophilized to afford (4-(cyclopropylamino)piperidin-1-yl)(6-((5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-methylpyridin-3-yl)methanone (27.7 mg, 49.4 μmol, 16.0%) as a white amorphous solid. m / z (ES + )[M+H] + =561.25; HPLC tR=0.537min. 1 H NMR(400MHz, DMSO-d6)10.23(s,1H),8.72(d,J=3.8Hz,1H),8.32(d,J=1.3Hz,1H),8.15(d,J=8.5Hz,1H),7.71(dd ,J=12.0,1.3Hz,1H),7.56(d,J=8.5Hz,1H),4.84(h,J=7.0Hz,1H),4.32(d,J=12.9Hz,1H),3.41(d,J=13.4Hz,1H) ,3.33(s,1H),3.03(dt,J=23.5,12.1Hz,2H),2.80(s,1H),2.65(s,3H),2.36(s,3H),2.10(s,1H),1.94(d,J=12.1 Hz, 1H), 1.79 (d, J = 9.7Hz, 1H), 1.64 (d, J = 6.9Hz, 6H), 1.37-1.05 (m, 2H), 0.39 (d, J = 6.2Hz, 2H), 0.25-0.21 (m, 2H).

[0990] Example 2

[0991] (S)-N-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (Compound I-21)

[0992]

[0993] 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole

[0994]

[0995] Step 1: Under a nitrogen atmosphere, to a mixture of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (1.00 g, 3.00 mmol), 2,4-dichloro-5-fluoropyrimidine (0.80 g, 5.00 mmol) and Na2CO3 (1.00 g, 9.00 mmol) in DME:H2O=5:1 (12 mL) was added bis-(triphenylphosphine)palladium chloride (0.20 g, 0.30 mmol). The mixture was stirred at 80 ° C for 16 hours. The reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized. The precipitated solid was collected by filtration and washed with EtOAc to give 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (730 mg, 70%) as a yellow amorphous solid. m / z (ES + )[M+H] + =323.05; HPLC tR=1.098min.

[0996] (S)-N,N-Dimethyl-1-(6-nitropyridin-3-yl)pyrrolidin-3-amine

[0997]

[0998] Step 2: A round-bottom flask was charged with (S)-N,N-dimethylpyrrolidin-3-amine (500 mg, 4.38 mmol), 5-chloro-2-nitropyridine (1.04 g, 6.57 mmol), K2CO3 (2.42 g, 17.50 mmol), a stirring bar and ACN (10 mL), and the solution was stirred at 70°C for 5 hours. The reaction mixture was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase, aqueous ACN, 10% to 70% gradient over 15 minutes; wavelength: 254 nm). The desired fractions were combined and then concentrated in vacuo to give (S)-N,N-dimethyl-1-(6-nitropyridin-3-yl)pyrrolidin-3-amine (600 mg, 58.0%) as a yellow oil. m / z (ES + )[M+H] + =237.15; HPLC tR=0.417min.

[0999] (S)-5-(3-(Dimethylamino)pyrrolidin-1-yl)pyridin-2-amine

[1000]

[1001] Step 3: A resealable reaction vial was charged with (S)-N,N-dimethyl-1-(6-nitropyridin-3-yl)pyrrolidin-3-amine (400 mg, 1.69 mmol), zinc (443 mg, 6.77 mmol), saturated aqueous NH4Cl solution (2 mL), MeOH (6 mL) and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 60°C for 2 hours. The reaction mixture was filtered, the solids were washed with MeOH, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase, aqueous ACN, 10% to 80% gradient over 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give (S)-5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-amine (200 mg, 57.3%) as a pink amorphous solid. m / z (ES + )[M+H] + =207.00; HPLC tR=0.495min.

[1002] (S)-N-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (Compound I-21)

[1003]

[1004] Step 4: A resealable reaction vial was charged with (S)-5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-amine (100 mg, 0.49 mmol), 6-(2-chloro-5-fluoropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (156 mg, 0.49 mmol), 1,4-dioxane (6 mL), CsCO (316 mg, 0.97 mmol), Xantphos (28 mg, 0.045 mmol), Pd(dba) (44 mg, 0.05 mmol), and a stir bar, then evacuated and purged with nitrogen three times. The mixture was stirred at 110° C. for 4 h and then concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridgeShield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32% B to 57% B, 57% B over 8 minutes; wavelength: 220 nm; tR1 (min): 7.45). The desired fractions were combined and lyophilized to afford (S)-N-(5-(3-(dimethylamino)pyrrolidin-1-yl)pyridin-2-yl)-5-fluoro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-amine (55.8 mg, 23.4%) as a yellow amorphous solid. m / z (ES + )[M+H] + =493.35; HPLC tR=0.808min. 1 H NMR(400MHz, DMSO-d6)9.57(s,1H),8.59(d,J=3.9Hz,1H),8.26(d,J=1.3Hz,1H),7.96(d,J=8 .9Hz,1H),7.73-7.63(m,2H),7.02(dd,J=9.0,3.1Hz,1H),4.83(q,J=7.1Hz,2H),3.45(t,J=8. 2Hz,1H),3.38(s,1H),3.26(d,J=7.3Hz,1H),3.06(t,J=8.4Hz,1H),2.86-2.79(m,1H),2.64(s ,3H),2.21(s,6H),2.16(d,J=8.8Hz,1H),1.81(dd,J=21.1,9.9Hz,1H),1.62(d,J=6.9Hz,6H).

[1005] Example 3

[1006] (1R,3R,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexane-1,3-diol (Compound I-34)

[1007]

[1008] 6-(2,5-Dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole

[1009]

[1010] Step 1: A solution of 4-fluoro-1-isopropyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (3 g, 9 mmol), 2,4,5-trichloropyrimidine (2 g, 9 mmol) and sodium carbonate (3 g, 0.03 mol) in 1,2-dimethoxyethane and water was added to bis(triphenylphosphine)palladium(II) dichloride (0.3 g, 0.5 mmol). The reaction mixture was stirred at 80 °C under N2 atmosphere for 15 hours. The precipitated solid was collected by filtration and washed with EtOAc (100 mL). This gave 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (1.66 g, 50%) as a light yellow solid. m / z (ES + )[M+H] + =339.05; HPLC tR=0.759min.

[1011] 4-(Benzyloxy)cyclohexan-1-ol

[1012]

[1013] Step 2: To an ice bath cooled solution of 4-(benzyloxy)cyclohexan-1-one (25 g, 0.12 mol) in MeOH (40 mL) was added NaBH4 (5.6 g, 0.15 mol) in several batches over a period of 10 minutes, and the solution was then stirred at 20°C for 2 hours. The reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EtOAc (30:1). The desired fractions were combined and then concentrated in vacuo to give 4-(benzyloxy)cyclohexan-1-ol (8 g, 32%) as a colorless oil. m / z (ES + )[M+H] +=207.05; HPLC tR=0.698min.

[1014] ((Cyclohex-3-en-1-yloxy)methyl)benzene

[1015]

[1016] Step 3: To an ice-bath cooled solution of 4-(benzyloxy)cyclohexan-1-ol (10 g, 48 mmol) and DIEA (9.4 g, 73 mmol) in DCM (250 mL) was added Tf2O (10 g, 36 mmol) dropwise over 30 minutes, and the solution was stirred at 25°C for 16 hours. Next, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography eluting with PE / EtOAc (50:1). The desired fractions were combined and concentrated in vacuo to give ((cyclohex-3-en-1-yloxy)methyl)benzene (7.2 g, 79%) as a yellow oil. m / z (ES + )[M+ACN] + =230.20; HPLC tR=1.285min.

[1017] rac-(1R,3R,6S)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane

[1018]

[1019] Step 4: To a solution of ((cyclohex-3-en-1-yloxy)methyl)benzene (7.2 g, 38 mmol) in DCM (50 mL) was added 3-chlorobenzoperoxy acid (13 g, 76 mmol) at 0 ° C and stirred for 2 hours. The reaction mixture was diluted with H2O (50 mL) and the aqueous phase was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue (15 g) was purified by silica gel chromatography eluting with PE / EtOAc 30:1 to give the product as a mixture (4.2 g). The mixture was purified by flash chromatography eluting with PE / EtOAc (10:1). The desired fractions were combined and then concentrated in vacuo to give racemic-(1R,3R,6S)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (1.1 g, 28%) as a colorless oil. m / z(ES + )[M+H] - =205.15; HPLC tR=1.061min.

