COMPOUNDS CONTAINING A SULFONIC GROUP AS KAT INHIBITORS

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

##STR00001##

Claims

1. A compound of formula I: ##STR00682## or a pharmaceutically acceptable salt thereof, wherein: Ring A is selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, an 8-10 membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; L is a 3- to 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic; wherein: two atoms of L may, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; R.sup.a is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, or optionally substituted C.sub.1-4 aliphatic; Z is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, —(C.sub.1-3 aliphatic)-Cy or optionally substituted C.sub.1-4 aliphatic; Cy is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; each R is independently hydrogen or an optionally substituted group selected from C.sub.1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; n is 0 or 1; and x is 0, 1, 2, or 3.

2. The compound according to claim 1, wherein L is a 3-atom linker.

3. The compound according to claim 2, wherein L is ##STR00683##

4. The compound according to claim 1, wherein L is a 4-atom linker.

5. The compound according to claim 4, wherein L is selected from the group consisting of ##STR00684##

6. (canceled)

7. The compound according to claim 1, wherein L is a 5-atom linker.

8. The compound according to claim 7, wherein L is selected from the group consisting of ##STR00685##

9. The compound according to claim 1, wherein Z is optionally substituted C.sub.1-4 aliphatic.

10. (canceled)

11. The compound according to claim 1, wherein Z is —Cy.

12-14. (canceled)

15. The compound according to claim 1, wherein Ring B is an optionally substituted 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

16-22. (canceled)

23. The compound according to claim 1, wherein Ring A is phenyl.

24. The compound according to claim 1, wherein Ring A is a 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur.

25. The compound according to claim 1, wherein Ring A is a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

26. The compound according to claim 1, wherein the compound is selected from formulae I-a, I-b, I-c, I-d, I-e, I-f, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, or I-s: ##STR00686## ##STR00687## or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 1, wherein the compound is selected from a compound of formulae II, III, IV or V: ##STR00688## or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof according to claim 1, and a pharmaceutically acceptable excipient.

29. A method of treating a disease or disorder associated with KAT-5 in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

30. A method of modulating protein acetylation in a subject in need thereof, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

31. A method of treating cancer in a subject, comprising administering to the subject an effective amount of a compound or pharmaceutically acceptable salt thereof according to claim 1.

32. The method of claim 31, further comprising administering to the subject an additional therapeutic agent.

Description

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0073] According to some aspects, the present invention provides a compound of formula I:

##STR00011## [0074] or a pharmaceutically acceptable salt thereof, wherein: [0075] Ring A is selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, an 8-10 membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0076] L is a 3- to 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic; wherein: [0077] two atoms of L may, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; [0078] Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0079] R.sup.a is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, or optionally substituted C.sub.1-4 aliphatic; [0080] Z is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, —(C.sub.1-3 aliphatic)-Cy or optionally substituted C.sub.1-4 aliphatic; [0081] Cy is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0082] each R is independently hydrogen or an optionally substituted group selected from C.sub.1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0083] n is 0 or 1; and [0084] x is 0, 1, 2, or 3.

[0085] According to some aspects, the present invention provides a compound of formula I′:

##STR00012## [0086] or a pharmaceutically acceptable salt thereof, wherein: [0087] Ring A is selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, an 8-10 membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0088] L is a 2- to 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic; wherein: [0089] two atoms of L may, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; [0090] Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0091] R.sup.a is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, or optionally substituted C.sub.1-4 aliphatic; [0092] Z is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, —(C.sub.1-3 aliphatic)-Cy or optionally substituted C.sub.1-4 aliphatic; [0093] Cy is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0094] each R is independently hydrogen or an optionally substituted group selected from C.sub.1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic amyl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0095] y is 1 or 2; [0096] n is 0 or 1; and [0097] x is 0, 1, 2 or 3.

[0098] According to some aspects, the present invention provides a compound of formula I″:

##STR00013## [0099] or a pharmaceutically acceptable salt thereof, wherein: [0100] Ring A is selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, an 8-10 membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0101] L is a 2- to 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic; wherein: [0102] two atoms of L may, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur; [0103] Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected front nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0104] R.sup.a is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, or optionally substituted C.sub.1-4 aliphatic; [0105] Z is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —N(R)C(O).sub.2R, —N(R)C(O)N(R).sub.2, —S(O).sub.2R, —Cy, —(C.sub.1-3 aliphatic)-Cy or optionally substituted C.sub.1-4 aliphatic; [0106] Cy is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0107] each R is independently hydrogen or an optionally substituted group selected from C.sub.1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur; [0108] y is 1 or 2; [0109] n is 0 or 1; and [0110] x is 0, 1, 2, or 3.

[0111] As defined above, Ring A is selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, an 8-10 membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur.

[0112] In some embodiments, Ring A is phenyl.

[0113] In some embodiments, Ring A is a 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is a 5-6 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0114] In some embodiments, Ring A is a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is a 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is selected from piperazinyl or morpholinyl. In some embodiments, Ring A is a 6-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is piperidinyl.

[0115] In some embodiments, Ring A is a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring A is selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, and pyrimidinyl.

[0116] In some embodiments, Ring A is a 8-10 membered bicyclic aryl ring. In some embodiments, Ring A is naphthyl.

[0117] In some embodiments, Ring A is an 8-10 membered bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring A is indolinyl, 3H-indolyl or isoindolinyl.

[0118] In some embodiments, Ring A is a 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring A is a 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring A is a 9-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, A is selected from indazolyl, benzimidazolyl, indolyl, or isoindolyl. In some embodiments, Ring A is a 10-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, A is selected from quinolyl, isoquinolyl, or quinazolinyl.

[0119] In some embodiments, Ring A-(R.sup.a).sub.x is selected from the group consisting of

##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018## ##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023## ##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028## ##STR00029## ##STR00030##

[0120] As defined above, Ring B is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur.

[0121] In some embodiments, Ring B is optionally substituted phenyl.

[0122] In some embodiments, Ring B is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Ring B is an optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

[0123] In some embodiments, Ring B 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, Ring B is an optionally substituted 3-4 membered saturated heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is an optionally substituted 5-6 membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is selected from optionally substituted azetidinyl, pyrrolidinyl and piperidinyl.

[0124] In some embodiments, Ring B is an optionally substituted 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Ring B is an optionally substituted pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyridyl, or pyrimidinyl.

[0125] In some embodiments, Ring B is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, Ring B is optionally substituted naphthyl.

[0126] In some embodiments, Ring B is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring B is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring B is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring B is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring B is optionally substituted indazolyl, benzimidazolyl, indolyl, or isoindolyl. In some embodiments, Ring B is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Ring B is optionally substituted quinolyl, isoquinolyl, or quinazolinyl.

[0127] In some embodiments, Ring B is selected from the group consisting of

##STR00031##

[0128] In some embodiments, Ring B is not

##STR00032##

[0129] As defined above for formula I, L is a 3- to 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic; wherein: [0130] two atoms of L may, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0131] As defined above for formulae I′ and I″, L is a 2- to 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic; wherein: [0132] two atoms of L may, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur

[0133] As used herein, the terms “2- to 6-atom linker” and “3- to 6-atom linker”; or any of variation thereof (e.g., “3- to 5-atom linker”, “4-atom linker”, etc.), mean a bivalent moiety which is 2- to 6-atoms in linear length or 3- to 6-atoms in linear length, respectively. Exemplary 4-atom linkers include, by way of example,

##STR00033##

[0134] It will be appreciated that when a L comprises a C.sub.1-3 aliphatic, such C.sub.1-3 aliphatic may be unsubstituted or substituted as defined above for an “optionally substituted group”.

[0135] In some embodiments of formulae I′ and I″, L is a 2- to 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 2- to 6-atom linker comprising at least one —C(O)— group and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 2- to 4-atom linker comprising at least one —C(O)— group and 1-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 2- to 4-atom linker comprising at least one —C(O)— group and 2-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 3- to 4-atom linker comprising at least one —C(O)— group and 2-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic.

[0136] In some embodiments of formulae I′ and I″, L is a 3- to 4-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-2 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 1. Accordingly, in some embodiments of formulae I′ and I″, L is a 3- to 4-atom linker comprising at least one group selected from —C(O)— and —S(O)— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic.

[0137] In some embodiments of formulae I′ and I″, L is a 2- to 6-atom linker comprising at least one —S(O)— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 4-atom linker comprising at least one —S(O)— group and 2-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 4-atom linker comprising at least one —S(O)— group and 2-3 additional groups independently selected from —C(O)—. —NR—, —O—, and C.sub.1-3 aliphatic.

[0138] In some embodiments of formulae I′ and I″, L is a 2- to 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 2-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1 additional group independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic.

[0139] In some embodiments, L is a 3- to 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic.

[0140] In some embodiments, L is a 3- to 6-atom linker comprising one —S(O).sub.2— group and 1 additional group selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 1 additional group selected from —C(O)—, —NR—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0141] In some embodiments, L is a 3- to 6-atom linker comprising one —S(O).sub.2— group and 1 additional group selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 1 additional group selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0142] In some embodiments, L is a 3- to 6-atom linker comprising one —S(O).sub.2— group and 1 additional group selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 1 additional group selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0143] In some embodiments, L is a 3- to 6-atom linker comprising one —S(O).sub.2— group and 2 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 2 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0144] In some embodiments, L is a 3- to 6-atom linker comprising one —S(O).sub.2— group and 2 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 2 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0145] In some embodiments, L is a 3- to 6-atom linker comprising one —S(O).sub.2— group and 2 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 3- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 2 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0146] In some embodiments, L is a 4- to 6-atom linker comprising one —S(O).sub.2— group and 3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 4- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0147] In some embodiments of formulae I′ and I″, L is a 4- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 1 and R is hydrogen.

[0148] In some embodiments, L is a 4- to 6-atom linker comprising one —S(O).sub.2— group and 3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 4- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0149] In some embodiments of formulae I′ and I″, L is a 4- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 1 and R is hydrogen.

[0150] In some embodiments, L is a 4- to 6-atom linker comprising one —S(O).sub.2— group and 3 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 4- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 3 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0151] In some embodiments of formulae I′ and I″, L is a 4- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 3 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 1 and R is hydrogen.

[0152] In some embodiments, L is a 5- to 6-atom linker comprising one —S(O).sub.2— group and 4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 5- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0153] In some embodiments, L is a 5- to 6-atom linker comprising one —S(O).sub.2— group and 4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 5- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0154] In some embodiments, L is a 5- to 6-atom linker comprising one —S(O).sub.2— group and 4 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 5- to 6-atom linker comprising one group selected from —C(O)— and —S(O).sub.y— and 4 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0155] In some embodiments, L is a 3-atom linker comprising at least one —S(O).sub.2— group and 1-2 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 3-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-2 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0156] In some embodiments, L is a 3-atom linker comprising at least one —S(O).sub.2— group and 1-2 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 3-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-2 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0157] In some embodiments, L is a 3-atom linker comprising at least one —S(O).sub.2— group and 1-2 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 3-atom linker comprising at least one group selected from —C(O)— and —S(O)— and 1-2 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0158] In some embodiments, L is a 4-atom linker comprising at least one —S(O).sub.2— group and 1-3 additional groups independently selected from —C(O)—, —NH—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 4-atom linker comprising al least one group selected from —C(O)— and —S(O).sub.y— and 1-3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0159] In some embodiments, L is a 4-atom linker comprising at least one —S(O).sub.2— group and 2-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 4-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 2-3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0160] In some embodiments, L is a 4-atom linker comprising at least one —S(O).sub.2— group and 2-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 4-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 2-3 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0161] In some embodiments, L is a 4-atom linker comprising at least one —S(O).sub.2— group and 2-3 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 4-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 2-3 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0162] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 5-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0163] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 5-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0164] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 5-atom linker comprising at least one group selected from —C(O)— and —S(O)— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0165] In some embodiments, L is a 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic. In some embodiments of formulae I′ and I″, L is a 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and C.sub.1-3 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0166] In some embodiments, L is a 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic. In some embodiments of formulae I′ and I″, L is a 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and —C.sub.1-2 aliphatic. In some such embodiments, y is 2 and R is hydrogen.

[0167] In some embodiments, L is a 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and —CH.sub.2—. In some embodiments of formulae I′ and I″, L is a 6-atom linker comprising at least one group selected from —C(O)— and —S(O).sub.y— and 1-4 additional groups independently selected from —C(O)—, —NR—, —O—, and —CH.sub.2—. In some such embodiments, y is 2 and R is hydrogen.

[0168] In some embodiments, L is selected from the group consisting of

##STR00034## ##STR00035##

[0169] In some embodiments, L is selected from the group consisting of

##STR00036## ##STR00037## ##STR00038##

[0170] In some embodiments, L is a 3- to 6-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0171] In some embodiments, L is a 4- to 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, or a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0172] In some embodiments, L is a 4- to 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0173] In some embodiments, L is a 4-atom linker comprising at least one —S(O).sub.2— group and 1-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0174] In some embodiments, L is a 4-atom linker comprising at least one —S(O).sub.2— group and 1-3 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0175] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0176] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 4-6 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0177] In some embodiments, L is a 4- to 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0178] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-3 aliphatic, wherein two atoms of L, together with their intervening atoms, form a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0179] In some embodiments, L is a 5-atom linker comprising at least one —S(O).sub.2— group and 1-4 additional groups independently selected from —C(O)—, —NH—, —O—, and C.sub.1-2 aliphatic, wherein two atoms of L, together with their intervening atoms, forth a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0180] In some embodiments, L is selected from the group consisting of

##STR00039## ##STR00040##

[0181] As defined above, R.sup.a is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —CO(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, or optionally substituted C.sub.1-4 aliphatic.

[0182] In some embodiments, R.sup.a is halogen.

[0183] In some embodiments, R.sup.a is selected from —CN, —NO.sub.2, —C(O)R, —C(O).sub.2R, and —C(O)N(R).sub.2.

[0184] In some embodiments, R.sup.a is selected from —OR, —SR, and —N(R).sub.2.

[0185] In some embodiments, R.sup.a is selected from —OC(O)R and —N(R)C(O)R.

[0186] In some embodiments, R.sup.a is Cy.

[0187] In some embodiments, R.sup.a is optionally substituted C.sub.1-4 aliphatic. In some embodiments, R.sup.a is methyl.

[0188] In some embodiments, R.sup.a is —Cy.

[0189] As defined above, Z is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —Cy, —(C.sub.1-3 aliphatic)-Cy or optionally substituted C.sub.1-4 aliphatic.

[0190] In some embodiments, Z is optionally substituted C.sub.1-4 aliphatic. In some embodiments, Z is optionally substituted C.sub.1-2 aliphatic. In some embodiments, Z is optionally substituted methyl. In some embodiments, Z is optionally substituted ethyl. In some embodiments, Z is optionally substituted i-propyl. In some embodiments, Z is optionally substituted t-butyl.

[0191] In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with halogen. In some such embodiments, Z is —CF.sub.3. In some embodiments, Z is —CH.sub.2CF.sub.3.

[0192] In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with one or more groups selected from oxo, —(CH.sub.2).sub.0-4R.sup.∘, and —(CH.sub.2).sub.0-4OR.sup.∘. In some such embodiments, R.sup.∘ is selected from hydrogen, C.sub.1-6 aliphatic, or a 5-6-membered saturated, partially unsaturated, or aryl ring having heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen or —(CH.sub.2).sub.0-2OR.

[0193] In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with oxo.

[0194] In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘. In some such embodiments, R.sup.∘ is a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, wherein R.sup.∘ is phenyl optionally substituted with halogen or —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0195] In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with —(CH.sub.2).sub.0-4OR.sup.∘. In some such embodiments, R.sup.∘ is hydrogen or C.sub.1-6 aliphatic. In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with —(CH.sub.2).sub.0-2OR.sup.∘. In some such embodiments, R.sup.∘ is hydrogen or C.sub.1-6 aliphatic. In some embodiments, Z is C.sub.1-4 aliphatic optionally substituted with —OR.sup.∘, —CH.sub.2OR.sup.∘ or —CH.sub.2CH.sub.2OR.sup.∘.

[0196] In some embodiments, Z is —Cy.

[0197] In some embodiments, Z is —(C.sub.1-3 aliphatic)-Cy. In some embodiments, Z is —(C.sub.1-2 aliphatic)-Cy. In some embodiments, Z is —(C.sub.3 aliphatic)-Cy. In some embodiments, Z is —CH.sub.2-Cy, —CH.sub.2CH.sub.2—Cy, —CH(CH.sub.3)—Cy, —C(CH.sub.3).sub.2—Cy, or

##STR00041##

[0198] In some embodiments, Z is selected from halogen, —CN, and —NO.sub.2. In some embodiments, Z is selected from halogen.

