WO2023102162A1 - Tgonovel hdac inhibitors and therapeutic use thereof - Google Patents

Tgonovel hdac inhibitors and therapeutic use thereof Download PDF

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Publication number
WO2023102162A1
WO2023102162A1 PCT/US2022/051616 US2022051616W WO2023102162A1 WO 2023102162 A1 WO2023102162 A1 WO 2023102162A1 US 2022051616 W US2022051616 W US 2022051616W WO 2023102162 A1 WO2023102162 A1 WO 2023102162A1
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Prior art keywords
compound
pharmaceutically acceptable
alkyl
acceptable salt
cancer
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PCT/US2022/051616
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English (en)
French (fr)
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WO2023102162A8 (en
Inventor
John P. Maxwell
Xinyuan Wu
David Guerin
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Tango Therapeutics Inc
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Tango Therapeutics Inc
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Priority to KR1020247022111A priority Critical patent/KR20240152822A/ko
Priority to CN202280087838.1A priority patent/CN118715206A/zh
Priority to MX2024006684A priority patent/MX2024006684A/es
Priority to CA3240229A priority patent/CA3240229A1/en
Priority to JP2024532769A priority patent/JP2024543207A/ja
Priority to EP22846975.5A priority patent/EP4441033A1/en
Priority to AU2022402913A priority patent/AU2022402913A1/en
Priority to IL313081A priority patent/IL313081A/en
Publication of WO2023102162A1 publication Critical patent/WO2023102162A1/en
Publication of WO2023102162A8 publication Critical patent/WO2023102162A8/en
Anticipated expiration legal-status Critical
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    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
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    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • Histone deacetylases are a class of epigenetic proteins implicated in a variety of diseases, including cancers, and inhibition of specific HDACs in certain patients may treat or otherwise ameliorate such diseases.
  • HDAC Histone deacetylases
  • Some HDAC inhibitors have been approved by the United States Food and Drug Administration (FDA), but currently approved HDAC therapies are not known to be specific to only a few HDAC isoforms, increasing the potential for adverse effects due to broad inhibitory properties.
  • FDA United States Food and Drug Administration
  • a compound of Formula (I) e salt thereof wherein A is an optionally substituted aryl or heteroaryl; L 1 is -CR’2-, -CR’2CR’2-, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring; each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, each optionally substituted; R 5 is NH 2 or OH; R 6 is H or C 1 -C 6 alkyl; R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(CH 2
  • provided is a composition comprising a compound as described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • a method of treating a disease or disorder that can be treated by inhibition of HDAC comprising administering to a patient in need thereof a compound described herein or a composition described herein.
  • HDAC histone deacetylase
  • provided is a use of a compound disclosed herein in the manufacture of a medicament for the treatment of cancer.
  • HDAC histone deacetylase
  • a compound of Formula (I) or “compounds of Formula (I)” refers to all embodiments of Formula (I), including, for example, compounds of Formulas (Ia), (Ib), (Ic), (Id), (Ie), and (If), as well as the compounds of Table 1.
  • provided are compounds of Formula (I) or pharmaceutically acceptable salts thereof.
  • the compounds of Formula (I) are provided as pharmaceutically acceptable salts.
  • the compounds of Formula (I) are provided as the corresponding free base (i.e., are not salts).
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A is an optionally substituted aryl or heteroaryl; L 1 is -CR’2-, -CR’2CR’2-, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring; each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, each optionally substituted; R 5 is NH 2 or OH; R 6 is H or C 1 -C 6 alkyl; R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(CH 2 ) 0-2 -phenyl, -(CH 2 ) 0-2
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A is an aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups;
  • L 1 is -CR’ 2 -, -CR’ 2 CR’ 2 -, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring;
  • each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen;
  • R 2 is aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and R 2
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein A is an aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups;
  • L 1 is -CR’ 2 -, -CR’ 2 CR’ 2 -, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring;
  • each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen;
  • R 2 is aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and R 2 is substitute
  • A is an optionally substituted aryl or heteroaryl.
  • A is an aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups, wherein R 9 is as defined herein.
  • A is phenyl or heteroaryl, wherein heteroaryl has 5, 6 or 9 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups.
  • A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, benzthiophene, thienopyridine (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-b]pyridine) or furopyridine (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3- b]pyridine), each substituted with 0-9 R 9 groups.
  • thienopyridine e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-b]pyridine
  • furopyridine e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3- b]pyridine
  • A is phenyl, benzofuran, or benzthiophene, each substituted with 0-9 R 9 groups. [0019] In some embodiments, A is phenyl substituted with 0-9 R 9 groups. [0020] In some embodiments, A is benzofuran substituted with 0-9 R 9 groups. [0021] In some embodiments, A is benzthiophene substituted with 0-9 R 9 groups. [0022] In some embodiments, A is thiazole substituted with 0-9 R 9 groups. In some embodiments, A is thiophene substituted with 0-9 R 9 groups. In some embodiments, A is pyridine substituted with 0-9 R 9 groups.
  • A is pyridazine substituted with 0-9 R 9 groups.
  • A is thienopyridine (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3-b]pyridine) substituted with 0-9 R 9 groups.
  • A is furopyridine (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3- b]pyridine) substituted with 0-9 R 9 groups.
  • A is selected from: , each substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0024] In some embodiments, A is selected from: each substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, or benzthiophene; e.g., wherein A is or ; and A is substituted with 0-4 R 9 groups.
  • a i ubstituted with 0-9 R 9 groups wherein the left attachment point represents the attachment poin 1 t to L and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point 1 represents the attachment point to L and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0031] In some embodiments, A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0032] In some embodiments, A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0034] In some embodiments, A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0035] In some embodiments, A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is N substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is N substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0040] In some embodiments, A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl. [0041] In some embodiments, A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • A is not substituted with any R 9 groups.
  • L 1 is -CR’2-, -CR’2CR’2-, or a bond, wherein R’ is as defined herein.
  • L 1 is a bond.
  • L 1 is –CR’ 2 –.
  • L 1 is –CR’ 2 CR’ 2 –.
  • L 1 is selected from a bond, –CH 2 – and .
  • L 1 is selected from a bond and –CH 2 – .
  • L 1 is selected from a bond and .
  • L 1 is –CH 2 –.
  • L 1 is .
  • each R 1 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen.
  • R 1 is H.
  • R 1 is selected from H, –Me, –CF 3 , –Cl and –F.
  • each R 3 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen.
  • R 3 is H.
  • R 3 is selected from H, –Me, –CF 3 , –Cl and –F.
  • each R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen. In some embodiments of a compound of Formula (I), R 4 is H. In some embodiments, R 4 is selected from H, –Me, –CF 3 , –Cl and –F. [0051] In some embodiments of a compound of Formula (I), R 1 is H, or R 3 is H, or R 4 is H, or each of R 1 , R 3 and R 4 is H. [0052] As generally defined herein, R 5 is –NH 2 or –OH. In some embodiments of a compound of Formula (I), R 5 is –NH 2 .
  • R 5 is –OH.
  • R 6 is H or C 1 -C 6 alkyl. In some embodiments of a compound of Formula (I), R 6 is H. In some embodiments, R 6 is selected from H and –Me. In some embodiments, R 6 is Me.
  • each R 2 is independently aryl or heteroaryl, wherein the aryl and heteroaryl are optionally substituted.
  • R 2 is aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and R 2 is substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is phenyl or monocyclic heteroaryl, wherein heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms selected from N, O, and S, and R 2 is substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is phenyl substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is monocyclic heteroaryl, wherein heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms selected from N, O, and S, and R 2 is substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is monocyclic heteroaryl, wherein heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, or thiophene, (e.g., wherein R 2 is 2-thiophenyl), each R 2 substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is selected from phenyl, pyridine, pyrimidine, pyridazine, pyrazine, thiazole and thiophene, each substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups).
  • R 2 is selected from phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, 4-pyridine, 3-pyridazine, pyrazine, 2-thiazole, 5-thiazole, 2-thiophene and 3- thiophene, each substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is selected from phenyl, 2-pyridine, 3-pyridine, 4-pyridine, 2-pyrimidine, 4-pyridine, 3-pyridazine, 5-thiazole, 2-thiophene and 3-thiophene, each substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is selected from phenyl and thiophene, each substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is selected from phenyl and 2-thiophene, each substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is thiophene substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is 2-thiophene substituted with 0-4 R 10 groups (e.g., 0, 1, 2, 3 or 4 R 10 groups), wherein R 10 is as defined herein.
  • R 2 is unsubstituted.
  • R 2 is substituted with 1 R 10 , wherein R 10 is as defined herein. In some embodiments, R 2 is substituted with 2 R 10 , wherein R 10 is as defined herein. In some embodiments, R 2 is substituted with 3 R 10 , wherein R 10 is as defined herein. In some embodiments, R 2 is substituted with 4 R 10 , wherein R 10 is as defined herein. [0063] In some embodiments of a compound of Formula (I), R 2 is selected from the group consisting of e.g., wherein R 2 i [0064] In some embodiments, R 2 is selected from the group consisting of:
  • R 2 is selected from the group consisting of: [0066] In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is
  • R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is . In some embodiments, R 2 is .
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(CH 2 ) 0-2 -phenyl, - (CH 2 ) 0-2 -C 3 -C 7 cycloalkyl, -(CH 2 ) 0-2 -heteroaryl or -(CH 2 ) 0-2 -heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl is optionally substituted or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N, and wherein the heterocycle is optionally substituted.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(CH 2 )0-2-phenyl, - (CH 2 )0-2-C 3 -C 7 cycloalkyl, -(CH 2 )0-2-heteroaryl or -(CH 2 )0-2-heterocyclyl, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl is optionally substituted.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(CH 2 )0-2-phenyl, - (CH 2 )0-2-C 3 -C 7 cycloalkyl, -(CH 2 )0-2-heteroaryl or -(CH 2 )0-2-heterocyclyl; wherein heteroaryl has 5-10 ring atoms with 1 to 4 ring atoms selected from N, O, and S, and wherein heterocyclyl has 4-11 ring atoms with 1 to 4 ring atoms selected from N, O, and S; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups) or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, -(CH 2 ) 0-2 -phenyl, - (CH 2 )0-2-C 3 -C 7 cycloalkyl, -(CH 2 )0-2-heteroaryl or -(CH 2 )0-2-heterocyclyl; wherein heteroaryl has 5-10 ring atoms with 1 to 4 ring atoms selected from N, O, and S, and wherein heterocyclyl has 4-11 ring atoms with 1 to 4 ring atoms selected from N O and S; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, heteroaryl or heterocyclyl is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups), wherein R 11 is as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms selected from N, O, and S; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl and heteroaryl is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups); or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is substituted with 0-4 R 10 groups, wherein R 10 and R 11 are as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms selected from N, O, and S; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl and heteroaryl is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups); wherein R 11 is as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms being N; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl and heteroaryl is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups); or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0-4 R 10 groups, wherein R 10 and R 11 are as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms being N; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl and heteroaryl is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups), wherein R 11 is as defined herein.
  • R 7 is selected from –Me, –Et, ––CF 3 , CH 2 CH 2 OMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyridinon-yl; each of which is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups); or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5 or 6 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with or 1 instances of methyl or phenyl, wherein R 10 and R 11 are as defined herein.
  • R 7 is selected from –Me, –Et, ––CF 3 , CH 2 CH 2 OMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyridinon-yl; each of which is substituted with 0-4 R11 groups (i.e., 0, 1, 2, 3 or 4 R11 groups); wherein R11 is as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or 6-membered heteroaryl wherein heteroaryl has 1 or 2 nitrogen ring atoms; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N; and R 7 is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups), wherein R 11 is as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or 6-membered heteroaryl wherein heteroaryl has 1 or 2 nitrogen ring atoms, and R 7 is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups), wherein R 11 is as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or 6-membered heteroaryl wherein heteroaryl has 1 or 2 nitrogen ring atoms; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N; and R 7 is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups), wherein R 11 is as defined herein.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or 6-membered heteroaryl wherein heteroaryl has 1 or 2 nitrogen ring atoms; and R 7 is substituted with 0-4 R 11 groups (i.e., 0, 1, 2, 3 or 4 R 11 groups), wherein R 11 is as defined herein. [0081] In some embodiments, R 7 is not substituted (i.e., is substituted with 0 R 11 groups). In some embodiments, R 7 is substituted with 1 R 11 group.
  • R 7 is substituted with 2 R 11 groups. In some embodiments, R 7 is substituted with 3 R 11 groups. In some embodiments, R 7 is substituted with 4 R 11 groups. R 11 is as defined herein. [0082] In some embodiments, R 7 is selected from –Me, –Et, –CF 3 , –CH 2 CH 2 OMe, ,
  • R 7 and R 8 are taken together with the atoms to which they are attached to form: [0083]
  • R 7 is selected from –Me, –Et, –CF 3 , –CH 2 CH 2 OMe, ,
  • R 7 is selected from the group consisting of Me, Ph, CF 3 , -CH 2 CH 2 OCH 3 , cyclopropyl, e.g., wherein R 7 is Me. [0085] In some embodiments, R 7 is Me or cyclopropyl. [0086] In some embodiments of a compound of Formula (I), R 7 is Me. In some embodiments, R 7 is –Et. In some embodiments, R 7 is –CF 3 . In some embodiments, R 7 is – CH 2 CH 2 OMe. In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is .
  • R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is
  • R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is
  • R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . In some embodiments, R 7 is . [0087] As generally defined herein, R 8 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R’, or CO 2 -R’, wherein each alkyl, heteroalkyl, phenyl, cycloalkyl, or heterocyclyl is optionally substituted; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N, and wherein the heterocycle is optionally substituted and wherein R’ is as defined herein.
  • R 8 is H, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, phenyl, cycloalkyl, heterocyclyl, cyano, CO-R’, or CO 2 -R’, wherein heterocyclyl has 4-11 ring atoms with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is substituted with 0-4 groups independently selected from halogen and OH, and each phenyl, cycloalkyl, or heterocyclyl is substituted with 0-4 R 10 groups; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N, and wherein the heterocycle is substituted with 0-4 R 10 groups, wherein R’ and R 10 are as defined herein.
  • R 8 is H, C 1 -C 6 alkyl, cycloalkyl, cyano, CO-R’, or CO 2 -R’, or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4- 7 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0-4 R 10 groups, wherein R’ and R 10 are as defined herein.
  • R 8 is H, C 1 -C 6 alkyl, cycloalkyl, cyano, CO-C 1 -C 6 alkyl, or CO2-C 1 -C 6 alkyl or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5-6 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0 or 1 R 10 groups, wherein R 10 is as defined herein.
  • R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or-CO2-t-butyl or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5-6 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0 or 1 instances of methyl or phenyl.
  • R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or-CO 2 -t-butyl or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form N N S S O , , , , O , , or .
  • R 8 is H, C 1 -C 6 alkyl, cycloalkyl, cyano, CO-R’, or CO2-R’, wherein R’ is as defined herein.
  • R 8 is H, C 1 -C 6 alkyl, cycloalkyl, cyano, CO-C 1 -C 6 alkyl, or CO 2 -C 1 -C 6 alkyl.
  • R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or-CO 2 -t-butyl.
  • R 8 is H. In some embodiments, R 8 is Me. In some embodiments, R 8 is Et. In some embodiments, R 8 is CN. In some embodiments, R 8 is cyclopropyl. In some embodiments, R 8 is CO-t-butyl.
  • R 8 is-CO 2 -t-butyl.
  • R 8 is H, Me, Et, CN, cyclopropyl, or-CO2-t-butyl, e.g., wherein R 8 is H.
  • R 8 is H.
  • R 7 and R 8 are joined together to form a propylene (-CH 2 -CH 2 -CH 2 -).
  • R 7 and R 8 are joined together to form a ethylene (-CH 2 -CH 2 -).
  • R 7 and R 8 are taken together with the atoms to which they are attached to form In some embodiments, R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to for [0099] In some embodiments, R 7 and R 8 are taken together with the atoms to which they are attached to form [0100] In some embodiments, R 7 and R 8 are taken together with the atoms to which they are attached to form (e.g., including individual enantiomers thereof).
  • each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, hydroxy, cyano, or halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1-4 groups independently selected from halogen and OH.
  • each R 9 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, hydroxy, cyano, or halogen. In some embodiments, each R 9 is independently selected from –Me, -Et, –iPr, –tBu, –CF 3 , –OMe, cyclopropyl, hydroxy, cyano, –F or –Cl. In some embodiments, each R 9 is independently selected from –Me and –F.
  • each R 10 is independently selected from C 1 -C 6 alkyl, C 1 - C 6 alkenyl, C 1 -C 6 heteroalkyl, phenyl, C 3 -C 7 cycloalkyl, heterocyclyl, C 1 -C 6 alkylene-phenyl, C 1 - C 6 alkylene- C 3 -C 7 cycloalkyl, C 1 -C 6 alkylene- heterocyclyl, hydroxy, cyano, CO-R C , NR D 2 , or halogen, wherein heterocyclyl has 4-11 ring atoms with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is optionally substituted with 1-4 groups independently selected from halogen and OH, and wherein each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-4 R E , wherein R C , R D , R E are as defined
  • each R 10 is independently selected from phenyl, cyano, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, and CO-R C , wherein R C is as defined herein and wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from halogen and OH.
  • each R 10 is independently selected from phenyl, halogen, C1- C6 alkyl, and CO-R C , wherein R C is -NH 2 and wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from halogen and OH.
  • each R 10 is independently selected from halogen, C 1 -C 6 alkyl, and CO-R C , wherein R C is -NH 2 and wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from halogen and OH.
  • each R 10 is independently selected from halogen, C 1 -C 6 alkyl, and CO-R C , wherein R C is -NH 2 and wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from F and OH.
  • each R 10 is independently selected from halogen and C 1 -C 6 alkyl, wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from halogen and OH. In some embodiments, each R 10 is independently selected from halogen and C 1 -C 6 alkyl, wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from F and OH. In some embodiments, each R 10 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl. In some embodiments, each R 10 is independently halogen or C 1 -C 6 alkyl. In some embodiments, R 10 is halogen.
  • R 10 is C 1 -C 6 alkyl.
  • each R 10 is independently selected from phenyl, –F, –Cl, – Me, CF 3 , –CONH 2 and –CH(OH)CH 3 .
  • each R 10 is independently selected from –F, –Cl, – Me, CF 3 , –CONH 2 and –CH(OH)CH3.
  • each R 10 is independently selected from –F and – Me.
  • R 10 is –F.
  • R 10 is –Me.
  • R 10 is phenyl.
  • each R 11 is independently selected from C 1 -C 6 alkyl, C1- C6 alkenyl, C 1 -C 6 heteroalkyl, phenyl, C 3 -C 7 cycloalkyl, heterocyclyl, C 1 -C 6 alkylene-phenyl, C1- C6 alkylene- C 3 -C 7 cycloalkyl, C 1 -C 6 alkylene- heterocyclyl, hydroxy, cyano, CO-R C , NR D 2, or halogen, wherein heterocyclyl has 4-11 ring atoms with 1 to 4 ring atoms selected from N, O, and S; each alkyl or heteroalkyl is optionally substituted with 1-4 groups independently selected from halogen and OH, and wherein each phenyl, cycloalkyl, or heterocyclyl is optionally substituted with 1-4 R E , wherein R C , R D , R E are as defined herein.
  • each R 11 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, hydroxy, cyano, and halogen, wherein the alkyl and heteroalkyl are optionally substituted with 1-4 groups independently selected from halogen and OH.
  • each R C is independently H, OH, NR 12 2, C 1 -C 6 alkyl, C1- C6 alkoxy, C 1 -C 6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1-4 substituents independently selected from halogen and OH, wherein R 12 is as defined herein.
  • each R C is independently H, OH, NH 2 , NHMe, NMe2, Me, Et, i Pr, t Bu, OMe, OEt, O i Pr, O t Bu or CH 2 CH 2 OMe.
  • each R C is independently NH 2 , NHMe, NMe2, OMe, OEt, O i Pr or O t Bu. In some embodiments, each R C is independently NH 2 .
  • each R D is independently H, C 1 -C 6 alkyl, CO-C 1 -C 6 alkyl; CO2-C 1 -C 6 alkyl; SOw-C 1 -C 6 alkyl; C 1 -C 6 heteroalkyl, wherein each alkyl or heteroalkyl is optionally substituted with 1-4 substituents independently selected from halogen and OH; or two R D attached to the same nitrogen are taken together with the nitrogen to which they are attached to form a 3-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N, and wherein the heterocycle is optionally substituted with 1-4 substituents independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 hal
  • each R D is selected from H, Me, Et, COMe, COtBu, COOMe, COOtBu, SOMe and SO 2 Me, or two R D are taken together to form a heterocyclic ring selected from azetidine, pyrrolidine, and piperidine.