[1020] (1R,2R,5R)-5-(Benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol

[1021]

[1022] Step 5: A round-bottom flask was charged with rac-(1R,3R,6S)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (400 mg, 1.96 mmol), 4A-MS (100 mg), lithium perchlorate (417 mg, 3.92 mmol) and (S)-1-phenylethan-1-amine (308 mg, 2.55 mmol) in ACN (3 mL) and a stirring bar, and the solution was stirred at 25 ° C for 16 hours. The reaction mixture was diluted with H2O (50 mL) and the aqueous phase was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase A: water (10 mM NH 4 HCO 3 ); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 33% B to 58% B, 58% B in 8 minutes; wavelength: 220 nm and 254 nm; tR1 (min): 7.27; and column: XBridge Shield RP18 OBD column, 30×150 mm, 5 μm). The desired fractions were combined and then lyophilized to give (1R,2R,5R)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol (100 mg, 50.0%) as a colorless oil. m / z (ES + )[M+H] - =326.20; HPLC tR=1.098min.

[1023] (1R,3R,4R)-4-Aminocyclohexane-1,3-diol

[1024]

[1025] Step 6: A stirred mixture of (1R,2R,5R)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol (100 mg, 0.31 mmol) and Pd(OH)2 / C (43 mg, 0.31 mmol) in EtOH (8 mL) was treated with H2 at 50°C for 3 hours. The reaction mixture was filtered through a pad of celite, the pad was washed with EtOH, and the filtrate was concentrated in vacuo. This afforded (1R,3R,4R)-4-aminocyclohexane-1,3-diol (50 mg, 87%) as a yellow oil. m / z (ES + )[M+H] + =132.10; HPLC tR=0.158min.

[1026] (1R,3R,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexane-1,3-diol (Compound I-34)

[1027]

[1028] Step 7: To a mixture of (1R,3R,4R)-4-aminocyclohexane-1,3-diol (60 mg, 0.46 mmol) and 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (0.16 g, 0.46 mmol) in NMP (6 mL) was added DIEA (0.18 g, 1.4 mmol). The mixture was stirred at 150° C. for 4 hours. The solution was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase, aqueous ACN, gradient from 20% to 60% over 15 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to afford (1R,3R,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexane-1,3-diol (11 mg, 5.4%) as an off-white amorphous solid. m / z (ES + )[M+H] - =434.15; HPLC tR=1.492min. 1 H NMR (400MHz, DMSO-d6)8.39(s,1H),7.93(s,1H),7.42(s,1H),7.23(s,1H),4.81(p,J=6.9Hz,1H),4.65(t,J=6.4Hz,2H),3.55 (s,1H),3.44(s,2H),2.63(s,3H),2.09(d,J=11.6Hz,1H),1.92(s,1H),1.78(s,1H),1.59(d,J=6.9Hz,6H),1.27-1.11(m,3H).

[1029] Example 4

[1030] 2'-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound I-22)

[1031]

[1032] tert-Butyl ((1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate

[1033]

[1034] Step 1. To a solution of tert-butyl ((1-aminocyclohexyl) methyl) carbamate (5.24 g, 1 equivalent, 22.9 mmol) and KCO (4.76 g, 1.5 equivalents, 34.4 mmol) in DMF (20 mL) was added 2,4-dichloro-5-iodopyrimidine (6.94 g, 1.1 equivalents, 25.2 mmol), and the resulting solution was stirred at 60 ° C overnight. The mixture was diluted with EtOAc (100 mL) and washed with brine (3x120 mL). The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography using PE / EtOAc (10: 1) as the wash-out solvent. The desired fractions were combined and concentrated in vacuo to give tert-butyl ((1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate (2.8 g, 5.9 mmol, 26%, 98% purity) as a white solid. m / z (ES + )[M+H] + =466.95; HPLC tR=1.219min.

[1035] tert-Butyl ((1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate

[1036]

[1037] Step 2. To a solution of tert-butyl ((1-((2-chloro-5-iodopyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate (200 mg, 1 eq, 428 μmol), 3,3-diethoxyprop-1-yne (93.4 mg, 1.7 eq, 728 μmol) and N-ethyl-N-isopropylpropan-2-amine (95.8 mg, 1.73 eq, 741 μmol) in THF (10 mL) was added copper (I) iodide (8.16 mg, 0.1 eq, 42.8 μmol) and Pd(Pph)Cl (12.0 mg, 0.04 eq, 17.1 μmol) and the resulting solution was stirred at room temperature under N for 6 h. The mixture was diluted with EtOAc (50 mL) and then washed with brine (3x60 mL). The organic phase was dried over anhydrous NaSO and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with PE / EtOAc (10:1). The desired fractions were combined and concentrated in vacuo to afford tert-butyl ((1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate (180 mg, 368 μmol, 86.0%, 95.6% purity) as a light yellow solid. m / z (ES + )[M+H] + =467.15; HPLC tR=1.204min.

[1038] tert-Butyl ((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate

[1039]

[1040] Step 3. To a solution of tert-butyl ((1-((2-chloro-5-(3,3-diethoxyprop-1-yn-1-yl)pyrimidin-4-yl)amino)cyclohexyl)methyl)carbamate (300 mg, 1 eq, 642 μmol) in THF (20 mL) was added tetrabutylammonium fluoride (504 mg, 3 eq, 1.93 mmol) and the resulting solution was stirred at 60 °C for 4 hours. The mixture was diluted with EtOAc (100 mL) and washed with brine (3 x 120 mL). The organic phase was dried over anhydrous NaSO and then concentrated under reduced pressure. The crude product was purified by preparative HPLC using the following conditions (column: Xselect CSH C18 OBD column 30 x 150 mm 5 μm, n; mobile phase A: water (0.1% FA); mobile phase B: ACN; flow rate: 60 mL / min; 68% B to 78% B in 7 minutes; wavelength: 254; 220 nm; tR1 (min): 6.5). The desired fractions were combined and then lyophilized to yield tert-butyl ((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (140 mg, 0.28 mmol, 44%, 95% purity) as a light yellow solid. m / z (ES + )[M+H] + =467.15; HPLC tR=1.212min.

[1041] tert-Butyl ((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate

[1042]

[1043] Step 4. To a solution of tert-butyl ((1-(2-chloro-6-(diethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (70 mg, 1 eq, 0.15 mmol) in THF (2 mL) and H2O (2 mL) was added acetic acid (27 mg, 3 eq, 0.45 mmol) and the resulting solution was stirred at 60 °C for 2 h. The mixture was concentrated under reduced pressure. The crude material was diluted with EtOAc (20 mL) and washed with brine (3x30 mL). The organic phase was dried over anhydrous Na2SO4 and then concentrated under reduced pressure to give tert-butyl ((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (60 mg, 0.14 mmol, 91%, 89.1% purity) as a yellow solid. m / z(ES + )[M+H] +=393.10; HPLCtR=1.204min.

[1044] tert-Butyl 2'-chloro-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate

[1045]

[1046] Step 5. To a mixture of tert-butyl ((1-(2-chloro-6-formyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)methyl)carbamate (38 mg, 1.5 eq, 98 μmol) in DMF (6 mL) was added oxone (40 mg, 1 eq, 65 μmol) at 25 °C and the resulting solution was stirred for 3 hours. The desired product was detected by LC / MS. The mixture was diluted with EtOAc (20 mL) and washed with brine (3x20 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product tert-butyl 2'-chloro-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (30 mg, 61 μmol, 94%, 80% purity) was used in the next step without further purification. m / z (ES + )[M+H] + =391.10; HPLC tR=1.159min.

[1047] 2'-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (Compound I-22)

[1048]

[1049] Step 6. To a solution of tert-butyl 2'-chloro-6'-oxo-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidine]-7'(8'H)-carboxylate (40 mg, 1 eq, 0.10 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.13 g, 10 eq, 1.0 mmol) in NMP (3 mL) was added (3S, 4R)-3-hydroxytetrahydro-2H-pyran-4-ammonium chloride (63 mg, 4 eq, 0.41 mmol) and the resulting solution was stirred at 130 ° C overnight. The solution was diluted with EtOAc (20 mL) and washed with brine (3x30 mL). The resulting mixture was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 0% to 100% in 30 minutes; UV detector wavelength: 254 nm). The desired fractions were combined and then concentrated in vacuo to give 2'-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)-7',8'-dihydro-6'H-spiro[cyclohexane-1,9'-pyrazino[1',2':1,5]pyrrolo[2,3-d]pyrimidin]-6'-one (5.4 mg, 14 μmol, 14%, 98.0% purity) as a white solid. m / z (ES + )[M+H] + =372.10; HPLC tR=0.537min.