[0199] In some embodiments, Z is selected from —OR, —SR, and —N(R).sub.2. In some embodiments, Z is —N(R).sub.2. In some embodiments, Z is —OR.

[0200] In some embodiments, Z is selected from —C(O)R, —C(O).sub.2R, and —C(O)N(R).sub.2. In some embodiments, Z is —C(O)R. In some embodiments, Z is —C(O).sub.2R. In some embodiments, Z is —C(O)N(R).sub.2.

[0201] In some embodiments, Z is selected from —OC(O)R and —N(R)C(O)R. In some embodiments, Z is —N(R)C(O)R.

[0202] As defined above formula I″, Z is selected from halogen, —CN, —NO.sub.2, —OR, —SR, —N(R).sub.2, —C(O)R, —C(O).sub.2R, —OC(O)R, —C(O)N(R).sub.2, —N(R)C(O)R, —N(R)C(O).sub.2R, —N(R)C(O)N(R).sub.2, —S(O).sub.2R, —Cy, —(C.sub.1-3 aliphatic)-Cy or optionally substituted C.sub.1-4 aliphatic.

[0203] In some embodiments of formula I″, Z is —C(O)R, —C(O).sub.2R, —C(O)N(R).sub.2, or —S(O).sub.2R. In some embodiments of formula I″, Z is —OC(O)R, —N(R)C(O)R, —N(R)C(O).sub.2R, or —N(R)C(O)N(R).sub.2.

[0204] In some embodiments of formula I″, Z is —N(R)C(O).sub.2R.

[0205] In some embodiments of formula I″, Z is —N(R)C(O)N(R).sub.2.

[0206] In some embodiments of formula Z is —S(O).sub.2R.

[0207] In some embodiments, Z is selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, tert-butyl, phenyl, —OH, —OCH.sub.3, —CH.sub.2OH, or the groups in Table 1:

TABLE-US-00001 TABLE 1 [00042] [00043] [00044] [00045] [00046] [00047] [00048] [00049] [00050] [00051] [00052] [00053] [00054] [00055] [00056] [00057] [00058] [00059] [00060] [00061] [00062] [00063] [00064] [00065] [00066] [00067] [00068] [00069] [00070] [00071] [00072] [00073] [00074] [00075] [00076] [00077] [00078] [00079] [00080] [00081] [00082] [00083] [00084] [00085] [00086] [00087] [00088] [00089] [00090] [00091] [00092] [00093] [00094] [00095] [00096] [00097] [00098] [00099] [00100] [00101] [00102] [00103] [00104] [00105] [00106] [00107] [00108] [00109] [00110] [00111] [00112] [00113] [00114] [00115] [00116] [00117] [00118] [00119] [00120] [00121] [00122] [00123] [00124] [00125] [00126] [00127] [00128] [00129] [00130] [00131] [00132] [00133] [00134] [00135] [00136] [00137] [00138] [00139] [00140] [00141] [00142] [00143] [00144] [00145] [00146] [00147] [00148] [00149] [00150] [00151] [00152] [00153] [00154] [00155] [00156] [00157] [00158] [00159] [00160] [00161] [00162] [00163] [00164] [00165] [00166] [00167] [00168] [00169] [00170] [00171]

[0208] In some embodiments, Z is selected from the group consisting of fluoro, chloro, methyl, ethyl, isopropyl, —OH, —OCH.sub.3, —CH.sub.2CH.sub.2OCH.sub.3, —CH.sub.2OH, —CH.sub.2CH.sub.2OH, —CO.sub.2H, or the groups in Table 2:

TABLE-US-00002 TABLE 2 [00172] [00173] [00174] [00175] [00176] [00177] [00178] [00179] [00180] [00181] [00182] [00183] [00184] [00185] [00186] [00187] [00188] [00189] [00190] [00191] [00192] [00193] [00194] [00195] [00196] [00197] [00198] [00199] [00200] [00201] [00202] [00203] [00204] [00205] [00206] [00207] [00208] [00209] [00210] [00211] [00212] [00213]

[0209] In some embodiments, Z is selected from the group consisting of the groups in Table 3:

TABLE-US-00003 TABLE 3 [00214] [00215] [00216] [00217] [00218] [00219] [00220] [00221] [00222] [00223] [00224] [00225] [00226] [00227] [00228] [00229] [00230] [00231] [00232] [00233] [00234] [00235] [00236] [00237] [00238] [00239] [00240] [00241] [00242] [00243] [00244] [00245] [00246] [00247] [00248] [00249] [00250] [00251] [00252] [00253] [00254] [00255] [00256] [00257] [00258] [00259] [00260] [00261] [00262] [00263] [00264] [00265] [00266] [00267] [00268] [00269] [00270] [00271] [00272] [00273] [00274] [00275] [00276] [00277] [00278] [00279] [00280]

[0210] In some embodiments, Z is selected from the group consisting of methyl isopropyl, tert-butyl, phenyl, —CF.sub.3, —CH.sub.2CF.sub.3, or the groups in Table 4:

TABLE-US-00004 TABLE 4 [00281] [00282] [00283] [00284] [00285] [00286] [00287] [00288] [00289] [00290] [00291] [00292] [00293] [00294] [00295] [00296] [00297] [00298] [00299] [00300] [00301] [00302] [00303] [00304] [00305] [00306] [00307] [00308] [00309] [00310] [00311] [00312] [00313] [00314] [00315] [00316] [00317] [00318] [00319] [00320] [00321] [00322] [00323] [00324] [00325] [00326] [00327] [00328] [00329] [00330] [00331] [00332] [00333] [00334] [00335] [00336]

[0211] In some embodiments, Z is selected from the groups in Table 5:

TABLE-US-00005 TABLE 5 [00337] [00338] [00339] [00340] [00341] [00342] [00343] [00344] [00345] [00346] [00347] [00348] [00349] [00350] [00351] [00352] [00353] [00354] [00355] [00356] [00357] [00358] [00359] [00360] [00361] [00362] [00363] [00364] [00365] [00366] [00367] [00368] [00369] [00370] [00371] [00372] [00373] [00374] [00375] [00376] [00377] [00378] [00379] [00380] [00381] [00382] [00383] [00384] [00385] [00386] [00387] [00388] [00389] [00390] [00391] [00392] [00393] [00394] [00395] [00396] [00397] [00398] [00399] [00400] [00401] [00402] [00403] [00404] [00405] [00406] [00407] [00408] [00409] [00410] [00411] [00412] [00413] [00414] [00415] [00416] [00417] [00418] [00419] [00420] [00421] [00422] [00423] [00424] [00425] [00426] [00427] [00428] [00429] [00430] [00431] [00432] [00433] [00434] [00435] [00436] [00437] [00438] [00439] [00440] [00441] [00442] [00443] [00444] [00445] [00446] [00447] [00448] [00449] [00450] [00451] [00452] [00453] [00454] [00455] [00456] [00457] [00458] [00459] [00460] [00461] [00462] [00463] [00464] [00465] [00466] [00467] [00468] [00469] [00470] [00471] [00472] [00473] [00474] [00475] [00476] [00477] [00478] [00479] [00480] [00481] [00482] [00483] [00484] [00485] [00486] [00487] [00488] [00489] [00490] [00491] [00492] [00493] [00494] [00495] [00496] [00497] [00498] [00499] [00500] [00501] [00502] [00503] [00504] [00505] [00506] [00507] [00508] [00509] [00510] [00511] [00512] [00513] [00514] [00515] [00516] [00517] [00518] [00519] [00520] [00521] [00522] [00523] [00524] [00525] [00526] [00527] [00528] [00529] [00530] [00531] [00532] [00533] [00534] [00535] [00536] [00537] [00538] [00539] [00540] [00541] [00542] [00543] [00544] [00545] [00546] [00547] [00548] [00549] [00550] [00551] [00552] [00553]

[0212] In some embodiments, Z is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, phenyl,

##STR00554## ##STR00555##

[0213] In some embodiments, Z is selected from the group consisting of

##STR00556## ##STR00557## ##STR00558##

[0214] In some embodiments, Z is selected from the group consisting of fluoro, chloro, —OCH.sub.3, methyl, ethyl, isopropyl,

##STR00559##

[0215] In some embodiments, Z is selected from the group consisting of chloro, fluoro, methyl, ethyl, isopropyl, tert-butyl, phenyl, —OCH.sub.3,

##STR00560##

[0216] In some embodiments, Z is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, —CH(CH.sub.2OH).sub.2, —CF.sub.3CH.sub.2CH.sub.3.

[0217] In some embodiments, Z is selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, —CH(CH.sub.2OH).sub.2, —CF.sub.3 or —CH.sub.2CF.sub.3, or the groups in any of Table 1, Table 2, Table 3, Table 4 or Table 5.

[0218] In some embodiments, Z is not phenyl. In some embodiments, Z is not

##STR00561##

In some embodiments, Z is not

##STR00562##

In some embodiments, Z is not phenyl,

##STR00563##

[0219] As defined above, Cy is an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic amyl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur.

[0220] In some embodiments, Cy is an optionally substituted phenyl.

[0221] In some embodiments, Cy is phenyl optionally substituted with a group selected from halogen, —NO.sub.2, —CN, —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4OR.sup.∘, —O(CH.sub.2).sub.0-4R.sup.∘, —O—(CH.sub.2).sub.0-4C(O)OR.sup.∘, —(CH.sub.2).sub.0-4 CH(OR.sup.∘).sub.2, —(CH.sub.2).sub.0-4 SR.sup.∘, —(CH.sub.2).sub.0-4 Ph which may be substituted with R.sup.∘, —(CH.sub.2).sub.0-4O(CH.sub.2).sub.0-1Ph which may be substituted with —(CH.sub.2).sub.0-4N(R.sup.∘).sub.2, —(CH.sub.2).sub.0-4N(R.sup.∘)C(O)R.sup.∘, —(CH.sub.2).sub.0-4N(R.sup.∘)C(O)OR.sup.∘, —(CH.sub.2).sub.0-4C(O)R.sup.∘, —(CH.sub.2).sub.0-4C(O)OR.sup.∘, —(CH.sub.2).sub.0-4OC(O)R.sup.∘, —(CH.sub.2).sub.0-4C(O)NR.sup.∘.sub.2, —(CH.sub.2).sub.0-4 OC(O)NR.sup.∘.sub.2, —(CH.sub.2).sub.0-4 S(O).sub.2R.sup.∘, —(CH.sub.2).sub.0-4S(O).sub.2OR.sup.∘, —(CH.sub.2).sub.0-4OS(O).sub.2R.sup.∘, —S(O).sub.2NR.sup.∘.sub.2, —(CH.sub.2).sub.0-4 S(O)R.sup.∘, and —N(R.sup.∘S(O).sub.2R.sup.∘, wherein each R.sup.∘ is independently hydrogen, C.sub.1-6 aliphatic. —CH.sub.2Ph, —O(CH.sub.2).sub.0-1Ph, —CH.sub.2— (5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R.sup.∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, Cy is phenyl optionally substituted with halogen or —(CH.sub.2).sub.0-4OR.sup.∘.

[0222] In some embodiments, Cy is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy is an optionally substituted 3-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy is an optionally substituted 4-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy is an optionally substituted 5-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy is an optionally substituted 6-membered saturated or partially unsaturated carbocyclic ring. In some embodiments, Cy is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0223] In some embodiments, Cy is a 3-7 membered saturated or partially unsaturated carbocyclic ring optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘.

[0224] In some embodiments, Cy 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, Cy is an optionally substituted 4-membered saturated or partially unsaturated heterocyclic ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted group selected from optionally substituted azetidinyl or oxetanyl.

[0225] In some embodiments, Cy is azetidinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4 OR.sup.∘, or —(CH.sub.2).sub.0-4C(O)R.sup.∘. In some such embodiments, R.sup.∘ is selected from hydrogen, C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen or —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0226] In some embodiments, Cy is azetidinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4OR.sup.∘, —(CH.sub.2).sub.0-4C(O)R.sup.∘ or —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is selected from hydrogen, C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen or —(CH.sub.2).sub.0-2 OR.sup..circle-solid..

[0227] In some embodiments, Cy is azetidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic optionally substituted with —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0228] In some embodiments, Cy is azetidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)OR.sup.∘.

[0229] In some embodiments, Cy is azetidinyl optionally substituted on the nitrogen atom with —R.sup.†, —C(O)R.sup.†, —C(O)OR.sup.†,

[0230] In some such embodiments, R.sup.† is optionally substituted with —OH, —OR.sup..circle-solid.,

[0231] In some embodiments, Cy is an optionally substituted 5-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted pyrrolidinyl.

[0232] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘ or —(CH.sub.2).sub.0-4C(O)R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen or —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0233] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4OR.sup.∘, —(CH.sub.2).sub.0-4C(O)R.sup.∘, or —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is hydrogen, C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen, —(CH.sub.2).sub.0-2OR.sup.∘, —(CH.sub.2).sub.0-2 NHR.sup.∘, or —(CH.sub.2).sub.0-2NR.sup.∘.sub.2.

[0234] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4OR.sup.∘.

[0235] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic optionally substituted with —(CH.sub.2).sub.0-2OR.sup.∘ or —(CH.sub.2).sub.0-2OH.

[0236] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic.

[0237] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)N(R.sup.∘.sub.2, wherein R.sup.∘ is hydrogen or C.sub.1-6 aliphatic.

[0238] In some embodiments, Cy is pyrrolidinyl optionally substituted with —(CH.sub.2).sub.0-4SO.sub.2R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic.

[0239] In some embodiments, Cy is pyrrolidinyl optionally substituted on the nitrogen atom with —R.sup.†, —C(O)R.sup.†, —C(O)OR.sup.†, —C(O)NR.sup.†.sub.2, or —S(O).sub.2R.sup.†. In some such embodiments, R.sup.† is optionally substituted with —OR.sup..circle-solid., —NH.sub.2, —NHR.sup..circle-solid., or —NR.sup..circle-solid..sub.2.

[0240] In some embodiments, Cy is an optionally substituted 6-membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted piperidinyl. In some embodiments, Cy is tetrahydro-2H-pyranyl. In some such embodiments, Cy is tetrahydro-2H-pyran-4-yl.

[0241] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4OR.sup.∘, —(CH.sub.2).sub.0-4C(O)R.sup.∘, or —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen or —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0242] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4OR.sup.∘, —(CH.sub.2).sub.0-4C(O)R.sup.∘, —(CH.sub.2).sub.0-4C(O)OR.sup.∘, or —(CH.sub.2).sub.0-4C(O)N(R.sup.∘).sub.2. In some such embodiments, R.sup.∘ is hydrogen, C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen, —(CH.sub.2).sub.0-2OR.sup.∘, —(CH.sub.2).sub.0-2NHR.sup..circle-solid., or —(CH.sub.2).sub.0-2NR.sup..circle-solid..sub.2.

[0243] In some embodiments, is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4OR.sup.∘.

[0244] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic optionally substituted with —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0245] In some embodiments, is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)R.sup.∘, wherein R.sup.∘ is C.sub.1-6 aliphatic optionally substituted with —(CH.sub.2).sub.0-2 NHR.sup..circle-solid. or —(CH.sub.2).sub.0-2NR.sup..circle-solid..sub.2.

[0246] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)R.sup.∘, wherein R.sup.∘ is a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.∘ is a 6-membered saturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some such embodiments, R.sup.∘ is tetrahydropyranyl.

[0247] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic.

[0248] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)N(R.sup.∘).sub.2.

[0249] In some embodiments, Cy is piperidinyl optionally substituted with —(CH.sub.2).sub.0-4 SO.sub.2R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic.

[0250] In some embodiments, Cy is piperidinyl optionally substituted on the nitrogen atom with —R.sup.†, —C(O)R.sup.†, —C(O)OR.sup.†, —C(O)NR.sup.†.sub.2, or —S(O).sub.2R.sup.†. In some such embodiments, R.sup.† is optionally substituted with —OH, —OR.sup..circle-solid., —NH.sub.2, —NHR.sup..circle-solid., or —NR.sup..circle-solid..sub.2.

[0251] In some embodiments, Cy is morpholinyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘, —(CH.sub.2).sub.0-4OR.sup.∘, —(CH.sub.2).sub.0-4C(O)R.sup.∘, or —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur optionally substituted with halogen or —(CH.sub.2).sub.0-2OR.sup..circle-solid..

[0252] In some embodiments, Cy is morpholinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)OR.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic.

[0253] In some embodiments, Cy is morpholinyl optionally substituted with —(CH.sub.2).sub.0-4C(O)R.sup.∘. In some such embodiments, R.sup.∘ is C.sub.1-6 aliphatic.