  • each R D is selected from H and Me, or two R D are taken together to form a heterocyclic ring selected from azetidine, pyrrolidine, and piperidine.
  • each R D is selected from H and Me.
  • two R D are taken together to form a heterocyclic ring selected from azetidine, pyrrolidine, and piperidine.
  • each R D is independently H.
  • each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring. In some embodiments, each R’ is independently H or Me; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring. In some embodiments, each R’ is independently H or Me; or two R’ together with the carbon or carbons to which they are attached form a 3-4-membered cycloalkyl ring.
  • each R’ is independently H or Me; or two R’ together with the carbon or carbons to which they are attached form cyclopropyl ring. In some embodiments, both R’ are H. In some embodiments, one R’ is Me and the remaining R’ are H. In some embodiments, two R’ on the same carbon atom are Me. In some embodiments, two R’ together with the carbon to which they are attached form a cyclopropyl. [0118] In some embodiments, each R’ is independently H, Me, Et, i Pr or t Bu. In some embodiments, R’ is Me. In some embodiments, R’ is t Bu.
  • each R E is independently H, halo, OH, O-C 1 -C 6 alkyl, - C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl. In some embodiment, each R E is independently H or C 1 -C 6 alkyl. In some embodiments, each R E is independently H, Cl, F, OH, OMe, CF 3 or Me. In some embodiments, each R E is H. In some embodiments, each R E is Me. [0120] As generally defined herein, each R 12 is independently H or C 1 -C 6 alkyl. In some embodiments, each R 12 is independently H or Me. In some embodiments, each R 12 is independently H.
  • each R 12 is independently Me.
  • w is 0, 1 or 2. In some embodiments, w is 0 or 1. In some embodiments, w is 1 or 2. In some embodiments, w is 0. In some embodiments, w is 1. In some embodiments, w is 2. [0122] In some embodiments of a compound of Formula (I), the compound is of Formula (Ia) (Ia), or a pharmaceutically acceptable salt thereof, wherein X 1 is N or CH; X 2 is N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is of Formula (Ib) (Ib) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 5 , R 7 and R 8 are as defined herein. [0124] In some embodiments of a compound of Formula (I), the compound is of Formula (Ic)
  • the compound is of Formula (Id) (Id), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • the compound is of Formula (Id) (Id), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • the compound is of Formula (Ie) (Ie), or a pharmaceutically acceptable salt thereof, wherein X 4 is N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is of Formula (If) (If), or a pharmaceutically acceptable salt thereof, wherein X 4 is N or CH; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Ig) (Ig), or a pharmaceutically acceptable salt thereof, wherein X 5 is N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Ih) (Ih), or a pharmaceutically acceptable salt thereof, wherein X 5 is N or CH; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Ii)
  • the compound is a compound of Formula (Ij) (Ij) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; X6 is N or CH; X 7 is N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Ij) (Ij) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; X6 is N or CH; X7 is N or CH; and R2, R5, R7 and R8 are as defined herein.
  • X 6 is N and X 7 is CH.
  • X 6 is CH and X 7 is N.
  • the compound is a compound of Formula (Ik) (Ik), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; X 8 is N or CH; X 9 is N or CH; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Im) (Im) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; X 8 is N or CH; X 9 is N or CH; and R 2 , R 5 , R 7 and R 8 are as defined herein. [0136] In some embodiments, X 8 is N and X 9 is CH. [0137] In some embodiments, X 8 is CH and X 9 is N.
  • the compound is a compound of Formula (In) (In), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Io) (Io) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Ip)
  • the compound is a compound of Formula (Iq) (Iq) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Ir) (Ir), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein.
  • the compound is a compound of Formula (Is) (Is) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; and R 2 , R 5 , R 7 and R 8 are as defined herein.
  • X 3 is S.
  • X 3 is O.
  • a compound of Formula (I) the compound is selected from the compounds disclosed in Table 1, or a pharmaceutically acceptable salt thereof, or elsewhere in the specification and figures.
  • provided herein is a composition comprising a compound described herein and a pharmaceutically acceptable excipient.
  • the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof.
  • the absolute stereochemistry of all chiral atoms is as depicted.
  • Compounds marked with (or) or (rel) in Table 1 and the Examples section are single enantiomers wherein the absolute stereochemistry was arbitrarily assigned (e.g., based on chiral SFC elution as described in the Examples section).
  • Compounds marked with (and) or (rac) are mixtures of enantiomers wherein the relative stereochemistry is as shown.
  • Compounds that have a stereogenic center where the configuration is not indicated in the structure as depicted and that have no designation in the stereochemistry column of Table 1 are mixtures of enantiomers at that center.
  • a method of treating a disease or disorder that can be treated by inhibition of HDAC comprising administering to a patient in need thereof a compound described herein or a composition described herein.
  • methods of treating human or animal subjects having or having been diagnosed with a disease or disorder that can be treated by inhibition of HDAC comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of Formula (I) or a compound of Table 1) or a pharmaceutically acceptable salt thereof.
  • the disease or disorder is cancer.
  • the cancer is glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium, urinary
  • the cancer is brain tumors such as astrocytoma and glioblastoma, brain metastases, medulloblastomas, meningiomas and oligodendrogliomas; tumors of the peripheral or central nervous systems; nerve tumors; non-Hodgkin's lymphomas, such as for example low-malignancy non-Hodgkin's lymphomas, Burkitt's lymphoma; lymphoma (lymphosarcoma); Hodgkin's disease, non-Hodgkin's lymphomas; bone cancers; leukemias, such as acute lymphatic/lymphoblastic leukemia, acute myeloid leukemia, chronic lymphatic leukemia, chronic myeloid leukemia; intestinal cancers such as for example carcinomas of the rectum, colon, colorectal carcinoma, anal carcinoma, large bowel; pancreatic cancer or carcinoma of the pancreas; gallbladder cancer; bile duct cancer; liver tumors such as astrocyto
  • the cancer is a HDAC-related glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, end
  • the cancer e.g., the HDAC-related cancer
  • the cancer is carcinoma of unknown primary (CUP), colorectal cancer (e.g., colorectal carcinoma), cervical cancer or non- small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • NSCLC non-small cell lung cancer
  • the cancer is cervical cancer.
  • the cancer is colorectal cancer (e.g., colorectal carcinoma).
  • the cancer is carcinoma of unknown primary (CUP).
  • the compounds described herein e.g., a compound of Formula (I) or a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a HDAC inhibitor e.g., a compound of Formula (I) or a compound of Table 1, or pharmaceutically acceptable salts thereof
  • the subject in need thereof suffers from a cancer selected from glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endo
  • the cancer is selected from the group consisting of a melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreas cancer, and stomach cancer.
  • a compound of the disclosure in the manufacture of a medicament for the treatment of cancer.
  • Cancers Cancer cells grow quickly and in low oxygen environments by activating different elements of the cellular stress response. Without wishing to be bound by a theory, compounds of Formula (I) or subformulas thereof may also be used for treatment of cancer, as a greater understanding of the role of HDACs in cancer has recently begun to emerge.
  • HDAC inhibitors can be combined with one or more cancer therapies, such as chemotherapy and radiation therapy.
  • a “cancer” in a subject refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.
  • cancer cells will be in the form of a tumor, but such cells may exist alone within an animal, or may be a non-tumorigenic cancer cell, such as a leukemia cell. In some circumstances, cancer cells will be in the form of a tumor; such cells may exist locally within an animal, or circulate in the blood stream as independent cells, for example, leukemic cells.
  • Exemplary cancers include but are not limited to glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endometrium,
  • Another exemplary list of cancers includes but is not limited to brain tumors such as astrocytoma and glioblastoma, brain metastases, medulloblastomas, meningiomas and oligodendrogliomas; tumors of the peripheral or central nervous systems; nerve tumors; non- Hodgkin's lymphomas, such as for example low-malignancy non-Hodgkin's lymphomas, Burkitt's lymphoma; lymphoma (lymphosarcoma); Hodgkin's disease, non-Hodgkin's lymphomas; bone cancers; leukemias, such as acute lymphatic/lymphoblastic leukemia, acute myeloid leukemia, chronic lymphatic leukemia, chronic myeloid leukemia; intestinal cancers such as for example carcinomas of the rectum, colon, colorectal carcinoma, anal carcinoma, large bowel; pancreatic cancer or carcinoma of the pancreas; gallbladder cancer; bile
  • the cancer is a HDAC-related glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney, breast, endo
  • MPNST malignant
  • the cancer is a HDAC-related brain tumor such as astrocytoma and glioblastoma, brain metastases, medulloblastomas, meningiomas and oligodendrogliomas; tumors of the peripheral or central nervous systems; nerve tumors; non-Hodgkin's lymphomas, such as for example low-malignancy non-Hodgkin's lymphomas, Burkitt's lymphoma; lymphoma (lymphosarcoma); Hodgkin's disease, non-Hodgkin's lymphomas; bone cancers; leukemias, such as acute lymphatic/lymphoblastic leukemia, acute myeloid leukemia, chronic lymphatic leukemia, chronic myeloid leukemia; intestinal cancers such as for example carcinomas of the rectum, colon, colorectal carcinoma, anal carcinoma, large bowel; pancreatic cancer or carcinoma of the pancreas; gallbladder cancer; bile
  • the cancer e.g., the HDAC-related cancer
  • the cancer is carcinoma of unknown primary (CUP), colorectal cancer (e.g., colorectal carcinoma), cervical cancer or non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • NSCLC non-small cell lung cancer
  • the cancer is cervical cancer.
  • the cancer is colorectal cancer (e.g., colorectal carcinoma).
  • the cancer is carcinoma of unknown primary (CUP).
  • the subject in need thereof suffers from a cancer selected from glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, cancer of the brain, stomach, kidney,
  • MPNST malignant
  • Combination Therapy Provided herein are methods of treatment of diseases or disorders (e.g., cancers) with a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) in combination with a second therapeutic agent.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof
  • Combination refers to either a fixed combination in one dosage unit form, or a combined administration where a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is)or a compound of Table 1, or pharmaceutically acceptable salts thereof) and a combination partner (e.g., another drug as explained below, also referred to as “therapeutic agent” or “co-agent”) may be administered independently at the same time or separately within time intervals, especially where these time intervals allow that the combination partners show a cooperative, e.g., synergistic effect.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (
  • the single components may be packaged in a kit or separately.
  • One or both of the components e.g., powders or liquids
  • co-administration or “combined administration” or the like as utilized herein are meant to encompass administration of the selected combination partner to a single subject in need thereof (e.g., a patient), and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.
  • pharmaceutical combination as used herein means a product that results from the mixing or combining of more than one therapeutic agent and includes both fixed and non–fixed combinations of the therapeutic agents.
  • fixed combination means that the therapeutic agents, e.g., a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) and a combination partner, are both administered to a patient simultaneously in the form of a single entity or dosage.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof
  • non- fixed combination means that the therapeutic agents, e.g., a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) and a combination partner, are both administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq),
  • cocktail therapy e.g., the administration of three or more therapeutic agent.
  • combination therapy refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients. Alternatively, such administration encompasses co-administration in multiple, or in separate containers (e.g., tablets, capsules, powders, and liquids) for each active ingredient. Powders and/or liquids may be reconstituted or diluted to a desired dose prior to administration.
  • compounds of the present invention are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti-allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.
  • General Chemotherapeutic agents considered for use in combination therapies include anastrozole (Arimidex®), bicalutamide (Casodex®), bleomycin sulfate (Blenoxane®), busulfan (Myleran®), busulfan injection (Busulfex®), capecitabine (Xeloda®), N4- pentoxycarbonyl-5-deoxy-5-fluorocytidine, carboplatin (Paraplatin®), carmustine (BiCNU®), chlorambucil (Leukeran®), cisplatin (Platinol®), cladribine (Leustatin®), cyclophosphamide (Cytoxan® or Neosar®), cytarabine, cytosine arabinoside (Cytosar-U®), cytarabine liposome injection (DepoCyt®), dacarbazine (DTIC-Dome®), d
  • EGFR-inhibitors such as cetuximab, panitumimab, erlotinib, gefitinib and EGFRi NOS
  • MAPK-pathway inhibitors such as BRAFi, panRAFi, MEKi, ERKi
  • PI3K- mTOR pathway inhibitors such as alpha-specific PI3Ki, pan-class I PI3Ki and mTOR/PI3Ki, particularly everolimus and analogues thereof.
  • Specific compounds and classes of compounds acting via specific mechanisms can be particularly effective in conjunction with compounds of Formula (I) (e.g., compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof).
  • PRMT5 is known to associate with SWI/SNF chromatin remodeling complexes along with other co-repressor molecules like HDAC2.
  • HDAC inhibitors can be effective (e.g., synergistic) when used in conjunction with PRMT5 inhibitors (WO 011/079236).
  • compound of Formula (I) can be used in combination with other compounds, for example: PRMT5 inhibitor or DNA methyltransferase inhibitor.
  • the DNA methyltransferase inhibitor is 5-azacytidine.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) and a MAT2A inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) and an inhibitor of a protein which interacts with or is required for PRMT5 function, including, but not limited to, pICIN, WDR77 or RIOK1.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) and an HDM2 inhibitor and/or with 5-FU.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), or a compound of Table 1, or pharmaceutically acceptable salts thereof) and a CDK4 inhibitor, including, but not limited to, LEE011 or a CDK 4/6 inhibitor (e.g., palbociclib (Ibrance®), ribociclib (Kisqali®), and abemaciclib (Verzenio ®).
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and targeted treatments contingent on the dependency of individual target tumors on relevant pathways as determined by suitable predictive markers, including but not limited to: inhibitors of HDM2i, PI3K/mTOR-I, MAPKi, RTKi (EGFRi, FGFRi, METi, IGFiRi, JAKi, and WNTi.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (I
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and immunotherapy.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and an immunotherapeutic agent.
  • the immunotherapeutic agent is a cancer vaccine such as a neoantigen.
  • the immunotherapeutic agent is an oncolytic virus.
  • the immunotherapeutic agent is a STING pathway agonist.
  • Exemplary STING agonists include MK-1454 and ADU-S100.
  • the immunotherapeutic agent is an anti-CTLA-4 antibody.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and an anti–CTLA-4 antibody (e.g., ipilimumab, tremelimumab).
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir
  • the immunotherapeutic agent is an anti-PD-1 ligand or an anti- PD-L1 ligand.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and an anti-PD-1 ligand (e.g., PD-LI (e.g., B7–HI or CD274); or PD-L2 (e.g., B7-DC or CD273)).
  • PD-LI e.g., B7–HI or CD274
  • PD-L2 e.g.,
  • the immunotherapeutic agent is an anti-PD-1 antibody (e.g., anti-PD-1 or anti-PD-L1).
  • the immunotherapeutic agent is an anti-PD-1 agent (e.g., an anti-PD-1 antibody, e.g., nivolumab (i.e., MDX-1106, BMS– 936558, ONO-4538); CT-011; AMP-224; pembrolizumab (MK-3475); pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).
  • an anti-PD-1 antibody e.g., an anti-PD-1 antibody, e.g., nivolumab (
  • the immunotherapeutic agent is an anti-PD-L1 agent (e.g., an anti-PD-L1 antibody, e.g., BMS936559 (i.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C); envafolimab; cosibelimab; sugemalimab, AUNP-12 or atezolizumab (MPDL- 3280A) or an anti-PD-L1 small molecule (e.g., CA-170)).
  • an anti-PD-L1 agent e.g., an anti-PD-L1 antibody, e.g., BMS936559 (i.e., MDX-1105); durvalumab (MEDI4736); avelumab (MSB0010718C); envafolimab; cosibelimab; sugemalimab, AUNP-12 or atezolizumab (MPDL- 3280
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a KRAS inhibitor.
  • the KRAS inhibitor is a KRAS G12C inhibitor.
  • the KRAS inhibitor is sotorasib.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a checkpoint blocking antibody (e.g., anti-TIM3, anti-LAG3, anti- TIGIT including IMP321 and MGA271).
  • a checkpoint blocking antibody e.g., anti-TIM3, anti-LAG3, anti- TIGIT including IMP321 and MGA271.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a checkpoint inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a cell-based therapy.
  • the cell-based therapy is a CAR-T therapy.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a co-stimulatory antibody (e.g., anti-4-1BB, anti–OX40, anti-GITR, anti–CD27, anti–CD40).
  • a co-stimulatory antibody e.g., anti-4-1BB, anti–OX40, anti-GITR, anti–CD27, anti–CD40.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a disease-specific huMABs (e.g., an anti–HER3 huMAB).
  • a disease-specific huMABs e.g., an anti–HER3 huMAB
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and ADCs/ADCCs contingent on the expression of relevant surface targets on target tumors of interest.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a
  • anti-allergic agents include corticosteroids, including, but not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known as cortisone, hydrocortisone sodium succinate, hydrocortisone sodium phosphate, and sold under the tradenames Ala–Cort®, hydrocortisone phosphate, Solu–Cortef®, Hydrocort Acetate® and Lanacort®), prednisolone (sold under the tradenames Delta–Cortel®, Orapred®, Pediapred® and Prelone®), prednisone (sold under the tradenames Deltasone®, Liquid Red®, Meticorten® and Ora
  • corticosteroids including, but not limited to, dexamethasone (e.g., Decadron®), beclomethasone (e.g., Beclovent®), hydrocortisone (also known
  • anti–emetics are used in preventing nausea (upper stomach) and vomiting.
  • Suitable anti-emetics include aprepitant (Emend®), ondansetron (Zofran®), granisetron HCl (Kytril®), lorazepam (Ativan®. dexamethasone (Decadron®), prochlorperazine (Compazine®), casopitant (Rezonic® and Zunrisa®), and combinations thereof.
  • Medication to alleviate the pain experienced during the treatment period is often prescribed to make the patient more comfortable.
  • opioid analgesic drugs including, but not limited to, hydrocodone/paracetamol or hydrocodone/acetaminophen (e.g., Vicodin®), morphine (e.g., Astramorph® or Avinza®), oxycodone (e.g., OxyContin® or Percocet®), oxymorphone hydrochloride (Opana®), and fentanyl (e.g., Duragesic®) are also useful for moderate or severe pain.
  • hydrocodone/paracetamol or hydrocodone/acetaminophen e.g., Vicodin®
  • morphine e.g., Astramorph® or Avinza®
  • oxycodone e.g., OxyContin® or Percocet®
  • OxyContin® oxymorphone hydrochloride
  • fentanyl e.g., Duragesic®
  • cytoprotective agents such as neuroprotectants, free-radical scavengers, cardioprotectors, anthracycline extravasation neutralizers, nutrients and the like
  • Suitable cytoprotective agents include Amifostine (Ethyol®), glutamine, dimesna (Tavocept®), mesna (Mesnex®), dexrazoxane (Zinecard® or Totect®), xaliproden (Xaprila®), and leucovorin (also known as calcium leucovorin, citrovorum factor and folinic acid).
  • the present invention provides pharmaceutical compositions comprising at least one compound of Formula (I) (e.g., e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1) or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier suitable for administration to a human or animal subject, either alone or together with other anti-cancer agents.
  • compositions will either be formulated together as a combination therapeutic or administered separately.
  • the compound of Formula (I) and other anti-cancer agent(s) may be administered either simultaneously, concurrently or sequentially with no specific time limits, wherein such administration provides therapeutically effective levels of the two compounds in the body of the patient.
  • the compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • the other anti-cancer agent(s) is generally administered sequentially in any order by infusion or orally.
  • the dosing regimen may vary depending upon the stage of the disease, physical fitness of the patient, safety profiles of the individual drugs, and tolerance of the individual drugs, as well as other criteria well-known to the attending physician and medical practitioner(s) administering the combination.
  • the compound of the present invention and other anti-cancer agent(s) may be administered within minutes of each other, hours, days, or even weeks apart depending upon the particular cycle being used for treatment.
  • the cycle could include administration of one drug more often than the other during the treatment cycle and at different doses per administration of the drug.
  • kits that include one or more compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a second therapeutic agent as disclosed herein are provided.
  • a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof are provided.
  • kits include (a) a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof), (b) at least one other therapeutic agent, e.g., as indicated above, whereby such kit may comprise a package insert or other labeling including directions for administration.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) may also be used in combination with known therapeutic processes, for example, the administration of hormones or especially radiation.
  • a compound of Formula (I) may in particular be used as a radiosensitizer, especially for the treatment of tumors which exhibit poor sensitivity to radiotherapy.
  • compounds of the present invention are combined with other therapeutic agents, including, but not limited to, other anti-cancer agents, anti–allergic agents, anti-nausea agents (or anti-emetics), pain relievers, cytoprotective agents, and combinations thereof.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a CAAP1 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a AKAP17A inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a BCL2L1 inhibitor.