[1050] Example 5

[1051] (1R,2R)-2-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol (Compound I-32)

[1052]

[1053] Step 1. Under nitrogen atmosphere, (1R,2R)-2-aminocyclohexan-1-ol (122 mg, 1 eq, 1.06 mmol), KCO (439 mg, 3 eq, 3.18 mmol) and Pd(dppf)Cl (86.6 mg, 0.1 eq, 106 μmol) were added to a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (360 mg, 1 eq, 1.06 mmol) in 1,4-dioxane (10 mL). The reaction mixture was heated at 100° C. with vigorous stirring for 16 hours. The mixture was then concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 27% B to 57% B, 57% B over 8 minutes; wavelength: 220 nm; tR1 (min): 7.58). The desired fractions were combined and lyophilized to afford (1R,2R)-2-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexan-1-ol (77.6 mg, 0.18 mmol, 17%, 99% purity) as an off-white solid. m / z (ES + )[M+H] + =418.20; HPLC tR=0.701min. 1 H NMR (400MHz, DMSO-d6)8.38(s,1H),7.92(s,1H),7.32(d,J=51.8Hz,2H),4.80(h,J=6.9Hz,1H),4.59(d,J=4.9H z,1H),3.60(s,1H),3.41(s,1H),2.62(s,3H),2.17-1.80(m,2H),1.58(d,J=6.8Hz,7H),1.20(t,J=8.9Hz,4H).

[1054] Example 6

[1055] (4R,5R)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol and (4S,5S)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (Compounds I-36 and I-37)

[1056]

[1057] (E)-6,7-Dihydropyrazolo[1,5-a]pyridine-4(5H)-one oxime

[1058]

[1059] Step 1. To a solution of 6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (5.0 g, 37 mmol) in pyridine (50 mL) was added hydroxylamine hydrochloride (2.6 g, 37 mmol) and the solution was stirred at 80 ° C for 16 hours. The resulting mixture was concentrated under reduced pressure. The crude product was diluted with water (100 mL) and extracted with DCM (3x100 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure to give (E)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one oxime (6.5 g, 37 mmol, 85%). m / z (ES + )[M+H] - =152.05; HPLC tR=0.404min

[1060] (E)-6,7-Dihydropyrazolo[1,5-a]pyridin-4(5H)-one O-toluenesulfonyl oxime

[1061]

[1062] Step 2. To a stirred solution of (E)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one oxime (5.5 g, 36 mmol) in anhydrous pyridine (100 mL) was added TsCl (6.9 g, 36 mmol) and the resulting solution was stirred at 25°C for 48 hours. The progress of the reaction was monitored by LC / MS. After completion of the reaction, the resulting mixture was concentrated under reduced pressure to give the crude product, which was further purified by flash chromatography (eluent: aqueous ACN; gradient: 0% to 100% in 20 minutes). The desired fractions were combined and then concentrated in vacuo to give the desired compound (E)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one O-tosyl oxime (9 g, 0.03 mol, 80%, 97.2% purity). m / z (ES + )[M+H] + =306.05; HPLC tR=0.884min

[1063] 5-Amino-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one

[1064]

[1065] Step 3. To a stirred solution of (E)-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one O-toluenesulfonyl oxime (5.0 g, 16 mmol) in EtOH (50 mL) and toluene (100 mL) was added potassium tert-butoxide (3.7 g, 33 mmol) and the resulting mixture was stirred at 25 °C for 2 hours. The reaction progress was monitored by LC / MS. After completion of the reaction, the resulting mixture was filtered and the residue was washed with hexane (3x5 mL). 36% HCl (2.5 mL) was added dropwise to the filtrate, and a white precipitate formed. After the mixture was stirred at room temperature for 16 hours, the solid was filtered off and then washed with acetone (2x5 mL) to give the desired product, 5-amino-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (0.82 g, 5.4 mmol, 33%, 99.9% purity). m / z (ES + )[M+H] + =151.95; HPLC tR=0.475min.

[1066] Racemic-(4S,5S)-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

[1067]

[1068] Step 4. To a solution of 5-amino-6,7-dihydropyrazolo[1,5-a]pyridin-4(5H)-one (600 mg, 3.97 mmol) in MeOH (10 mL) was added NaBH4 (225 mg, 5.95 mmol), and the mixture was stirred at room temperature for 30 minutes. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 0% to 100% in 20 minutes; wavelength: 254 nm). The resulting liquid was concentrated under reduced pressure to give rac-(4S,5S)-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (260 mg, 1.56 mmol, 39.3%, 91.9% purity). m / z (ES + )[M+H] + =154.00; HPLC tR=0.262min.

[1069] rac-(4R,5R)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

[1070]

[1071] Step 5. To a solution of rac-(4R,5R)-5-amino-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (100 mg, 653 μmol) and 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (221 mg, 653 μmol) in NMP (3 mL) was added N-ethyl-N-isopropylpropan-2-amine (844 mg, 6.53 mmol), and the resulting solution was stirred at 150° C. for 2 h. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: water in ACN; gradient: 0% to 100% over 30 min; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give rac-(4R,5R)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (120 mg, 262 μmol, 40.1%, 99.4% purity) as a yellow solid. m / z (ES + )[M+H] - =456.10; HPLC tR=0.822min.

[1072] rel-(4R,5R)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol and

[1073] rel-(4S,5S)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol

[1074]

[1075] Step 6. Purification of the mixture rac-(4R,5R)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (120 mg) by chiral preparative HPLC (column: CHIRALPAK IG, 2x25 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: 60% B to 60% in 12 minutes B; wavelength: 220 nm and 254 nm; tR1 (min): 4.59; tR2 (min): 7.73; sample solvent: EtOH / DCM (1:1) HPLC; injection volume: 1 mL; number of runs: 4). The desired fractions were combined and then concentrated in vacuo to give (tR1)rel-(4R,5R)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (33.3 mg, 69.8 μmol, 26.5%, 95.5% purity) as a yellow solid. m / z (ES + )[M+H] + =456.15; HPLC tR=1.571min 1H NMR (400MHz, DMSO-d6)8.48(s,1H),7.95(s,1H),7.66(s,1H),7.40(d,J=1.8Hz,2H),6.22(d,J=1.8Hz,1H),5.67(d,J=6.5Hz,1H),4.81(dt,J= 14.3,7.0Hz,2H),4.28(dd,J=12.1,6.2Hz,1H),4.14(d,J=8.2Hz,2H),2.62(s,3H),2.38(d,J=12.0Hz,1H),2.08(s,1H),1.58(d,J=6.8Hz,6H). Next, the same purification (tR2) gave rel-(4S,5S)-5-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol (37.5 mg, 81.8 μmol, 62%, 99.4% purity) as a white solid. m / z (ES + )[M+H] + =456.10; HPLC tR=1.544min 1 H NMR (400MHz, DMSO-d6)8.48(s,1H),7.97(s,1H),7.67(s,1H),7.40(d,J=1.8Hz,2H),6.22(s,1H),5.69(s,1H),4.87-4. 75(m,2H),4.29(d,J=11.6Hz,1H),4.12(s,2H),2.62(s,3H),2.35(d,J=12.0Hz,1H),2.07(s,1H),1.58(d,J=6.9Hz,6H).

[1076] Example 7

[1077] (1S,3R,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexane-1,3-diol (Compound I-95)

[1078]

[1079] (1S,3R,4R)-4-((tert-Butoxycarbonyl)amino)-3-((tert-Butyldimethylsilyl)oxy)cyclohexyl 4-nitrobenzoate

[1080]

[1081] Step 1. To a mixture of tert-butyl ((1R, 2R, 4R)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate (300 mg, 0.87 mmol), 4-nitrobenzoic acid (174 mg, 1.04 mmol) and PhP (524 mg, 2.00 mmol) in THF (10 mL) was added DIAD (404 mg, 2.00 mmol) dropwise at 0 ° C. The mixture was slowly warmed to room temperature and stirred at 25 ° C. for 12 hours. The resulting mixture was diluted with H O (30 mL), and the aqueous phase was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by preparative TLC using PE / EtOAc (4: 1) as eluent. The desired fractions were combined and concentrated in vacuo to give (1S,3R,4R)-4-((tert-butyloxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl 4-nitrobenzoate (220 mg, 51.2%) as an oil. m / z (ES + )[M+H] + =495.35; HPLC tR=1.327min.

[1082] tert-Butyl ((1R,2R,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate

[1083]

[1084] Step 2. A resealable reaction vial was charged with (1S,3R,4R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl 4-nitrobenzoate (220 mg, 0.45 mmol), LiOH (1.33 mL, 1.33 mmol), THF / MeOH (2 mL), and a stir bar. The mixture was then evacuated and flushed with nitrogen three times, and stirred at 25°C for 1 hour. The resulting mixture was diluted with H2O (5 mL), then adjusted to pH 9-10 with 1M LiOH, and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. This gave crude tert-butyl ((1R,2R,4S)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate (158 mg, 99%) as an oil. m / z (ES + )[M+H] + =346.25; HPLC tR=1.160min.