[0254] In some embodiments, Cy is morpholinyl optionally substituted on the nitrogen atom with —R.sup.†, —C(O)R.sup.†, or —C(O)OR.sup.†.

[0255] In some embodiments, Cy is an optionally substituted 6-8 membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an 8-membered bridged bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally substituted on a nitrogen atom with —R.sup.†, —C(O)R.sup.†, or —C(O)OR.sup.†.

[0256] In some embodiments, Cy is an optionally substituted 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted 5-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted 5-membered heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is optionally substituted pyrazolyl.

[0257] In some embodiments, Cy is optionally substituted imidazolyl. In some such embodiments, Cy is imidazolyl optionally substituted with —(CH.sub.2).sub.0-4R.sup.∘.

[0258] In some embodiments, Cy is imidazolyl optionally substituted on a nitrogen atom with —R.sup.†. In some such embodiments, —R.sup.† is optionally substituted with —OH or —OR.sup..circle-solid..

[0259] In some embodiments, Cy is an optionally substituted 6-membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is an optionally substituted 6-membered heteroaryl ring having 1 heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, Cy is optionally substituted pyridinyl or pyrimdinyl.

[0260] In some embodiments, Cy is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, Cy is optionally substituted naphthyl.

[0261] In some embodiments, Cy is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Cy is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Cy is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Cy is an optionally substituted 1H-pyrazolo[3,4-H]pyridinyl. In some embodiments, Cy is an optionally substituted benzo[d]isoxazolyl. In some embodiments, Cy is an optionally substituted 9-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Cy is an optionally substituted indazolyl, benzimidazolyl, indolyl, or isoindolyl. In some embodiments, Cy is an optionally substituted 10-membered bicyclic heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, Cy is an optionally substituted quinolyl, isoquinolyl, or quinazolinyl.

[0262] In some embodiments, Cy is selected from the group consisting of phenyl,

##STR00564##

[0263] In some embodiments, Cy is selected from the group consisting of:

##STR00565## ##STR00566## ##STR00567## ##STR00568## ##STR00569## ##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574##

[0264] As defined above, each R is independently hydrogen or an optionally substituted group selected from C.sub.1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur.

[0265] In some embodiments, R is hydrogen.

[0266] In some embodiments, R is an optionally substituted group selected from C.sub.1-4 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, a 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur, an 8-10 membered bicyclic aryl ring, and an 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur,

[0267] In some embodiments, R is an optionally substituted C.sub.1-4 aliphatic. In some embodiments, R is optionally substituted methyl. In some embodiments, R is optionally substituted ethyl. In some embodiments, R is optionally substituted i-propyl. In some embodiments, R is optionally substituted t-butyl.

[0268] In some embodiments, R is an optionally substituted phenyl.

[0269] In some embodiments, R is an optionally substituted 3-7 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is an optionally substituted 5-6 membered saturated or partially unsaturated carbocyclic ring. In some embodiments, R is selected from optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

[0270] 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 azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or azepinyl.

[0271] In some embodiments, R is an optionally substituted 5-6 membered heteroaryl ring having 1-2 heteroatoms independently selected from nitrogen, oxygen and sulfur. In some embodiments, R is an optionally substituted pyrrolyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridyl, or pyrimidinyl.

[0272] In some embodiments, R is an optionally substituted 8-10 membered bicyclic aryl ring. In some embodiments, R is optionally substituted naphthyl.

[0273] In some embodiments, R is an optionally substituted 8-10 membered bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some such embodiments, R is an optionally substituted 9-10 bicyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen oxygen and sulfur. In some embodiments, R is indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, or isoquinolyl.

[0274] As defined above, y is 1 or 2. In some embodiments, y is 1. In some embodiments, y is 2.

[0275] As defined above, n is 0 or 1. In some embodiments, n is 0. In some embodiments, n is 1.

[0276] As defined above, x is 0, 1, 2, or 3. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, x is 3.

[0277] In some embodiments, the present invention provides a compound of formulae I-a, I-b, I-c, I-d, I-e, I-g, I-h, I-j, I-k, I-l, I-m, I-n, I-o, I-p, I-q, I-r, or I-s:

##STR00575## ##STR00576##

or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the present invention provides a compound of formulae II, III, IV or V:

##STR00577##

or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compound of formula I is selected from the group consisting of

##STR00578## ##STR00579## ##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591##

##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598## ##STR00599## ##STR00600## ##STR00601## ##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614##

##STR00615## ##STR00616## ##STR00617## ##STR00618## ##STR00619## ##STR00620## ##STR00621## ##STR00622## ##STR00623## ##STR00624## ##STR00625## ##STR00626## ##STR00627## ##STR00628##

##STR00629## ##STR00630## ##STR00631## ##STR00632## ##STR00633## ##STR00634## ##STR00635## ##STR00636## ##STR00637## ##STR00638## ##STR00639## ##STR00640## ##STR00641## ##STR00642## ##STR00643## ##STR00644## ##STR00645## ##STR00646## ##STR00647##

or a pharmaceutically acceptable salt thereof.

Acetyl Transferases

[0280] Histone acetylation and deacetylation are processes by which lysine residues within the N-terminal tail protruding from histone cores of the nucleosome are acetylated and deacetylated. Without wishing to be hound by any particular theory, it is believed that histone acetylation is a part of gene regulation. Histone Acetyltransferases, also known as HATs, are a family of enzymes that acetylate the histone tails of the nucleosome among other nuclear and cytoplasmic non-histone targets. Some HATS acetylate a lysine residue, and such Lysine Acetyltransferases are also referred to as KATs.

[0281] KATs can be divided into families based on their structure and sequence similarity. KAT families include, for example, the Gcn5-related N-acetyltransferase (GNAT) family, which includes GCN5 and PCAF, the CREBBP/EP300 family and the MYST (MOZ, Ybf2/Sas3, Sas2, Tip60) family, which includes Tat interacting protein, 60 kDa (Tip60), monocytic leukemia zinc finger protein/MOZ-related factor protein (MOZ/MORF). Different KATs may contain various other domains in addition to the HAT domain which facilitate interactions with other proteins, including reader domains for acetylation and other modifications. See, e.g., Farria et al. Oncogene (2015) 34, 4901-4913, incorporated herein by reference. Some KATs, for example those in the GNAT and CREBBP/EP300 families, contain bromodomains. Bromodomains help KATs recognize and bind to acetylated lysine residues on histone substrates. Together these domains allow for specificity and diversity in KAT substrates. All KATs examined to date have important functions in cellular differentiation and embryo development. Several KATs have also been associated with oncogenesis. For example, CREBBP/EP300, have been implicated in cancer development and progression. See, e.g., Farria et al. Oncogene (2015) 34, 4901-4913; Lee et al, Nat. Rev. Mol. Cell Biol. 8 (4): 284-95; and Avvakumov et al. Oncogene (2007) 26, 5395-5407, the entire contents of each of which are incorporated herein by reference, Inhibitors of KATs and histone deacetylase inhibitors (HDACs) have potential as anti-cancer therapies.

[0282] KAT-5, also known as Lysine Acetyltransferase 5, TIP60, or HTATIP, belongs to the MYST family of histone acetyl transferases and was originally isolated as an HIV-1 TAT-interactive protein. KAT-5 has been reported to play important roles in regulating chromatin remodeling, transcription. DNA repair, and apoptosis, and is also thought to play an important role in signal transduction. Alternative splicing of this gene results in multiple transcript variants. The protein sequences of exemplary KAT-5 proteins have been reported. Exemplary human KAT-5 protein sequences include, for example, and without limitation, the sequences provided below. Additional KAT-5 sequences, including KAT5-sequences from other species and additional human KAT-5 sequences will be apparent to those of ordinal), skill in the art, and include, for example, and without limitation, those KAT-5 sequences listed in the NCBI and ENSEMBL gene databases.

TABLE-US-00006 >NP_874369. 1 histone acetyltransferase KAT5 isoform 1 [Homo sapiens] (SEQ ID NO: 1) MAEVVSPVPGAGRREPGEVGRARGPPVADPGVALSPQGEIIEGCRLPVLR RNQDNEDEWPLAEILSVKDISGRKLFYVHYIDFNKRLDEWVTHERLDLKK IQFPKKEAKTPTKNGLPGSRPGSPEREVPASAQASGKTLPIPVQITLRFN LPKEREAIPGGEPDQPLSSSSCLQPNHRSTKRKVEVVSPATPVPSETAPA SVFPQNGAARRAVAAQPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLV SDRSHDDIVTRMKNIECIELGRHRLKTWYFSPYPQELTTLPVLYLCEFCL KYGRSLKCLQRHLTKCDLRHPPGNEIYRKGTISFFEIDGRKNKSYSQNLC LLAKCFLDHKTLYYDTDPFLFYVMTEYDCKGFHIVGYFSKEKESTEDYNV ACILTLPPYQRRGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSY WSQTILEILMGLKSESGERPQITINEISEITSLKKEDVISTLQYLNLINY YKGQYILTLSEDIVDGHERAMLKRLLRIDSKCLHFTPKDWSKRGKW >NP_006379.2 histone acetyltransferase KAT5 isoform 2 [Homo sapiens] (SEQ ID NO: 2) MAEVGEIIEGCRLPVLRRNQDNEDEWPLAEILSVKDISGRKLFYVHYIDF NKRLDEWVTHERLDLKKIQFPKKEAKTPTKNGLPGSRPGSPEREVPASAQ ASGKTLPIPVQITLRFNLPKEREAIPGGEPDQPLSSSSCLQPNHRSTKRK VEVVSPATPVPSETAPASVFPQNGAARRAVAAQPGRKRKSNCLGTDEDSQ DSSDGIPSAPRMTGSLVSDRSHDDIVTRMKNIECIELGRHRLKPWYFSPY PQELTTLPVLYLCEFCLKYGRSLKCLQRHLTKCDLRHPPGNEIYRKGTIS FFEIDGRKNKSYSQNLCLLAKCFLDHKTLYYDTDPFLFYVMTEYDCKGFH IVGYFSKEKESTEDYNVACILTLPPYQRRGYGKLLIEFSYELSKVEGKTG TPEKPLSDLGLLSYRSYWSQTILEILMGLKSESGERPQITINEISEITSI KKEDVISTLQYLNLINYVKGQYILTLSEDIVDGHERAMLKRLLRIDSKCL HFTPKDWSKRGKW >NP_874368.1 histone acetyltransferase KAT5 isoform 3 [Homo sapiens] (SEQ ID NO: 3) MAEVGEIIEGCRLPVLRRNQDNEDEWPLAEILSVKDISGRKLFYVHYIDF NKRLDEWVTHERLDLKKIQFPKKEAKTPTKNGLPGSRPGSPEREVKRKVE VVSPATPVPSETAPASVFPQNGAARRAVAAQPGRKRKSNCLGTDEDSQDS SDGIPSAPRMTGSLVSDRSHDDIVTRMKNIECIELGRHRLKPWYFSPYPQ ELTTLPVLYLCEFCLKYGRSLKCLQRHLTKCDLRHPPGNEIYRKGTISFF EIDGRKNKSYSQNLCLLAKCFLDHKTLYYDTDPFLFYVMTEYDCKGFHIV GYFSKEKESTEDYNVACILTLPPYQRRGYGKLLIEFSYELSKVEGKTGTP EKPLSDLGLLSYRSYWSQTILEILMGLKSESGERPQITINEISEITSIKK EDVISTLQYLNLINYYKGQYILTLSEDIVDGHERAMLKRLLRIDSKCLHF TPKDWSKRGKW >NP_001193762.1 histone acelyltransferase KAT5 isoform 4 [Homo sapiens] (SEQ ID NO: 4) MAEVVSPVPGAGRREPGEVGRARGPPVADPGVALSPQGEIIEGCRLPVLR RNQDNEDEWPLAEILSVKDISGRKLFYVHYIDFNKRLDEWVTHERLDLKK IQFPKKEAKTPTKNGLPGSRPGSPEREVKRKVEVVSPATPVPSETAPASV FPQNGAARRAVAAQPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLVSD RSHDDIVTRMKNIECIELGRHRLKPWYFSPYPQELTTLPVLYLCEFCLKY GRSLKCLQRHLTKCDLRHPPGNEIYRKGTISFFEIDGRKNKSYSQNLCLL AKCFLDHKTLYYDTDPFLFYVMTEYDCKGFHIVGYFSKEKESTEDYNVAC ILTLPPYQRRGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSYWS QTILEILMGLKSESGERPQITINEISEITSIKKEDVISTLQYLNLINYYK GQYILTLSEDIVDGHERAMLKRLLRIDSKCLHFTPKDWSKRGKW

[0283] In some embodiments, the present invention provides inhibitors of KATs, and in particular, KAT-5, for use as histone acetyltransferase inhibitors, e.g., in vitro or in vivo. In certain embodiments, the present invention provides inhibitors of KATs, e.g., KAT-5, for use in treating diseases or disorders that are characterized by an abnormal KAT-5 activity, e.g., certain cancers.

[0284] Some aspects of this disclosure provide methods for modulating protein acetylation, e.g., histone acetylation, e.g., in a cell or tissue, by contacting a histone acetylase, e.g., KAT-5, or a cell or tissue expressing such a histone acetylase, e.g., KAT-5, with a compound of formulae I, I′ or I″ in an amount sufficient to modulate the activity of the histone acetylase, e.g., of KAT-5, e.g., as measured by a reduction in the acetylation of a target protein of the histone acetyltransferase, e.g., a histone acetylated by KAT-5 activity. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo, e.g., by administering the compound of formulae I, I′ or I″, or a pharmaceutically acceptable salt thereof, to a subject, e.g., a human subject. In some embodiments, the subject is a subject having or diagnosed with a cancer or a precancerous condition.

Cancers and Tumors

[0285] The present disclosure provides, inter alia, compounds and compositions useful in the treatment of cancer, e.g., for the treatment of a tumor in a subject.

[0286] In some embodiments, the present invention provides a method of treating a disease or disorder associated with KAT-5. In certain embodiments, the disease or disorder is a KAT-5-mediated disorder.

[0287] Cancers that can be treated with the methods and compositions provided herein, e.g., include, for example, adrenocortical carcinoma, astrocytoma, basal cell carcinoma, carcinoid, cardiac, cholangiocarcinoma, chordoma, chronic myeloproliferative neoplasms, craniopharyngioma, ductal carcinoma in situ, ependymoma, intraocular melanoma, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic disease, glioma, histiocytosis, leukemia (e.g., acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), hairy cell leukemia, myelogenous leukemia, and myeloid leukemia), lymphoma (e.g., Burkitt lymphoma (non-Hodgkin lymphoma), cutaneous T-cell lymphoma, Hodgkin lymphoma, mycosis fungoides, Sezary syndrome, AIDS-related lymphoma, follicular lymphoma, diffuse large B-cell lymphoma), melanoma, merkel cell carcinoma, mesothelioma, myeloma (e.g., multiple myeloma), myelodysplastic syndrome, papillomatosis, paraganglioma, pheochromacytoma, pleuropulmonary blastoma, retinoblastoma, sarcoma (e.g., Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, vascular sarcoma), Wilms' tumor, and/or cancer of the adrenal cortex, anus, appendix, bile duct, bladder, bone, brain, breast, bronchus, central nervous system, cervix, colon, endometrium, esophagus, eye, fallopian tube, gall bladder, gastrointestinal tract, germ cell, head and neck, heart, intestine, kidney (e.g., Wilms' tumor), larynx, liver, lung (e.g., non-small cell lung cancer, small cell lung cancer), mouth, nasal cavity, oral cavity, ovary, pancreas, rectum, skin, stomach, testes, throat, thyroid, penis, pharynx, peritoneum, pituitary, prostate, rectum, salivary gland, ureter, urethra, uterus, vagina, or vulva.

[0288] In some embodiments, the present disclosure provides methods and compositions for treating a tumor in a subject. In some embodiments, the tumor is a solid tumor. In some embodiments, the tumor is a liquid or disperse tumor. In some embodiments, the tumor is associated with a hematologic malignancy, including but not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, AIDS-related lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, Langerhans cell histiocytosis, multiple myeloma, or myeloproliferative neoplasms.

[0289] In some embodiments, a tumor comprises a solid tumor. In some embodiments, solid tumors include but are not limited to tumors of the bladder, breast, central nervous system, cervix, colon, esophagus, endometrium, head and neck, kidney liver, lung, ovary, pancreas, skin, stomach, uterus, or upper respiratory tract. In some embodiments, a tumor that may be treated by the compositions and methods of the present disclosure is a breast tumor. In some embodiments, a tumor that may be treated by the compositions and methods of the present disclosure is not a lung tumor.