  • the BCL2L1 inhibitor is AT-101.
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a TSC1/2 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a UBE2H inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a NF2 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a ZC3HC1 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a MGEA5 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a CNOT4 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a API5 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a HEXIM1 inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a PTEN inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • a method of treating a disease or disorder comprising administering or coadministering, in any order, to a patient in need thereof, a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof) and a DNA damage pathway inhibitor.
  • a compound of Formula (I) e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Im), (In), (Io), (Ip), (Iq), (Ir) or (Is), a compound of Table 1, or pharmaceutically acceptable salts thereof
  • the DNA damage pathway inhibitor is selected from the group consisting of bleomycin, an ATM inhibitor (e.g., AZD1390), a USP1 inhibitor, a WEE1 inhibitor (e.g., AZD1775), and a Chk1 inhibitor (e.g., AZD7762).
  • an ATM inhibitor e.g., AZD1390
  • USP1 inhibitor e.g., AZD1390
  • WEE1 inhibitor e.g., AZD1775
  • Chk1 inhibitor e.g., AZD7762
  • the terms “compounds” and “agent” are used interchangeably to refer to the inhibitors/antagonists/agonists of the invention.
  • the compounds are small organic or inorganic molecules, e.g., with molecular weights less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000, 1500, 1000, 750, 600, or 500 amu.
  • one class of small organic or inorganic molecules are non- peptidyl, e.g., containing 2, 1, or no peptide and/or saccharide linkages.
  • administer refers to the placement of a composition into a subject by a method or route which results in at least partial localization of the composition at a desired site such that desired effect is produced.
  • a compound or composition described herein can be administered by any appropriate route known in the art including, but not limited to, oral or parenteral routes, including intravenous, intramuscular, subcutaneous, transdermal, airway (aerosol), pulmonary, nasal, rectal, intrathecal, and topical (including buccal and sublingual) administration.
  • the terms “decrease”, “reduced”, “reduction”, “decrease” or “inhibit” are all used herein generally to mean a decrease by a statistically significant amount.
  • the terms “reduced”, “reduction”, “decrease” or “inhibit” mean a decrease by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% decrease (e.g. absent level as compared to a reference sample), or any decrease between 1-100%, e.g., 10-100% as compared to a reference level.
  • a 100% decrease e.g. absent level as compared to a reference sample
  • the terms “increased”, “increase”, “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount.
  • the terms “increased”, “increase”, “enhance” or “activate” mean an increase by at least 0.1% as compared to a reference level, for example a decrease by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase (e.g.
  • treatment delaying or preventing the onset of such a disease or disorder, reversing, alleviating, ameliorating, inhibiting, slowing down or stopping the progression, aggravation or deterioration the progression or severity of a condition associated with such a disease or disorder.
  • At least one symptom of a disease or disorder is alleviated by at least about 1%, or at least about 5%, or at least about 10%, or at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%.
  • an amount of a compound or combination effective to treat a disorder refers to an amount of the compound or combination which is effective, upon single or multiple dose administration(s) to a subject, in treating a subject, or in curing, alleviating, relieving or improving a subject with a disorder (e.g., a disorder as described herein) beyond that expected in the absence of such treatment. Determination of a therapeutically effective amount is well within the capability of those skilled in the art.
  • a therapeutically effective amount can vary with the subject’s history, age, condition, sex, as well as the severity and type of the medical condition in the subject, and administration of other pharmaceutically active agents.
  • a “subject” means a human or animal. Usually the animal is a vertebrate such as a primate, rodent, domestic animal or game animal. Primates include chimpanzees, cynomologous monkeys, spider monkeys, and macaques, e.g., Rhesus. Rodents include mice, rats, woodchucks, ferrets, rabbits and hamsters.
  • Domestic and game animals include cows, horses, pigs, deer, bison, buffalo, feline species, e.g., domestic cat, canine species, e.g., dog, fox, wolf, avian species, e.g., chicken, emu, ostrich, and fish, e.g., trout, catfish and salmon.
  • Patient or subject includes any subset of the foregoing, e.g., all of the above, but excluding one or more groups or species such as humans, primates or rodents.
  • the subject is a mammal, e.g., a primate, e.g., a human.
  • the terms, “patient” and “subject” are used interchangeably herein.
  • nucleic acid refers to a polymeric form of nucleotides, either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • nucleotides either ribonucleotides or deoxynucleotides or a modified form of either type of nucleotide.
  • the terms should also be understood to include, as equivalents, analogs of either RNA or DNA made from nucleotide analogs, and, as applicable to the embodiment being described, single-stranded (such as sense or antisense) and double-stranded polynucleotides.
  • the term “inhibitor of HDAC” refers to compounds and compositions of Formula (I) (e.g., Formula (I), (Ia), (Ib), (Ic), and (Id), Compounds for Table 1, or pharmaceutically acceptable salts thereof) that are capable of inhibiting the deacetylase activity of HDAC enzymes.
  • Formula (I) e.g., Formula (I), (Ia), (Ib), (Ic), and (Id), Compounds for Table 1, or pharmaceutically acceptable salts thereof
  • these include, as non-limiting examples, any compound inhibiting the posttranslational modification of the protein, the enzymatic activity of the protein, the interaction of same with protein complexes, interaction with substrate, etc.
  • the term also refers to any agent that inhibits the cellular function of the HDAC protein, either by ATP-competitive inhibition of the active site, allosteric modulation of the protein structure, disruption of protein-protein interactions, or by inhibiting the transcription, translation, post-translational modification, or stability of HDAC protein.
  • Selected Chemical Definitions [0229] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • each variable can be a different moiety selected from the Markush group defining the variable.
  • the two R groups can represent different moieties selected from the Markush group defined for R.
  • alkyl refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 24 carbon atoms (“C 1 -C 24 alkyl”).
  • an alkyl group has 1 to 12 carbon atoms (“C 1 -C 12 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1 -C 8 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1 -C 6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1 -C 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1 -C 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1 -C 3 alkyl”).
  • an alkyl group has 1 to 2 carbon atoms (“C1-C2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-C6 alkyl”).
  • C 1 -C 6 alkyl groups include methyl (C1), ethyl (C2), n–propyl (C3), isopropyl (C3), n–butyl (C4), tert–butyl (C4), sec–butyl (C4), iso–butyl (C4), n–pentyl (C5), 3–pentanyl (C5), amyl (C5), neopentyl (C5), 3–methyl–2–butanyl (C5), tertiary amyl (C5), and n–hexyl (C6).
  • alkyl groups include n–heptyl (C7), n–octyl (C8) and the like.
  • Each instance of an alkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C1–10 alkyl (e.g., –CH3).
  • the alkyl group is substituted C1–6 alkyl.
  • alkylene refers to a diradical of an alkyl group.
  • An exemplary alkylene group is –CH 2 CH 2 -.
  • alkenyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon double bonds, and no triple bonds (“C 2 -C 24 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms (“C 2 -C 10 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C 2 -C 8 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C 2 - C6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-C5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-C4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-C3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon– carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1–butenyl).
  • Examples of C2-C4 alkenyl groups include ethenyl (C2), 1–propenyl (C3), 2–propenyl (C3), 1– butenyl (C4), 2–butenyl (C4), butadienyl (C4), and the like.
  • Examples of C2-C6 alkenyl groups include the aforementioned C2–4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like.
  • Each instance of an alkenyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C 2–10 alkenyl.
  • the alkenyl group is substituted C 2–6 alkenyl.
  • alkynyl refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 24 carbon atoms, one or more carbon–carbon triple bonds (“C2-C24 alkenyl”).
  • an alkynyl group has 2 to 10 carbon atoms (“C2-C10 alkynyl”).
  • an alkynyl group has 2 to 8 carbon atoms (“C2-C8 alkynyl”).
  • an alkynyl group has 2 to 6 carbon atoms (“C2-C6 alkynyl”).
  • an alkynyl group has 2 to 5 carbon atoms (“C2-C5 alkynyl”).
  • an alkynyl group has 2 to 4 carbon atoms (“C2-C4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-C3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”).
  • the one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl).
  • C2-C4 alkynyl groups examples include ethynyl (C2), 1–propynyl (C3), 2–propynyl (C3), 1– butynyl (C4), 2–butynyl (C4), and the like.
  • Each instance of an alkynyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkynyl group is unsubstituted C 2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2–6 alkynyl.
  • the term "heteroalkyl,” refers to a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P, S, and Si may be placed at any position of the heteroalkyl group.
  • heteroalkyl Up to two or three heteroatoms may be consecutive, such as, for example, -CH 2 -NH- OCH 3 and -CH 2 -O-Si(CH 3 ) 3 .
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as –CH 2 O, –NR C R D , or the like, it will be understood that the terms heteroalkyl and –CH 2 O or –NR C R D are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as –CH 2 O, –NR C R D , or the like.
  • One type of heteroalkyl group is an “alkoxyl” group.
  • alkoxyl or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An “ether” is two hydrocarbons covalently linked by an oxygen.
  • an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, O-alkynyl, -O- (CH 2 )mm-R aaa , where mm is an integer (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11) and R aaa may be halogen, haloalkyl, nitrile, -NH 2 , -NO2, -SO2, Si(CH3)3, cycloalkyl, heterocyclyl, aryl, or heteroaryl. are described above.
  • haloalkoxyl refers to an alkoxyl group that is substituted with at least one halogen.
  • haloalkoxyl is an alkoxyl group that is substituted with at least one fluoro group.
  • the haloalkoxyl is an alkoxyl group that is substituted with from 1-6, 1-5, 1-4, 2-4, or 3 fluoro groups.
  • aryl refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6 -C 14 aryl”).
  • aromatic ring system e.g., having 6, 10, or 14 ⁇ electrons shared in a cyclic array
  • an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl).
  • An aryl group may be described as, e.g., a C 6 -C 10 - membered aryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
  • Each instance of an aryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents.
  • the aryl group is unsubstituted C6-C14 aryl.
  • the aryl group is substituted C6-C14 aryl.
  • heteroaryl refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 ⁇ electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”).
  • heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system.
  • Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom e.g., indolyl, quinolinyl, carbazolyl, and the like
  • the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl).
  • a heteroaryl group may be described as, e.g., a 6-10-membered heteroaryl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”).
  • a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heteroaryl”).
  • a heteroaryl group is a 5–6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heteroaryl”).
  • the 5–6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Each instance of a heteroaryl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents.
  • the heteroaryl group is unsubstituted 5–14 membered heteroaryl.
  • the heteroaryl group is substituted 5–14 membered heteroaryl.
  • Exemplary 5–membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl.
  • Exemplary 5–membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl.
  • Exemplary 5–membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
  • Exemplary 5–membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl.
  • Exemplary 6–membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl.
  • Exemplary 6–membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6– membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively.
  • Exemplary 7–membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl.
  • Exemplary 5,6– bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl.
  • Exemplary 6,6–bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
  • Other exemplary heteroaryl groups include heme and heme derivatives.
  • heteroaryl also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more heterocycloalkyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of carbons continue to designate the number of carbons in the heteroaryl ring system.
  • ring systems of this type include 7,8-dihydro-5H-pyrano[4,3-b]pyridine and 1,4,6,7-tetahydropyrano[4,3-b]pyrrole.
  • cycloalkyl refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3 -C 10 cycloalkyl”) and zero heteroatoms in the non–aromatic ring system.
  • a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-C8cycloalkyl”).
  • a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-C6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-C10 cycloalkyl”).
  • a cycloalkyl group may be described as, e.g., a C4-C7-membered cycloalkyl, wherein the term “membered” refers to the non-hydrogen ring atoms within the moiety.
  • Exemplary C3-C6 cycloalkyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like.
  • Exemplary C3-C8 cycloalkyl groups include, without limitation, the aforementioned C 3 -C 6 cycloalkyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), cubanyl (C 8 ), bicyclo[1.1.1]pentanyl (C 5 ), bicyclo[2.2.2]octanyl (C 8 ), bicyclo[2.1.1]hexanyl (C 6 ), bicyclo[3.1.1]heptanyl (C 7 ), and the like.
  • Exemplary C 3 -C 10 cycloalkyl groups include, without limitation, the aforementioned C 3 -C 8 cycloalkyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like.
  • the cycloalkyl group is either monocyclic (“monocyclic cycloalkyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic cycloalkyl”) and can be saturated or can be partially unsaturated.
  • “Cycloalkyl” also includes ring systems wherein the cycloalkyl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is on the cycloalkyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the cycloalkyl ring system.
  • Each instance of a cycloalkyl group may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-C10 cycloalkyl.
  • the cycloalkyl group is a substituted C3-C10 cycloalkyl.
  • Heterocyclyl refers to a radical of a 3– to 10–membered non–aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”).
  • the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated.
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • Heterocyclyl also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more cycloalkyl groups wherein the point of attachment is either on the cycloalkyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl or aryl or heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • a heterocyclyl group may be described as, e.g., a 3-7-membered heterocyclyl, wherein the term “membered” refers to the non-hydrogen ring atoms, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon, within the moiety.
  • Each instance of heterocyclyl may be independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl.
  • the heterocyclyl group is substituted 3–10 membered heterocyclyl.
  • a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”).
  • a heterocyclyl group is a 5–8 membered non– aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”).
  • a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”).
  • the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, aziridinyl, oxiranyl, thiorenyl.
  • Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione.
  • Exemplary 5–membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin–2–one.
  • Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl.
  • Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5–membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6–membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.
  • cyano refers to the radical –CN.
  • halo or “halogen,” independently or as part of another substituent, mean, unless otherwise stated, a fluorine (F), chlorine (Cl), bromine (Br), or iodine (I) atom.
  • haloalkyl can include alkyl structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl includes haloalkyl groups in which the halo is fluorine (e.g., -C 1 -C 6 alkyl-CF 3 , -C 1 -C 6 alkyl-CH 2 F).
  • haloalkyl include trifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl, difluoromethyl, and fluroisopropyl.
  • hydroxy refers to the radical –OH.
  • nitro refers to –NO2.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocyclyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring- forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring-forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring- forming substituents are attached to non-adjacent members of the base structure.
  • the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer.
  • Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses.
  • a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess).
  • an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form.
  • enantiomerically pure or “pure enantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 99% by weight, more than 99.5% by weight, or more than 99.9% by weight, of the enantiomer.
  • the weights are based upon total weight of all enantiomers or stereoisomers of the compound.
  • an enantiomerically pure compound can be present with other active or inactive ingredients.
  • a pharmaceutical composition comprising enantiomerically pure R–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R–compound.
  • the enantiomerically pure R–compound in such compositions can, for example, comprise, at least about 95% by weight R–compound and at most about 5% by weight S–compound, by total weight of the compound.
  • a pharmaceutical composition comprising enantiomerically pure S–compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S–compound.
  • the enantiomerically pure S– compound in such compositions can, for example, comprise, at least about 95% by weight S– compound and at most about 5% by weight R–compound, by total weight of the compound.
  • the active ingredient can be formulated with little or no excipient.
  • Compound described herein may also comprise one or more isotopic substitutions.
  • H may be in any isotopic form, including 1 H, 2 H (D or deuterium), and 3 H (T or tritium);
  • C may be in any isotopic form, including 12 C, 13 C, and 14 C;
  • O may be in any isotopic form, including 16 O and 18 O; and the like.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • substituted whether preceded by the term “optionally” or not
  • an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position.
  • a moiety described as “optionally substituted” e.g., optionally substituted with a number or range of numbers of substituents selected from a list
  • can be unsubstituted or substituted e.g., can be unsubstituted or substituted with the number of substituents indicated).
  • a moiety that is optionally substituted with 1-4 R groups can be unsubstituted, substituted with one R group, substituted with two R groups, substituted with 3 R groups or substituted with 4 R groups.
  • Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable substituents for an optionally substituted alkyl, alkylene, heteroalkyl, heteroalkylene, carbocyclyl, heterocyclyl, aryl group and heteroaryl group include halogen, ⁇ O, —CN, —OR cc , —NR dd R ee , —S(O) kk R cc , —NR cc S(O)2R cc , —S(O)2NR dd R ee , —C( ⁇ O)OR cc , — OC( ⁇ O)OR cc , —OC( ⁇ O)R cc , —OC( ⁇ S)OR cc , —C( ⁇ S)OR cc , —O(C ⁇ S) R cc , —C( ⁇ S)OR cc , —O(C ⁇ S) R cc , —C( ⁇ O)NR dd R ee ,
  • Contemplated equivalents of the compounds described above include compounds which otherwise correspond thereto, and which have the same general properties thereof (e.g., the ability to inhibit HDAC), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of the compound.
  • the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
  • the term "hydrocarbon” is contemplated to include all permissible compounds having at least one hydrogen and one carbon atom.
  • the permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds which can be substituted or unsubstituted.
  • compositions and Routes of Administration [0266]
  • Pharmaceutical compositions containing compounds described herein such as a compound of Formula (I) or pharmaceutically acceptable salt thereof can be used to treat or ameliorate a disorder described herein, for example, a neurodegenerative disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection.
  • a disorder described herein for example, a neurodegenerative disease, a cancer, an ophthalmological disease (e.g., a retinal disease), or a viral infection.
  • the amount and concentration of compounds of Formula (I) in the pharmaceutical compositions, as well as the quantity of the pharmaceutical composition administered to a subject, can be selected based on clinically relevant factors, such as medically relevant characteristics of the subject (e.g., age, weight, gender, other medical conditions, and the like), the solubility of compounds in the pharmaceutical compositions, the potency and activity of the compounds, and the manner of administration of the pharmaceutical compositions.
  • medically relevant characteristics of the subject e.g., age, weight, gender, other medical conditions, and the like
  • solubility of compounds in the pharmaceutical compositions e.g., the solubility of compounds in the pharmaceutical compositions
  • the potency and activity of the compounds e.g., the solubility of compounds in the pharmaceutical compositions
  • the potency and activity of the compounds e.g., the solubility of compounds in the pharmaceutical compositions
  • the manner of administration of the pharmaceutical compositions e.g., administration of the pharmaceutical compositions.
  • a pharmaceutical formulation wherein a compound described herein is combined with one or more pharmaceutically acceptable excipients.
  • the compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine.
  • the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms such as described below or by other conventional methods known to those of skill in the art.
  • compositions comprising a therapeutically effective amount of one or more of the compounds described above, formulated together with one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions disclosed herein may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), lozenges, dragees, capsules, pills, tablets (e.g., those targeted for buccal, sublingual, and systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or
  • compounds can be implanted into a patient or injected using a drug delivery system. See, for example, Urquhart, et al., (1994) Ann Rev Pharmacol Toxicol 24:199-236; Lewis, ed. “Controlled Release of Pesticides and Pharmaceuticals” (Plenum Press, New York, 1981); U.S. Patent No.3,773,919; and U.S. Patent No.353,270,960.
  • terapéuticaally effective amount means that amount of a compound, material, or composition comprising a compound of the present invention, which is effective for producing some desired therapeutic effect, e.g., by inhibiting HDAC, in at least a sub-population of cells in an animal and thereby blocking the biological consequences of that function in the treated cells, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • systemic administration means the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient's system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • phrases "pharmaceutically acceptable excipient” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, carrier, solvent or encapsulating material, involved in carrying or transporting the subject antagonists from one organ, or portion of the body, to another organ, or portion of the body.
  • Each excipient must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable excipients include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydro
  • pharmaceutically acceptable salt is meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, e.g., Berge et al, Journal of Pharmaceutical Science 66: 1-19 (1977)).
  • Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts may be prepared by methods known to those skilled in the art.
  • Other pharmaceutically acceptable excipients known to those of skill in the art are suitable for the present invention.
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with an excipient material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient that can be combined with an excipient material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound disclosed herein with the excipient and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid excipients (e.g., carriers), or finely divided solid excipients (e.g., carriers), or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • lozenges using a flavored basis, usually sucrose and acacia or tragacanth
  • a compound disclosed herein may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as par
  • the pharmaceutical compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres.
  • compositions may be sterilized by, for example, filtration through a bacteria- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions that can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions disclosed herein for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device.
  • compositions can be formulated for delivery via a dialysis port.
  • Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention.
  • Exemplary modes of administration include, but are not limited to, injection, infusion, instillation, inhalation, or ingestion.
  • “Injection” includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intraventricular, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, sub capsular, subarachnoid, intraspinal, intracerebro spinal, and intrasternal injection and infusion.
  • the compositions are administered by intravenous infusion or injection.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous excipients examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • microorganisms Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. [0293] In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.
  • the compounds of the present invention When administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable excipient.