[1085] (1S,3R,4R)-4-Aminocyclohexane-1,3-diol

[1086]

[1087] Step 3. A resealable reaction vial was charged with tert-butyl ((1R,2R,4S)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate (70 mg, 0.20 mmol), MeOH (2 mL), 4 M HCl in dioxane (1 mL), and a stir bar, then evacuated and flushed with nitrogen three times, and the mixture was stirred at 25°C for 1 hour. The resulting mixture was concentrated in vacuo to afford (1S,3R,4R)-4-aminocyclohexane-1,3-diol (20 mg, 75%) as a white solid. m / z (ES + )[M+H] + =132.15; HPLC tR=0.168min.

[1088] (1S,3R,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexane-1,3-diol

[1089]

[1090] Step 4. A resealable reaction vial was charged with (1S,3R,4R)-4-aminocyclohexane-1,3-diol (20 mg, 0.15 mmol), 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (62 mg, 0.18 mmol), DIEA (120 mg, 0.91 mmol), NMP (1 mL), and a stir bar. The mixture was then evacuated and flushed with nitrogen three times, and the mixture was stirred at 150° C. for 1 hour. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 10% to 50% over 20 minutes; wavelength: 254 nm) and concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 15% B to 40% B, 40% B over 8 minutes; wavelength: 220 nm; tR1 (min): 8.00; injection volume: 0.8 mL; number of runs: 2). The desired fractions were combined and then lyophilized to afford (1S,3R,4R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)cyclohexane-1,3-diol (28.4 mg, 43%) as a white amorphous solid. m / z (ES + )[M+H] + =434.10; HPLC tR=0.852min. 1 H NMR (400MHz, DMSO-d) δ8.39(s,1H),7.92(s,1H),7.30(s,2H),4.80(p,J=6.8Hz,1H),4.51(d,J=5.1Hz,1H),4.42(d,J=2.9Hz ,1H),3.92(s,1H),3.79(s,1H),3.68-3.56(m,1H),2.62(s,3H),1.99-1.72(m,2H),1.58(d,J=6.9Hz,8H),1.50-1.31(m,2H).

[1091] Example 8

[1092] (1S,3S,4S)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxycyclohexyl methylcarbamate (Compound I-113)

[1093]

[1094]

[1095] 4-(Benzyloxy)cyclohexan-1-ol

[1096]

[1097] Step 1. To an ice bath cooled solution of 4-(benzyloxy)cyclohexan-1-one (50 g, 0.24 mol) in MeOH (500 mL) was added NaBH4 (14 g, 0.37 mol) in several batches over a period of 10 minutes, and the resulting solution was stirred at 20°C for 2 hours. The reaction mixture was diluted with saturated NH4Cl aqueous solution (100 mL), and the aqueous phase was extracted with EtOAc (3x600 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE / EtOAc (30:1). The desired fractions were combined and then concentrated in vacuo to give 4-(benzyloxy)cyclohexan-1-ol (49 g, 97%) as a colorless oil. m / z (ES + )[M+H] + =207.10; HPLC tR=0.767min.

[1098] ((Cyclohex-3-en-1-yloxy)methyl)benzene

[1099]

[1100] Step 2. 4-(benzyloxy)cyclohexan-1-ol (49g, 0.24mol), DIEA (46g, 0.36mol) and stirring rod in DCM (500mL) are loaded into a round-bottom flask, then vacuumized, and purged three times with nitrogen. Tf2O (74g, 0.26mol) is added dropwise at 0°C, and the reaction system is stirred for 30 minutes at 0°C. The gained mixture is stirred at 20°C and under a nitrogen atmosphere for 16 hours, then diluted with water (150mL) at 0°C. The aqueous phase is extracted with DCM (3x150mL). The combined organic layer is washed with salt water, dried over sodium sulfate, filtered, and then concentrated in vacuo. Eluted with PE / EtOAc (16:1), the crude product is purified by silica gel chromatography (500g column). The desired fractions were combined and concentrated in vacuo to give ((cyclohex-3-en-1-yloxy)methyl)benzene (37 g, 83%) as a yellow oil. m / z (ES + )[M+H] + =189.15; HPLC tR=1.285min.

[1101] rac-(1R,3R,6S)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane

[1102]

[1103] Step 3. To a solution of ((cyclohex-3-en-1-yloxy)methyl)benzene (39 g, 0.21 mol) in DCM (600 mL) was added m-CPBA (71 g, 0.41 mol) at 0°C and the resulting mixture was stirred for 2 hours. The mixture was then diluted with H2O (50 mL) and the aqueous phase was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by silica gel chromatography (column: 60 g) eluting with PE / EtOAc (30:1). The product mixture (30 g) was obtained. This mixture was purified by flash chromatography eluting with PE / EtOAc (10:1). The desired fractions were combined and concentrated in vacuo to give rac-(1R,3R,6S)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (4 g, 20%) as a colorless oil. m / z (ES + )[M+H] + =205.15; HPLC tR=1.002min.

[1104] Mixture of (1R,2R,5R)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol and (1S,2S,5S)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol

[1105]

[1106] Step 4. To a mixture of racemic-(1R, 3R, 6S)-3-(benzyloxy)-7-oxabicyclo[4.1.0]heptane (4.4 g, 22 mmol) and (S)-1-phenylethyl-1-amine (3.5 g, 29 mmol) in ACN (35 mL) was added lithium perchlorate (4.6 g, 43 mmol) in portions at 0°C under a nitrogen atmosphere. The mixture was stirred at room temperature for 16 hours. The mixture was then diluted with H2O (50 mL) and the aqueous phase was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. This gave the desired product as a mixture of (1R,2R,5R)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol and (1S,2S,5S)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol (total: 6.3 g), which was used in the next step without further purification. m / z (ES + )[M+H] + =326.15; HPLCtR=0.917min.

[1107] (1S,2S,4S)-4-(Benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-N-((S)-1-phenylethyl)cyclohexan-1-amine

[1108]

[1109] Step 5. To an ice-cold solution of a mixture of (1R, 2R, 5R)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol and (1S, 2S, 5S)-5-(benzyloxy)-2-(((S)-1-phenylethyl)amino)cyclohexan-1-ol (6.3 g, 19 mmol) and triethylamine (5.9 g, 58 mmol) in DCM (70 mL) was added TBSOTf (15 g, 58 mmol). The resulting mixture was stirred at room temperature for 16 hours. Next, the reaction mixture was diluted with H2O (50 mL), and the aqueous phase was extracted with EtOAc (3x100 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The crude product was purified by silica gel chromatography (column: 30 g) eluted with PE / EtOAc (gradient: 7: 1 to 3: 1). The desired fractions were combined and concentrated in vacuo to give (1S,2S,4S)-4-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-N-((S)-1-phenylethyl)cyclohexan-1-amine (4.4 g, 94%) as a dark yellow oil. m / z (ES + )[M+H] -=440.35; HPLC tR=1.118min.

[1110] tert-Butyl ((1S,2S,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate

[1111]

[1112] Step 6. A stirred mixture of (1S,2S,4S)-4-(benzyloxy)-2-((tert-butyldimethylsilyl)oxy)-N-((S)-1-phenylethyl)cyclohexane-1-amine (4.2 g, 9.6 mmol), (Boc)2O (2.2 g, 10 mmol) and Pd(OH)2 (4.2 g, 30 mmol) in EtOH (50 mL) was treated with H2 at 50°C for 2 h. The resulting mixture was filtered through a pad of celite, the pad was washed with EtOAc, and the filtrate was concentrated in vacuo. This gave the crude product, tert-butyl ((1S,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate (2.9 g, 88%) as a gray solid. m / z (ES + )[M+H] + =346.30; HPLC tR=1.135min.

[1113] tert-Butyl ((1S,2S,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclohexyl)carbamate

[1114]

[1115] Step 7. To a mixture of tert-butyl ((1S,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate (500 mg, 1.45 mmol), DMAP (18 mg, 145 μmol) and DIEA (561 mg, 4.34 mmol) in THF (10 mL) was added dropwise a solution of 4-nitrophenyl chloroformate (583 mg, 2.89 mmol) dissolved in 1 mL of THF at 0°C under a nitrogen atmosphere. The mixture was stirred at 70°C for 2 hours. The mixture was then diluted with H2O (20 mL) and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 90% to 100% over 6 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to provide tert-butyl ((1S,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclohexyl)carbamate (495 mg, 67.0%) as a tan oil. m / z (ES + )[Mt-Bu+H] - =455.15; HPLC tR=1.548min.