[0290] In some embodiments, a tumor or cancer suitable for treatment with the methods and compositions provided herein includes, for example, Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenal Cortex Cancer, Adrenocortical Carcinoma, AIDS-Related Cancer (e.g., Kaposi Sarcoma, AIDS-Related Lymphoma, Primary CNS Lymphoma), Anal Cancer, Appendix Cancer, Astrocytoma, Atypical Rhabdoid Tumor, Basal Cell. Carcinoma, Bile Duct Cancer, Bladder Cancer, Bone Cancer Brain Tumor, Breast Cancer, Bronchial Tumor, Burkitt Lymphoma, Carcinoid Tumor, Carcinoma, Cardiac (Heart) Tumor, Central Nervous System Tumor, Cervical Cancer, Cholangiocarcinoma, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic Myelogenous Leukemia (CML), Chronic Myeloproliferative Neoplasm, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ (DCIS), Embryonal Tumor, Endometrial Cancer, Endometrial Sarcoma, Ependymoma, Esophageal, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Eye Cancer, Fallopian Tube Cancer, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumor (GIST), Germ Cell Tumor, Gestational Trophoblastic Disease, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular (Liver) Cancer. Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumor, Kaposi Sarcoma, Kidney Tumor, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Lip and Oral Cavity Cancer, Liver Cancer, Lung Cancer, Lymphoma, Male Breast Cancer, Malignant Fibrous Histiocytoma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Mouth Cancer, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndrome Myelodysplastic/Myeloproliferative Neoplasm, Nasal Cavity Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumor (Islet Cell Tumor), Paraganglioma, Paranasal Sinus Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Pleuropulmonary Blastoma, Primary Central Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma Retinoblastoma, Rhabdomyosarcoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Sézary Syndrome, Skin Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer, Stomach (Gastric) Cancer. T-Cell Lymphoma, Testicular Cancer, Testicular Cancer, Throat Cancer, Thymic Carcinoma, Thymoma, Thyroid Cancer, Urethral Cancer, Uterine Sarcoma, Uterine Sarcoma, Vaginal Cancer, Vascular Tumor, Vulvar Cancer, Waldenstrom Macroglobulinemia, Wilms' Tumor.

Pharmaceutical Compositions

[0291] In some embodiments, the present invention provides a pharmaceutical composition comprising an inhibitor of KAT-5 as described herein. In some embodiments, a KAT-5 inhibitor, e.g., a compound of formulae I, I′ or I″ provided herein, can be administered to a subject, e.g., to a human patient, alone, e.g., in the form of a pharmaceutically acceptable salt, a solvated or hydrated form of a compound of formulae I, I′ or I″, and any polymorph or crystal form thereof. In some embodiments, a KAT-5 inhibitor, e.g., a compound of formulae I, I′ or I″, can be administered in the form of a pharmaceutical composition, e.g., where the compound of formulae I, I′ or I″ is admixed with a suitable carrier or excipient. A pharmaceutical composition typically comprises or can be administered at a dose sufficient to treat or ameliorate a disease or condition in the recipient subject, e.g., to treat or ameliorate a cancer as described herein. Accordingly, a pharmaceutical composition is formulated in a manner suitable for administration to a subject, e.g., in that it is free from pathogens and formulated according to the applicable regulatory standards for administration to a subject, e.g., for administration to a human subject. As an example, a formulation for injection is typically sterile and essentially pyrogen-free.

[0292] A compound of formulae I, I′ or I″ can also be administered to a subject as a mixture with other agents, e.g., with one or more additional therapeutic agents), e.g., in a suitably formulated pharmaceutical composition. For example, some aspects of the present disclosure relate to pharmaceutical compositions comprising a therapeutically effective dose of a compound of formulae I, I′ or I″, or a pharmaceutically acceptable salt, hydrate, enantiomer or stereoisomer thereof; and a pharmaceutically acceptable diluent or carrier.

[0293] Techniques for formulation and administration of a compound of formulae I, I′ or I″ may be found in references well known to one of ordinary skill in the art, such as Remington's “The Science and Practice of Pharmacy.” 21st ed., Lippincott Williams & Wilkins 2005, the entire contents of which are incorporated herein by reference.

[0294] Pharmaceutical compositions as provided herein are typically formulated for a suitable route of administration. Suitable routes of administration may, for example, include enteral administration, e.g., oral, rectal, or intestinal administration; parenteral administration, e.g., intravenous, intramuscular, intraperitoneal, subcutaneous, or intramedullary injection, as well as intrathecal, direct intraventricular, or intraocular injections; topical delivery, including eyedrop and transdermal; and intranasal and other transmucosal delivery, or any suitable route provided herein or otherwise apparent to those of ordinary skill in the art.

[0295] The pharmaceutical compositions provided herein may be manufactured, e.g., by mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping, or lyophilizing processes, or by any other suitable processes known to those of ordinary skill in the art.

[0296] Pharmaceutical compositions for use in accordance with the present invention may be formulated using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of a compound of formulae I, I′ or I″ into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.

[0297] For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Flanks' solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants are used in the formulation appropriate to the barrier to be permeated. Such penetrants are generally known in the alt.

[0298] For oral administration, a compound of formulae I, I′ or I″ can be formulated readily by combining the compound with pharmaceutically acceptable carriers known in the art. Such carriers enable a compound of formulae I, I′ or I″ to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the compound of formulae I, I′ or I″ with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.

[0299] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of doses.

[0300] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredient(s), e.g., a compound of formulae I, I′ or I″, in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the compound of formulae I, I′ or I″ may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.

[0301] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0302] For administration by inhalation, a compound of formulae I, I′ or I″ for use according to the present disclosure is conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound of formulae I, I′ or I″ and a suitable powder base such as lactose or starch.

[0303] Suitable compound(s) of formulae I, I′ or I″ can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules, or in multi-dose containers, and, in some embodiments, may contain an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulators, agents such as suspending, stabilizing and/or dispersing agents.

[0304] Pharmaceutical formulations for parenteral administration include aqueous solutions of compounds) of formulae I, I′ or I″ in water-soluble form. Additionally, suspensions of compound(s) of formulae I, I′ or I″ may be prepared as appropriate injection suspensions, e.g., aqueous or oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes, Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of compound(s) of formulae I, I′ or I″ to allow for the preparation of highly concentrated solutions.

[0305] Alternatively, the active ingredient(s), e.g., compounds) of formulae I, I′ or I″, may be in powder form for reconstitution before use with a suitable vehicle, e.g., sterile pyrogen-free water.

[0306] Compound(s) of formulae I, I′ or I″ may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases, such as cocoa butter or other glycerides.

[0307] In addition to the formulations described previously, a compound of formulae I, I′, or I″ may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, a compound of formulae I, I′ or I″ may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (for example, as a sparingly soluble salt).

[0308] Alternatively, other delivery systems for hydrophobic pharmaceutical compound(s) of formulae I, I′ or I″ may be employed. Liposomes and emulsions are examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed. Additionally, a compound of formulae I, I′ or I″ may be delivered using a sustained-release system, such as semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compound(s) of formulae I, I′ or I″ for a few hours, a few days, a few weeks, or a few months, e.g., up to over 100 days.

[0309] The pharmaceutical compositions may also comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers, such as polyethylene glycols.

[0310] Additional suitable pharmaceutical compositions and processes and strategies for formulating a suitable compound of formulae I, I′ or I″ will be apparent to the skilled artisan based on the present disclosure. The disclosure is not limited in this respect.

Methods of Treatment

[0311] Some aspects of this disclosure provide methods for modulating protein acetylation, e.g., histone acetylation, in a subject in need thereof by administering a compound of formulae I, I′ or I″ to the subject in an amount sufficient to modulate acetylation of a target protein, e.g., a histone acetylated by KAT-5 activity. In some embodiments, the subject is a subject having or diagnosed with a cancer or a precancerous condition.

[0312] Provided herein are methods of treating, preventing or alleviating a symptom of conditions and diseases, such as cancers and precancerous conditions, the course of which can be influenced by modulating the acetylation status of histones or other proteins that are acetylated by KAT-5, wherein said acetylation status is mediated at least in part by the activity of CREBBP. Modulation of the acetylation status of histones can in turn influence the level of expression of target genes activated by acetylation, and/or target genes suppressed by acetylation.

[0313] For example, some aspects of the invention provide methods for treating or alleviating a symptom of cancer or precancerous condition. In some embodiments, the method comprises the step of administering to a subject having a cancer or a precancerous condition a compound of formulae I, I′ or I″, e.g., in the form of a pharmaceutical composition, at a therapeutically effective amount.

[0314] In some embodiments, compound of formulae I, I′ or I″ inhibits histone acetyltransferase activity of KAT-5. In some embodiments, compound of formulae I, I′ or I″ selectively inhibits histone acetyltransferase activity of KAT-5.

[0315] In some embodiments, the subject is diagnosed with a disease or disorder known to be associated with a dysregulation of histone acetylation, e.g., with a dysfunction, of KAT-5. In some embodiments, the subject is diagnosed with a disease or disorder mediated by KAT-5. In some embodiments, the subject has been diagnosed with a cancer.

[0316] Dysregulated histone acetylation has been reported to be involved in aberrant expression of certain genes in cancers and other diseases. Compounds described herein can be used to treat such histone acetylation-associated diseases, e.g., to inhibit KAT-5-mediated histone acetylation in affected cells, tissues, or subjects.

[0317] Modulators of histone acetylation can be used for modulating cell proliferation, of cells harboring a mutation resulting in aberrant histone acetylation, or for inducing cell death in cells depending on KAT-5 histone acetylation for survival or proliferation. Accordingly, diseases that may be treated with compound(s) of formulae I, I′ or I″ include hyperproliferative diseases, such as benign cell growth and malignant cell growth (cancer).

[0318] Exemplary cancers that may be treated with compound provided herein include, without limitation, lymphomas, including non-Hodgkin lymphoma, follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL); melanoma; and leukemia, including CML; Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Adrenocortical Carcinoma; AIDS-Related. Cancers; AIDS-Related Lymphoma; Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, Childhood Cerebral; Basal Cell Carcinoma, see Skin Cancer (non-Melanoma); Bile Duct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer, osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; Brain Tumor; Brain Tumor; Cerebellar Astrocytoma; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma; Brain Tumor, Ependymoma; Brain Tumor, Medulloblastoma; Brain Tumor, Supratentorial Primitive Neuroectodermal Tumors; Brain Tumor, Visual Pathway and Hypothalamic Glioma; Breast Cancer; Bronchial Adenomas/Carcinoids; Burkitt's Lymphoma; Carcinoid Tumor; Carcinoid Tumor, Gastrointestinal; Carcinoma of Unknown Primary; Central Nervous System Lymphoma, Primary; Cerebellar Astrocytoma; Cervical Cancer; Childhood Cancers; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, Hairy Cell; Chronic Myeloproliferative Disorders; Colon Cancer; Colorectal Cancer; Cutaneous T-Cell Lymphoma, see Mycosis Fungoides and Sezary Syndrome; Endometrial Cancer; Esophageal Cancer; Ewing's Family of Tumors; Extrahepatic Bile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer, Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer; Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial; Germ Cell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; Gestational Trophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma, Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway and Hypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hepatocellular (Liver) Cancer, Adult (Primary); Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma; Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamic and Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma (Endocrine Pancreas); Kaposi's Sarcoma; Kidney (Renal Cell) Cancer; Kidney Cancer; Laryngeal Cancer; Leukemia; Lip and Oral Cavity Cancer; Liver Cancer, Adult (Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-Small Cell; Lung Cancer, Small Cell; Lymphoma, Primary Central Nervous System; Macroglobulinemia, Waldenstrom's; Malignant Fibrous Histiocytoma of Bone/Osteosarcoma; Medulloblastoma; Melanoma; Merkel Cell Carcinoma; Mesothelioma; Mesothelioma, Adult Malignant; Metastatic Squamous Neck Cancer with Occult Primary; Multiple Endocrine Neoplasia Syndrome; Multiple Myeloma; Multiple Myeloma/Plasma Cell Neoplasm. Mycosis Fungoides; Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases; Myeloid Leukemia, Adult Acute; Myeloid Leukemia, Childhood Acute; Myeloproliferative Disorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer; Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's Lymphoma; Non-Hodgkin's Lymphoma During Pregnancy; Oral Cancer; Oral Cavity Cancer, Lip and; Oropharyngeal Cancer; Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer; Ovarian Epithelial Cancer; Ovarian Low Malignant Potential Tumor; Pancreatic Cancer; Pancreatic Cancer, Islet Cell; Paranasal Sinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer; Pheochromocytoma; Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors; Pituitary Tumor; Plasma Cell Neoplasm/Multiple Myeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer; Prostate Cancer; Rectal Cancer; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer; Sarcoma, Ewing's Family of Tumors; Sarcoma, Soft Tissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer; Skin Cancer (non-Melanoma); Small Intestine Cancer; Soft Tissue Sarcoma; Squamous Cell Carcinoma, see Skin Cancer (non-Melanoma); Squamous Neck Cancer with Occult Primary, Metastatic; Stomach (Gastric) Cancer; Testicular Cancer; Thymoma; Thymoma and Thymic Carcinoma; Thyroid Cancer; Transitional Cell Cancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational; Unknown Primary Site, Cancer of; Unusual Cancers of Childhood; Urethral Cancer; Uterine Cancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Visual Pathway and Hypothalamic Glioma; Vulvar Cancer; Waldenstrom's Macroglobulinemia; Wilms' Tumor; and Women's Cancers, Exemplary precancerous conditions that can be treated with compound(s) of formulae I, I′ or I″ include myelodisplastic syndrome (MDS; formerly known as preleukemia).

[0319] Any other disease in which histone acetylation mediated by KAT-5 plays a role may be treatable or preventable using compounds and methods described herein.

Administration

[0320] In some embodiments, an active agent for use in accordance with the present disclosure is formulated, dosed, and/or administered in a therapeutically effective amount using pharmaceutical compositions and dosing regimens that are consistent with good medical practice and appropriate for the relevant agent(s) and subject(s). In principle, therapeutic compositions can be administered by any appropriate method known in the art, including, without limitation, oral, mucosal, by-inhalation, topical, buccal, nasal, rectal, or parenteral (e.g. intravenous, infusion; intratumoral, intranodal, subcutaneous, intraperitoneal, intramuscular, intradermal, transdermal, or other kinds of administration involving physical breaching of a tissue of a subject and administration of the therapeutic composition through the breach in the tissue).

[0321] In some embodiments, a dosing regimen for a particular active agent may involve intermittent or continuous (e.g., by perfusion or other slow release system) administration, for example to achieve a particular desired pharmacokinetic profile or other pattern of exposure in one or more tissues or fluids of interest in the subject receiving therapy.

[0322] In some embodiments, different agents administered in combination may be administered via different routes of delivery and/or according to different schedules. Alternatively or additionally, in some embodiments, one or more doses of a first active agent is administered substantially simultaneously with, and in some embodiments via a common route and/or as part of a single composition with, one or more other active agents.

[0323] Factors to be considered when optimizing routes and/or dosing schedule for a given therapeutic regimen may include, for example, the particular indication being treated, the clinical condition of a subject (e.g., age, overall health, prior therapy received and/or response thereto) the site of delivery of the agent, the nature of the agent (e.g. small molecule, an antibody or other polypeptide-based compound), the mode and/or route of administration of the agent, the presence or absence of combination therapy, and other factors known to medical practitioners. For example, in the treatment of cancer, relevant features of the indication being treated may include, for example, one or more of cancer type, stage, location.

[0324] In some embodiments, one or more features of a particular pharmaceutical composition and/or of a utilized dosing regimen may be modified over time (e.g., increasing or decreasing the amount of active agent in any individual dose, increasing or decreasing time intervals between doses), for example in order to optimize a desired therapeutic effect or response.

[0325] In general, type, amount, and frequency of dosing of active agents in accordance with the present invention are governed by safety and efficacy requirements that apply when one or more relevant agent(s) is/are administered to a mammal, preferably a human. In general, such features of dosing are selected to provide a particular, and typically detectable, therapeutic response as compared to what is observed absent therapy.

[0326] In the context of the present invention, an exemplary desirable therapeutic response may involve, but is not limited to, inhibition of and/or decreased tumor growth, tumor size, metastasis, one or more of the symptoms and side effects that are associated with a tumor, as well as increased apoptosis of cancer cells, therapeutically relevant decrease or increase of one or more cell marker or circulating markers. Such criteria can be readily assessed by any of a variety of immunological, cytological, and other methods that are disclosed in the literature.