  • the addition of the active compound of the invention to animal feed is preferably accomplished by preparing an appropriate feed premix containing the active compound in an effective amount and incorporating the premix into the complete ration. Alternatively, an intermediate concentrate or feed supplement containing the active ingredient can be blended into the feed.
  • biocompatible polymers including hydrogels
  • biocompatible polymers including hydrogels
  • biodegradable and non- degradable polymers can be used to form an implant for the sustained release of a compound at a particular target site.
  • the subject is a mammal.
  • the mammal can be a human, non-human primate, mouse, rat, dog, cat, horse, or cow, but are not limited to these examples.
  • Mammals other than humans can be advantageously used as subjects that represent animal models of disorders associated with neurodegenerative disease or disorder, cancer, or viral infections.
  • the methods described herein can be used to treat domesticated animals and/or pets.
  • a subject can be male or female.
  • a subject can be one who has been previously diagnosed with or identified as suffering from or having a neurodegenerative disease or disorder, a disease or disorder associated with cancer, a disease or disorder associated with viral infection, or one or more complications related to such diseases or disorders but need not have already undergone treatment.
  • Dosages [0300] Actual dosage levels of the active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the compound and the pharmaceutically active agent can be administrated to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).
  • the compound and the pharmaceutically active agent can be administered within 5 minutes, 10 minutes, 20 minutes, 60 minutes, 2 hours, 3 hours, 4, hours, 8 hours, 12 hours, 24 hours of administration of the other agent.
  • routes of administration can be different.
  • the amount of compound that can be combined with an excipient material to produce a single dosage form will generally be that amount of the inhibitor that produces a therapeutic effect. Generally out of one hundred percent, this amount will range from about 0.1% to 99% of inhibitor, preferably from about 5% to about 70%, most preferably from 10% to about 30%.
  • Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD 50 /ED 50 .
  • Compositions that exhibit large therapeutic indices are preferred.
  • the data obtained from the cell culture assays and animal studies can be used in formulating a range of dosage for use in humans.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • the therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the therapeutic which achieves a half-maximal inhibition of symptoms) as determined in cell culture.
  • Levels in plasma may be measured, for example, by high performance liquid chromatography.
  • the effects of any particular dosage can be monitored by a suitable bioassay.
  • the dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment.
  • the present invention contemplates formulation of the subject compounds in any of the aforementioned pharmaceutical compositions and preparations. Furthermore, the present invention contemplates administration via any of the foregoing routes of administration.
  • Embodiment 1 A compound of Formula (I) (I), or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted aryl or heteroaryl; L 1 is -CR’2-, -CR’2CR’2-, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring; each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, each optionally substituted; R 5 is NH 2 or OH; R 6 is H or C 1 -C 6 alkyl; R 7 is C 1 -C 6 alky
  • Embodiment 2 A compound of Formula (I) (I), or a pharmaceutically acceptable salt thereof, wherein A is an aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups; L 1 is -CR’ 2 -, -CR’ 2 CR’ 2 -, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring; each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and R 2 is substituted with
  • Embodiment 3 A compound of Formula (I) (I), or a pharmaceutically acceptable salt thereof, wherein A is an aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups; L 1 is -CR’ 2 -, -CR’ 2 CR’ 2 -, or a bond; each R’ is independently H or C 1 -C 6 alkyl; or two R’ together with the carbon or carbons to which they are attached form a 3-6-membered cycloalkyl ring; each R 1 , R 3 and R 4 is independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halogen; R 2 is aryl or heteroaryl, wherein heteroaryl has 5-10 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and R 2 is substituted with
  • Embodiment 4 The compound of any one of embodiments 1-3, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or heteroaryl, wherein heteroaryl has 5, 6 or 9 ring atoms, 1 to 4 ring atoms selected from N, O, and S, and wherein A is substituted with 0-4 R 9 groups, wherein each R 9 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, hydroxy, cyano, or halogen, wherein each alkyl or heteroalkyl is optionally substituted with 1-4 groups independently selected from halogen and OH. [0312] Embodiment 5.
  • A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, benzthiophene, thienopyridine (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3- b]pyridine) or furopyridine (e.g., furo[3,2-b]pyridine, furo[3,2-c]pyridine, furo[2,3-b]pyridine), each substituted with 0-9 R 9 groups.
  • A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, benzthiophene, thienopyridine (e.g., thieno[3,2-b]pyridine, thieno[3,2-c]pyridine, thieno[2,3- b]pyridine) or furopyridine (e.g., furo[3,
  • Embodiment 7 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is phenyl substituted with 0-9 R 9 groups.
  • Embodiment 8 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is benzofuran substituted with 0-9 R 9 groups.
  • Embodiment 9. The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is benzthiophene substituted with 0-9 R 9 groups.
  • Embodiment 13 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is phenyl, thiazole, thiophene, pyridine, pyridazine, benzofuran, or benzthiophene; e.g., wherein A is , , , , , , or ; and A is substituted with 0-4 R 9 groups.
  • Embodiment 13 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 14 Embodiment 14.
  • Embodiment 15 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 16 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 17 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 18 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 19 Embodiment 19.
  • Embodiment 20 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 21 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 22 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 23 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 24 Embodiment 24.
  • Embodiment 25 The compound of embodiment 4, or a pharmaceutically acceptable N salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 26 The compound of embodiment 4, or a pharmaceutically acceptable N salt thereof, wherein A is N substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 27 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 28 The compound of embodiment 4, or a pharmaceutically acceptable salt thereof, wherein A is substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 29 Embodiment 29.
  • Embodiment 30 The compound of embodiment 4, or a pharmaceutically acceptable S salt thereof, wherein A is N substituted with 0-9 R 9 groups, wherein the left attachment point represents the attachment point to L 1 and the right attachment point represents the attachment point to the carbonyl.
  • Embodiment 31 The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein A is not substituted with any R 9 groups.
  • Embodiment 32 The compound of any one of embodiments 1-30, or a pharmaceutically acceptable salt thereof, wherein A is not substituted with any R 9 groups.
  • Embodiment 33 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein L 1 is a bond.
  • Embodiment 34 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein L 1 is –CR’2CR’2–.
  • Embodiment 35 The compound of any one of embodiments 1-34, or a pharmaceutically acceptable salt thereof, wherein each R’ is independently H.
  • Embodiment 36 Embodiment 36.
  • Embodiment 37 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from a bond, –CH 2 – and .
  • Embodiment 38 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein L 1 is –CH 2 –.
  • Embodiment 39 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein L 1 is .
  • Embodiment 40 The compound of any one of embodiments 1-31, or a pharmaceutically acceptable salt thereof, wherein L 1 is .
  • Embodiment 41 The compound of any one of embodiments 1-40, or a pharmaceutically acceptable salt thereof, wherein R 3 is H.
  • Embodiment 42 The compound of any one of embodiments 1-41, or a pharmaceutically acceptable salt thereof, wherein R 4 is H.
  • Embodiment 43 The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, or R 3 is H, or R 4 is H, or each of R 1 , R 3 and R 4 is H.
  • Embodiment 44 The compound of any one of embodiments 1-6, or a pharmaceutically acceptable salt thereof, wherein R 1 is H, or R 3 is H, or R 4 is H, or each of R 1 , R 3 and R 4 is H.
  • Embodiment 45 The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, wherein R 5 is –NH 2 .
  • Embodiment 45 The compound of any one of embodiments 1-43, or a pharmaceutically acceptable salt thereof, wherein R 5 is –OH.
  • Embodiment 46 The compound of any one of embodiments 1-45, or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
  • Embodiment 47 Embodiment 47.
  • R 2 is phenyl or monocyclic heteroaryl, wherein heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms selected from N, O, and S, and R 2 is substituted with 0-4 R 10 groups, wherein each R 10 is independently C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, phenyl, C 3 -C 7 cycloalkyl, heterocyclyl, C 1 -C 6 alkylene-phenyl, C 1 -C 6 alkylene- C 3 -C 7 cycloalkyl, C 1 -C 6 alkylene- heterocyclyl, hydroxy, cyano, CO-R C , NR D 2 , or halogen, wherein heterocyclyl has 4-11 ring atoms with 1 to 4 ring atoms selected from N, O, and S; each al
  • Embodiment 48 The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted with 0-4 R 10 groups.
  • Embodiment 49 The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl substituted with 0-4 R 10 groups, and optionally wherein each R 10 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • Embodiment 50 The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R 2 is a monocyclic heteroaryl substituted with 0-4 R 10 groups.
  • Embodiment 51 Embodiment 51.
  • Embodiment 53 Embodiment 53.
  • Embodiment 55 The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl and thiophene, each substituted with 0-4 R 10 groups.
  • Embodiment 56 The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from phenyl and 2-thiophene, each substituted with 0-4 R 10 groups.
  • Embodiment 57 The compound of embodiment 47, or a pharmaceutically acceptable salt thereof, wherein R 2 is thiophene substituted with 0-4 R 10 groups.
  • Embodiment 58 Embodiment 58.
  • Embodiment 59 The compound of any one of embodiments 2-58, or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from halogen, C 1 -C 6 alkyl, and CO-R C , wherein R C is -NH 2 and wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from halogen and OH.
  • Embodiment 60 Embodiment 60.
  • each R 10 is independently selected from halogen and C 1 -C 6 alkyl, wherein the alkyl is unsubstituted or substituted with 1-4 groups independently selected from halogen and OH.
  • Embodiment 61 The compound of any one of embodiments 2-58, or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from –F, – Cl, – Me, CF 3 , –CONH 2 and –CH(OH)CH3.
  • Embodiment 62 Embodiment 62.
  • Embodiment 63 The compound of any one of embodiments 2-58, or a pharmaceutically acceptable salt thereof, wherein each R 10 is independently selected from –F, and – Me.
  • Embodiment 63 The compound of any one of embodiments 2-58, or a pharmaceutically acceptable salt thereof, wherein R 2 is monocyclic heteroaryl, wherein heteroaryl is pyridine, pyrimidine, pyridazine, pyrazine, thiazole, or thiophene, e.g., wherein R 2 is 2-thiophenyl, and each R 2 is substituted with 0-4 R 10 groups, and optionally wherein each R 10 is independently halogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.
  • Embodiment 64 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of S , , , , Me , , , , , , , , , , , , , , , and , e.g., wherein R 2 is .
  • Embodiment 65 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of: , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .
  • Embodiment 66 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of: , and .
  • Embodiment 67 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 68 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 69 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 70 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 71 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 72 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 73 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 74 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 75 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 76 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 77 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 78 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 79 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 80 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 81 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 82 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 83 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 84 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 85 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 86 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 87 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 88 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 89 The compound of any one of embodiments 1-46, or a pharmaceutically acceptable salt thereof, wherein R 2 is .
  • Embodiment 90 Embodiment 90.
  • R 7 is C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms selected from N, O, and S; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl and heteroaryl is substituted with 0-4 R 11 groups; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N, wherein the heterocycle is substituted with 0-4 R 10 groups.
  • Embodiment 91 The compound of any one of embodiments 2-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or a monocyclic heteroaryl, wherein the heteroaryl has 5 or 6 ring atoms with 1 to 2 ring atoms being N; wherein each alkyl, heteroalkyl, phenyl, cycloalkyl and heteroaryl is substituted with 0-4 R 11 groups; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with 0-4 R 10 groups.
  • Embodiment 92 The compound of any one of embodiments 2-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from –Me, –Et, ––CF 3 , CH 2 CH 2 OMe, phenyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyridinon- yl; each of which is substituted with 0-4 R 11 groups; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 5 or 6 membered heterocycle with 0 additional ring heteroatoms, wherein the heterocycle is substituted with or 1 instances of methyl or phenyl.
  • Embodiment 93 The compound of any one of embodiments 2-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, phenyl, or 6-membered heteroaryl wherein heteroaryl has 1 or 2 nitrogen ring atoms; or R 7 and R 8 are taken together with the nitrogen and sulfur to which they are attached to form a 4-7 membered heterocycle with 0-2 additional ring heteroatoms selected from O, S, and N; and R 7 is substituted with 0-4 R 11 groups.
  • Embodiment 94 Embodiment 94.
  • each R 11 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, hydroxy, cyano, and halogen, wherein the alkyl and heteroalkyl are optionally substituted with 1-4 groups independently selected from halogen and OH.
  • Embodiment 95 is independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 7 cycloalkyl, hydroxy, cyano, and halogen, wherein the alkyl and heteroalkyl are optionally substituted with 1-4 groups independently selected from halogen and OH.
  • Embodiment 98 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is –Me.
  • Embodiment 99 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is wherein R 7 is –Et. [0406] Embodiment 100.
  • Embodiment 101 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is –CF 3 .
  • Embodiment 101 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is –CH 2 CH 2 OMe.
  • Embodiment 102 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 i
  • Embodiment 103 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is [0410] Embodiment 104.
  • Embodiment 105 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 106 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 107 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 108 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 109 Embodiment 109.
  • Embodiment 110 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 111 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 112. The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 113 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 114 Embodiment 114.
  • Embodiment 115 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 116 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 117 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 118 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 119 Embodiment 119.
  • Embodiment 120 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 120 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 121 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 122 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 123 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 124 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 125 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 126 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 127 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 128 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 129 Embodiment 129.
  • Embodiment 130 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 131 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 132 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 133 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 134 Embodiment 134.
  • Embodiment 135. The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 136. The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 137. The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 138 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 140 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 141 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 142 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 143 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 144 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 145 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 146 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 147 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 148 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 is .
  • Embodiment 149 Embodiment 149.
  • Embodiment 150 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are taken together with the atoms to which they are attached to form.
  • Embodiment 151 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are taken together with the atoms to which they are attached to form .
  • Embodiment 152 The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are taken together with the atoms to which they are attached to form.
  • Embodiment 153 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is H, Me, Et, CN, cyclopropyl, CO-t-butyl, or-CO2-t-butyl.
  • Embodiment 154 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is H, Me, Et, CN, cyclopropyl, or-CO2-t- butyl, e.g., wherein R 8 is H.
  • Embodiment 155 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is H.
  • Embodiment 156 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is Me.
  • Embodiment 157 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is Et.
  • Embodiment 158 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is CN.
  • Embodiment 159 Embodiment 159.
  • Embodiment 160 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is CO-t-butyl.
  • Embodiment 161 The compound of any one of embodiments 1-148, or a pharmaceutically acceptable salt thereof, wherein R 8 is-CO 2 -t-butyl.
  • Embodiment 162. The compound of any one of embodiments 1-89, or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are joined together to form a propylene (-CH 2 -CH 2 -CH 2 -).
  • Embodiment 163 The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ia) (Ia), or a pharmaceutically acceptable salt thereof, wherein: X 1 is N or CH; X 2 is N or CH.
  • Embodiment 164 The compound of embodiment 163 of Formula (Ib) or a pharmaceutically acceptable salt thereof.
  • Embodiment 165 The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ic)
  • Embodiment 166 The compound of embodiment 165 of Formula (Id) (Id) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 167 The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ie) (Ie), or a pharmaceutically acceptable salt thereof, wherein X 4 is N or CH.
  • Embodiment 168 The compound of embodiment 167 of Formula (If) (If), or a pharmaceutically acceptable salt thereof, wherein X 4 is N or CH.
  • Embodiment 169 Embodiment 169.
  • Embodiment 170 The compound of embodiment 169 of Formula (Ih) (Ih), or a pharmaceutically acceptable salt thereof, wherein X 5 is N or CH.
  • Embodiment 171. The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ii)
  • Embodiment 172 The compound of embodiment 171 of Formula (Ij) (Ij) or a pharmaceutically acceptable salt thereof, wherein X3 is O or S; X 6 is N or CH; and X 7 is N or CH.
  • Embodiment 173 The compound of embodiment 170 or 171, or a pharmaceutically acceptable salt thereof, wherein X 6 is N and X 7 is CH.
  • Embodiment 174 The compound of embodiment 170 or 171, or a pharmaceutically acceptable salt thereof, wherein X 6 is CH and X 7 is N.
  • Embodiment 175. The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ik) (Ik), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; X 8 is N or CH; and X 9 is N or CH.
  • Embodiment 176. The compound of embodiment 175 of Formula (Im) (Im) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S; X 8 is N or CH; and X 9 is N or CH.
  • Embodiment 177. The compound of embodiment 175 or 176, or a pharmaceutically acceptable salt thereof, wherein X 8 is N and X 9 is CH.
  • Embodiment 179 The compound of any one of embodiments 1-3 and 40 to 162 of Formula (In) (In), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 180 The compound of embodiment 179 of Formula (Io) (Io) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 181. The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ip) (Ip), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 182 The compound of embodiment 181 of Formula (Iq) (Iq) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 183 The compound of any one of embodiments 1-3 and 40 to 162 of Formula (Ir) (Ir), or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 184 The compound of embodiment 183 of Formula (Is) (Is) or a pharmaceutically acceptable salt thereof, wherein X 3 is O or S.
  • Embodiment 185 Embodiment 185.
  • Embodiment 186 The compound of any one of embodiments 165, 166 and 171-184, or a pharmaceutically acceptable salt thereof, wherein X 3 is S.
  • Embodiment 186 The compound of any one of embodiments 165, 166 and 171-184, or a pharmaceutically acceptable salt thereof, wherein X3 is O.
  • Embodiment 187 A compound selected from the compounds disclosed in Table 1, or a pharmaceutically acceptable salt thereof, or elsewhere in the specification and figures.
  • Embodiment 188 A compound of any one of embodiments 1-186 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
  • Embodiment 189 A composition comprising a compound of any one of embodiments 1-188, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Embodiment 190 A method of treating a disease or disorder that can be treated by inhibition of a histone deacetylase (HDAC), the method comprising administering to a patient in need thereof a compound of any one of embodiments 1-188, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 189.
  • HDAC histone deacetylase
  • Embodiment 191 The method of embodiment 190, wherein the disease or disorder is cancer.
  • Embodiment 192 Embodiment 192.
  • the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, and cancer of the brain, stomach, kidney, breast,
  • MPNST malignant
  • Embodiment 193 The method of embodiment 191, wherein the cancer is selected from the group consisting of a melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreas cancer, and stomach cancer.
  • the cancer e.g., the HDAC-related cancer
  • the cancer is carcinoma of unknown primary (CUP), colorectal cancer (e.g., colorectal carcinoma), cervical cancer or non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • CUP unknown primary
  • NSCLC non-small cell lung cancer
  • Embodiment 195 Embodiment 195.
  • Embodiment 191 wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • NSCLC non-small cell lung cancer
  • Embodiment 196 The method of embodiment 191, wherein the cancer is cervical cancer.
  • Embodiment 197 The method of embodiment 191, wherein the cancer is colorectal cancer (e.g., colorectal carcinoma).
  • Embodiment 198 The method of embodiment 191, wherein the cancer is carcinoma of unknown primary (CUP).
  • Embodiment 199 The method of any one of embodiments 189-198, further comprising use of at least one additional therapeutic agent.
  • Embodiment 200 The method of any one of embodiments 189-198, further comprising use of at least one additional therapeutic agent.
  • Embodiment 201 The method of embodiment 199, wherein the at least one additional therapeutic agent is chemotherapy or radiation.
  • the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti- PD-L1 ligand).
  • Embodiment 202 Embodiment 202.
  • the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).
  • an anti-PD-1 antibody e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; torip
  • Embodiment 204 Use of a compound of any one of embodiments 1-188, or a pharmaceutically acceptable salt thereof, or a composition of embodiment 189 in the manufacturing of a medicament for treating a disease or disorder that can be treated by inhibition of a histone deacetylase (HDAC).
  • HDAC histone deacetylase
  • Embodiment 205 The use of embodiment 204, wherein the disease or disorder is cancer.
  • Embodiment 206. The use of embodiment 205, wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach
  • MPNST mal
  • Embodiment 207 The use of embodiment 205, wherein the cancer is selected from the group consisting of a melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreas cancer, and stomach cancer.
  • Embodiment 208 The use of embodiment 205, wherein the cancer (e.g., the HDAC- related cancer) is carcinoma of unknown primary (CUP), colorectal cancer (e.g., colorectal carcinoma), cervical cancer or non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • CUP unknown primary
  • NSCLC non-small cell lung cancer
  • embodiment 205 wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • NSCLC non-small cell lung cancer
  • Embodiment 210 The use of embodiment 205, wherein the cancer is cervical cancer.
  • Embodiment 211 The use of embodiment 205, wherein the cancer is colorectal cancer (e.g., colorectal carcinoma).
  • Embodiment 212 The use of embodiment 205, wherein the cancer is carcinoma of unknown primary (CUP).
  • Embodiment 213. The use of any one of embodiments 204-212, wherein the medicament is configured for administration with at least one additional therapeutic agent.
  • Embodiment 214 The use of embodiment 213, wherein the at least one additional therapeutic agent is chemotherapy or radiation.