[1116] (1S,3S,4S)-4-((tert-Butoxycarbonyl)amino)-3-((tert-Butyldimethylsilyl)oxy)cyclohexyl methylcarbamate

[1117]

[1118] Step 8. DIEA (368 mg, 2.85 mmol) was added to a solution of methylamine hydrochloride (128 mg, 1.90 mmol) in THF (7 mL), and the resulting mixture was stirred at room temperature for 10 minutes. Next, tert-butyl ((1S, 2S, 4S)-2-((tert-butyldimethylsilyl)oxy)-4-(((4-nitrophenoxy)carbonyl)oxy)cyclohexyl)carbamate (485 mg, 0.95 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was then diluted with H o (15 mL), processed with 5 mL 1 M LiOH, and the aqueous phase was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to give the crude product, (1S,3S,4S)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl methylcarbamate (330 mg, 86.3%), as a yellow solid. m / z (ES + )[M+Na]+ =425.10; HPLC tR=1.383min.

[1119] (1S,3S,4S)-4-amino-3-hydroxycyclohexyl methylcarbamate

[1120]

[1121] Step 9. To a solution of (1S,3S,4S)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl methylcarbamate (160 mg, 397 μmol) in MeOH (2 mL) was added 4 M HCl in dioxane (2 mL) and the resulting mixture was stirred at room temperature for 1 hour. Concentration in vacuo gave the crude product, (1S,3S,4S)-4-amino-3-hydroxycyclohexyl methylcarbamate (68 mg, 91%), as a yellow solid. m / z (ES + )[M+H] + =189.20; HPLC tR=0.143min.

[1122] (1S,3S,4S)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxycyclohexyl methylcarbamate

[1123]

[1124] Step 10. To a solution of 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (0.12 g, 0.35 mmol) in NMP (4 mL) was added (1S,3S,4S)-4-amino-3-hydroxycyclohexyl methylcarbamate (63 mg, 0.33 mmol) and DIEA (0.17 g, 1.3 mmol), and the mixture was heated at 150 °C for 1 h. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 26% B to 48% B, 48% B over 8 minutes) and lyophilized to afford the desired final product, (1S,3S,4S)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-3-hydroxycyclohexyl methylcarbamate (33.4 mg, 20%), as an off-white solid. m / z (ES + )[M+H] +=491.15; HPLC tR=1.118min. 1 H NMR(400MHz, DMSO-d6)8.39(s,1H),7.91(s,1H),7.31(d,J=39.7Hz,2H),7.00-6.93(m,1H),4.86-4.75(m,2H),4.59-4.37(m,1H),3.60(s,1H),3 .52(s,1H),2.62(s,3H),2.55(d,J=4.6Hz,3H),2.17(d,J=11.7Hz,1H),1 .88(s,1H),1.58(d,J=6.9Hz,6H),1.31(ddt,J=35.9,25.6,13.1Hz,4H).

[1125] Example 9

[1126] 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound I-116)

[1127]

[1128] 4,4-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

[1129]

[1130] Step 1. To a solution of 6-bromo-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (300 mg, 1.18 mmol) and bis(pinacolato)diboron (600 mg, 2.36 mmol) in 1,4-dioxane (3 mL) was added KOAc (348 mg, 3.54 mmol) and Pd(pph)Cl (83 mg, 0.12 mmol), and the resulting mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The solution was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 10% to 50% over 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (124 mg, 30%) as a black oil. m / z (ES + )[M+H] + =302.25; HPLC tR=1.018min.

[1131] 6-(2,5-Dichloropyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

[1132]

[1133] Step 2. To a solution of 4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (124 mg, 0.41 mmol) and 2,4,5-trichloropyrimidine (151 mg, 0.82 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added Na2CO3 (131 mg, 1.24 mmol) and Pd(dppf)Cl2 (30 mg, 0.04 mmol), and the resulting mixture was stirred at 80°C under a nitrogen atmosphere for 12 hours. The solution was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase, aqueous ACN, gradient from 0% to 100% over 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 6-(2,5-dichloropyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (104 mg, 63%) as a black solid. m / z (ES + )[M+H] + =321.95; HPLC tR=0.858min

[1134] 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound I-116)

[1135]

[1136] Step 3. A round-bottom flask was charged with 6-(2,5-dichloropyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (99 mg, 0.31 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (57 mg, 0.37 mmol), and DIEA (120 mg, 0.92 mmol) in NMP (1 mL) along with a stir bar, and the resulting solution was stirred at 150° C. for 12 hours. The solution was then purified by reverse-phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 0% to 100% over 25 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (65.4 mg, 51%) as a yellow amorphous solid. m / z (ES + )[M+H] + =403.10;HPLC tR=1.318min 1 HNMR(400MHz, DMSO-d6)8.43(s,1H),8.09(s,1H),7.96(d,J=8.0Hz,1H),7.70(s,2H),7.51(s,1H),4.92(d,J=5.4Hz,1H),3.81(q,J=5.4Hz,3H), 3.51(d,J=14.6Hz,1H),3.31(s,1H),3.23(d,J=3.0Hz,2H),3.02(t,J=10 .4Hz,1H),1.92(d,J=13.1Hz,1H),1.59-1.44(m,1H),1.37-1.21(m,6H).

[1137] Example 10

[1138] (1S,2S,5S)-2-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-5-isopropoxycyclohexan-1-ol (Compound I-117)

[1139]

[1140] tert-Butyl ((1S,2S,4S)-2-((tert-Butyldimethylsilyl)oxy)-4-isopropoxycyclohexyl)carbamate

[1141]

[1142] Step 1. A resealable reaction vial was charged with tert-butyl ((1S,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-hydroxycyclohexyl)carbamate (400 mg, 1.16 mmol), Ag2O (537 mg, 2.32 mmol), 2-iodopropane (5 mL) and a stirring bar, then evacuated and purged with nitrogen three times, and the resulting mixture was stirred at 50 °C for 5 days. The resulting crude material was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 57% B to 80% B, 80% B over 8 minutes; wavelength: 220 nm and 254 nm; tR1 (min): 7.17 / 7.67; injection volume: 0.6 mL; number of runs: 6). The desired fractions were combined and then concentrated in vacuo to give tert-butyl ((1S,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-isopropoxycyclohexyl)carbamate (80 mg, 18%) as an oil. m / z (ES + )[M+H] + =388.35; HPLC tR=1.310min.

[1143] (1S,2S,5S)-2-Amino-5-isopropoxycyclohexan-1-ol

[1144]

[1145] Step 2. A resealable reaction vial was charged with tert-butyl ((1S,2S,4S)-2-((tert-butyldimethylsilyl)oxy)-4-isopropoxycyclohexyl)carbamate (80 mg, 0.21 mmol); a 1:1 mixture of MeOH and 4M HCl in dioxane (1 mL); and a stir bar, then evacuated and purged with nitrogen three times, and the resulting mixture was stirred at 25°C for 1 hour. Concentration in vacuo afforded (1S,2S,5S)-2-amino-5-isopropoxycyclohexan-1-ol (30 mg, 84%) as a white solid. m / z (ES + )[M+H] + =174.20; HPLC tR=0.185min.

[1146] (1S,2S,5S)-2-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-5-isopropoxycyclohexan-1-ol

[1147]

[1148] Step 3. A resealable reaction vial was charged with (1S,2S,5S)-2-amino-5-isopropoxycyclohexan-1-ol (50 mg, 0.29 mmol), 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (0.10 g, 0.30 mmol), DIEA (0.22 g, 1.7 mmol), NMP (3 mL), and a stir bar. The mixture was then evacuated and flushed with nitrogen three times, and the resulting mixture was stirred at 150° C. for 1 hour. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 10% to 50% over 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give the crude material, which was then purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30x150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.1% NH3·H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 28% B to 57% B, 57% B in 8 minutes; wavelength: 220 nm; tR1 (min): 7.57; injection volume: 0.07 mL; number of runs: 3). The desired fractions were combined and lyophilized to give (1S,2S,5S)-2-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-5-isopropoxycyclohexan-1-ol (100.2 mg, 73%) as a white amorphous solid. m / z (ES + )[M+H] + =476.10; HPLC tR=1.062min 1 H NMR (400MHz, DMSO-d6) δ8.39(s,1H),7.92(s,1H),7.38(s,1H),7.25(s,1H),4.81(p,J=6.9Hz,1H),4.69(d,J=5.2Hz,1H),3.68(p,J=6.1Hz ,1H),3.56(d,J=8.9Hz,1H),3.45(s,1H),3.30(s,1H),2.62(s,3H),2.14(d,J=12.2Hz,1H),2.08-1.74(m,2H),1.58(d,J=6.9Hz,6H),1.28 -1.11(m,3H),1.06(dd,J=6.1,1.0Hz,6H).