[0327] In some embodiments, an effective dose (and/or a unit dose) of an active agent, may be at least about 0.01 μg/kg body weight, at least about 0.05 μg/kg body weight; at least about 0.1 μg/kg body weight, at least about 1 μg/kg body weight, at least about 2.5 μg/kg body weight, at least about 5 μg/kg body weight, and not more than about 100 μg/kg body weight. It will be understood by one of skill in the art that in some embodiments such guidelines may be adjusted for the molecular weight of the active agent. The dosage may also be varied for route of administration, the cycle of treatment, or consequently to dose escalation protocol that can be used to determine the maximum tolerated dose and dose limiting toxicity (if any) in connection to the administration of a compound of formulae I, I′ or I″ and/or an additional therapeutic agent at increasing doses. Consequently, the relative amounts of the each agent within a pharmaceutical composition may also vary, for example, each composition may comprise between 0001% and 100% (w/w) of the corresponding agent.

[0328] In some embodiments, a “therapeutically effective amount” or “therapeutically effective dose” is an amount of a compound of formulae I, I′ or I″, or a combination of two or more compounds of formulae I, I′ or I″, or a combination of a compound of formulae I, I′ or I″ with one or more additional therapeutic agent(s), which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition. In some embodiments, a therapeutically effective amount can be an amount which is prophylactically effective. In some embodiments, an amount which is therapeutically effective may depend upon a patient's size and/or gender, the condition to be treated, severity of the condition and/or the result sought. In some embodiments, a therapeutically effective amount refers to that amount of a compound of formulae I, I′ or I″ that results in amelioration of at least one symptom in a patient. In some embodiments, for a given patient, a therapeutically effective amount may be determined by methods known to those of skill in the art.

[0329] In some embodiments, toxicity and/or therapeutic efficacy of a compound of formulae I, I′ or I″ can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the ED.sub.50 (effective dose for 50% maximal response). Typically, the dose ratio between toxic and therapeutic effects is the therapeutic index; in some embodiments, this ratio can be expressed as the ratio between MTD and ED.sub.50. Data obtained from such cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.

[0330] In some embodiments, dosage may be guided by monitoring the effect of a compound of formulae I, I′ or I″ on one or more pharmacodynamic markers of enzyme inhibition (e.g., histone acetylation or target gene expression) in diseased or surrogate tissue. For example, cell culture or animal experiments can be used to determine the relationship between doses required for changes in pharmacodynamic markers and doses required for therapeutic efficacy can be determined in cell culture or animal experiments or early stage clinical trials. In some embodiments, dosage of a compound of formulae I, I′ or I″ lies preferably within a range of circulating concentrations that include the ED.sub.50 with little or no toxicity. In some embodiments, dosage may vary within such a range, for example depending upon the dosage form employed and/or the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. In the treatment of crises or severe conditions, administration of a dosage approaching the MTD may be required to obtain a rapid response.

[0331] In some embodiments, dosage amount and/or interval may be adjusted individually, for example to provide plasma levels of an active moiety which are sufficient to maintain, for example a desired effect, or a minimal effective concentration (MEC) for a period of time required to achieve therapeutic efficacy. In some embodiments, MEC for a particular compound of formulae I, I′ or I″ can be estimated, for example, from in vitro data and/or animal experiments. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. In some embodiments, high pressure liquid chromatography (HPLC) assays or bioassays can be used to determine plasma concentrations.

[0332] In some embodiments, dosage intervals can be determined using the MEC value. In certain embodiments, compound(s) of formulae I, I′ or I″ should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of a symptom is achieved. In other embodiments, different MEC plasma levels will be maintained for differing amounts of time. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0333] One of skill in the art can select from a variety of administration regimens and will understand that an effective amount of a particular compound of formulae I, I′ or I″ may be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and/or the judgment of the prescribing physician.

Combination Therapy

[0334] In some embodiments, a compound of formulae I, I′ or I″ can be used in combination with another therapeutic agent to treat diseases such as cancer. In some embodiments, a compound of formulae I, I′ or I″, or a pharmaceutical composition thereof, can optionally be administered in combination with one or more additional therapeutic agents, such as a cancer therapeutic agent, e.g., a chemotherapeutic agent or a biological agent. An additional agent can be, for example, a therapeutic agent that is art-recognized as being useful to treat the disease or condition being treated by a compound of formulae I, I′ or I″ e.g., an anti-cancer agent, or an agent that ameliorates a symptom associated with the disease or condition being treated. The additional agent also can be an agent that imparts a beneficial attribute to the therapeutic composition (e.g., an agent that affects the viscosity of the composition). For example, in some embodiments, a compound of formulae I, I′ or I″ is administered to a subject who has received, is receiving, and/or will receive therapy with another therapeutic agent or modality (e.g., with a chemotherapeutic agent, surgery, radiation, or a combination thereof).

[0335] Some embodiments of combination therapy modalities provided by the present disclosure provide, for example, administration of a compound of formulae I, I′ or I″ and additional agent(s) in a single pharmaceutical formulation. Some embodiments provide administration of a compound of formulae I, I′ or I″ and administration of an additional therapeutic agent in separate pharmaceutical formulations.

[0336] Examples of chemotherapeutic agents that can be used in combination with a compound of formulae I, I′ or I″ described herein include platinum compounds (e.g., cisplatin, carboplatin, and oxaliplatin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chlorambucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, streptozocin, temozolomide, dacarbazine, and bendamustine), antitumor antibiotics (e.g., daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantrone, bleomycin, mytomycin C, plicamycin, and dactinomycin), taxanes (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, cytarabine, premetrexed, thioguanine, floxuridine, capecitabine, and methotrexate), nucleoside analogues (e.g., fludarabine, clofarabine, cladribine, pentostatin, and nelarabine), topoisomerase inhibitors (e.g., topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteosome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), vinca alkaloids (e.g., vicristine, vindesine, vinorelbine, and vinblastine), tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, sorafenib, and sunitinib), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), hexamethylmelamine, mitotane, angiogenesis inhibitors (e.g., thalidomide and lenalidomide), steroids (e.g., prednisone, dexamethasone, and prednisolone), hormonal agents (e.g., tamoxifen, raloxifene, leuprolide, bicaluatmide, granisetron, and flutamide), aromatase inhibitors (e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, nonselective cyclooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory agents, salicylates, aspirin, piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, tolmetin, ketoprofen, nabumetone, and oxaprozin), selective cyclooxygenase-2 (COX-2) inhibitors, or any combination thereof.

[0337] Examples of biological agents that can be used in the compositions and methods described herein include monoclonal antibodies (e.g., rituximab, cetuximah, panetumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozolzarnicin, bevacizumab, catumaxomab, denosumab, obinutuzumab, ofatwnumab, ramucirumab, pertuzumab, ipilimumab, nivolumab, nimotuzumab, lambrolizumab, pidilizumab, siltuximab, BMS-936559, RG7446/MPDL3280A, MEDI41736, tremeliniumab, or others known in the art), enzymes (e.g., L-asparaginase), cytokines (e.g., interferons and interleukins), growth factors (e.g., colony stimulating factors and erythropoietin), cancer vaccines, gene therapy vectors, or any combination thereof.

[0338] In some embodiments, a compound of formulae I, I′ or I″ is administered to a subject in need thereof in combination with another agent for the treatment of cancer, either in the same or in different pharmaceutical compositions. In some embodiments, the additional agent is an anticancer agent. In some embodiments, the additional agent affects (e.g., inhibits) histone modifications, such as histone acetylation or histone methylation. In certain embodiments, an additional anticancer agent is selected from the group consisting of chemotherapeutics (such as 2CdA, 6-Mercaptopurine, 6-TG, Abraxane™ Accutane®, Actinomycin-D, Adriamycin®, Alimta®, all-trans retinoic acid, amethopterin, Ara-C, Azacitadine, BCNU, Blenoxane®, Camptosar®, CeeNU®, Clofarabine, Clolar™, Cytoxan®, daunorubicin hydrochloride, DaunoXome®, Dacogen®, DIC, Doxil®, Ellence®, Eloxatin®, Emcyt®, etoposide phosphate, Fludara®, FUDR®, Gemzar®, Gleevec®, hexamethylmelamine, Hycamtin®, Hydrea®, Idamycin®, ixabepilone, Ixempra®, L-asparaginase, Leukeran®, liposomal Ara-C, L-PAM, Lysodren, Matulane®, mithracin, Mitontycin-C, Myleran®, Navelbine®, Neutrexin®, nitotinib, Nipent®, Nitrogen Mustard, Novantrone®, Oncaspar®, Panretin®, Paraplatin®, Platinol®, prolifeprospan 20 with carmustine implant, Sandostatin®, Targretin®, Tasigna®, Taxotere®, Temodar®, TESPA, Trisenox®, Valstar®, Velban®, Vidaza™, vincristine sulfate, VM 26, Xeloda® and Zanosar®; biologics (such as Alpha Interferon, Bacillus Calmette-Guerin, Bexxar®, Campath®, Ergamisol®, Eriotinib, Herceptin®, Interleukin-2, Iressa®, lenalidomide, Mylotarg®, Ontak®, Pegasys®, Revlimid®, Rituxan®, Tarceva™, Thalomid®, Velcade® and Zevalin™); small molecules (such as Tykerb®); corticosteroids (such as dexamethasone sodium phosphate, DeltaSone® and Delta-Cortef®); hormonal therapies (such as Arimidex®, Aromasin®, Casodex®, Cytadren®, Eligord®, Eulexin®, Evista®, Falodex®, Fermara®, Halotestin®, Megace®, Nilandron®, Nolvadex®, Plenaxis™ and Zoladex®); and radiopharmaceuticals (such as Iodotope®, Metastron®, Phosphocol® and Samarium SM-153).

[0339] The additional agents that can be used in combination with a compound of formulae I, I′ or I″ as set forth above are for illustrative purposes and not intended to be limiting. The combinations embraced by this disclosure, include, without limitation, one or more compounds of formulae I, I′ or I″ as provided herein and at least one additional agent selected from the lists above or otherwise provided herein. Compounds of formulae I, I′ or I′ can also be used in combination with one or with more than one additional agent, e.g., with two, three, four, five, or six, or more, additional agents.

[0340] In some embodiments, treatment methods described herein are performed on subjects for which other treatments of the medical condition have failed or have had less success in treatment through other means, e.g., in subjects having a cancer refractory to standard-of-care treatment. Additionally, the treatment methods described herein can be performed in conjunction with one or more additional treatments of the medical condition, e.g., in addition to or in combination with standard-of-care treatment. For instance, the method can comprise administering a cancer-therapeutic regimen, e.g., nonmyeloablative chemotherapy, surges r, hormone therapy, and/or radiation, prior to, substantially simultaneously with, or after the administration of a compound of formulae I, I′ or I″ described herein, or composition thereof. In certain embodiments, a subject to which compound of formula I, I′ or I″ described herein is administered can also be treated with antibiotics and/or one or more additional pharmaceutical agents.

EXAMPLES

Synthetic Experimentals

[0341] Materials and Methods

[0342] Equipment: .sup.1H NMR Spectra were recorded at 400 MHz using a Bruker AVANCE 400 MHz spectrometer. LC-MS equipment and conditions are as follows:

[0343] LC-MS (Agilent): LC: Agilent Technologies 1290 series, Binary Pump, Diode Array Detector. Agilent. Poroshell 120 EC—C18, 2.7 μm, 41.6×50 mm column. Mobile phase: A: 0.05% Formic acid in water (v/v), B: 0.05% Formic acid in ACN (v/v). Flow Rate: 1 mL/min at 25° C. Detector: 214 nm, 254 nm. Gradient stop time, 5 min, Timetable:

TABLE-US-00007 T (min) A(%) B(%) 0.0 90 10 0.5 90 10 4.5 0 100 4.51 90 10 5.0 90 10

[0344] MS: G6120A, Quadrupole LC/MS, ion Source: ES-API, TIC: 70˜1000 m/z, Fragmentor: 60, Drying gas flow: 10 L/min, Nebulizer pressure: 35 psi, Drying gas temperature: 350° C., Vcap: 3000V.

[0345] Sample preparation: samples were dissolved in ACN or methanol at ˜100 μg/mL, then filtered through a 0.22 μm filter membrane. Injection volume: 1˜10 μL.

[0346] Definitions: Boc (tert-butoxycarbonyl); CDCl.sub.3 (deuterated chloroform); DMF (NA-dimethylformamide): DMSO (dimethylsulfoxide); DMSO-d.sub.6 (deuterated dimethylsulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide); eq (equivalent); ES-API (electrospray atmospheric pressure ionization); Et.sub.3N (triethylamine); Et.sub.2O (diethyl ether); EtOAc (ethyl acetate); g (gram); h (hour); HATU (2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate); NMR (proton nuclear magnetic resonance); HOBt (hydroxybenzotriazole); Hz (hertz); L (litre); LC-MS (liquid chromatography-mass spectrometry); M (molar); MeOH (methanol); mg (milligrams); MHz (megahertz); min (minutes); mL (millilitres), mmol (millimoles); Pet. ether or PE (petroleum ether); ppm (parts per million); psi (pounds per square inch); R.sub.t (retention time); RT (room temperature); THF (tetrahydrofuran); TLC (thin layer chromatography); v/v (volume/volume).

Synthesis of Intermediate A (4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbohydrazide)

[0347] ##STR00648##

Step 1: 5-bromo-2-fluoro-3-methylbenzoic acid

[0348] ##STR00649##

[0349] To a solution of 4-bromo-1-fluoro-2-methylbenzene (5.0 g, 26.4 mmol) in THF was added dropwise LDA (2 M in THF, 29.0 mmol) at −65° C. under N.sub.2 atmosphere. The resulting mixture was stirred at −65° C. for 2 h, after which excess solid carbon dioxide was added. The mixture was stirred for 30 min and warmed to room temperature. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×2). The aqueous layer was acidified to pH 3 by 2 M HCl and extracted with EtOAc (50 mL×2), The combined organic layers were washed with brine (50 mL), dried over Na.sub.2SO.sub.4 and concentrated to give 5-bromo-2-fluoro-3-methylbenzoic acid (3.4 g, 52%), which was used for the next step without further purification.

[0350] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 13.47 (s, 1H), 7.75 (d, J=6.0 Hz, 2H), 2.26 (d, 1.6 Hz, 3H).

Step 2: 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid

[0351] ##STR00650##

[0352] To a mixture of 5-bromo-2-fluoro-3-methylbenzoic acid (3.5 g, 15.0 mmol) and phenylboronic acid (2.19 g, 18.0 mmol) in dioxane/water (60 mL, 5:1) were added PdCl.sub.2(dppf).sub.2 (1.09 g, 1.50 mmol) and potassium carbonate (8.29 g, 60.0 mmol) at room temperature under N.sub.2 atmosphere. After heating at 90° C. for 6 h, the reaction mixture was poured into 1 M HCl solution and extracted with EA (150 mL×2). The combined organic layers were washed with 1 M HCl (100 mL×2), water (100 mL) and brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was recrystallized from hexane to give 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid (3 g, 82%) as a yellow solid.

[0353] LC-MS (Agilent): R.sub.t 3.51 min; m/z calculated for C.sub.14H.sub.11FO.sub.2 [M−H].sup.− 229.1, found 229.1.

[0354] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 8.06 (d, J=6.0 Hz, 1H), 7.64 (d, J=6.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.2 Hz, 1H), 2.40 (s, 3H).

Step 3: 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbohydrazide

[0355] ##STR00651##

[0356] A solution of 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid (3 g, 13.0 mmol) in thionyl chloride (15.4 g, 130 mmol) was heated to reflux for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (50 mL) and hydrazine hydrate (26.0 g, 650 mmol) was added dropwise. The mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with water (100 mL) and extracted with DCII (150 mL×2). The combined organic layers were washed with water (200 mL) and brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by silica gel column (CH.sub.2Cl.sub.2/MeOH=50:1 to 20:1, v/v) to give 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbohydrazide (1.7 g, 50%) as a yellow solid.

[0357] LC-MS (Agilent): R.sub.t 2.87 min; m/z calculated for C.sub.14H.sub.13FN.sub.2O [M+H].sup.+ 245.1, found 245.1.

[0358] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 8.11 (d, J=6.4 Hz, 1H), 7.57-7.53 (m, 3H), 7.43 (t, J=7.6 Hz, 2H), 7.35 (t, J=7.2 Hz, 1H), 2.37 (s, 3H).

[0359] General Procedure 1

[0360] To a mixture of 4-fluoro-5-methyl[1,1″-biphenyl]-3-carbohydrazide (1.0 eq) and sodium carbonate (2.0 eq) in DCM at 0° C. under N.sub.2 atmosphere was added sulfonyl chloride (1.2 eq). After stirring at room temperature for 18 h, the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by Prep-TLC to afford the desired product.