  • Embodiment 215. The use of embodiment 213, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand).
  • Embodiment 216 Embodiment 216.
  • the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).
  • an anti-PD-1 antibody e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; torip
  • embodiment 215 wherein the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; envafolimab; cosibelimab; sugemalimab, AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170)).
  • an anti-PD-L1 antibody e.g., BMS936559; durvalumab; avelumab; envafolimab; cosibelimab; sugemalimab, AUNP-12; or atezolizumab
  • an anti-PD-L1 small molecule e.g., CA-170
  • Embodiment 220 The use of embodiment 219, wherein the disease or disorder is cancer.
  • embodiment 220 wherein the cancer is selected from the group consisting of glioblastoma, malignant peripheral nerve sheath tumors (MPNST), esophageal cancer (e.g., esophageal squamous cell carcinoma or esophageal adenocarcinoma), bladder cancer (e.g., bladder urothelial carcinoma), pancreatic cancer (e.g., pancreatic adenocarcinoma), mesothelioma, melanoma, non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma), astrocytoma, undifferentiated pleiomorphic sarcoma, diffuse large B-cell lymphoma (DLBCL), leukemia, head and neck cancer, stomach adenocarcinoma, myxofibrosarcoma, cholangiosarcoma, and cancer of the brain, stomach, kidney, breast
  • Embodiment 222 The use of embodiment 220, wherein the cancer is selected from the group consisting of a melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreas cancer, and stomach cancer.
  • Embodiment 223. The use of embodiment 220, wherein the cancer (e.g., the HDAC- related cancer) is carcinoma of unknown primary (CUP), colorectal cancer (e.g., colorectal carcinoma), cervical cancer or non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • CUP unknown primary
  • NSCLC non-small cell lung cancer
  • Embodiment 224 Embodiment 224.
  • Embodiment 220 wherein the cancer is non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • NSCLC non-small cell lung cancer
  • Embodiment 225 The use of embodiment 220, wherein the cancer is cervical cancer.
  • Embodiment 226 The use of embodiment 220, wherein the cancer is colorectal cancer (e.g., colorectal carcinoma).
  • Embodiment 227 The use of embodiment 220, wherein the cancer is carcinoma of unknown primary (CUP).
  • Embodiment 228 The use of any one of embodiments 219-227, wherein the use further comprises administration of at least one additional therapeutic agent.
  • Embodiment 228, wherein the at least one additional therapeutic agent is chemotherapy or radiation.
  • Embodiment 230 The use of embodiment 228, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand).
  • an immunotherapeutic agent e.g., an anti-PD-1 ligand or an anti-PD-L1 ligand.
  • embodiment 230 wherein the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).
  • an anti-PD-1 antibody e.g., nivolumab; CT-011; AMP-224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizum
  • embodiment 230 wherein the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; envafolimab; cosibelimab; sugemalimab, AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170)).
  • an anti-PD-L1 antibody e.g., BMS936559; durvalumab; avelumab; envafolimab; cosibelimab; sugemalimab, AUNP-12; or atezolizumab
  • an anti-PD-L1 small molecule e.g., CA-170
  • HDAC histone deacetylase
  • Embodiment 236 The compound or composition for use of embodiment 234, wherein the cancer is selected from the group consisting of a melanoma, bladder cancer, colorectal cancer, head and neck cancer, esophageal cancer, liver cancer, lung cancer, pancreas cancer, and stomach cancer.
  • Embodiment 237 The compound or composition for use of embodiment 235, wherein the cancer (e.g., the HDAC-related cancer) is carcinoma of unknown primary (CUP), colorectal cancer (e.g., colorectal carcinoma), cervical cancer or non-small cell lung cancer (NSCLC; e.g., lung squamous or lung adenocarcinoma).
  • CUP unknown primary
  • NSCLC non-small cell lung cancer
  • Embodiment 238 Embodiment 238.
  • Embodiment 239. The compound or composition for use of embodiment 235, wherein the cancer is cervical cancer.
  • Embodiment 240 The compound or composition for use of embodiment 235, wherein the cancer is colorectal cancer (e.g., colorectal carcinoma).
  • Embodiment 241. The compound or composition for use of embodiment 235, wherein the cancer is carcinoma of unknown primary (CUP).
  • Embodiment 243 The compound or composition for use of embodiment 242, wherein the at least one additional therapeutic agent is chemotherapy or radiation.
  • Embodiment 244. The compound or composition for use of embodiment 242, wherein the at least one additional therapeutic agent is an immunotherapeutic agent (e.g., an anti- PD-1 ligand or an anti-PD-L1 ligand).
  • the immunotherapeutic agent is an anti-PD-1 antibody (e.g., nivolumab; CT-011; AMP- 224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab; toripalimab; retifanlimab; MEDI0680; budigalimab; geptanolimab).
  • an anti-PD-1 antibody e.g., nivolumab; CT-011; AMP- 224; pembrolizumab; pidilizumab; cemiplimab; dostarlimab; prolgolimab; spartalizumab; camrelizumab; sasanlimab, sintilimab; tislelizumab;
  • the immunotherapeutic agent is an anti-PD-L1 antibody (e.g., BMS936559; durvalumab; avelumab; envafolimab; cosibelimab; sugemalimab, AUNP-12; or atezolizumab) or an anti-PD-L1 small molecule (e.g., CA-170)).
  • an anti-PD-L1 antibody e.g., BMS936559; durvalumab; avelumab; envafolimab; cosibelimab; sugemalimab, AUNP-12; or atezolizumab
  • an anti-PD-L1 small molecule e.g., CA-170
  • the chemical reagents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent Company), and used without further purification.
  • purification of intermediates and final compounds was performed using HPLC (H 2 O – MeOH; Agilent 1260 Infinity systems equipped with DAD and mass- detectors.
  • HPLC H 2 O – MeOH; Agilent 1260 Infinity systems equipped with DAD and mass- detectors.
  • mass spectra were recorded on an Agilent 1100 Series LC/MSD system with DAD ⁇ ELSD and Agilent LC ⁇ MSD VL (G1956A), SL (G1956B) mass-spectrometer or an Agilent 1200 Series LC/MSD system with DAD ⁇ ELSD and Agilent LC ⁇ MSD SL (G6130A), SL (G6140A) mass-spectrometer. All the LC/MS data were obtained using positive/negative mode switching.
  • 0-30CD Gradient: B from 0% ⁇ 30% over 2 minutes and holding at 30% for 0.48 minutes; 0-60CD: Gradient: B from 0% ⁇ 60% over 2 minutes and holding at 60% for 0.48 minutes; 10-80CD: Gradient: B from 10% ⁇ 80% over 2 minutes and holding at 80% for 0.48 minutes; 30-90CD: Gradient: B from 30% ⁇ 90% over 2 minutes and holding at 90% for 0.48 minutes; 50-100CD: Gradient: B from 50% ⁇ 100% over 2 minutes and holding at 100% for 0.48 minutes.
  • 0-30AB Gradient: B from 0% ⁇ 30% over 3 minutes and holding at 30% for 0.5 minutes
  • 0-60AB Gradient: B from 0% ⁇ 60% over 3 minutes and holding at 30% for 0.5 minutes
  • 10-80AB Gradient: B from 10% ⁇ 80% over 3 minutes and holding at 30% for 0.5 minutes
  • 30-90AB Gradient: B from 0% ⁇ 30% over 3 minutes and holding at 30% for 0.5 minutes
  • 50-100AB Gradient: B from 50% ⁇ 100% over 3 minutes and holding at 100% for 0.5 minutes.
  • Instrument Shimadzu LC20; Column: Xbridge Shield RP-1850 * 2.1 mm, 5 ⁇ m; Mobile Phase A: H 2 O with 0.01% NH3-H 2 O; Mobile Phase B: MeCN; Flow Rate: 1.2 mL/min; Wavelength: UV 220nm, 215nm, 254nm; Column temperature: 40 °C.
  • 0-30CD Gradient: B from 0 ⁇ 30% over 6 minutes and holding at 30% for 2 minutes; 0-60CD: Gradient: B from 0 ⁇ 60% over 6 minutes and holding at 60% for 2 minutes; 10-80CD: Gradient: B from 10 ⁇ 80% over 6 minutes and holding at 80% for 2 minutes; 30-90CD: Gradient: B from 30 ⁇ 90% over 6 minutes and holding at 90% for 2 minutes; 50-100CD: Gradient: B from 10 ⁇ 80% over 6 minutes and holding at 100% for 2 minutes.
  • Acid condition (HCOOH): Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Agela Durashell C18150 * 25 mm 5 ⁇ m; Mobile phase A: H 2 O (0.0225% HCOOH); Mobile phase B: MeCN; Gradient: B from 7% to 37% in 9 min, hold 100% B for 0 min; Flow Rate: 25 mL/min; Column Temperature: 30 °C; Wavelength: 220 nm, 254 nm.
  • Acid condition (HCl): Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Xtimate C18150 * 25 mm * 5 ⁇ m; Mobile phase A: H 2 O with 0.05% HCl (v%); Mobile phase B: MeCN; Gradient: B from 0% to 30% in 6.5 min, hold 100% B for 2.5 min; Flow Rate: 25 mL/min; Column Temperature: 30 °C; Wavelength: 220 nm, 254 nm).
  • Neutral condition (NH4HCO3): (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; Mobile phase A: H 2 O with 10 mmol NH4HCO3; Mobile phase B: MeCN; Gradient: B from 39% to 69% in 10 min, hold 100% B for 2.5 min; Flow Rate: 25 mL/min; Column Temperature: 30 °C; Wavelength: 220 nm, 254 nm).
  • Acid condition Instrument: Shimadzu LC-20AP Pumps, Shimadzu CBM-20A System Controller Shimadzu SPD-20AV UV/VIS Detector; Column: Phenomenex luna C18250 ⁇ 50 mm ⁇ 10 ⁇ m; Mobile phase A: H 2 O with 0.1% TFA (v%); Mobile phase B: MeCN; Gradient: B from 0% to 25% in 15 min, hold 100% B for 4 min; Flow Rate: 120 mL/min; Column Temperature: 30 °C; Wavelength: 220 nm, 254 nm.
  • Exemplary preparative chiral SFC method [0576] Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD- 10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.
  • the compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative pyrazoles that have been listed herein.
  • the compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.
  • Exemplary general method for preparative HPLC Column: Waters RBridge prep 10 ⁇ m C18, 19*250 mm.
  • Step 1 Synthesis of tert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl-carbamate
  • 4-bromo-2-nitro-aniline 30 g, 0.138 mol
  • tert-butoxycarbonyl tert- butyl carbonate about 79 mL, 0.344 mol
  • DMAP about 5 g, 40.9 mmol
  • TEA about 58 mL, 0.416 mol
  • Step 2 Synthesis of tert-butyl N-(4-bromo-2-nitro-phenyl)carbamate
  • Step 3 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-nitro-phenyl]carbamate
  • tert-butyl N-(4-bromo-2-nitro-phenyl)carbamate 46 g, 0.145 mol
  • (4-fluorophenyl)boronic acid about 26 g, 0.186 mol
  • K 2 CO 3 about 58 g, 0.420 mol
  • dioxane about 300 mL
  • H 2 O about 30 mL
  • Step 4 Synthesis of tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate [0586] To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-nitro-phenyl]carbamate (about 33 g, 99.3 mmol) in MeOH (about 300 mL) was added Pd/C (about 12 g, 10% Pd/C with 50% of water, wt%). The resulting mixture was sealed and degassed under vacuum and purged with N2 for three times, and then stirred at about 20°C for about 12 hours under H 2 (in balloon).
  • Step 5 Synthesis of methyl 4-sulfanylbenzoate [0587] To a solution of 4-sulfanylbenzoic acid (about 50 g, 0.324 mol) in MeOH (about 300 mL) was added sulfuric acid (about 10 mL, 0.188 mol). The reaction mixture was stirred at about 70°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was triturated with MeOH (about 40 mL). The mixture was filtered. The filter cake was dried under reduced pressure to give desired product (about 23 g). The filtrate was concentrated under reduced pressure. The residue was triturated with MeOH (about 20 mL) again. The mixture was filtered. The filter cake was dried under reduced pressure to give desired product (about 20 g).
  • Step 6 Synthesis of methyl 4-(3-chloropropylsulfanyl)benzoate [0588] To a mixture of methyl 4-sulfanylbenzoate (about 20 g, 0.119 mol) and 1-bromo-3- chloro-propane (about 24 mL, 0.243 mol) in THF (about 100 mL) was added N,N- diethylethanamine (about 33 mL, 0.237 mol). The mixture was stirred at about 20°C for about 2 hours. The reaction mixture was concentrated under reduced pressure.
  • Step 7 Synthesis of methyl 4-(3-chloropropylsulfonimidoyl)benzoate
  • methyl 4-(3-chloropropylsulfanyl)benzoate about 26.6 g, 0.109 mol
  • MeOH about 200 mL
  • ammonia carbamic acid
  • [acetoxy(phenyl)-iodanyl] acetate about 87.5 g, 0.272 mol
  • the reaction mixture was diluted with H 2 O (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • Step 8 Synthesis of methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate
  • a mixture of methyl 4-(3-chloropropylsulfonimidoyl)benzoate (about 19 g, 68.9 mmol) in 0.1 wt% NH 3 -H 2 O (about 200 mL) was stirred at about 80°C for about 2 hours.
  • the reaction mixture was concentrated under reduced pressure to afford methyl 4-(1-oxo-4,5- dihydro-3H-isothiazol-1-yl)benzoate (about 17 g), which was directly used without further purification.
  • Step 9 Synthesis of 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoic acid
  • methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate 17.94 g, 0.213 mol
  • MeOH about 100 mL
  • H 2 O about 30 mL
  • LiOH-H 2 O about 8.94 g, 0.213 mol
  • Step 10 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H-isothiazol-1- yl)benzoyl]amino]phenyl]carbamate
  • tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate about 21 g, 69.5 mmol
  • EDCI about 20 g, 0.104 mol
  • Step 11 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H- isothiazol-1-yl)benzamide [0593] To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H- isothiazol-1-yl)benzoyl]amino]phenyl]carbamate (about 8 g, 15.7 mmol) in DCM (about 100 mL) was added TFA (about 25 mL, 0.325 mol).
  • Step 12 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1R)-1-oxo-4,5-dihydro-3H- isothiazol-1-yl]benzamide and N-[2-amino-5-(4-fluorophenyl)phenyl]-4-[rel-(1S)-1-oxo-4,5- dihydro-3H-isothiazol-1-yl]benzamide [0594] N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H-isothiazol-1- yl)benzamide (about 6 g, 14.7 mmol) was purified by Chiral SFC separation (Instrument: Berger, multigr AM-II; Column: Daicel chiralpak AS 250 ⁇ 50 mm I.D.10 ⁇ m; Mobile phase: supercritical CO 2 /
  • Step 2 Synthesis of tert-butyl N-[2-amino-4-(4-chlorophenyl)phenyl]carbamate
  • Step 3 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(4- chlorophenyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate
  • a solution of tert-butyl N-[2-amino-4-(4-chlorophenyl)phenyl]carbamate about 100 mg, 0.313 mmol
  • 4-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzoic acid about 94 mg, 0.313 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride about 60 mg, 0.313 mmol) in pyridine (about 5 mL) was stirred at about 50°C for about 1 hour.
  • Step 4 Synthesis of N-[2-amino-5-(4-chlorophenyl)phenyl]-4-(methylsulfonimidoyl)benzamide
  • Step 3 Synthesis of methyl 4-(pyrimidin-5-ylsulfonimidoyl)benzoate
  • Step 4 Synthesis of 4-(pyrimidin-5-ylsulfonimidoyl)benzoic acid
  • methyl 4-(pyrimidin-5-ylsulfonimidoyl)benzoate about 350 mg, 1.26 mmol
  • MeOH about 6 mL
  • lithium;hydroxide;hydrate about 530 mg, 12.6 mmol
  • the mixture was stirred at about 0°C for about 3 hours.
  • the resulting mixture was extracted with EtOAc (about 20 mL * 3).
  • Step 5 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(pyrimidin-5- ylsulfonimidoyl)benzoyl]amino]phenyl]carbamate
  • Step 6 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5- ylsulfonimidoyl)benzamide and N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5- ylsulfonimidoyl)benzamide [0606] To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(pyrimidin-5- ylsulfonimidoyl)benzoyl]amino]phenyl]carbamate (about 300 mg, 0.548 mmol) in DCM (about 6 mL) was added TFA (about 1 mL, 13.0 mmol).
  • the mixture was stirred at about 20°C for about 2 hours.
  • the combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • N-[2-amino-5-(4- fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide [0609] N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyrimidin-5-ylsulfonimidoyl)benzamide (about 9.1 mg, single enantiomer, Peak 2, Retention time: 2.042 min).
  • Step 1 Synthesis of methyl 5-bromobenzothiophene-2-carboxylate [0610] A mixture of 5-bromo-2-fluoro-benzaldehyde (about 5 g, 24.6 mmol), K 2 CO 3 (about 13.6 g, 98.4 mmol) in DMF (about 50 mL) methyl 2-sulfanylacetate (about 2.9 g, 27.3 mmol) was added. The mixture was stirred at about 60°C for about 15 hours. The resulting mixture was quenched by addition of water (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • Step 2 Synthesis of methyl 5-(3-methoxy-3-oxo-propyl)sulfanylbenzothiophene-2-carboxylate [0611] A mixture of methyl 5-bromobenzothiophene-2-carboxylate (about 1 g, 3.69 mmol), methyl 3-sulfanylpropanoate (about 488 mg, 4.06 mmol), (1E,4E)-1,5-diphenylpenta-1,4-dien-3- one;palladium (about 338 mg, 0.369 mmol), (5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)- diphenyl-phosphane (about 427 mg, 0.738 mmol), N-ethyl-N-isopropyl-propan-2-amine (about 1.4 g, 10.8 mmol) in dioxane (about 10 mL) was stirred at about 100°C for about 12 hours.
  • Step 4 Synthesis of methyl 5-methylsulfanylbenzothiophene-2-carboxylate [0613] A mixture of methyl 5-sulfanylbenzothiophene-2-carboxylate (about 180 mg, 0.803 mmol), iodomethane (about 0.1 mL, 1.61 mmol), K 2 CO 3 (about 333 mg, 2.41 mmol) in MeCN (about 3 mL) was stirred at about 60°C for about 12 hours. The resulting mixture was quenched by addition of water (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • Step 5 Synthesis of methyl 5-methylsulfinylbenzothiophene-2-carboxylate [0614] To a mixture of methyl 5-methylsulfanylbenzothiophene-2-carboxylate (about 125 mg, 0.524 mmol) in DCM (about 3 mL) was added 3-chlorobenzenecarboperoxoic acid (about 136 mg, 0.788 mmol, 85 wt%) at about 0°C. The mixture was stirred at about 20°C for about 1 hour. The resulting mixture was quenched by addition of water (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • Step 6 Synthesis of methyl 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzothiophene-2- carboxylate
  • Step 7 Synthesis of 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzothiophene-2- carboxylic acid
  • Step 8 Synthesis of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamate [0617] A mixture of 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzothiophene-2- carboxylic acid (about 70 mg, 0.197 mmol), tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate (about 65 mg, 0.217 mmol), 3-(ethyliminomethyleneamino)- N,N-dimethyl-propan-1-amine;hydrochloride (about 45 mg, 0.236 mmol) in pyridine (about 2 mL) was stirred at about 50°C for about 30 minutes.
  • Step 9 Synthesis of N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamate [0618] A mixture of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]benzothiophen-5-yl]-methyl-oxo-sulfanylidene]carbamate (about 100 mg, 0.156 mmol) in TFA (about 1.5 mL) and DCM (about 5 mL) was stirred at about 25°C for 1 hour.
  • Step 2 Synthesis of methyl 4-(3-pyridylsulfinyl)benzoate
  • Step 3 Synthesis of methyl 4-(3-pyridylsulfonimidoyl)benzoate
  • Step 4 Synthesis of 4-(3-pyridylsulfonimidoyl)benzoic acid
  • Step 5 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(3- pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate
  • 4-(3-pyridylsulfonimidoyl)benzoic acid about 198 mg, 0.755 mmol
  • tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate about 251 mg, 0.830 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride about 174 mg, 0.908 mmol
  • Step 6 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(3-pyridylsulfonimidoyl)benzamide
  • the mixture was adjusted pH to about 8 with 25 wt% NH3-H 2 O.