[1149] Example 11

[1150] (3S,4R)-4-((4-(3-(tert-butyl)imidazo[1,2-a]pyridin-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (Compound I-158)

[1151]

[1152] (3-(tert-Butyl)imidazo[1,2-a]pyridin-6-yl)boronic acid

[1153]

[1154] Step 1. A resealable reaction vial was charged with 6-bromo-3-(tert-butyl)imidazo[1,2-a]pyridine (100 mg, 0.40 mmol) and bis(pinacolato)diboron (120 mg, 0.47 mmol) in 1,4-dioxane (4 mL) along with a stir bar. Potassium acetate (116 mg, 1.19 mmol) and PdCl2(dppf) (28.9 mg, 0.04 mmol) were then added and the resulting mixture was evacuated and purged with nitrogen three times, then stirred at 80°C under a nitrogen atmosphere for 16 hours. The crude material was filtered through a pad of celite, the pad was washed with 1,4-dioxane, and the filtrate was concentrated in vacuo to give the title compound, which was used in the next step without any further purification. m / z (ES + )[M+H] + =219.05; HPLC tR=0.385min.

[1155] 3-(tert-Butyl)-6-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine

[1156]

[1157] Step 2. A resealable reaction vial was charged with crude (3-(tert-butyl)imidazo[1,2-a]pyridin-6-yl)boronic acid (86.5 mg, 0.40 mmol), 2,4,5-trichloropyrimidine (84.1 mg, 0.46 mmol), NaCO (146 mg, 1.38 mmol), Pd(PPh)Cl (28 mg, 0.04 mmol), dioxane (4 mL), HO (1 mL), and a stir bar, then evacuated and purged with nitrogen three times. The resulting mixture was stirred at 60°C for 2 hours. The crude material was purified by flash chromatography (mobile phase: acetonitrile / water; gradient: 50% to 90% over 15 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 3-(tert-butyl)-6-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (35 mg, 24%) as a yellow amorphous solid. m / z (ES + )[M+H] + =321.10; HPLC tR=0.910min.

[1158] (3S,4R)-4-((4-(3-(tert-Butyl)imidazo[1,2-a]pyridin-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol

[1159]

[1160] Step 3. A resealable reaction vial was charged with 3-(tert-butyl)-6-(2,5-dichloropyrimidin-4-yl)imidazo[1,2-a]pyridine (30 mg, 0.09 mmol) and (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (14 mg, 0.09 mmol) in NMP (1 mL); a stirring bar and DIEA (60 mg, 0.47 mmol). The resulting mixture was evacuated and purged with nitrogen three times, then stirred at 150°C under nitrogen atmosphere for 1 hour. The resulting crude material was purified by preparative HPLC (column: XBridge Prep OBD C18 column, 30 x 150 mm, 5 μm; mobile phase A: 10 mmol NH4HCO3 + 0.05% NH3H2O; mobile phase B: ACN; flow rate: 60 mL / min; gradient: 24% B to 49% B, 49% B over 8 minutes; wavelength: 254 nm; tR1 (min): 7.48; injection volume: 0.8 mL; number of runs: 2). The desired fractions were combined and then lyophilized to afford (3S,4R)-4-((4-(3-(tert-butyl)imidazo[1,2-a]pyridin-6-yl)-5-chloropyrimidin-2-yl)amino)tetrahydro-2H-pyran-3-ol (5.3 mg, 14%) as an off-white solid. m / z (ES + )[M+H] + =402.10; HPLC tR=0.972min. 1 H NMR (400MHz, DMSO-d6)8.99(s,1H),8.44(s,1H),7.71-7.52(m,3H),7.44(s,1H),4.96(d,J=5.3Hz,1 H), 3.89-3.77 (m, 3H), 3.51 (s, 1H), 3.27 (s, 1H), 3.02 (t, J = 10.3Hz, 1H), 1.95 (s, 1H), 1.48 (s, 10H).

[1161] Example 12

[1162] (4S,5S)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol and (4R,5R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (Compounds I-182 and I-183)

[1163]

[1164] 6-(Methoxymethyl)-1a,2,3,7b-tetrahydroepoxy[2,3-c]pyrazolo[1,5-a]pyridine

[1165]

[1166] Step 1. To a mixture of 2-(methoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyridine (260 mg, 1.58 mmol) in dichloromethane (5 mL) was added m-CPBA (820 mg, 4.75 mmol) and sodium bicarbonate (532 mg, 6.33 mmol) portionwise at 0°C under nitrogen atmosphere, and the resulting mixture was stirred at 0°C for 6 hours. The crude residue was purified by silica gel chromatography (60 g column; eluted with PE / EtOAc [4:5]). Concentration in vacuo afforded 6-(methoxymethyl)-1a,2,3,7b-tetrahydrooxirano[2,3-c]pyrazolo[1,5-a]pyridine (100 mg, 0.50 mmol, 32%, 90% purity) as a white solid. m / z (ES + )[M+H] + =181.10; HPLC tR=0.438min.

[1167] rac-(4R,5R)-4-azido-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol

[1168]

[1169] Step 2. To a solution of 6-(methoxymethyl)-1a,2,3,7b-tetrahydrooxirano[2,3-c]pyrazolo[1,5-a]pyridine (100 mg, 555 μmol) in THF / EtOH / H2O (1:2:0.25, 1.325 mL) was added trimethylsilyl azide (83.1 mg, 721 μmol) and ammonium chloride (47.5 mg, 888 μmol), and the resulting mixture was heated at 50°C overnight. After cooling, the residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase, acetonitrile in water, gradient from 10% to 50% over 10 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give rac-(4R,5R)-4-azido-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (40 mg, 0.14 mmol, 26%, 80% purity) as a white solid. m / z (ES + )[M+H] +=224.15; HPLC tR=0.843min.

[1170] rac-(4R,5R)-4-amino-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol

[1171]

[1172] Step 3. A stirred mixture of rac-(4R,5R)-4-azido-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (40 mg, 0.18 mmol) and Pd / C (4.0 mg, 38 μmol) in MeOH (5 mL) was treated with H2 at 25°C for 3 h. The reaction mixture was filtered and the filtrate was concentrated to afford rac-(4R,5R)-4-amino-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (60 mg, 0.15 mmol, 85%, 50% purity) as a white solid. m / z (ES + )[M+H] + =198.10; HPLC tR=0.298min.

[1173] rac-((4R,5R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol

[1174]

[1175] Step 4. To a solution of rac-(4R,5R)-4-amino-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (60 mg, 0.30 mmol) and 6-(2,5-dichloropyrimidin-4-yl)-4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazole (93.0 mg, 0.27 mmol) in NMP (1 mL) was added DIEA (39.0 mg, 53 μL, 0.30 mmol) at room temperature. The solution was stirred at 150°C for 1 hour. The mixture was cooled to room temperature and then purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: acetonitrile in water, gradient from 10% to 50% over 10 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give rac-((4R,5R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (40 mg, 76 μmol, 25%, 95% purity)) as a white solid. m / z (ES + )[M+H] + =500.05; HPLC tR=0.850min.

[1176]

[1177] Step 5. The crude product (50 mg) obtained in step 4 was purified by preparative chiral HPLC (column: CHIRALPAK IG, 2x25 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: isocratic; wavelength: 220 nm and 254 nm; tR1 (min): 7.97; sample solvent: EtOH / DCM (1:1) HPLC; injection volume: 0.7 mL; number of runs: 3) to give rel-(4R,5R)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (15.2 mg, 30.3 μmol, 61%, 99.7% purity) as an off-white amorphous solid: m / z (ES + )[M+H] + =500.10; HPLC tR=0.883min. 1H NMR (400MHz, DMSO-d6)8.47(s,1H),7.93(d,J=8.0Hz,2H),7.37(d,J=11.7Hz,1H),6.03(s,1H),5.32(s,1H),5 .09(s,1H),4.80(p,J=6.9Hz,1H),4.25(s,2H),4.10(q,J=6.2,5.7Hz,3H),3.21(s,3H),2.62(s,3H),2.32(s,1 H), 2.02 (dt, J=14.2, 7.0 Hz, 1H), 1.57 (m, 6H); and rel-(4S,5S)-4-((5-chloro-4-(4-fluoro-1-isopropyl-2-methyl-1H-benzo[d]imidazol-6-yl)pyrimidin-2-yl)amino)-2-(methoxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-5-ol (15.6 mg, 30.8 μmol, 62%, 98.7% purity) as an off-white amorphous solid: m / z (ES + )[M+H] + =500.10; HPLC tR=1.438min. 1 H NMR (400MHz, DMSO-d6)8.49(s,1H),7.93(d,J=7.9Hz,2H),7.37(d,J=11.7Hz,1H),6.03(s,1H),5.32(s,1H),5.09(s,1H),4.80(p,J =7.0Hz,1H),4.25(s,2H),4.10(m,3H),3.21(s,3H),2.62(s,3H),2.32(m,1H),2.02(dt,J=14.2,7.0Hz,1H),1.57(d,J=6.8Hz,6H).