[0361] General Procedure 2

[0362] To a solution of 4-fluoro-5-methyl[1,1′-biphenyl]-3-carbohydrazide (1.0 eq) and triethylamine (2.0 eq) in DCM was added sulfonyl chloride (1.0-1.2 eq) at 0° C. under N.sub.2 atmosphere. After stirring at room temperature for 18 h, the reaction mixture was diluted with water and extracted with DCM, me combined organic layers were washed with water and brine, dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by Prep-TLC to afford the desired product.

[0363] The following compounds were synthesized via the general procedures

TABLE-US-00008 Compound Procedure LCMS .sup.1HNMR [00652] 1 [M − 1] = 321.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.67 (s, 1H), 9.72 (s, 1H), 7.77 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.63-7.61 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.04 (s, 3H), 2.35 (s, 3H). [00653] 2 [M − 1] = 335.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.60 (s, 1H), 9.67 (s, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.61-7.59 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.28 (q, J = 7.2 Hz, 2H), 2.34 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). [00654] 2 [M − 1] = 349.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.53 (s, 1H), 9.58 (s, 1H), 7.77 (d, J = 6.4 Hz, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.59-7.57 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.28 (m, 1H), 2.34 (s, 3H), 1.36 (s, 3H), 1.33 (s, 3H). [00655] 2 [M − 1] = 347.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.63 (s, 1H), 9.70 (s, 1H), 7.77 (d, J = 6.8 Hz, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.59-7.57 (m, 1H), 7.48 (t, J = 7.2 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 2.63-2.57 (m, 1H), 2.35 (s, 3H), 1.00-0.98 (m, 4H) [00656] 2 [M − 1] = 431.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.77 (s, 1H), 10.03 (s, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.70-7.65 (m, 4H), 7.47-7.53 (m, 3H), 7.39-7.41 (m, 3H), 4.67 (s, 2H), 2.36 (s, 3H). [00657] 2 [M − 1] = 431.0 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.68 (s, 1H), 9.86 (s, 1H), 7.78- 7.79 (m, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.63-7.65 (m, 2H), 7.47-7.51 (m, 3H), 7.39-7.43 (m, 3H), 4.49 (s, 2H), 2.36 (s, 3H). [00658] 2 [M − 1] = 431.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.64 (s, 1H), 9.74 (s, 1H), 7.77 (d, J = 5.2 Hz, 1H), 7.69 (d, J = 7.6 Hz, 2H), 7.65-7.62 (m, 1H), 7.55- 7.34 (m, 7H), 4.47 (s, 2H), 2.35 (s, 3H). [00659] 2 [M − 1] = 397.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ ppm: 10.67 (s, 1H), 9.77 (s, 1H), 7.79 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 7.3 Hz, 2H), 7.65 (d, J = 5.2 Hz, 1H), 7.55-7.45 (m, 4H), 7.37-7.39 (m, 4H), 4.46 (s, 2H), 2.36 (s, 3H) [00660] 2 [M − 1] = 361.1 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.56 (brs, 1H), 9.62 (brs, 1H); 7.76 (d, J = 6.4 Hz, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 6.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.95 (m, 1H), 2.40-2.29 (m, 7H), 1.97-1.87 (m, 2H). [00661] 2 [M − 1] = 375.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.55 (s, 1H), 9.60 (s, 1H), 7.76 (d, J = 6.4 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.59 (d, J = 6.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.66-3.58 (m, 1H), 2.34 (s, 3H), 2.01-1.91 (m, 4H), 1.72-1.64 (m, 2H), 1.59-1.57 (m, 2H). [00662] 2 [M − 1] = 389.2 .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 10.50 (s, 1H), 9.56 (s, 1H), 7.76 (d, J = 6.0 Hz, 1H), 7.67 (d, J = 7.2 Hz, 2H), 7.57 (d, J = 6.0 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.39 (t, J = 7.2 Hz, 1H), 3.02 (t, J = 11.6 Hz, 1H), 2.35 (s, 3H), 2.26 (d, J = 12.0 Hz, 2H), 1.80 (d, J = 12.0 Hz, 2H), 1.65- 1.40 (m, 6H).

Synthesis of Benzyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (I-121)

[0364] ##STR00663##

Step 1: Benzyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0365] ##STR00664##

[0366] Methanesulfonyl chloride (13.6 g, 119 mmol) was added to a solution of benzyl 3-hydroxyazetidine-1-carboxylate (20.7 g, 99.8 mmol) and triethylamine (15.0 g, 149 mmol) in DCM (200 mL) at 0° C. After stirring at room temperature for 15 h, the reaction mixture was washed with 1 M HCl (50 mL) and the aqueous layer extracted with DCM (100 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to give benzyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (28 g, 98%) as a colourless oil, which was used for the next step without further purification.

[0367] LC-MS (Agilent): 3.02 min; m/z calculated for C.sub.12H.sub.15NO.sub.5S [M+1].sup.+ 286.1, found 286.1.

[0368] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 7.38-7.31 (m, 5H), 5.25-5.20 (m, 1H), 5.11 (s, 2H), 4.38-4.34 (m, 2H), 4.19-4.16 (m, 2H), 3.06 (s, 3H).

Step 2: Benzyl 3-(acetylthio)azetidine-1-carboxylate

[0369] ##STR00665##

[0370] Thioacetic acid (5.99 g, 78.7 mmol) was added dropwise to a mixture of potassium carbonate (10.8 g, 78.7 mmol) and benzyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (15 g, 52.5 mmol) in DMF (100 mL) at 10° C. After heating at 80° C. for 10 h, the reaction mixture was diluted with H.sub.2O (300 mL) and extracted with EA (150 mL×3). The combined organic layers were washed with brine (200 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EA=5:1, v/v) to afford benzyl 3-(acetylthio)azetidine-1-carboxylate (9.5 g, 68%) as an off-white solid.

[0371] LC-MS (Agilent): R.sub.t 3.45 min, m/z calculated for C.sub.13H.sub.15NO.sub.3S [M+1].sup.+ 266.1, found 266.1.

Step 3: Benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate

[0372] ##STR00666##

[0373] H.sub.2O (4 mL) was added to a solution of benzyl 3-(acetylthio)azetidine-1-carboxylate. (300 mg, 1.13 mmol) in DCM (8 mL) and chlorine was bubbled through the mixture at 0-10° C. with stirring for 1 h. The organic phase was separated, washed with H2O 2O (8 mL), sat. NaHCO.sub.3 (10 mL) and brine (10 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate (250 mg, 76%) as a colourless oil, which was used for the next step directly.

[0374] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 7.39-7.34 (m, 5H), 5.13 (s, 2H), 4.56-4.50 (m, 1H), 4.49-4.39 (m, 4H).

Step 4: Benzyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (I-121)

[0375] ##STR00667##

[0376] To a solution of 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbohydrazide (1.05 g, 4.30 mmol) and triethylamine (871 mg, 8.61 mmol) in DCM (70 mL) was added a solution of benzyl 3-(chlorosulfonyl)azetidine-1-carboxylate (1.5 g, 5.17 mmol) in DCM (80 mL) under N.sub.2 atmosphere at 0° C. After warming to room temperature and stirring for overnight, the mixture was diluted with water (150 mL) and extracted with DCM (150 mL×2). The combined organic layers were washed with H.sub.2O (150 mL) and brine (150 mL), dried (Na.sub.2SO.sub.4) and concentrated. The residue was purified by column chromatography (PE/EA=3:1, v/v) to afford benzyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (500 mg, 21%) as a white solid.

[0377] LC-MS (Agilent): R.sub.t 3.84 min; m/z calculated for C.sub.25H.sub.24FN.sub.3O.sub.5S [M−1].sup.− 496.2, found 496.2.

[0378] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ (ppm): 10.77 (s, 1H), 10.11 (s, 1H), 7.82-7.74 (m, 1H), 7.72-7.64 (m, 2H), 7.63-7.57 (m, 1H), 7.54-7.27 (m, 8H), 5.07 (s, 2H), 4.37-4.06 (m, 5H), 2.34 (s, 3H).

Synthesis of tert-Butyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (I-119) and N′-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)azetidine-3-sulfonohydrazide hydrochloride (I-120)

[0379] ##STR00668##

Step 1: tert-Butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate

[0380] ##STR00669##

[0381] Methanesulfonyl chloride (21.4 g, 187 mmol) was added to a solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (25 g, 144 mmol) and triethylamine (21.8 g, 216 mmol) in DCM (500 mL) at 0° C. After stirring at room temperature for 6 h, the reaction mixture was washed with 1 M HCl (50 mL) and the aqueous layer was extracted with DCM (100 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to give tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (36 g, 99%) as a colourless oil.

[0382] .sup.1H NMR (400 MHz, CDCl.sub.3) δ(ppm): 5.21-5.16 (m, 1H), 4.28-424 (m, 2H), 4.10-4.07 (m, 2H), 3.05 (s, 3H), 1.43 (s, 9H).

Step 2: tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

[0383] ##STR00670##

[0384] Potassium thioacetate (19.5 g, 171 mmol) was added to a solution of tert-butyl 3-((methylsulfonyl)oxy)azetidine-1-carboxylate (36 g, 143 mmol) in DMF (500 ML). After heating at 80° C. for 15 h, the reaction mixture was diluted with H.sub.2O (1 L) and extracted with EA (250 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography (PE/EA=10:1, v/v) to afford tert-butyl 3-(acetylthio) azetidine-1-carboxylate (9.5 g, 28%) as a brown oil.

[0385] LC-MS (Agilent): R.sub.t 3.42 min: m/z calculated for C.sub.10H.sub.17NO.sub.3S [M+1].sup.+ 232.1, found [M+1-56].sup.+ 176.1.

[0386] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 4.36 (t, J=8.8 Hz, 2H), 4.18-4.13 (m, 1H), 3.83-3.79 (m, 2H), 2.22 (s, 3H), 1.43 (s, 9H).

Step 3: tert-Butyl 3-(chlorosulfonyl) azetidine-1-carboxylate

[0387] ##STR00671##

[0388] H.sub.2O (5 mL) was added to a solution of tert-butyl 3-(acetylthio) azetidine-1-carboxylate (3.6 g, 15.5 mmol) in DCM (30 mL), and chlorine was bubbled through the mixture at 0° C. with stirring for 0.5 h. The organic phase was separated, washed with sat. NaHCO.sub.3 (20 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4 and concentrated to afford tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (3.7 g, 93%) as a colourless oil, which was used for the next step directly.

[0389] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 4.52-4.48 (m, 1H), 4.40-4.33 (m, 4H), 1.45 (s, 9H).

Step 4: tert-Butyl 3-(hydrazinylsulfonyl) azetidine-1-carboxylate

[0390] ##STR00672##

[0391] 80% hydrazine hydrate (1.65 g, 33.1 mmol) was added into a solution of tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate (3.7 g, 14.4 mmol) in THF (40 mL) at 0° C., After stirring at room temperature for 2 h, the reaction mixture was concentrated and the residue was purified by column chromatography (DCM/MeOH=20:1, v/v) to afford tert-butyl 3-(hydrazinylsulfonyl) azetidine-1-carboxylate (3 g, 83%) as a yellow oil.

[0392] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 4.28-4.17 (m, 5H), 1.43 (s, 9H).

Step 5: tert-Butyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (I-119)

[0393] ##STR00673##

[0394] To a solution of 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid (695 mg, 3.02 mmol) in NMP (30 mL) was added diisopropylethylamine (780 mg, 6.04 mmol) and HATU (1.72 g, 4.53 mmol). After stirring at room temperature for 1 h, tert-butyl 3-(hydrazinylsulfonyl) azetidine-1-carboxylate (760 mg, 3.02 mmol) was added. After stirring at rt for 2 h, the reaction mixture was diluted with water (80 mL) and extracted with EA (40 mL×3). The combined organic layers were washed by brine (50 mL), dried and concentrated. The crude product was purified by column chromatography (PE:EA:=3:1, v/v) to give tert-butyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (1.4 g, 90%) as a yellow solid.

[0395] LC-MS (Agilent): R.sub.t 3.83 min; m/z calculated for C.sub.22H.sub.26FN.sub.3O.sub.5S [M+1].sup.+ 464.1, found [M+1−56].sup.+ 408.1.

[0396] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ (ppm): 10.77 (s, 1H), 10.08 (s, 1H), 7.82-7.76 (m, 1H), 7.72-7.65 (m, 2H), 7.64-7.56 (m, 1H), 7.53-7.44 (m, 2H), 7.44-7.34 (m, 1H), 4.25-3.99 (m, 5H), 2.34 (s, 3H), 1.38 (s, 9H).

Step 6: N′-(4-Fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)azetidine-3-sulfonohydrazide hydrochloride (I-120)

[0397] ##STR00674##

[0398] To a solution of 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)azetidine-1-carboxylate (800 mg, 1.72 mmol) in EA (20 mL) was added HCl (2) in EA solution (10 mL). After stirring at room temperature overnight, the resulting solid was filtered and washed by EA (5 mL) to give N′-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)azetidine-3-sulfonohydrazide hydrochloride (660 mg, 91%) as a white solid.

[0399] LC-MS (Agilent): R.sub.t 2.31 min; m/z calculated for C.sub.17H.sub.19ClFN.sub.3O.sub.3S [M+1−36.5].sup.+ 364.1, found 364.1

[0400] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ (ppm): 10.90 (s, 1H), 10.35 (s, 1H), 9.62 (brs, 1H), 9.39 (brs, 1H), 7.82-7.77 (m, 1H), 7.72-7.66 (m, 2H), 7.66-7.61 (m, 1H), 7.51-7.45 (m, 2H), 7.43-7.36 (m, 1H), 4.54-4.42 (m, 4.35-4.24 (m, 2H), 4.23-4.10 (m, 2H), 2.35 (s, 3H).

Synthesis of tert-Butyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl) sulfonyl)pyrrolidine-1-carboxylate (I-118)

[0401] ##STR00675##

Step 1: (R)-tert-Butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate

[0402] ##STR00676##

[0403] Methanesulfonyl chloride (19.7 g, 172 mmol) was added to a solution of (R)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (25 g, 133 mmol) and triethylamine (20.1 g, 199 mmol) in DCM (500 mL) at ° C. After stirring at room temperature for 6 it, the reaction mixture was washed with 1 M HCl (50 mL) and the aqueous layer was extracted with DCM (100 mL×2). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to give (R)-tert-butyl 3-((methylsulfonyl)oxy)pyrrolidine-1-carboxylate (35 g, 99%) as a yellow oil.

[0404] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 5.28-5.23 (m, 1H), 3.70-3.40 (m, 4H), 3.04 (s, 3H), 2.34-2.07 (m, 2H), 1.46 (s, 9H).

Step 2: (R)-tert-Butyl 3-acetylthio) pyrrolidine-1-carboxylate

[0405] ##STR00677##

[0406] Potassium thioacetate 17.9 g, 157 mmol) was added to a solution of (R)-tert-butyl 3-((methylsulfonyl)oxy) pyrrolidine-1-carboxylate (35 g, 131 mmol) in DMF (500 mL) After heating at 80° C. for 16 h, the reaction mixture was diluted with H.sub.2O (1 L) and extracted with EA (250 mL×3). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography (PE/EA=10:1, v/v) to afford (R)-tert-butyl 3-acetylthio)pyrrolidine-1-carboxylate (4.1 g pure and 9.5 g 90% purity) as a brown oil.

[0407] .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 4.00-3.93 (m, 1H), 3.78-3.73 (m, 1H), 3.42-3.21 (m, 3H), 2.33 (s, 3H), 2.28-2.21 (m, 1H), 1.92-1.82 (m, 1H), 1.45 (s, 9H).

Step 3: tert-Butyl 3-(chlorosulfonyl) pyrrolidine-1-carboxylate

[0408] ##STR00678##

[0409] Chlorine (g) was bubbled through a pre-cooled solution of (S)-tert-butyl 3-(acetylthio)pyrrolidine-1-carboxylate (4.1 g, 16.7 mmol) in THF (150 mL) at −10° C. with stirring for 1 h. The reaction mixture was concentrated to afford tert-butyl 3-(chlorosulfonyl)pyrrolidine-1-carboxylate (4.4 g, 97%) as a yellow oil, which was used for the next step directly.

Step 4: tert-Butyl 3-(hydrazinylsulfonyl) pyrrolidine-1-carboxylate

[0410] ##STR00679##

[0411] 80% Hydrazine hydrate (2.33 g, 37.4 mmol) was added into a solution of tert-butyl 3-(chlorosulfonyl)pyrrolidine-1-carboxylate (4.4 g, 16.3 mmol) in TI-IF (50 mL) at 0° C. After stirring at room temperature for 30 min, the reaction mixture was concentrated. The residue was diluted with DCVI (60 mL) and washed with water (20 mL), brine (20 mL), dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by column chromatography (PE:EA=2:1 to DCM:MeOH=10:1) to give tert-butyl 3-(hydrazinylsulfonyl)pyrrolidine-1-carboxylate (1.80 g, 41%) as a white solid.