  • the mixture was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: 2_Phenomenex Gemini C1875 * 40 mm * 3 ⁇ m; Mobile phase A: water (NH4HCO3); Mobile phase B: MeCN; Gradient: B from 35% to 65% in 9.5 min, hold 100% B for 2 min; Flow Rate: 30 mL/min; Column Temperature: 30°C; Wavelength: 220 nm, 254 nm) to afford N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(3-pyridylsulfonimidoyl)benzamide (about 103.8 mg).
  • Step 1 Synthesis of tert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl-carbamate [0625] To a solution of 4-bromo-2-nitro-aniline (about 5 g, 23.0 mmol), TEA (about 9.5 mL, 68.2 mmol), DMAP (about 1.40 g, 11.5 mmol) in DCM (about 50 mL) was added Boc2O (about 13.5 mL, 58.75 mmol) at about 20°C and the reaction mixture was stirred at about 20°C for about 16 hours.
  • 4-bromo-2-nitro-aniline about 5 g, 23.0 mmol
  • TEA about 9.5 mL, 68.2 mmol
  • DMAP about 1.40 g, 11.5 mmol
  • Boc2O about 13.5 mL, 58.75 mmol
  • Step 2 Synthesis of tert-butyl (4-bromo-2-nitrophenyl)carbamate [0626] To a solution of tert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl- carbamate (about 7.4 g, 17.7 mmol) in DCM (about 75 mL) was added TFA (about 2.1 mL, 27.26 mmol) at about 20°C and the mixture was stirred at about 20°C for about 1 hour. The reaction mixture was quenched by addition water (about 100 mL) at about 20°C, extracted with DCM (about 100 mL * 3).
  • Step 3 Synthesis of tert-butyl (4'-fluoro-3-nitro-[1,1'-biphenyl]-4-yl)carbamate [0627] To a solution of tert-butyl N-(4-bromo-2-nitro-phenyl)carbamate (about 500 mg, 1.58 mmol), (4-fluorophenyl)boronic acid (about 265 mg, 1.89 mmol) and K 2 CO 3 (about 545 mg, 3.94 mmol) in H 2 O (about 1 mL) and dioxane (about 10 mL) was added Pd(dppf)Cl 2 (about 57 mg, 0.079 mmol) at about 20°C and the mixture was stirred at about 100°C for about 4 hours.
  • Step 4 Synthesis of tert-butyl (3-amino-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate [0628] To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-nitro-phenyl]carbamate (about 500 mg, 1.50 mmol) in THF (about 10 mL) was added Pd/C (about 100 mg, 0.823 mmol) (10 wt% Pd with 50 wt% water) at about 20°C and the mixture was stirred at about 20°C for about 16 hours under H 2 (in balloon). The reaction solution was filtered, and the filter cake containing Pd/C was washed with water.
  • Step 5 Synthesis of methyl 5-(methylthio)benzofuran-2-carboxylate [0629] To a solution of 2-hydroxy-5-methylsulfanyl-benzaldehyde (about 500 mg, 2.97 mmol) and dicesium;carbonate (about 1.94 g, 5.94 mmol) in DMF (about 5 mL) / MeCN (about 5 mL) was added methyl 2-bromoacetate (about 0.33 mL, 3.57 mmol) at about 20°C and the mixture was stirred at about 85°C for about 16 hours. The reaction mixture was quenched by addition water (about 30 mL) at about 20°C, extracted with EtOAc (about 30 mL * 3).
  • Step 6 Synthesis of methyl 5-(methylsulfinyl)benzofuran-2-carboxylate [0630] To a solution of methyl 5-methylsulfanylbenzofuran-2-carboxylate (about 300 mg, 1.35 mmol) in DCM (about 10 mL) was added m-CPBA (about 329 mg, 1.62 mmol, 85% purity) at about 0°C and the mixture was stirred at about 0°C for about 1 hour. The reaction mixture was added saturated sodium thiosulfate solution was used to quench. The reaction mixture was quenched by addition water (about 30 mL) at about 20°C, extracted with DCM (about 30 mL * 3).
  • Step 7 Synthesis of methyl 5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran-2- carboxylate
  • methyl 5-methylsulfinylbenzofuran-2-carboxylate about 140 mg, 0.588 mmol
  • PhI(OAc) 2 about 284 mg, 0.882 mmol
  • NH 2 BOC about 138 mg, 1.18 mmol
  • MgO about 121 mg, 2.93 mmol
  • Rh 2 (OA) 4 about 26 mg, 0.059 mmol
  • Step 8 Synthesis of 5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran-2-carboxylic acid
  • methyl 5-(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)benzofuran-2-carboxylate about 200 mg, 0.566 mmol
  • H 2 O about 5 mL
  • LiOH-H 2 O about 238 mg, 5.67 mmol
  • Step 9 Synthesis of tert-butyl (3-(5-(N-(tert-butoxycarbonyl)-S-methylsulfonimidoyl)benzofuran- 2-carboxamido)-4'-fluoro-[1,1'-biphenyl]-4-yl)carbamate [0633] To a solution of 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzofuran-2- carboxylic acid (about 100 mg, 0.295 mmol) and tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate (about 89 mg, 0.294 mmol) in pyridine (about 2 mL) was added EDCI (about 68 mg, 0.355 mmol) at about 20°C and the mixture was stirred at about 50°C for about 1 hour.
  • reaction mixture was quenched by addition water (about 20 mL) at about 20°C, extracted with EtOAc (about 20 mL * 3). The combined organic layers were washed with brine (about 15 mL * 3), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 10 Synthesis of N-(4-amino-4'-fluoro-[1,1'-biphenyl]-3-yl)-5-(S- methylsulfonimidoyl)benzofuran-2-carboxamide
  • tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]benzofuran-5-yl]-methyl-oxo-sulfanylidene]carbamate about 180 mg, 0.289 mmol
  • DCM about 5 mL
  • TFA about 329 mg, 2.89 mmol
  • the mixture was heated to about 85°C and stirred for about 16 hours.
  • the mixture was filtered and concentrated in reduced pressure at about 50°C.
  • the residue was poured into ice-water (about 30 mL) and stirred for about 10 mins.
  • the aqueous phase was extracted with ethyl acetate (about 50 mL * 2).
  • the combined organic phase was washed with H 2 O (about 50 mL * 2), brine (about 50 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • Step 2 Synthesis of methyl 5-(bromomethyl)benzofuran-2-carboxylate
  • Step 3 Synthesis of methyl 5-(methylsulfanylmethyl)benzofuran-2-carboxylate [0637] To a mixture of methyl 5-(bromomethyl)benzofuran-2-carboxylate (about 7.0 g, 26.0 mmol) in DMF (about 100 mL) was cooled to 0°C, then added sodium methanethiolate (about 2.50 g, 35.6 mmol) in portions at about 0-5°C under N2. The mixture was stirred at about 25°C for about 3 hours. The mixture was poured into ice-water (about 100 mL) and extracted with ethyl acetate (about 50 mL*2).
  • Step 4 Synthesis of methyl 5-(methylsulfinylmethyl)benzofuran-2-carboxylate [0638] To a solution of methyl 5-(methylsulfanylmethyl)benzofuran-2-carboxylate (about 1 g, 4.23 mmol) in DCM (about 20 mL) was added 3-chlorobenzenecarboperoxoic acid (about 859 mg, 4.23 mmol, 85% purity). The mixture was stirred at about 25°C for about 1 hour. The mixture was quenched by addition of saturated Na2SO3 aqueous solution (about 20 mL), saturated Na 2 CO 3 aqueous solution (about 20 mL) and extracted with DCM (about 20 mL * 2).
  • Step 5 Synthesis of methyl 5-[(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)methyl]benzofuran-2-carboxylate
  • methyl 5-(methylsulfinylmethyl)benzofuran-2-carboxylate about 650 mg, 2.58 mmol
  • tert-butyl carbamate about 604 mg, 5.15 mmol
  • MgO about 532 mg, 12.9 mmol
  • rhodium(ii)acetatedimer about 57 mg, 129 ⁇ mol
  • (diacetoxyiodo)benzene about 1.24 g, 3.86 mmol
  • Step 6 Synthesis of 5-[(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl]benzofuran-2- carboxylic acid
  • methyl 5-[(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)methyl]benzofuran-2-carboxylate about 200 mg, 544 ⁇ mol
  • MeOH/H 2 O about 4 mL
  • LiOH.H 2 O about 69.0 mg, 1.63 mmol
  • the mixture was filtered.
  • the filter cake was dried under reduced pressure to afford 5- [(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl]benzofuran-2-carboxylic acid (about 115 mg).
  • Step7 Synthesis of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]benzofuran-5-yl]methyl-methyl-oxo-sulfanylidene]carbamate [0641] A mixture of 5-[(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl]benzofuran- 2-carboxylic acid (about 115 mg, 325.5 ⁇ mol), tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate (about 82 mg, 271 ⁇ mol) and EDCI (about 78 mg, 407 ⁇ mol) in pyridine (about 3 mL) was stirred at about 50°C for about 1 hr.
  • the mixture was concentrated under reduced pressure to give a product.
  • the product was dissolved into DCM (about 6 mL), washed with H 2 O (about 10 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 8 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-5- [(methylsulfonimidoyl)methyl]benzofuran-2-carboxamide
  • Step 1 Synthesis of methyl 6-methylsulfanylpyridine-3-carboxylate [0643] To a solution of methyl 6-chloropyridine-3-carboxylate (about 5 g, 29.1 mmol) in DMF (about 50 mL) was added sodium;methanethiolate (about 2.26 g, 32.2 mmol) at about 0°C. After addition, the mixture was stirred at about 20°C for about 12 hours. The reaction solution was added with water (about 50 mL) and extracted with EtOAc (about 80 mL * 3). The combined organic layers were washed with brine (about 80 mL * 3), dried over anhydrous Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Step 2 Synthesis of methyl 6-methylsulfinylpyridine-3-carboxylate [0644] To a solution of methyl 6-methylsulfanylpyridine-3-carboxylate (about 4.1 g, 22.4 mmol) in DCM (about 50 mL) was added 3-chlorobenzenecarboperoxoic acid (about 5.1 g, 25.1 mmol, 85 wt%) at about 0°C. After addition, the mixture was stirred at about 20°C for about 1 hour. The reaction mixture was quenched with saturated NaHCO 3 aqueous (about 50 mL) and extracted with DCM (about 60 mL * 3). The combined organic layers were dried over Na 2 SO 4 and filtered.
  • Step 3 Synthesis of methyl 6-(methylsulfonimidoyl)pyridine-3-carboxylate [0645] To a solution of methyl 6-methylsulfinylpyridine-3-carboxylate (about 3.2 g, 16.1 mmol) in MeOH (about 30 mL) were added [acetoxy(phenyl)-iodanyl] acetate (about 12.9 g, 40.2 mmol) and ammonia;carbamic acid (about 2.5 g, 32.0 mmol). The mixture was stirred at about 20°C for about 2 hours. The resulting mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of methyl 6-(N-ethyl-S-methyl-sulfonimidoyl)pyridine-3-carboxylate [0646] To a mixture of methyl 6-(methylsulfonimidoyl)pyridine-3-carboxylate (about 2 g, 9.34 mmol) in DCM (about 20 mL) was added 1M triethyloxonium;tetrafluoroborate/DCM (about 28 mL, 28.0 mmol). The mixture was stirred at about 20°C for about 1 hour. Then disodium;carbonate (about 5 g, 47.2 mmol) was added. The mixture was stirred at about 20°C for about 12 hours.
  • Step 5 Synthesis of 6-(N-ethyl-S-methyl-sulfonimidoyl)pyridine-3-carboxylic acid
  • methyl 6-(N-ethyl-S-methyl-sulfonimidoyl)pyridine-3-carboxylate about 400 mg, 1.65 mmol
  • MeOH about 6 mL
  • H 2 O about 3 mL
  • lithium;hydroxide;hydrate about 700 mg, 16.7 mmol
  • the mixture was stirred at about 20°C for about 1 hour.
  • Step 6 Synthesis of tert-butyl N-[2-[[6-(N-ethyl-S-methyl-sulfonimidoyl)pyridine-3- carbonyl]amino]-4-(4-fluorophenyl)phenyl]carbamate [0648] To a solution of 6-(N-ethyl-S-methyl-sulfonimidoyl)pyridine-3-carboxylic acid (about 100 mg, 0.438 mmol) in pyridine (about 3 mL) was added tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate (about 120 mg, 0.397 mmol) and 3- (ethylim
  • the mixture was stirred at about 100°C for about 12 hours.
  • the reaction mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the combined organic layers were washed with brine (about 20 mL), dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 2 Synthesis of isopropyl 4-(4-pyridylsulfonimidoyl)benzoate
  • isopropyl 4-(4-pyridylsulfanyl)benzoate about 540 mg, 1.98 mmol
  • DCM about 8 mL
  • 3-chlorobenzenecarboperoxoic acid about 480 mg, 2.36 mmol, 85 wt%.
  • the mixture was stirred at about 20°C for about 2 hours.
  • the mixture was quenched by addition of saturated Na 2 SO 3 aqueous solution (about 10 mL) and saturated NaHCO 3 aqueous solution (about 10 mL).
  • Step 3 Synthesis of isopropyl 4-(4-pyridylsulfonimidoyl)benzoate
  • isopropyl 4-(4-pyridylsulfonimidoyl)benzoate about 350 mg, 1.21 mmol
  • MeOH about 5 mL
  • [acetoxy(phenyl)-iodanyl] acetate about 975 mg, 3.03 mmol
  • ammonia;carbamic acid about 190 mg, 2.43 mmol
  • Step 4 Synthesis of isopropyl 4-[N-(2,2-dimethylpropanoyl)-S-(4- pyridyl)sulfonimidoyl]benzoate
  • pyridine about 0.12 mL, 1.48 mmol
  • 2,2- dimethylpropanoyl chloride about 0.14 mL, 1.14 mmol
  • Step 5 Synthesis of 4-[N-(2,2-dimethylpropanoyl)-S-(4-pyridyl)sulfonimidoyl]benzoic acid
  • isopropyl 4-[N-(2,2-dimethylpropanoyl)-S-(4-pyridyl)sulfonimidoyl]benzoate about 200 mg, 0.514 mmol
  • H 2 O about 0.5 mL
  • the mixture was stirred at about 20°C for about 12 hours.
  • the mixture was concentrated under reduced pressure to remove the organic solvent.
  • the mixture was filtered.
  • the filter cake was dried under reduced pressure to give 4- [N-(2,2-dimethylpropanoyl)-S-(4-pyridyl)sulfonimidoyl]benzoic acid (about 260 mg).
  • Step 6 Synthesis of tert-butyl N-[2-[[4-[N-(2,2-dimethylpropanoyl)-S-(4- pyridyl)sulfonimidoyl]benzoyl]amino]-4-(4-fluorophenyl)phenyl]carbamate [0654] To a solution of 4-[N-(2,2-dimethylpropanoyl)-S-(4-pyridyl)sulfonimidoyl]benzoic acid (about 160 mg, 0.461 mmol) in pyridine (about 5 mL) was added EDCI (about 130 mg, 0.678 mmol) and tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 170 mg, 0.562 mmol).
  • Step 8 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(4-pyridylsulfonimidoyl)benzamide
  • a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(4- pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate (about 100 mg, 0.182 mmol) in HFIP (about 12 mL) was taken up into a microwave tube. The sealed tube was heated at about 90°C for about 1 hour in microwave. The reaction mixture was concentrated under reduced pressure.
  • Step 1 Synthesis of methyl 5-methylbenzothiophene-2-carboxylate [0657] To a mixture of 2-fluoro-5-methyl-benzaldehyde (about 2 g, 14.5 mmol) in DMF (about 30 mL) was added K 2 CO 3 (about 4.00 g, 28.9 mmol) and 2-fluoro-5-methyl- benzaldehyde (about 2 g, 14.5 mmol). The resulting mixture was stirred at about 80°C for about 4 hours under N2. The resulting mixture was cooled to about 25°C and filtered, the filtrate was poured into ice-water (about 40 mL) and extracted with EtOAc (about 20 mL * 2).
  • Step 2 Synthesis of methyl 5-(bromomethyl)benzothiophene-2-carboxylate [0658] A mixture of methyl 5-methylbenzothiophene-2-carboxylate (about 1.5 g, 7.27 mmol) in CCl4 (about 30 mL) was added NBS (about 1.29 g, 7.27 mmol) and 2,2'- azobis(isobutyronitrile) (about 119 mg, 727 ⁇ mol) was heated to about 80°C and stirred for about 12 hours under N2. The resulting mixture was cooled to about 25°C and filtered, the filtrate was concentrated. The mixture was filtered and the filtrate was evaporated.
  • Step 3 Synthesis of methyl 5-(methylsulfanylmethyl)benzothiophene-2-carboxylate
  • Step 4 Synthesis of methyl 5-(methylsulfinylmethyl)benzothiophene-2-carboxylate [0660] To a solution of methyl 5-(methylsulfanylmethyl)benzothiophene-2-carboxylate (about 710 mg, 2.81 mmol) in DCM (about 20 mL) was added 3-chlorobenzenecarboperoxoic acid (about 571 mg, 2.81 mmol, 85% purity). The mixture was stirred at about 25°C for about 2 hours. The mixture was quenched by addition of saturated Na 2 SO 3 aqueous solution (about 10 mL), saturated Na 2 CO 3 aqueous solution (about 10 mL) and extracted with DCM (about 10 mL * 2).
  • Step 5 Synthesis of methyl 5-[(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl] benzothiophene-2-carboxylate
  • methyl 5-(methylsulfinylmethyl) benzothiophene-2-carboxylate 390 mg, 1.45 mmol
  • tert-butyl carbamate about 340 mg, 2.91 mmol
  • MgO about 300 mg, 7.27 mmol
  • rhodium(II)acetatedimer about 32.1 mg, 72.7 ⁇ mol
  • Step 6 Synthesis of 5-[(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl] benzothiophene- 2-carboxylic acid
  • the mixture was filtered.
  • the filter cake was dried under reduced pressure to give 5- [(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl]benzothiophene-2-carboxylic acid (about 130 mg), which was directly used without further purification.
  • Step 7 Synthesis of tert-butyl N-[[2-[[2-(tert-butoxycarbonylamino)-5-(4-fluorophenyl)phenyl] carbamoyl]benzothiophen-5-yl]methyl-methyl-oxo-sulfanylidene]carbamate [0663] A mixture of tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 90 mg, 298 ⁇ mol), 5-[(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl]benzothiophene-2- carboxylic acid (about 132 mg, 357 ⁇ mol) and EDCI (about 85.6 mg, 447 ⁇ mol) in pyridine (about 3 mL) was stirred at about 50°C for about 1 hour.
  • Step 8 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-5-[(methylsulfonimidoyl)methyl] benzothiophene-2-carboxamide
  • the reaction was stirred at about 20°C for about 16 hours.
  • the combined organic layer was concentrated under reduced pressure to give a product.
  • Step 1 Synthesis of isopropyl 4-(2-pyridylsulfanyl)benzoate [0665] To a mixture of methyl 4-iodobenzoate (about 3 g, 11.5 mmol), pyridine-2-thiol (about 1.29 g, 11.6 mmol), CuI (about 450 mg, 2.36 mmol), K 2 CO 3 (about 3.16 g, 22.9 mmol) and ethylene glycol (about 1.35 mL, 24.2 mmol) was added isopropyl alcohol (about 15 mL). The mixture was stirred at about 100°C for about 12 hours under N 2 atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure.
  • Step 2 Synthesis of isopropyl 4-(2-pyridylsulfinyl)benzoate [0666] To a solution of isopropyl 4-(2-pyridylsulfanyl)benzoate (about 680 mg, 2.49 mmol) in DCM (about 8 mL) was added 3-chlorobenzenecarboperoxoic acid (about 464 mg, 2.29 mmol, 85 wt%). The mixture was stirred at about 20°C for about 1 hour. To the mixture was added 3-chlorobenzenecarboperoxoic acid (about 464 mg, 2.29 mmol, 85 wt%). The mixture was stirred at about 20°C for about 1 hour.