[1178] Example 13

[1179] 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound I-201)

[1180]

[1181] 2-Bromo-4-chloro-N-(2,4-dimethoxybenzyl)-6-fluorobenzamide

[1182]

[1183] Step 1. To a mixture of 2-bromo-4-chloro-6-fluorobenzoic acid (2.00 g, 8.00 mmol) and DIEA (1.86 g, 14.4 mmol) in DCM (10 mL) was added HATU (2.73 g, 7.18 mmol) in portions at 25 ° C under a nitrogen atmosphere, and the resulting mixture was stirred at 25 ° C for 30 minutes. Then, a DCM solution of (2,4-dimethoxyphenyl)methylamine (0.80 g, 4.78 mmol) was added, and the reaction mixture was stirred at 25 ° C for another 1 hour. The crude mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: ACN aqueous solution; gradient: 0% to 100% in 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 2-bromo-4-chloro-N-(2,4-dimethoxybenzyl)-6-fluorobenzamide (1.15 g, 59.7%) as a colorless oil. m / z (ES + )[M+H] + =402.15; HPLC tR=1.149min.

[1184] 2-Bromo-4-chloro-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(2-methylallyl)benzamide

[1185]

[1186] Step 2. To a solution of 2-bromo-4-chloro-N-(2,4-dimethoxybenzyl)-6-fluorobenzamide (1.15 g, 2.86 mmol) in THF (15 mL) was added NaH (0.34 g, 60 wt %, 8.57 mmol) in portions at 0 ° C., and the resulting mixture was stirred for 30 minutes. Then, 3-bromo-2-methylprop-1-ene (0.46 g, 3.43 mmol) was added, and the reaction mixture was warmed to 25 ° C. and then stirred for 12 hours. The crude mixture was diluted with ice water (15 mL), and the aqueous phase was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: ACN aqueous solution; gradient: 0% to 100% in 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 2-bromo-4-chloro-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(2-methylallyl)benzamide (0.86 g, 65.9%) as a colorless oil. m / z (ES + )[M+H] +=456.10; HPLC tR=1.268min.

[1187] 6-Chloro-2-(3,5-dimethoxybenzyl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

[1188]

[1189] Step 3. To a solution of 2-bromo-4-chloro-N-(3,5-dimethoxybenzyl)-6-fluoro-N-(2-methylallyl)benzamide (1.60 g, 3.5 mmol) and sodium formate (0.26 g, 3.9 mmol) in DMF (4 mL) was added sodium acetate (0.63 g, 7.7 mmol), tetraethylammonium chloride (0.58 g, 3.5 mmol) and palladium diacetate (0.08 g, 0.35 mmol), and the resulting mixture was stirred at 70 ° C under a nitrogen atmosphere for 1 hour. The reaction mixture was diluted with H2O (15 mL), and the aqueous phase was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by preparative TLC using PE / EtOAc (4:1) as eluent. The desired fractions were combined and concentrated in vacuo to give 6-chloro-2-(3,5-dimethoxybenzyl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (1.5 g, 99%) as a yellow oil. m / z (ES + )[M+H] + =378.15; HPLC tR=1.048min.

[1190] 6-Chloro-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

[1191]

[1192] Step 4. A round-bottom flask was charged with 6-chloro-2-(2,4-dimethoxybenzyl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (460 mg, 1.22 mmol) in TFA (2 mL) and a stir bar, and the solution was stirred at 50°C for 1 hour. The mixture was quenched with saturated NaHCO3 (aq) and diluted with H2O (15 mL), and the aqueous phase was then extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 0% to 60% over 20 minutes; wavelength: 254 nm). The desired fractions were combined and concentrated in vacuo to give 6-chloro-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (250 mg, 86%) as a white solid. m / z (ES + )[M+H] + =228.10; HPLC tR=0.675min.

[1193] 8-Fluoro-4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one

[1194]

[1195] Step 5. To a solution of 6-chloro-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (100 mg, 0.44 mmol) and B2Pin2 (223 mg, 0.88 mmol) in 1,4-dioxane (1 mL) was added KOAc (129 mg, 1.32 mmol) and XPhos Pd G3 (37.2 mg, 0.04 mmol), and the resulting mixture was stirred at 110° C. under nitrogen atmosphere for 2 hours. The mixture was then diluted with H2O (15 mL), and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo to give crude 8-fluoro-4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (210 mg, 150%) as a black oil. m / z (ES + )[M+H] + =320.25; HPLC tR=1.135min.

[1196] 6-(2,5-Dichloropyrimidin-4-yl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one

[1197]

[1198] Step 6. To a solution of 8-fluoro-4,4-dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinolin-1(2H)-one (205 mg, 0.64 mmol) and 2,4,5-trichloropyrimidine (130 mg, 0.71 mmol) in 1,4-dioxane (2 mL) and H2O (0.4 mL) was added Na2CO3 (204 mg, 1.93 mmol) and Pd(dppf)Cl2 (47 mg, 0.06 mmol), and the resulting mixture was stirred at 80°C under a nitrogen atmosphere for 3 hours. The mixture was then diluted with H2O (15 mL), and the aqueous phase was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The residue was purified by reverse phase flash chromatography (column: C18 silica gel; mobile phase: aqueous ACN; gradient: 0% to 100% in 20 minutes; wavelength: 254 nm). The desired fractions were combined and then concentrated in vacuo to give 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (60 mg, 14%) as a black solid. m / z (ES + )[M+H] + =340.00; HPLC tR=0.732min.

[1199] 6-(5-chloro-2-(((3S,4R)-3-hydroxytetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (Compound I-201)

[1200]

[1201] Step 7. A round-bottom flask was charged with 6-(2,5-dichloropyrimidin-4-yl)-8-fluoro-4,4-dimethyl-3,4-dihydroisoquinolin-1(2H)-one (25 mg, 0.07 mmol), (3S,4R)-4-aminotetrahydro-2H-pyran-3-ol hydrochloride (12 mg, 0.08 mmol), and DIEA (28 mg, 0.22 mmol) in NMP (1 mL) along with a stir bar, and the solution was stirred at 150° C. for 1 hour. The resulting mixture was diluted with H 2 O (15 mL), and the aqueous phase was extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and then concentrated in vacuo. The resulting crude material was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 30 x 150 mm, 5 μm; mobile phase A: water (10 mM NH4HCO3 + 0.05% NH3H2O); mobile phase B: ACN; flow rate: 60 mL / min; gradient: 17% B to 38% B over 7 minutes; wavelength: 220 nm and 254 nm); tR1 (min): 7.0; number of ...

Claims

1. A compound of formula I': or a pharmaceutically acceptable salt thereof, wherein: Q is for L 1 ; Z is H, halogen or Cy B ; L is a covalent bond or a divalent C 1-3 An aliphatic group in which one carbon is optionally replaced by -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)-, -S(O)2-, C 3-6 is replaced by a cycloalkylene or a 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein said C 3-6 Each of the cycloalkylene and 3-6 membered heterocycloalkylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution; Cy A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m times A replace; Cy B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace; Cy X is phenyl, naphthyl, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-12 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated, partially unsaturated or aromatic bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-15 membered saturated, partially unsaturated or aromatic tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; Among them, Cy X L appeared by u 2 -X 0 replace; X 0 is hydrogen, halogen, oxo, CN or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X 0 R appears p times X replace; Y is N or CH; Each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being q A The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and R X Being q X The number of R 3 Replace; or Two occurrences of R A , two occurrences of R B , two occurrences of R X , two Xs appear 0 、X appears 0 and the appearance of R A or the appearance of R A and the appearance of R X Together with their intervening atoms, they form a 3-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace; L 1 and L 2 Each of is independently a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution; Each occurrence of R L Independently R 1 or R 2 , and is replaced by t occurrences of R 3 replace; Each occurrence of R 1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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 -P(O)R2; Each occurrence of R 2 Independently C 1-7 Aliphatic group; -OC 1-7 Aliphatic group; C 1-4 haloalkyl; 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 monocyclic 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; Each occurrence of R 3 and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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; Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a saturated or partially unsaturated 3-7 membered heterocyclic ring 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, or: The two R groups on the same nitrogen are taken together with their intervening atoms to 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 m, n, p, q A ,q B ,q X Each of r, t and u is independently 0, 1, 2, 3 or 4.