[0412] LC-MS (Agilent): R.sub.t 2.20 min; m/z calculated for C.sub.9H.sub.19N.sub.3O.sub.4S [M+H].sup.+ 265.1, found [M+H−56].sup.+ 210.1.

Step 5: tert-Butyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl) sulfonyl)pyrrolidine-1-carboxylate (I-118)

[0413] ##STR00680##

[0414] 4-fluoro-5-methyl-[1,1′-biphenyl]-3-carboxylic acid (1.37 g, 5.99 mmol) was dissolved in Thionyl chloride (14.1 g, 119 mmol). After heating at reflux for 1 h, SOCl.sub.2 was removed under reduced pressure. The residue was dissolved in DCM (20 mL) and added dropwise to a suspension of tert-butyl 3-(hydrazinylsulfonyl)pyrrolidine-1-carboxylate (1.59 g, 5.99 mmol) and sodium carbonate (1.26 g, 11.9 mmol) in DCM (10 mL). After stirring at room temperature for overnight, the reaction mixture was diluted with wafer (50 mL) and extracted with EA (80 mL×2). The combined organic layers were washed with water (60 mL) and brine (50 mL), dried and concentrated. The crude product was washed with (PE:EA=2:1, v/v) to give tert-butyl 3-((2-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)hydrazinyl)sulfonyl)pyrrolidine-1-carboxylate (1.67 g, 58%) as a white solid.

[0415] LC-MS (Agilent): R.sub.t 3.86 min; m/z calculated for C.sub.23H.sub.28FN.sub.3O.sub.5S [M+H].sup.+ 478.1, found [M+1−100].sup.+ 378.1.

[0416] .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ (ppm): 8.71 (dd, J=12.8, 4.4 Hz, 1H), 8.08-8.09 (m, 1H), 7.37-7.64 (m, 7H), 3.43-3.88 (m, 5H), 2.59-2.33 (m, 5H), 1.44 (5, 9H).

Synthesis of N′-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)-1-(2-methoxybenzyl)azetidine-3-sulfonohydrazide (I-22)

[0417] ##STR00681##

Step 1: N′-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)-1-(2-methoxybenzyl) azetidine-3-sulfonohydrazide

[0418] To a solution of N′-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)azetidine-3-sulfonohydrazide hydrochloride (55 mg, 0.137 mmol) in MeOH (5 mL) was added 2-methoxybenzaldehyde (30 mg, 0.2203 mmol). After stirring at room temperature for 1 h, Sodium cyanoborohydride (21.6 mg, 0.344 mmol) was added. After stirring at room temperature overnight, the reaction mixture was quenched with Sat. NaHCO.sub.3 solution (10 mL) and extracted with EA (30 mL×2). The combined organic layers were washed with H.sub.2O (20 mL) and brine, dried and concentrated. The crude product was purified by column chromatography (PE:EA=4:1) to give N′-(4-fluoro-5-methyl-[1,1′-biphenyl]-3-carbonyl)-1-(2-methoxybenzyl)azetidine-3-sulfonohydrazide (20 mg, 29%) as a white solid.

[0419] LC-MS (Agilent): R.sub.t 2.80 min; m/z calculated for C.sub.25H.sub.26FN.sub.3O.sub.4S [M+1].sup.+ 484.2, found 484.2.

[0420] .sup.1H NMR: (400 MHz, DMSO-d.sub.6) δ (ppm): 10.65 (s, 1H), 9.82 (s, 1H), 7.79-7.74 (m, 1H), 7.67 (d, J=7.2 Hz, 2H), 7.60-7.56 (m, 1H), 7.48 (t, J=7.6 Hz, 2H), 7.39 (t, J=7.2 Hz, 1H), 7.21 (t, J=8.0 Hz, 2H), 6.97-6.92 (m, 1H), 6.89 (t, J=7.2 Hz, 1H), 4.17-4.12 (m, 1H), 3.75 (s, 3H), 3.62-3.54 (m, 4H), 3.43 (t, J=7.2 Hz, 2H), 2.33 (s, 3H).

[0421] The following compounds were prepared according to the procedures above:

TABLE-US-00009 MS MS found Detection Mass Ion Compound (calc.) (ESI) Method Specks I-122 370.11 370.43 ESI M − 1 I-117 390.1413 390.47 ESI M + 1 I-123 384.0944 384.43 ES-API M − 1 I-124 356.0943 356.4 ESI M − 1 I-125 384.0944 384.43 +H I-126 384.0944 384.43 ES-API M − 1 I-127 328.0085 328.74 ESI M + 1 I-98 405.1522 405.49 ES-API M + 1 I-128 418.0554 418.87 ESI M − 1 I-129 400.0893 400.42 ES-API M + 1 I-130 328.0085 328.74 ESI M + 1 I-131 384.0944 384.43 +H I-97 391.1366 391.46 ES-API M + 1 I-132 389.0646 389.38 ES-API M + 1 I-133 278.0525 278.3 ESI M + 23 I-134 312.0886 312.27 ESI M + 1 I-61 453.1522 453.53 ES-API M + 1 I-135 308.0631 308.33 ESI M + 1 I-23 377.1209 377.43 ES-API M + 1 I-81 428.1206 428.48 ES-API M + 1-100 I-136 422.0303 422.83 ES-API M − 1 I-116 300.0944 300.35 ESI M + 1 I-137 517.2047 517.62 ES-API M + 1-100 I-138 258.0805 258.25 ESI M + 1 I-105 447.1628 447.53 ES-API M + 1 I-139 384.0944 384.43 ESI M + 1 I-27 497.1785 497.59 ES-API M + 1 I-140 455.1315 455.5 ES-API M − 1 I-92 433.1835 433.54 ES-API M + 1 I-141 405.1522 405.49 ES-API M + 1 I-53 392.0943 392.43 ES-API M + 1 I-14 391.0991 391.45 ES-API M + 1 I-109 477.1734 477.55 ES-API M + 1 I-142 384.0944 384.43 +H I-143 328.0085 328.74 ESI M + 1 I-144 352.0882 352.41 ESI M + 1 I-16 391.0991 391.45 ES-API M − 1 I-20 406.11 406.46 ES-API M + 1 I-145 306.0674 306.34 ESI M + 1 I-146 326.0725 326.37 ESI M + 1 I-147 414.105 414.45 ES-API M − 1 I-148 290.0725 290.34 ESI M + 1 I-15 311.1304 311.4 ES-API M + 1 I-149 310.0179 310.75 ESI M + 1 I-17 405.1147 405.47 ES-API M − 1 I-150 350.1543 350.4 ES-API M + 1 I-101 449.1785 449.54 ES-API M + 1 I-151 362.11 362.42 ES-API M + 1 I-152 404.0398 404.84 ES-API M − 1 I-153 328.0085 328.74 ES-API M − 1 I-154 388.0693 388.39 ES-API M − 1 I-155 402.085 402.42 ES-API M − 1 I-156 422.0303 422.83 ES-API M − 1 I-157 384.0944 384.43 +H I-158 315.0678 315.35 ESI M − 1 I-159 276.0569 276.31 ESI M + 1 I-160 328.0085 328.74 ES-API M − 1 I-161 422.0303 422.83 ES-API M − 1 I-162 401.0846 401.41 ES-API M + 1 I-42 407.1315 407.46 ES-API M + 1 I-12 288.0681 288.33 ES-API M + 1 I-163 294.0474 294.3 ESI M + 1 I-164 438.085 438.45 ES-API M − 1 I-13 302.0837 302.35 ES-API M + 1 I-165 294.0474 294.3 ESI M + 1 I-166 312.038 312.29 ES-API M − 1 I-167 378.0598 378.35 ES-API M + 1 I-80 428.1206 428.48 ES-API M + 1 I-102 433.1472 433.5 ES-API M + 1 I-37 487.1133 487.97 ES-API M + 1 I-168 369.0835 369.41 ES-API M + 1 I-38 483.1628 483.56 ES-API M + 1 I-169 244.1012 244.27 ESI M + 1 I-91 419.1679 419.52 ES-API M + 1 I-170 412.0208 412.8 ES-API M + 1 I-94 433.1472 433.5 ES-API M + 1 I-171 348.1274 348.38 ESI M + 1 I-172 392.0755 392.38 ES-API M + 1 I-173 309.1277 309.34 ES-API M + 1 I-174 324.058 324.33 ESI M + 1 I-175 385.0896 385.41 ES-API M − 1 I-176 414.105 414.45 ES-API M + 1 I-177 324.058 324.33 ESI M + 1 I-178 349.1478 349.4 ES-API M + 1 I-10 387.0741 387.4 ES-API M + 1 I-179 324.058 324.33 ESI M + 1 I-180 326.0725 326.37 ES-API M + 1 I-181 310.0179 310.75 ESI M + 1 I-36 481.1835 481.59 ES-API M + 1 I-39 322.0787 322.35 ES-API M + 1 I-55 364.0893 364.39 ES-API M + 1 I-182 306.0674 306.34 ESI M + 1 I-183 308.0631 308.33 ES-API M + 1 I-184 417.1522 417.5 ES-API M + 1 I-185 300.0569 300.33 ESI M − 1 I-186 414.105 414.45 ESI M + 1 I-187 418.0554 418.87 ES-API M − 1 I-188 398.11 398.45 ES-API M − 1 I-189 278.0474 278.29 ESI M + 1 I-190 310.0179 310.75 ESI M − 1 I-191 294.0474 294.3 ESI M − 1 I-192 306.0674 306.34 ESI M − 1 I-193 294.0474 294.3 ESI M + 1 I-194 277.0521 277.3 ESI M + 1 I-195 385.0896 385.41 ES-API M + 1 I-196 316.063 316.34 ESI M + 1 I-197 342.0787 342.37 ESI M + 1 I-110 447.1628 447.53 ES-API M − 1 I-114 433.1472 433.5 ES-API M + 1 I-113 419.1315 419.47 ES-API M + 1 I-62 467.1679 467.56 ES-API M + 1 I-198 379.9601 381.17 ES-API M − 1 I-199 409.1148 409.48 ES-API M + 1 I-200 380.1195 380.46 ES-API M − 1 I-40 405.1159 405.44 ES-API M + 1 I-65 317.0634 317.34 ES-API M + 1 I-99 419.1679 419.52 ES-API M + 1 I-201 424.1257 424.49 ES-API M + 1 I-100 433.1835 433.54 ES-API M + 1 I-106 463.1577 463.52 ES-API M + 1 I-202 385.0896 385.41 ES-API M + 1 I-203 323.0507 323.77 ES-API M + 1 I-204 385.0896 385.41 ES-API M + 1 I-90 405.1522 405.49 ES-API M + 1 I-205 384.0944 384.43 ES-API M − 1 I-107 447.1628 447.53 ES-API M + 1 I-104 433.1472 433.5 ES-API M − 1 I-206 491.189 491.58 ES-API M + 1-100 I-207 477.1734 477.55 ES-API M + 1-100 I-208 435.1628 435.51 ES-API M + 1 I-103 345.1159 345.39 ES-API M + 1 I-47 378.115 378.45 ES-API M + 1 I-67 393.0947 393.44 ES-API M + 1 I-21 364.1257 364.44 ES-API M + 1 I-209 385.0896 385.41 ES-API M + 1 I-108 461.1785 461.55 ES-API M + 1 I-210 490.1363 490.55 ES-API M − 1 I-211 400.0893 400.42 ES-API M − 1 I-88 491.189 491.58 ES-API M + 1-100 I-212 388.0693 388.39 ES-API M + 1 I-89 391.1366 391.46 ES-API M + 1 I-119 463.1577 463.52 ES-API M + 1-100 I-111 461.1785 461.55 ES-API M + 1 I-63 487.1133 487.97 ES-API M + 1 I-213 295.1121 295.32 ES-API M + 1 I-115 449.1421 449.5 ES-API M + 1 I-214 402.085 402.42 ES-API M − 1 I-82 416.1006 416.44 ES-API M − 1 I-215 398.11 398.45 ES-API M + 1 I-216 398.11 398.45 ES-API M + 1 I-217 418.0554 418.87 ES-API M + 1 I-31 391.1366 391.46 ES-API M + 1 I-32 481.1472 481.54 ES-API M − 1 I-218 426.1413 426.51 ES-API M + 1 I-30 501.1289 502 ES-API M + 1 I-219 441.1159 441.48 ES-API M − 1 I-29 501.1289 502 ES-API M + 1 I-43 421.1472 421.49 ES-API M + 1 I-220 404.0398 404.84 ES-API M − 1 I-221 412.1257 412.48 ES-API M − 1 I-222 498.1173 498.5 ES-API M + 1 I-73 423.1304 423.5 ES-API M + 1 I-223 402.085 402.42 ES-API M + 1 I-224 505.2047 505.61 ES-API M + 1-100 I-83 416.1006 416.44 ES-API M + 1 I-225 418.0554 418.87 ESI M − 1 I-226 384.0944 384.43 +H I-227 404.157 404.5 ES-API M − 1 I-228 336.0944 336.38 ES-API M − 1 I-84 416.1006 416.44 ES-API M + 1 I-229 384.0944 384.43 +H I-230 356.0943 356.4 ESI M + 1 I-231 350.11 350.41 ES-API M − 1 I-232 414.105 414.45 ES-API M + 1 I-233 388.0693 388.39 ESI M − 1 I-234 370.0787 370.4 +H I-235 400.0893 400.42 ES-API M − 1 I-236 344.0631 344.36 ES-API M + 1 I-26 497.1785 497.59 ES-API M + 1 I-237 414.105 414.45 ESI M + 1 I-238 344.0631 344.36 ESI M + 1 I-239 427.1002 427.45 ES-API M − 1 I-240 434.11 434.49 ESI M + 1 I-241 418.0554 418.87 ESI M − 1 I-242 398.11 398.45 ES-API M + 1 I-243 362.11 362.42 ES-API M − 1 I-244 441.1159 441.48 ES-API M − 1 I-245 280.0682 280.32 ESI M + 1 I-246 402.1038 402.47 ESI M − 1 I-247 512.1518 512.58 ES-API M + 1 I-248 512.1518 512.58 ES-API M + 1 I-249 376.1257 376.45 ES-API M − 1 I-112 477.1734 477.55 ES-API M + 1 I-28 487.1133 487.97 ES-API M + 1 I-250 388.0693 388.39 ES-API M − 1 I-251 384.0944 384.43 ESI M + 1 I-252 295.0427 295.29 ESI M + 1 I-253 370.0787 370.4 ESI M + 1 I-254 283.0991 283.35 ES-API M + 1 I-255 455.1315 455.5 ES-API M − 1 I-256 428.0842 428.43 ES-API M − 1 I-93 449.1785 449.54 ES-API M + 1 I-257 350.1794 350.44 ES-API M + 1 I-258 404.157 404.5 ES-API M − 1 I-24 501.1289 502 ES-API M + 1 I-25 497.1785 497.59 ES-API M + 1 I-259 392.0755 392.38 ES-API M + 1 I-33 467.1679 467.56 ES-API M + 1 I-260 346.1351 346.45 ES-API M + 1 I-261 414.105 414.45 ES-API M − 1 I-262 344.0631 344.36 ES-API M + 1 I-263 418.0554 418.87 ES-API M + 1 I-264 378.0598 378.35 ES-API M + 1 I-35 483.1628 483.56 ES-API M + 1

Biochemical Assays.

[0422] KAT5. Enzyme assay buffer was 50 mM Tris pH 8.0, 0.002% Tween20, 0.005% bovine skin gelatin, and 1 mM dithiothreitol (DTT). For determination of IC.sub.50 values, compounds were serially diluted with 2% (v/v) DMSO in the final reaction, pre-incubating each dilution of each compound with 40 μL of assay buffer containing KAT5 enzyme (9 nM final concentration). 10 μL of assay buffer containing 1 μM peptide substrate and 0.5 μM acetyl coenzyme A (final concentrations) was added. Reactions (50 μL total) were then carried out at 25° C. for 90 minutes. Reactions were terminated by the addition of 0.5% formic acid (final concentration), and a sample of each reaction was analyzed by SAMDI Tech, Inc. (Chicago, Ill.) using self-assembled monolayer desorption/ionization time-of-flight mass spectrometry (Mrksich, M. (2008) Mass spectrometry of self-assembled monolayers: a new tool for molecular surface science, ACS Nano 2, 7-18).