  • Step 3 Synthesis of isopropyl 4-(2-pyridylsulfonimidoyl)benzoate [0667] To a solution of isopropyl 4-(2-pyridylsulfinyl)benzoate (about 550 mg, 1.90 mmol) in MeOH (5 mL) was added [bis(acetoxy)iodo]benzene (about 1.53 g, 4.75 mmol) and ammonia;carbamic acid (about 297 mg, 3.80 mmol). The mixture was stirred at about 20°C for about 2 hours. The reaction mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of isopropyl 4-[N-(2,2-dimethylpropanoyl)-S-(2- pyridyl)sulfonimidoyl]benzoate
  • isopropyl 4-(2-pyridylsulfonimidoyl)benzoate about 200 mg, 0.657 mmol
  • DCM about 5 mL
  • pyridine about 0.08 mL, 0.989 mmol
  • 2,2- dimethylpropanoyl chloride about 0.1 mL, 0.817 mmol
  • Step 5 Synthesis of 4-[N-(2,2-dimethylpropanoyl)-S-(2-pyridyl)sulfonimidoyl]benzoic acid
  • isopropyl 4-[N-(2,2-dimethylpropanoyl)-S-(2- pyridyl)sulfonimidoyl]benzoate about 190 mg, 0.489 mmol
  • MeOH about 3 mL
  • H 2 O about 1 mL
  • LiOH-H 2 O about 21 mg, 0.500 mmol
  • Step 6 Synthesis of tert-butyl N-[2-[[4-[N-(2,2-dimethylpropanoyl)-S-(2- pyridyl)sulfonimidoyl]benzoyl]amino]-4-(4-fluorophenyl)phenyl]carbamate [0670] To a solution of 4-[N-(2,2-dimethylpropanoyl)-S-(2-pyridyl)sulfonimidoyl]benzoic acid (about 130 mg, 0.375 mmol) and tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate (about 113 mg, 0.375 mmol) in pyridine (about 5 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride (about 108 mg, 0.563 mmol).
  • Step 7 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(2- pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate [0671] To a solution of tert-butyl N-[2-[[4-[N-(2,2-dimethylpropanoyl)-S-(2- pyridyl)sulfonimidoyl]benzoyl]amino]-4-(4-fluorophenyl)phenyl]carbamate (about 120 mg, 0.190 mmol) in MeOH (about 2 mL) and THF (about 2 mL) was added 50% KOH aqueous solution (about 2.1 mL, 38.3 mmol).
  • Step 8 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(2-pyridylsulfonimidoyl)benzamide
  • N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(2-pyridylsulfonimidoyl)benzamide [0672]
  • tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(2- pyridylsulfonimidoyl)benzoyl]amino]phenyl]carbamate about 90 mg, 0.164 mmol
  • DCM about 5 mL
  • TFA about 0.25 mL, 3.24 mmol
  • Step 1 Synthesis of tert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl-carbamate.
  • DMAP about 1.4 g, 11.5 mmol
  • TEA about 9.5 mL, 68.2 mmol
  • Boc 2 O about 13.5 mL, 58.8 mmol
  • Step 2 Synthesis of tert-butyl (4-bromo-2-nitrophenyl)carbamate
  • a solution of tert-butyl N-(4-bromo-2-nitro-phenyl)-N-tert-butoxycarbonyl- carbamate (about 8.23 g, 19.7 mmol), TFA (about 3 mL, 39.4 mmol) in DCM (about 85 mL) was stirred at about 20°C for about 1 hour. The resulting mixture was quenched by addition of water (about 100 mL) and extracted with DCM (about 100 mL * 3).
  • Step 3 Synthesis of tert-butyl N-[4-(3-carbamoylphenyl)-2-nitro-phenyl] carbamate
  • tert-butyl N-(4-bromo-2-nitro-phenyl)carbamate about 500 mg, 1.58 mmol
  • (3-carbamoylphenyl)boronic acid about 312 mg, 1.89 mmol
  • K 2 CO 3 about 545 mg, 3.94 mmol
  • dioxane about 6 mL
  • H 2 O about 0.6 mL
  • Pd(dppf)Cl 2 -DCM about 128 mg, 0.158 mmol
  • Step 4 Synthesis of tert-butyl N-[2-amino-4-(3-carbamoylphenyl)phenyl]carbamate [0676] To a solution of tert-butyl N-[4-(3-carbamoylphenyl)-2-nitro-phenyl]carbamate (about 0.455 g, 1.27 mmol) in THF (about 8 mL) was added Pd/C (about 100 mg, 10 wt% Pd/C with 50 wt% water) and the mixture was stirred at about 20°C for about 12 hours under H 2 (about 15 psi).
  • Step 5 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(3- carbamoylphenyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate
  • a solution of tert-butyl N-[2-amino-4-(3-carbamoylphenyl)phenyl]carbamate about 100 mg, 0.305 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1- amine;hydrochloride about 70 mg, 0.366 mmol
  • pyridine about 5 mL
  • Step 6 Synthesis of 3-[4-amino-3-[[4-(methylsulfonimidoyl)benzoyl]amino]phenyl]benzamide
  • Step 1 Synthesis of methyl 6-sulfanylpyridine-3-carboxylate [0679] To a solution of methyl 6-chloropyridine-3-carboxylate (about 4 g, 23.3 mmol) in dioxane (about 50 mL) was added methyl 3-sulfanylpropanoate (about 3.36 g, 27.98 mmol), Pd 2 (dba) 3 (about 427 mg, 0.466 mmol), XantPhos (about 2.7 g, 4.66 mmol), Cs 2 CO 3 (about 22.8 g, 69.9 mmol). The reaction mixture was stirred at about 100°C for about 5 hours.
  • Step 2 Synthesis of methyl 6-cyclopropylsulfanylpyridine-3-carboxylate [0680] To a solution of methyl 6-sulfanylpyridine-3-carboxylate (about 0.85 g, 5.02 mmol) in 1,2-dichloroethane (about 10 mL) was added cyclopropylboronic acid (about 690 mg, 8.04 mmol), 2,2'-bipyridine (about 785 mg, 5.02 mmol), copper;diacetate;hydrate (about 912 mg, 5.02 mmol), dicesium;carbonate (about 1.64 g, 5.02 mmol). The reaction mixture was stirred at about 70°C for about 12 hours.
  • Step 3 Synthesis of methyl 6-cyclopropylsulfinylpyridine-3-carboxylate [0681] To a solution of m-CPBA (about 677 mg, 3.92 mmol, 85 wt%) in DCM (about 10 mL) was added methyl 6-cyclopropylsulfanylpyridine-3-carboxylate (about 0.8 g, 3.82 mmol). The mixture was stirred at about 20°C for about 2 hours. The mixture was quenched by addition of saturated Na 2 SO 3 aqueous solution (about 20 mL) and extracted with DCM (about 30 mL * 3).
  • Step 4 Synthesis of methyl 6-(N-tert-butoxycarbonyl-S-cyclopropyl-sulfonimidoyl)pyridine-3- carboxylate
  • NH 2 Boc about 1.87 g, 16.0 mmol
  • [bis(acetoxy)iodo]benzene 3.43 g, 10.7 mmol
  • MgO about 1.47 g, 35.5 mmol
  • diacetoxyrhodium about 157 mg, 0.710 mmol
  • DCM about 10 mL
  • methyl 6-cyclopropylsulfinylpyridine-3-carboxylate about 800 mg, 3.55 mmol.
  • reaction mixture was stirred at about 40°C for about 16 hours.
  • the resulting mixture was quenched by addition of water (about 30 mL) and extracted with EtOAc (about 30 mL * 3).
  • the combined organic layer was washed with brine (about 30 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 5 Synthesis of 6-(N-tert-butoxycarbonyl-S-cyclopropyl-sulfonimidoyl)pyridine-3-carboxylic acid
  • Step 6 Synthesis of tert-butyl N-[[5-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]-2-pyridyl]-cyclopropyl-oxo-sulfanylidene]carbamate [0684] To a solution of EDCI (about 153 mg, 0.797 mmol) in pyridine (about 5 mL) was added 6-(N-tert-butoxycarbonyl-S-cyclopropyl-sulfonimidoyl)pyridine-3-carboxylic acid (about 130 mg, 0.398 mmol) and tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 120 mg, 0.398 mmol).
  • EXAMPLE 14 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-6-(1-oxo-4,5-dihydro- 3H-isothiazol-1-yl)pyridine-3-carboxamide (Compound 178) Step 1: Synthesis of methyl 6-sulfanylpyridine-3-carboxylate [0686] To a solution of 6-sulfanylpyridine-3-carboxylic acid (about 3 g, 19.3 mmol) in MeOH (20 mL) was added H 2 SO 4 (about 1 mL, 19.3 mmol). The mixture was stirred at about 70°C for about 12 hours. The reaction mixture was poured into about 50 mL ice water.
  • the resultant mixture concentrated under reduced pressure to remove MeOH.
  • the mixture was extracted with EtOAc (about 80 mL * 3).
  • the combined organic layers were washed with brine (about 50 mL), dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure to afford methyl 6-methylsulfanylpyridine-3-carboxylate (about 1.7 g).
  • the combined organic layers were washed with brine (about 50 mL), dried over Na 2 SO 4 and filtered.
  • Step 3 Synthesis of methyl 6-(3-chloropropylsulfonimidoyl)pyridine-3-carboxylate [0688] To a solution of methyl 6-(3-chloropropylsulfanyl)pyridine-3-carboxylate (about 860 mg, 3.50 mmol) in MeOH (about 20 mL) was added ammonia;carbamic acid (about 600 mg, 7.69 mmol) and [acetoxy(phenyl)-iodanyl] acetate (about 3.01 g, 9.35 mmol). The mixture was stirred at about 20°C for about 2 hours.
  • Step 4 Synthesis of methyl 6-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)pyridine-3-carboxylate
  • Step 5 Synthesis of 6-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)pyridine-3-carboxylic acid
  • Step 6 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[6-(1-oxo-4,5-dihydro-3H-isothiazol-1- yl)pyridine-3-carbonyl]amino]phenyl]carbamate [0691] To a solution of 6-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)pyridine-3-carboxylic acid (about 120 mg, 0.530 mmol) in pyridine (about 5 mL) were added tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate (about 160 mg, 0.530 mmol) and 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride (about 160 mg, 0.835 mmol).
  • Step 7 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-6-(1-oxo-4,5-dihydro-3H-isothiazol- 1-yl)pyridine-3-carboxamide [0692] To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[6-(1-oxo-4,5-dihydro-3H- isothiazol-1-yl)pyridine-3-carbonyl]amino]phenyl]carbamate (about 58 mg, 0.113 mmol) in HFIP (about 12 mL) was heated at about 90°C for about 2 hours in microwave. The reaction mixture was concentrated under reduced pressure.
  • Step 2 Synthesis of methyl 4-(trifluoromethylsulfonimidoyl)benzoate
  • methyl 4-(trifluoromethylsulfanyl)benzoate about 100 mg, 0.423 mmol
  • CF 3 CH 2 OH about 2 mL
  • [acetoxy(phenyl)-iodanyl] acetate about 285 mg, 0.884 mmol
  • ammonia;carbamic acid about 50 mg, 0.640 mmol
  • Step 3 Synthesis of 4-(trifluoromethylsulfonimidoyl)benzoic acid
  • methyl 4-(trifluoromethylsulfonimidoyl)benzoate about 40 mg, 0.149 mmol
  • MeOH about 2 mL
  • H 2 O about 1 mL
  • lithium;hydroxide;hydrate about 30 mg, 0.714 mmol
  • the mixture was stirred at about 20°C for about 1 hour.
  • the mixture was concentrated under reduced pressure to remove the organic solvent.
  • Step 5 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4- (trifluoromethylsulfonimidoyl)benzamide
  • Step 1 Synthesis of tert-butyl N-[4-(5-carbamoyl-2-thienyl)-2-nitro-phenyl]carbamate
  • tert-butyl N-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate about 200 mg, 0.549 mmol
  • 5-bromothiophene-2-carboxamide about 86 mg, 0.419 mmol
  • dioxane about 3 mL
  • Pd(dppf)Cl 2 about 31 mg, 0.0420 mmol
  • K 2 CO 3 about 173 mg, 1.25 mmol
  • the resulting mixture was stirred at about 100°C for about 12 hours under N 2 .
  • the resulting mixture was quenched by addition of water (about 10 mL) and extracted with EtOAc (about 20 mL * 3).
  • the combined organic layer was washed with brine (about 10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl N-[2-amino-4-(5-carbamoyl-2-thienyl) phenyl]carbamate
  • Step 3 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(5-carbamoyl-2- thienyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate [0700] A mixture of tert-butyl N-[2-amino-4-(5-carbamoyl-2-thienyl)phenyl]carbamate (about 30 mg, 0.0900 mmol), 4-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzoic acid (about 30 mg, 0.0990 mmol) and EDCI (about 21 mg, 0.108 mmol) in
  • Step 4 Synthesis of 5-[4-amino-3-[[4-(methylsulfonimidoyl)benzoyl]amino]phenyl]thiophene-2- carboxamide [0701]
  • Step 2 Synthesis of methyl 6-(2-pyridylsulfinyl)pyridine-3-carboxylate [0703] To a mixture of methyl 6-(2-pyridylsulfanyl)pyridine-3-carboxylate (about 970 mg, 3.94 mmol) in DCM (about 10 mL) was added 3-chlorobenzenecarboperoxoic acid (about 1.20 g, 5.91 mmol, 85 wt%) at about 0°C. The mixture was stirred at about 20°C for about 1 hour. The resulting mixture was quenched by addition of water (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • Step 3 Synthesis of methyl 6-(2-pyridylsulfonimidoyl)pyridine-3-carboxylate
  • Step 4 Synthesis of 6-(2-pyridylsulfonimidoyl)pyridine-3-carboxylic acid
  • a mixture of methyl 6-(2-pyridylsulfonimidoyl)pyridine-3-carboxylate (about 270 mg, 0.974 mmol), lithium; hydroxide; hydrate (about 204 mg, 4.87 mmol) in H 2 O (about 2.5 mL) and MeOH (about 2.5 mL) was stirred at about 20°C for about 1 hour.
  • Step 5 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[6-(2-pyridylsulfonimidoyl)pyridine-3- carbonyl]amino]phenyl]carbamate
  • Step 6 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-6-(2-pyridylsulfonimidoyl)pyridine- 3-carboxamide
  • Step 2 Synthesis of methyl 4-pyridazin-3-ylsulfanylbenzoate
  • Step 3 Synthesis of methyl 4-pyridazin-3-ylsulfinylbenzoate [0710] To a solution of methyl 4-pyridazin-3-ylsulfanylbenzoate (about 1.1 g, 4.47 mmol) in DCM (about 10 mL) was added m-CPBA (about 1 g, 4.93 mmol, 85 wt%) at about 0°C. The mixture was stirred at about 20°C for about 13 hours. The mixture was quenched by addition of saturated Na2SO3 aqueous solution (about 30 mL), saturated Na 2 CO 3 aqueous solution (about 30 mL) and extracted with DCM (about 30 mL * 2).
  • Step 4 Synthesis of methyl 4-(pyridazin-3-ylsulfonimidoyl)benzoate
  • Step 5 Synthesis of 4-(pyridazin-3-ylsulfonimidoyl)benzoic acid
  • methyl 4-(pyridazin-3-ylsulfonimidoyl)benzoate about 380 mg, 1.37 mmol
  • MeOH about 3 mL
  • H 2 O about 1 mL
  • LiOH-H 2 O about 570 mg, 13.6 mmol
  • the mixture was stirred at about 20°C for about 1 hour.
  • the resulting mixture was concentrated under reduced pressure to remove MeOH.
  • Step 6 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(pyridazin-3- ylsulfonimidoyl)benzoyl]amino]phenyl]carbamate
  • Step 7 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(pyridazin-3- ylsulfonimidoyl)benzamide
  • Step 2 Synthesis of tert-butyl N-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate [0716] To a mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (about 6 g, 23.6 mmol), tert-butyl N-(4-bromo-2-nitro-phenyl)carbamate (about 5 g, 15.8 mmol) in 1,4-dioxane (about 30 mL) were added KOAc (about 8.9 g, 31.5 mmol) and cyclopentyl(diphenyl)phosphane;dichloromethane dichloropalladium;iron (about 1.29 g, 1.58 mmol).
  • Step 3 Synthesis of tert-butyl N-(2-nitro-4-pyrimidin-2-yl-phenyl)carbamate [0717] To a mixture of tert-butyl N-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate (about 1.50 g, 4.12 mmol), 2-bromopyrimidine (about 500 mg, 3.14 mmol) in dioxane (about 15 mL) and H 2 O (about 5 mL) were added Pd(dppf)Cl2 (about 230 mg, 0.315 mmol) and K 2 CO 3 (about 1.3 g, 9.41 mmol).
  • Step 4 Synthesis of tert-butyl N-(2-amino-4-pyrimidin-2-yl-phenyl)carbamate [0718] To a solution of tert-butyl N-(2-nitro-4-pyrimidin-2-yl-phenyl)carbamate (about 140 mg, 0.443 mmol) in THF (about 5 mL) was added Pd/C (about 50 mg, 10 wt% Pd with 50 wt% water). The suspension was degassed and purged with hydrogen for about 3 times. The mixture was stirred at about 20°C for about 12 hours under hydrogen (in balloon). The resulting mixture was filtered.
  • Step 5 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-pyrimidin-2-yl- phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate
  • a mixture of tert-butyl N-(2-amino-4-pyrimidin-2-yl-phenyl)carbamate about 120 mg, 0.419 mmol
  • 4-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzoic acid about 100 mg, 0.334 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1- amine;hydrochloride about 96 mg, 0.501 mmol) in pyridine (about 4 mL) was stirred at about 50°C for about 1 hour.
  • Step 6 Synthesis of N-(2-amino-5-pyrimidin-2-yl-phenyl)-4-(methylsulfonimidoyl)benzamide
  • Step 1 Synthesis of tert-butyl N-(2-nitro-4-pyridazin-3-yl-phenyl)carbamate
  • tert-butyl N-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]carbamate about 1 g, 2.75 mmol
  • 3-bromopyridazine about 360 mg, 2.26 mmol
  • dioxane about 15 mL
  • Pd(dppf)Cl2 about 333 mg, 0.456 mmol
  • K 2 CO 3 about 938 mg, 6.79 mmol
  • the resulting mixture was stirred at about 100°C for about 12 hours under N2.
  • the resulting mixture was quenched by addition of water (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • the combined organic layer was washed with brine (about 100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl N-(2-amino-4-pyridazin-3-yl-phenyl)carbamate
  • the suspension was degassed and purged with hydrogen for about 3 times.
  • the filtrate was concentrated under reduced pressure at about 20°C for about 5 hours.
  • Step 3 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-pyridazin-3-yl- phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate
  • a mixture of 4-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzoic acid about 100 mg, 0.334 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1- amine;hydrochloride about 96 mg, 0.501 mmol
  • tert-butyl N-(2-amino-4-pyridazin-3-yl- phenyl)carbamate about 106 mg, 0.370 mmol
  • pyridine about 4 mL
  • Step 4 Synthesis of N-(2-amino-5-pyridazin-3-yl-phenyl)-4-(methylsulfonimidoyl)benzamide
  • tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-pyridazin-3-yl- phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate about 70 mg, 0.123 mmol
  • TFA about 1.5 mL
  • the mixture was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column:2_Phenomenex Gemini C1875 * 40 mm * 3 ⁇ m; Mobile phase A: water (10mm NH 4 HCO 3 )-ACN; Mobile phase B: MeCN; Gradient: B from 7 % to 37 % in 7.8 min, hold 100% B for 1 min; Flow Rate: 30 mL/min; Column Temperature:30 °C; Wavelength: 220 nm, 254 nm) to afford N-(2-amino-5-pyridazin-3-yl-phenyl)-4-(methylsulfonimidoyl)benzamide (about 15 mg).
  • Step 1 Synthesis of 4-(2-methylthiazol-5-yl)-2-nitro-aniline [0725] A mixture of 4-bromo-2-nitro-aniline (about 330 mg, 1.52 mmol), 2-methyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole (about 445 mg, 1.98 mmol), cyclopentyl(diphenyl)phosphane;dichloromethane; dichloropalladium;iron (about 248 mg, 0.304 mmol), Na 2 CO 3 (about 483 mg, 4.56 mmol) in H 2 O (about 5 mL) and DME (about 15 mL) was stirred at about 120°C for about 2 hours in microwave.
  • Step 2 Synthesis of tert-butyl N-[4-(2-methylthiazol-5-yl)-2-nitro-phenyl]carbamate
  • the reaction mixture was diluted with H 2 O (about 20 mL) and extracted with dichloromethane (about 20 mL * 3). The combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The residue was diluted with DCM (about 5 mL). To the mixture was added TEA (about 0.6 mL, 4.30 mmol), DMAP (about 80 mg, 0.655 mmol) and tert-butoxycarbonyl tert-butyl carbonate (about 0.7 mL, 3.05 mmol), The mixture was stirred about 20°C for about 12 hours.
  • Step 3 Synthesis of tert-butyl N-[2-amino-4-(2-methylthiazol-5-yl)phenyl]carbamate [0727] To a solution of tert-butyl N-[4-(2-methylthiazol-5-yl)-2-nitro-phenyl]carbamate (about 143 mg, 0.426 mmol) in THF (about 5 mL) was added Pd-C (about 15 mg, 10% of Pd with 50% of water, wt%) under N2 atmosphere. The suspension was degassed and purged with hydrogen for about 3 times. The mixture was stirred under hydrogen (in balloon) at about 20°C for about 12 hours. The mixture was filtered.