2. The compound of claim 1, wherein the compound has Formula I: or a pharmaceutically acceptable salt thereof, wherein: Q is for L 1 ; Z is H or Cy B ; Cy A is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy A R appears m times A replace; Cy B is phenyl; a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring; a 3-8 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 7-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; a 10-14 membered saturated or partially unsaturated tricyclic heterocyclic ring having 1-6 heteroatoms independently selected from nitrogen, oxygen, phosphorus and sulfur; or a 10-14 membered tricyclic heteroaryl ring having 1-6 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein Cy B R appears by n B replace; Cy X yes in represents a bond to Q, and Indicates that Cy A Key; X is N or CL 2 -X 0 ; X 0 is hydrogen, halogen or a group selected from the following: C 1-8 aliphatic, a saturated or partially unsaturated 3-14 membered monocyclic or bicyclic carbocyclic ring, phenyl, a 3-10 membered saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, and a 5-14 membered monocyclic or bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein X 0 R appears p times X replace; Y is N or CH; Each occurrence of R A 、R B and R X Independently R 1 or R 2 , where R A Being q A The number of R 3 Replacement, R B Being q B The number of R 3 Replace, and R X Being q X The number of R 3 Replace; or Two occurrences of R A , two occurrences of R B , two occurrences of R X or the appearance of R A and the appearance of R X Together with their intervening atoms, they form a 4-8 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen and sulfur; wherein the ring is surrounded by r occurrences of R 3 replace; L 1 and L 2 Each of is independently a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, 3-6 membered heterocycloalkylene having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroarylene having 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, -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-; wherein said C 3-6 Each of cycloalkylene, 3-6 membered heterocycloalkylene and 5-6 membered heteroarylene is optionally replaced by one occurrence of R 1 or C 1-6 aliphatic substitution; Each occurrence of R L Independently R 1 or R 2 , and is replaced by t occurrences of R 3 replace; Each occurrence of R 1 is independently oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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; Each occurrence of R 2 Independently C 1-7 Aliphatic group; -OC 1-7 Aliphatic group; C 1-4 haloalkyl; 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 monocyclic 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; Each occurrence of R 3 and -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, -N(R)S(O)R, or an optionally substituted group selected from: C(O) 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated heterocyclic ring 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; Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 an aliphatic group, a saturated or partially unsaturated 3-7 membered carbocyclic ring, a phenyl group, a saturated or partially unsaturated 3-7 membered heterocyclic ring 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, or: The two R groups on the same nitrogen are taken together with their intervening atoms to 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 m, n, p, q A ,q B ,q X Each of r, r and t is independently 0, 1, 2, 3 or 4.

3. The compound of claim 1 or 2, wherein Z is Cy B .

4. The compound of claim 1 or 2, wherein Z is hydrogen.

5. The compound of any one of claims 1 to 4, wherein Q is a covalent bond or C 1-6 A saturated or unsaturated straight or branched hydrocarbon chain wherein one or two methylene units of the chain are optionally and independently replaced by -CH(R L )-、-C(R L )2-、C 3-6 Cycloalkylene, -NH-, -N(R L )- or -O- substitution.

6. The compound according to any one of claims 1 to 5, wherein Q is -NH-, in Indicates that Cy X covalent bonds, and Indicates that Cy B Or a covalent bond of Z.

7. The compound of claim 1, wherein the compound has Formula IA: or a pharmaceutically acceptable salt thereof.

8. The compound of any one of claims 1-7, wherein Y is N.

9. The compound of any one of claims 1-7, wherein Y is CH.

10. The compound of any one of claims 1 to 9, wherein X is -CL 2 -X 0 .

11. The compound of any one of claims 1 to 10, wherein L 2 It is a covalent bond.

12. The compound of claim 1, wherein the compound has Formula II, III, or IV: or a pharmaceutically acceptable salt thereof.

13. The compound of any one of claims 1 to 12, wherein Cy A is an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

14. The compound of any one of claims 1 to 12, wherein Cy A yes 15. The compound of claim 1, wherein the compound has the formula II-A, II-B, II-C, II-D, II-E, II-F, II-G, II-H, II-I, II-J, II-K, II-L, II-M, II-N, II-O, II-P, II-Q, II-R, II-S, II-T, II-U, II-V, II-W, II- X, II-Y, II-Z, II-AA, II-BB, II-CC, II-DD, II-EE, II-FF, II-GG, II-HH, II-II, II-JJ, II-KK, II-LL, II-MM, II-NN, II-OO, II-PP, II-QQ, II-RR, II-SS, II-TT, II-UU or II-VV: or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1 to 15, wherein Cy B is a 3-8 membered saturated carbocyclic ring wherein the ring is surrounded by n occurrences of R B replace.

17. The compound of any one of claims 1 to 15, wherein Cy B is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein the ring is surrounded by n occurrences of R B replace.

18. The compound of claim 1, wherein the compound has Formula II-A1, II-B1, II-C1, II-D1, II-E1, II-F1, II-G1, II-H1, II-I1, II-J1, II-K1, II-L1, II-M1, II-N1, II-O1, II-P1, or II-Q1: or a pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound has Formula II-A2, II-B2, II-C2, II-D2, II-E2, II-F2, II-G2, or II-H2: or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound has Formula V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, or XXII: or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound has Formula XXIII, XXIV, XXV, XXVI, or XXVII: or a pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound has Formula XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, or XXXIX: or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound has Formula XL, XLI, XLII, or XLIII: or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound has Formula XLIV, XLV, XLVI, XLVII, XLVIII, XLIX, L, LI, LII, LIII, LIV, or LV: or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound has Formula LVI, LVII, LVIII, or LIX: or a pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound has Formula LX, LXI, LXII, LXIII, LXIV, LXV, LXVI, LXVII, LXVIII, LXIX, LXX, or LXXI: or a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound has Formula LXXII, LXXIII, LXXIV, or LXXV: or a pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein the compound has Formula LXXVI, LXXVII, LXXVIII, LXXIX, LXXX, LXXXI, LXXXII, LXXXIII, LXXXIV, LXXXV, LXXXVI, or LXXXVII: or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1, wherein the compound has Formula LXXXVIII, LXXXIX, XC, or XCI: or a pharmaceutically acceptable salt thereof.

30. The compound of any one of claims 1 to 29, wherein X 0 It's a halogen.

31. The compound of claim 30, wherein X 0 It's Cl.

32. The compound of claim 30, wherein X 0 It's F.

33. The compound of any one of claims 1-32, wherein Q is -NH-.

34. A compound as described in any one of claims 1 to 33, wherein at least one occurrence of R B Is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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.

35. A compound as described in any one of claims 1 to 33, wherein at least one occurrence of R B It is -OH.

36. A compound as described in any one of claims 1 to 35, wherein at least one occurrence of R A Is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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.

37. The compound of claim 36, wherein at least one occurrence of R A It's a halogen.

38. A compound as described in any one of claims 1 to 35, wherein at least one occurrence of R A It is 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 monocyclic 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.

39. The compound of claim 38, wherein at least one occurrence of R A Is q A The number of R 3 Substituted C 1-7 Aliphatic group.

40. The compound of any one of claims 1 to 39, wherein at least one occurrence of R 3 Is oxo, halogen, -CN, -NO2, -OR, -SR, -NR2, -S(O)2R, -S(O)2NR2, -S(O)R, -S(O)NR2, -SR(O)NR, -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, or -N(R)S(O)2R.

41. A compound as described in any one of claims 1 to 40, wherein at least one occurrence of R 3 It's a halogen.

42. A compound as described in any one of claims 1 to 40, wherein at least one occurrence of R 3 It is -S(O)2R, -S(O)2NR2, -C(O)OR or -C(O)NR2.

43. A compound as described in any one of claims 1 to 39, wherein at least one occurrence of R 3 is an optionally substituted C 1-6 Aliphatic group.

44. The compound of claim 42, wherein at least one occurrence of R 3 It's methyl.

45. The compound of any one of claims 1-44, wherein the compound is selected from the compounds shown in Table 1 or pharmaceutically acceptable salts thereof.

46. ​​A pharmaceutical composition comprising a compound according to any one of claims 1 to 45 and a pharmaceutically acceptable carrier.

47. A method of inhibiting CDK4 signaling activity in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-45 or a pharmaceutical composition of claim 46.

48. A method of treating a CDK4-mediated disorder in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-45 or a pharmaceutical composition of claim 46.

49. A method of treating a condition in a subject, wherein the condition is ovarian cancer, endometrial cancer, gastric cancer, breast cancer, lung cancer, bladder cancer, cervical cancer, stomach cancer, sarcoma cancer, liver cancer, esophageal cancer, laryngeal cancer, multiple myeloma, colorectal cancer, rectal cancer, skin cancer, or pancreatic cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 45 or a pharmaceutical composition of claim 46.

50. The method of claim 49, wherein the bladder cancer is urothelial carcinoma.

51. The method of claim 49, wherein the liver cancer is hepatocellular carcinoma.

52. The method of claim 49, wherein the lung cancer is squamous cell lung carcinoma or non-small cell lung cancer.

53. The method of claim 49, wherein the laryngeal cancer is laryngeal squamous cell carcinoma.

54. The method of claim 49, wherein the skin cancer is melanoma.

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