[0423] KAT6A. Enzyme assay buffer was 50 mM Tris pH 8.0, 0.002% Tween20, 0.005% bovine skin gelatin, and 1 mM dithiothreitol (DTT). For determination of IC.sub.50 values, compounds were serially diluted with 2% (v/v) DMSO in the final reaction, pre-incubating each dilution of each compound with 40 μL of assay buffer containing KAT6A enzyme (12.5 nM final concentration). 10 μL of assay buffer containing 1 μM peptide substrate and 1 μM acetyl coenzyme. A (final concentrations) was added. Reactions (50 μL total) were then carried out at 25° C. for 90 minutes. Reactions were terminated by the addition of 0.5% formic acid (final concentration), and a sample of each reaction was analyzed by SAMDI Tech, Inc. (Chicago, Ill.) using self-assembled monolayer desorption/ionization time-of-flight mass spectrometry (Mrksich, M, (2008) Mass spectrometry of self-assembled monolayers: a, new tool for molecular surface science. ACS Nano 2, 7-18).

TABLE-US-00010 Assay Assay Assay [Acetyl Reaction Construct/ [Enz] [Peptide] CoA] Time Enzyme amino acids (nM) Peptide substrate (μM) (μM) (min) KAT5 Full length 9 H4 1-20 K5R K8R 1 0.5 90 K16R SGRGRGGRGLGKG GARRHRK(Biotin)- NH.sub.2 (SEQ ID NO: 9) KAT6A 501-784 12.5 H4 1-26 K20Me1 1 1 90 SGRGKGGKGLGKG GAKRHRK(Me1)VLR GGK(Biotin)-NH.sub.2 (SEQ ID NO: 10)

Enzyme Constructs

[0424]

TABLE-US-00011 KAT5FL: Original protein before affinity tag cleavage: (SEQ ID NO: 5) MHHHKHHSSGVDLGTENLYFQSNAMAEVGEIIEGCRLPVLRRNQDNEDEW PLAEILSVKDISGRKLFYVHYIDFNKRLDEWVTHERLDLKKIQFPKKEAK TPTKNGLPGSRPGSPEREVPASAQASGKTLPIPVQITLRFNLPKEREAIP GGEPDQPLSSSSCLQPNHRSTKRKVEVVSPATPVPSETAPASVFPQNGAA RRAVAAQPGRKRKSNCLGTDEDSQDSSDGIPSAPRMTGSLVSDRSHDDIV TRMKNIECIELGRHRLKPWYFSPYPQELTTLPVLYLCEFCLKYGRSLKCL QRHLTKCDLRHPFGNEIYRKGTISFFEIDGRKNKSYSQNLCLLAKCFLDH KTLYYDTDPFLFYVMT3YDCKGFHIVGYFSKEKESTEDYNVACILTLPPY QRRGYGKLLIEFSYELSKVEGKTGTPEKPLSDLGLLSYRSYWSQTILEIL MGLKSESGERPQITINEISEITSIKKEDVISTLQVLNLINYYKGQYILTL SEDIVDGHERAMLKRLLRIDSKCLHFTPKDHSKRGKWDYKDDDDK Final protein after affinity tag cleavage: (SEQ ID NO: 6) SNAMAEVGEIIEGCRLPVLRRNQDNEDEWPLAEILSVKDISGRKLFYVHY IDFNKRLDEWVTHERLDLKKIQFPKKEAKTPTKNGLPGSRPGSPEREVPA SAQASGKTLPIPVQITLRFNLPKEREAIPGGEPDQPLSSSSCLQPNHRST KRKVEVVSPATPVPSETAPASVFPQNGAARRAVAAQPGRKRKSNCLGTDE DSQDSSDGIPSAPRMTGSLVSDRSHDDIVTSMKNIECISLGRHRLKPWYF SPYPQELTTLPVLYLCEFCLKYGRSLKCLQRHLTKCDLRHPPGNSIYRKG TISFFEIDGRKNXSYSQNLCLLAKCFLDHXTLYYDTDPFLFYVMTEYDCK GFHIVGYFSKEKESTEDYNVACILTLPPYQRRGYGKLLIEFSYELSKVEG KTGTPEKPLSDLGLLSYRSYWSQTILEILMGLKSESGERPQITINEISEI TSIKKEDVISTLQYLNLINYYKGQYILTLSEDIVDGHERAMLKKLLRIDS KCLHFTPKDWSKRGKWDYKDDDDK KAT6A 501-784 Original protein before affinity tag cleavage: (SEQ ID NO: 7) MHHHHHHSSGVDLGTENLYFQSNAPPPPQVRCPSVIEFGKYEIHTWYSSP YPQEYSRLPKLYLCEFCLKYMKSRTILQQHMKKCGWFHPPANEIYRKNNI SVFEVDGNVSTIYCQNLCLLAKLFLDHKTLYYDVEPFLFYVLTQNDVKGC HLVGYFSKEKHCQQKYNVSCIMILPQYQRKGYGRFLIDFSYLLSKREGQA GSPEKPLSDLGRLSYMAYWKSVILECLYHQNDKQISIKKLSKLTGICPQD ITSTLHHLRMLDFRSDQFVIIRREKLIQDHMAKLQLNLRPVDVDPECLRW TPVIVSNS Final protein after affinity tag cleavage. (SEQ ID NO: 8) SNAPPDPQVRCPSVIEFGKYEIHTWYSSPYPQEYSRLPKLYLCEFCLKYM KSRTILQQHMKKCGWFHPPANEIYRKNNISVFEVDGNVSTIYCQNLCLLA KLFLDHKTLYYDVEPFLFYVLTQNDVKGCHLVGYFSKEKHCQQKYNVSCI MILPQYQRKGYGRFLIDFSYLLSKREGQAGSPEKPLSDLGRLSYMAYWKS VILECLYHQNDKQISIKKLSKLTGICPQDITSTLHHLRMLDFRSDQFVII RREKLIQDHMAKLQLNLRPVDVDEKCLRWTPVIVSNS underlined residues: His-TEV tag italicized residues: Flag tag

[0425] underlined residues: His-TEV tag

[0426] italicized residues: Flag tag

[0427] Table 6 shows the activity of selected compounds of this invention in the KAT5 and/or KAT6A inhibition assays. The compound numbers correspond to the compound numbers above. Compounds having an activity designated as “A” provided an IC.sub.50≤10 μM; compounds having an activity designated as “B” provided an IC.sub.50 10.01-50 μM; compounds having an activity designated as “C” provided an IC.sub.50 of 50.01-100 μM: and compounds having an activity designated as “D” provided an IC.sub.50 of >100 μM.

TABLE-US-00012 TABLE 6 IC.sub.50 His-TEV-FL IC.sub.50 His-TEV- # KAT5-Flag (μM) KAT6A 501-784 (μM) I-1 C B I-2 B B I-3 B C I-4 C C I-5 A A I-6 A A I-7 B B I-8 A A I-9 A A I-10 D D I-12 D D I-13 D D I-14 B B I-15 D D I-16 D C I-17 C D I-18 A A I-19 A B I-20 D D I-21 D D I-22 B B I-23 B B I-24 B B I-25 B B I-26 A A I-27 B B I-28 D D I-29 A A I-30 B B I-31 C B I-32 B A I-33 B B I-34 B B I-35 B B I-36 B B I-37 B B I-38 B B I-39 B D I-40 C B I-42 C B I-43 C B I-44 D D I-45 D D I-46 D D I-47 D D I-48 D D I-49 D D I-50 C D I-53 B B I-55 B B I-61 D B I-62 D B I-63 D D I-65 D D I-67 D D I-73 D D I-75 C B I-79 A A I-80 A A I-81 C B I-82 A A I-83 A A I-84 A A I-88 A A I-89 D D I-90 B B I-91 B C I-92 D D I-93 B B I-94 B B I-97 D C I-98 D B I-99 D B I-100 D C I-101 B B I-102 B B I-103 D D I-104 C B I-105 B B I-106 B B I-107 B B I-108 A B I-109 B B I-110 C A I-111 B A I-112 B B I-113 C B I-114 D B I-115 C B I-116 D D I-117 D C I-118 B A I-119 B B I-120 D D I-121 B B I-122 D D I-123 D D I-124 D D I-125 B A I-126 C A I-127 D B I-128 C B I-129 B A I-130 D D I-131 D A I-132 C A I-133 D D I-134 D D I-135 D D I-136 A A I-137 B B I-138 D D I-139 D D I-140 B A I-141 C D I-142 B A I-143 D B I-144 D A I-145 D D I-146 D B I-147 B A I-148 D D I-149 D D I-150 D D I-151 D D I-152 B A I-153 B A I-154 B A I-155 B A I-156 B A I-157 A A I-158 D D I-159 D C I-160 B A I-161 B A I-162 D A I-163 D B I-164 A A I-165 D B I-166 D B I-167 C B I-168 C C I-169 D D I-170 D C I-171 D D I-172 D B I-173 D D I-174 D D I-175 A A I-176 A A I-177 D B I-178 D D I-179 D — I-180 D D I-181 D — I-182 D — I-183 B A I-184 D D I-185 D D I-186 C B I-187 A A I-188 A A I-189 D D I-190 C B I-191 D C I-192 D D I-193 D C I-194 D D I-195 B A I-196 D C I-197 D D I-198 C A I-199 D D I-200 D D I-201 D — I-202 D B I-203 D D I-204 A A I-205 D C I-206 A A I-207 A A I-208 B B I-209 A A I-210 A A I-211 A A I-212 D C I-213 D D I-214 A A I-215 D B I-216 A A I-217 A A I-218 D — I-219 A A I-220 A A I-221 B A I-222 C A I-223 A A I-224 A A I-225 C B I-226 D A I-227 A A I-228 D D I-229 B B I-230 D D I-231 D D I-232 A A I-233 B A I-234 D A I-235 A A I-236 D D I-237 D C I-238 C B I-239 A A I-240 B B I-241 C B I-242 D B I-243 D D I-244 B A I-245 D D I-246 C A I-247 C B I-248 C B I-249 D D I-250 A A I-251 C A I-252 D C I-253 C B I-254 D D I-255 A A I-256 C A I-257 D D I-258 C C I-259 B A I-260 D D I-261 A A I-262 C A I-263 A A I-264 D C I-265 D D I-266 D D I-267 A A I-268 B B I-269 A B I-270 A B I-271 A A I-272 B C I-273 D C I-274 A A I-275 D D I-276 A B I-277 B B I-278 C D I-279 B A I-280 A A I-281 A A I-282 C B I-283 D D I-284 D D I-285 A A I-286 C A I-287 D D I-288 B B I-289 A A I-290 D D I-291 A A I-292 A A I-293 A C I-294 A A I-295 D D I-296 D D I-297 B A I-298 A B I-299 B C I-300 B C I-301 B C I-302 C C I-303 B A I-304 C A I-305 D B I-306 A A I-307 B A I-308 C D I-309 D D I-310 B A I-311 D D I-312 D D I-313 A B I-314 D D I-315 B B I-316 D D I-317 A B I-318 C C I-319 B c I-320 B B I-321 A B I-322 A A I-323 A A I-324 D D I-325 A B I-326 A A I-327 A A I-328 B B I-329 B B I-330 A A I-331 A A I-332 D D I-333 B B I-334 B B I-335 A A I-336 B B I-337 B B I-338 D D I-339 B B I-340 A A I-341 A A I-342 C C I-343 B B I-344 A A I-345 D D I-346 A A I-347 B D I-348 B B I-349 B B I-350 D A I-351 B D I-352 A A I-353 A A I-354 D D I-355 B B I-356 A A I-357 C D I-358 A B I-359 A A I-360 B B I-361 C D I-362 A A I-363 D D I-364 C C I-365 C D I-366 B C I-367 — — I-368 C C I-369 A A I-370 B D I-371 A A I-372 A A I-373 C C I-374 B B I-375 C C I-376 B B I-377 A A I-378 C D I-379 A A I-380 D C I-381 A B I-382 C C I-383 A A I-384 D A I-385 A A I-386 D B I-387 D D I-388 A A I-389 B B I-390 A A I-391 A D I-392 A B I-393 A D I-394 A B I-395 A A I-396 A A I-397 A A I-398 C B I-399 C C I-400 A A I-401 A A I-402 D D I-403 D D I-404 B B I-405 B D I-406 D D I-407 D D I-408 A B I-409 B B I-410 B B I-411 A B I-412 B D I-413 B D I-414 D D I-415 B A I-416 C C I-417 A A I-418 A A I-419 A A I-420 B D I-421 A B I-422 D D I-423 B D I-424 A A I-425 A A I-426 B A I-427 A A I-428 B A I-429 A A I-430 C D I-431 B C I-432 B B I-433 A B I-434 D D I-435 D D I-436 C D I-437 A A I-438 B B I-439 D D I-440 D D I-441 D D I-442 D D I-443 A A I-444 A A I-445 B D I-446 B C I-447 A B I-448 D D I-449 C C I-450 A A I-451 A B I-452 A A I-453 D D I-454 C B I-455 B D I-456 D D I-457 A A I-458 D D I-459 D A I-460 A B I-461 D D I-462 D D I-463 A D I-464 D D I-465 D C I-466 B B I-467 D D I-468 D D I-469 D D I-470 C D I-471 D D I-472 D D I-473 D D I-474 D D I-475 D D I-476 D D I-477 D D I-478 D D I-479 D C I-480 D D I-481 D D I-482 B B I-483 C D I-484 B B I-485 A B I-486 B B I-487 B B I-488 D D I-489 D D I-490 C B I-491 D D I-492 D D I-493 D D I-494 B A I-495 B B I-496 D D I-497 C B I-498 B B I-499 D D I-500 D D I-501 D D I-502 D D I-503 D D I-504 D D I-505 D D I-506 A — I-507 A A I-508 — — I-509 — — I-510 A D I-511 A D I-512 A D I-513 A D I-514 D D I-515 A D I-516 A D I-517 D D I-518 D D I-519 A A I-520 D D I-521 D D I-522 D D I-523 B B I-524 C B I-525 D —

EQUIVALENTS AND SCOPE

[0428] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents of the embodiments described herein. The scope of the present disclosure is not intended to be limited to the above description, but rather is as set forth in the appended claims.

[0429] Articles such as “a,” “an,” and “the” may mean one or more than one to indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between two or more members of a group are considered satisfied if one, more than one, or all of the group members are present, unless indicated to the contrary or otherwise evident from the context. The disclosure of a group that includes “or” between two or more group members provides embodiments in which exactly one member of the group is present, embodiments in which more than one members of the group are present, and embodiments in which all of the group members are present. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed.

[0430] It is to be understood that the invention encompasses all variations, combinations, and permutations in which one or more limitation, element, clause, or descriptive term, from one or more of the claims or from one or more relevant portion of the description, is introduced into another claim. For example, a claim that is dependent on another claim can be modified to include one or more of the limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a composition, it is to be understood that methods of making or using the composition according to any of the methods of making or using disclosed herein or according to methods known in the art, if any, are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.

[0431] Where elements are presented as lists, e.g., in Markush group format, it is to be understood that every possible subgroup of the elements is also disclosed, and that any element or subgroup of elements can be removed from the group. It is also noted that the term “comprising” is intended to be open and permits the inclusion of additional elements or steps. It should be understood that, in general, where an embodiment, product, or method is referred to as comprising particular elements, features, or steps, embodiments, products, or methods that consist, or consist essentially of, such elements, features, or steps, are provided as well. For purposes of brevity those embodiments have not been individually spelled out herein, but it will be understood that each of these embodiments is provided herein and may be specifically claimed or disclaimed.

[0432] Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value within the stated ranges in some embodiments, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. For purposes of brevity, the values in each range have not been individually spelled out herein, but it will be understood that each of these values is provided herein and may be specifically claimed or disclaimed. It is also to be understood that unless otherwise indicated or otherwise evident from the context and/or the understanding of one of ordinary skill in the art, values expressed as ranges can assume any subrange within the given range, wherein the endpoints of the subrange are expressed to the same degree of accuracy as the tenth of the unit of the lower limit of the range.

[0433] In addition, it is to be understood that any particular embodiment of the present invention may be explicitly excluded from any one or more of the claims. Where ranges are given, any value within the range may explicitly be excluded from any one or more of the claims. Any embodiment, element, feature, application, or aspect of the compositions and/or methods of the invention, can be excluded from any one or more claims. For purposes of brevity, all of the embodiments in which one or more elements, features, purposes, or aspects is excluded are not set forth explicitly herein.

[0434] All publications, patents, patent applications, publication, and database entries (e.g., sequence database entries) mentioned herein, e.g., in the Background, Summary, Detailed Description, Examples, and/or References sections, are hereby incorporated by reference in their entirety as if each individual publication, patent, patent application, publication, and database entry was specifically and individually incorporated herein by reference. In case of conflict, the present application, including any definitions herein, will control.