  • Step 5 Synthesis of N-[2-amino-5-(2-methylthiazol-5-yl)phenyl]-4- (methylsulfonimidoyl)benzamide
  • Step 1 Synthesis of 4-(2-cyclopropylethynyl)-2-nitro-aniline
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[4-(2-cyclopropylethynyl)-2-nitro- phenyl]carbamate
  • 4-(2-cyclopropylethynyl)-2-nitro-aniline about 880 mg, 4.35 mmol
  • THF about 10 mL
  • tert-butoxycarbonyl tert-butyl carbonate about 2.5 mL, 10.9 mmol
  • N,N-diethylethanamine about 1.8 mL, 13.1 mmol
  • N,N-dimethylpyridin-4-amine about 53 mg, 0.434 mmol.
  • the mixture was stirred at about 25°C for about 12 hours.
  • the reaction mixture was diluted with water (about 20 mL) and extracted with EtOAc (about 30 mL * 3).
  • the combined organic layers were washed with brine (about 30 mL), dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of tert-butyl N-[2-amino-4-(2-cyclopropylethynyl)phenyl]carbamate [0733] To a solution of tert-butyl N-[4-(2-cyclopropylethynyl)-2-nitro-phenyl]carbamate (about 915 mg, 3.03 mmol) in EtOH (about 9 mL) and H 2 O (about 3 mL) was added Iron (about 845 mg, 15.1 mmol) and ammonia;hydrochloride (about 809 mg, 15.1 mmol). The mixture was stirred at about 80°C for about 1 hour. The reaction mixture was filtered.
  • the mixture was stirred at about 50°C for about 1 hour.
  • the reaction mixture was diluted with NH 4 Cl (about 30 mL) and extracted with EtOAc (about 40 mL * 2).
  • the combined organic layers were washed with brine (about 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the mixture was stirred at about 20°C for about 12 hours.
  • the resultant mixture was dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Step 1 methyl 4-(3-chloropropylsulfanyl)benzoate
  • a mixture of methyl 4-sulfanylbenzoate (about 1 g, 5.94 mmol), 1-bromo-3-chloro- propane (about 1.2 mL, 11.9 mmol), N,N-diethylethanamine (about 1.7 mL, 11.9 mmol) in THF (about 30 mL) was stirred at about 20°C for about 2 hours.
  • the reaction mixture was diluted with H 2 O (about 20 mL) and extracted with EtOAc (about 40 mL * 2).
  • the combined organic layers were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 Synthesis of methyl 4-(3-chloropropylsulfonimidoyl)benzoate
  • methyl 4-(3-chloropropylsulfanyl)benzoate about 1.3 g, 5.31 mmol
  • MeOH about 20 mL
  • ammonia;carbamic acid about 0.83 g, 10.6 mmol
  • [acetoxy(phenyl)-iodanyl] acetate about 4.28 g, 13.3 mmol.
  • the reaction mixture was diluted with H 2 O (about 20 mL) and extracted with EtOAc (about 20 mL * 3).
  • Step 3 Synthesis of methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate
  • a methyl 4-(3-chloropropylsulfonimidoyl)benzoate (about 980 mg, 3.55 mmol) in 0.1 wt% NH 3 -H 2 O (about 10 mL) were taken up into a microwave tube.
  • the sealed tube was heated at about 80°C for about 1 hour in microwave.
  • the reaction mixture was concentrated under reduced pressure.
  • Step 4 Synthesis of 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoic acid [0739] To a solution of methyl 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoate (about 245 mg, 1.02 mmol) in MeOH (about 4 mL) and H 2 O (about 2 mL) was added LiOH-H 2 O (about 430 mg, 10.3 mmol). The mixture was stirred at about 20°C for about 1 hour. The mixture was filtered.
  • Step 5 Synthesis of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H-isothiazol-1- yl)benzoyl]amino]phenyl]carbamate [0740] To a solution of 4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzoic acid (about 600 mg, 0.453 mmol) and tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 137 mg, 0.453 mmol) in pyridine (about 6 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethyl- propan-1-amine;hydrochloride (about 130 mg, 0.678 mmol).
  • Step 6 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H-isothiazol- 1-yl)benzamide [0741] To a solution of tert-butyl N-[4-(4-fluorophenyl)-2-[[4-(1-oxo-4,5-dihydro-3H- isothiazol-1-yl)benzoyl]amino]phenyl]carbamate (about 70 mg, 0.137 mmol) in DCM (about 5 mL) was added TFA (about 0.2 mL, 2.60 mmol). The mixture was stirred at about 20°C for about 1 hour.
  • the mixture was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: Du-rashell 75 * 40 mm * 3 ⁇ m; Mobile phase A: H 2 O with 0.05% NH4HCO3 (v%); Mobile phase B: MeCN; Gradient: B from 35% to 65% in 7.8 min, hold 100% B for 2 min; Flow Rate: 30mL/min; Column Temperature: 30 o C; Wavelength: 220 nm, 254 nm) to afford N-[2- amino-5-(4-fluorophenyl)phenyl]-4-(1-oxo-4,5-dihydro-3H-isothiazol-1-yl)benzamide (about 24.4 mg).
  • Step 1 Synthesis of methyl 4-(N-cyano-S-methyl-sulfonimidoyl)benzoate
  • DCM dimethylethyl sulfoxide
  • DMAP about 150 mg, 1.23 mmol
  • BrCN about 140 mg, 1.32 mmol
  • the mixture was stirred at about 20°C for about 12 hours.
  • the reaction mixture was quenched with H 2 O.
  • the mixture was extracted with DCM (about 15 mL * 3). The combined organic layers were washed with brine (about 40 mL), dried over Na 2 SO 4 and then concentrated.
  • Step 2 Synthesis of 4-(N-cyano-S-methyl-sulfonimidoyl)benzoic acid
  • methyl 4-(N-cyano-S-methyl-sulfonimidoyl)benzoate about 230 mg, 0.965 mmol
  • MeOH about 2 mL
  • H 2 O about 1 mL
  • lithium;hydroxide;hydrate about 150 mg, 3.57 mmol
  • the mixture was stirred at about 20°C for about 1 hour.
  • the reaction mixture was concentrated under reduced pressure to remove the organic solvent.
  • the mixture was filtered.
  • Step 3 Synthesis of tert-butyl N-[2-[[4-(N-cyano-S-methyl-sulfonimidoyl)benzoyl]amino]-4-(2- thienyl)phenyl]carbamate
  • 4-(N-cyano-S-methyl-sulfonimidoyl)benzoic acid about 160 mg, 0.713 mmol
  • pyridine about 3 mL
  • EDCI about 200 mg, 1.04 mmol
  • tert- butyl N-[2-amino-4-(2-thienyl)phenyl]carbamate about 250 mg, 0.860 mmol.
  • the mixture was stirred at about 50°C for about 1 hour.
  • the reaction mixture was concentrated under reduced pressure.
  • the reaction mixture was dilute with water (about 5 mL) and extracted with DCM (about 10 mL * 3).
  • the combined organic layers were washed with brine (about 15 mL), dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of N-[2-amino-5-(2-thienyl)phenyl]-4-(N-cyano-S-methyl- sulfonimidoyl)benzamide
  • N-[2-amino-5-(2-thienyl)phenyl]-4-(N-cyano-S-methyl- sulfonimidoyl)benzamide [0745] To a solution of tert-butyl N-[2-[[4-(N-cyano-S-methyl- sulfonimidoyl)benzoyl]amino]-4-(2-thienyl)phenyl]carbamate (about 100 mg, 0.201 mmol) in HFIP (about 12 mL) was taken up into a microwave tube. The sealed tube was heated at about 90°C for about 2 hours in microwave. The mixture was concentrated under reduced pressure.
  • Step 1 Synthesis of methyl 6-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)pyridazine-3- carboxylate
  • methyl 6-methylsulfinylpyridazine-3-carboxylate about 1.3 g, 6.49 mmol
  • tert-butyl carbamate about 910 mg, 7.77 mmol
  • [acetoxy(phenyl)-iodanyl] acetate about 3.16 g, 9.82 mmol
  • oxomagnesium about 1.3 g, 32.3 mmol
  • DCM about 30 mL
  • the reaction mixture was stirred at about 40°C for about 8 hours.
  • the reaction mixture was concentrated under reduced pressure.
  • Step 2 Synthesis of 6-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)pyridazine-3-carboxylic acid
  • 6-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)pyridazine-3-carboxylic acid [0747] To a solution of methyl 6-(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)pyridazine-3-carboxylate (about 500 mg, 1.59 mmol) in THF (about 5 mL) and H 2 O (about 0.5 mL) was added lithium;hydroxide;hydrate (about 150 mg, 3.57 mmol). The mixture was stirred at about 0°C for about 1 hour.
  • the suspension was filtered and the filtrate was concentrated under reduced pressure to give 6-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)pyridazine-3-carboxylic acid (about 470 mg).
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 8.49 - 8.56 (m, 2 H), 3.60 (s, 3 H), 1.22 (s, 9 H).
  • Step 3 Synthesis of tert-butyl N-[[6-[[2-(tert-butoxycarbonylamino)-5-(5-fluoro-2- thienyl)phenyl]carbamoyl]pyridazin-3-yl]-methyl-oxo-sulfanylidene]carbamate
  • 6-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)pyridazine-3- carboxylic acid about 200 mg, 0.664 mmol
  • pyridine about 5 mL
  • tert-butyl N- [2-amino-4-(5-fluoro-2-thienyl)phenyl]carbamate about 90 mg, 0.291 mmol
  • 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride about 110 mg, 0.574 mmol).
  • the mixture was stirred at about 20°C for about 12 hours.
  • the combined organic layers were dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of N-[2-amino-5-(5-fluoro-2-thienyl)phenyl]-6- (methylsulfonimidoyl)pyridazine-3-carboxamide
  • Step 1 Synthesis of 2-nitro-4-pyrimidin-5-yl-aniline [0750] A mixture of 4-bromo-2-nitro-aniline (about 1 g, 4.61 mmol), pyrimidin-5-ylboronic acid (about 685 mg, 5.53 mmol), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (about 337 mg, 0.461 mmol) and tripotassium;carbonate (about 1.9 g, 13.8 mmol) in tetrahydrofuran (about 10 mL) and H 2 O (about 1 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at about 80°C for about 12 hours under N 2 atmosphere.
  • 4-bromo-2-nitro-aniline about 1 g, 4.61 mmol
  • pyrimidin-5-ylboronic acid about 685 mg, 5.53 mmol
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-(2-nitro-4-pyrimidin-5-yl- phenyl)carbamate
  • 2-nitro-4-pyrimidin-5-yl-aniline about 337 mg, 1.56 mmol
  • THF about 10 mL
  • tert-butoxycarbonyl tert-butyl carbonate about 0.9 mL, 3.89 mmol
  • N,N-diethylethanamine about 473 mg, 4.67 mmol, 0.651 mL
  • N,N-dimethylpyridin-4- amine about 19 mg, 0.156 mmol.
  • the mixture was stirred at about 25°C for about 12 hours.
  • the reaction mixture was diluted with water (about 20 mL), and extracted with EtOAc (about 30 mL * 3).
  • the combined organic layers were washed with brine (about 30 mL), dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 4 Synthesis of tert-butyl N-(2-amino-4-pyrimidin-5-yl-phenyl)carbamate
  • tert-butyl N-(2-nitro-4-pyrimidin-5-yl-phenyl)carbamate about 150 mg, 0.474 mmol
  • MeOH about 10 mL
  • Pd/C about 45 mg, 10 wt% Pd with 50 wt% water
  • the mixture was purged with H 2 for about 3 times and stirred at about 25°C for about 12 hours under H 2 (in balloon).
  • Step 5 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-pyrimidin-5-yl- phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate [0754] To a solution of tert-butyl N-(2-amino-4-pyrimidin-5-yl-phenyl)carbamate (about 120 mg, 0.419 mmol) in pyridine (about 2 mL) was added 4-(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)benzoic acid (about 150 mg, 0.501 mmol) and 3-(ethyliminomethyleneamino)- N,N-dimethyl-propan-1-amine;hydrochloride (about 120 mg, 0.626 mmol).
  • the mixture was stirred at about 50°C for 1 hour.
  • the reaction mixture was diluted with NH 4 Cl (30 mL) and extracted with EtOAc (about 40 mL * 2).
  • the combined organic layers were washed with brine (about 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 6 Synthesis of N-(2-amino-5-pyrimidin-5-yl-phenyl)-4-(methylsulfonimidoyl)benzamide
  • tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-pyrimidin-5-yl- phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate about 150 mg, 0.264 mmol
  • HFIP about 15 mL
  • Step 2 Synthesis of isopropyl 4-(2-pyridylsulfinyl)benzoate [0757] To a solution of isopropyl 4-(2-pyridylsulfanyl)benzoate (about 220 mg, 0.805 mmol) in DCM (about 8 mL) was added 3-chlorobenzenecarboperoxoic acid (about 150 mg, 0.869 mmol, 85 wt%). The mixture was stirred at about 20°C for about 1 hour. The mixture was quenched by addition of saturated Na 2 SO 3 aqueous solution (about 10 mL) and saturated NaHCO 3 aqueous solution (about 10 mL).
  • Step 3 Synthesis of isopropyl 4-[N-tert-butoxycarbonyl-S-(2-pyridyl)sulfonimidoyl]benzoate
  • isopropyl 4-(2-pyridylsulfinyl)benzoate about 220 mg, 0.760 mmol
  • NH 2 Boc about 180 mg, 1.54 mmol
  • [bis(acetoxy)iodo]benzene about 370 mg, 1.15 mmol
  • MgO about 160 mg, 3.87 mmol
  • DCM about 10 mL
  • the reaction mixture was stirred at about 40°C for about 12 hours.
  • the mixture was filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 5 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(2- thienyl)phenyl]carbamoyl]phenyl]-oxo-(2-pyridyl)-sulfanylidene]carbamate
  • tert-butyl N-[2-amino-4-(2-thienyl)phenyl]carbamate about 80 mg, 0.276 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride about 80 mg, 0.417 mmol
  • pyridine about 5 mL
  • Step 6 Synthesis of N-[2-amino-5-(2-thienyl)phenyl]-4-(2-pyridylsulfonimidoyl)benzamide
  • tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(2- thienyl)phenyl]carbamoyl]phenyl]-oxo-(2-pyridyl)-sulfanylidene]carbamate about 65 mg, 0.102 mmol
  • DCM about 2 mL
  • TFA about 0.2 mL, 2.60 mmol
  • Step 1 Synthesis of ethyl 4-(N-ethyl-S-methyl-sulfonimidoyl)benzoate
  • DMSO DMSO
  • potassium;hydroxide about 895 mg, 5.95 mmol
  • bromoethane about 2.17 g, 19.9 mmol
  • the mixture was stirred at about 20°C for about 12 hours.
  • the mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the resulting mixture was extracted with H 2 O (about 50 mL) and EtOAc (about 50 mL * 2).
  • Step 2 Synthesis of 4-(N-ethyl-S-methyl-sulfonimidoyl)benzoic acid
  • the mixture was concentrated under reduced pressure to afford a product (about 1.4 g).
  • Step 3 Synthesis of tert-butyl N-[2-[[4-(N-ethyl-S-methyl-sulfonimidoyl)benzoyl]amino]-4-(4- fluorophenyl)phenyl]carbamate
  • tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate about 185 mg, 0.612 mmol
  • 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine about 143 mg, 0.921 mmol
  • pyridine about 5 mL
  • Step 4 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(N-ethyl-S-methyl- sulfonimidoyl)benzamide
  • N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(N-ethyl-S-methyl- sulfonimidoyl)benzamide [0765] To a solution of tert-butyl N-[2-[[4-(N-ethyl-S-methyl- sulfonimidoyl)benzoyl]amino]-4-(4-fluorophenyl)phenyl]carbamate (about 270 mg, 0.528 mmol) in DCM (about 6 mL) was added TFA (about 0.4 mL, 5.28 mmol). The mixture was stirred at about 20°C for about 12 hours.
  • the resultant mixture was dried over Na 2 SO 4 and filtered. The filtrate was concentrated under reduced pressure.
  • the residue was purified by preparative HPLC (Instrument: 2_Phenomenex Gemini C1875 * 40 mm * 3 ⁇ m; Column: Waters Xbridge 150 * 25 mm * 5 ⁇ m; Mobile phase A: H 2 O with 0.05% NH3-H 2 O (v%); B: ACN; Gradient: B from 40% to 70% in 7.8 min, hold 100% B for 0 min; Flow Rate: 30 mL/min; Column Temperature: 30°C; Wavelength: 220 nm, 254 nm) to afford N-[2-amino-5-(4-fluorophenyl)phenyl]-4-(N-ethyl-S-methyl-sulfonimidoyl)benzamide (about 3
  • Step 2 Synthesis of methyl 2-methylsulfanylthiazole-5-carboxylate [0767] To a mixture of 2-methylsulfanylthiazole-5-carboxylic acid (about 950 mg, 5.42 mmol) in MeOH (about 10 mL) was dropwise added SOCl2 (about 4 mL, 55.1 mmol) at about 20°C. The mixture was stirred at about 20°C for about 12 hours. The mixture was concentrated under reduced pressure to remove solvent. Then saturated NaHCO3 aqueous solution was added to adjust pH to about 8. The mixture was extracted with EtOAc (about 10 mL * 3).
  • Step 4 Synthesis of methyl 2-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)thiazole-5- carboxylate
  • Step 5 Synthesis of 2-(methylsulfonimidoyl)thiazole-5-carboxylic acid
  • Step 6 Synthesis of tert-butyl N-[[5-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]thiazol-2-yl]-methyl-oxo-sulfanylidene]carbamate [0771] A mixture of 2-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)thiazole-5-carboxylic acid (about 40 mg, 0.131 mmol), tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 45 mg, 0.149 mmol) and EDCI (about 45 mg, 0.235 mmol) in pyridine (about 1 mL) was stirred at about 50°C for about 1 hour.
  • Step 7 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-2-(methylsulfonimidoyl)thiazole-5- carboxamide
  • Step 2 Synthesis of 4-(N-cyclopropyl-S-methyl-sulfonimidoyl)benzoic acid
  • methyl 4-(N-cyclopropyl-S-methyl-sulfonimidoyl)benzoate about 366 mg, 1.44 mmol
  • MeOH about 3 mL
  • LiOH-H 2 O about 61 mg, 1.45 mmol
  • the mixture was stirred at about 20°C for about 1 hour.
  • the reaction mixture was concentrated under reduced pressure.
  • Step 3 Synthesis of tert-butyl N-[2-[[4-(N-cyclopropyl-S-methyl-sulfonimidoyl)benzoyl]amino]- 4-(4-fluorophenyl)phenyl]carbamate [0775] To a solution of 4-(N-cyclopropyl-S-methyl-sulfonimidoyl)benzoic acid (about 102 mg, 0.43 mmol) and tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate (about 129 mg, 0.43 mmol) in pyridine (about 5 mL) was added 3-(ethyliminomethyleneamino)-N,N-dimethyl- propan-1-amine;hydrochloride (about 123 mg, 0.64 mmol).
  • the mixture was stirred at about 20°C for about 1 hour.
  • the reaction mixture was concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]phenyl]methyl-methyl-oxo-sulfanylidene]carbamate
  • tert-butyl N-[2-amino-4-(4-fluorophenyl)phenyl]carbamate about 110 mg, 0.364 mmol
  • EDCI about 70 mg, 0.365 mmol
  • Step 1 Synthesis of methyl 5-methylsulfanylthiophene-2-carboxylate [0780] To a solution of 5-methylsulfanylthiophene-2-carboxylic acid (about 2.9 g, 16.6 mmol) in MeOH (about 50 mL) was added SOCl 2 (about 12 mL, 0.165 mol). The mixture was stirred at about 20°C for about 12 hours. The mixture was concentrated under reduced pressure.
  • Step 2 Synthesis of methyl 5-methylsulfinylthiophene-2-carboxylate [0781] To a solution of methyl 5-methylsulfanylthiophene-2-carboxylate (about 2.8 g, 14.9 mmol) in DCM (about 30 mL) was added m-CPBA (about 3.3 g, 16.25 mmol, 85 wt%) at about 0°C. The mixture was stirred at 0°C for 1 hour. The resulting mixture was quenched by addition of saturated Na2SO3 aqueous solution (about 20 mL), saturated NaHCO3 aqueous solution (about 20 mL) and extracted with DCM (about 30 mL * 3).
  • Step 3 Synthesis of methyl 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)thiophene-2- carboxylate
  • Step 4 Synthesis of 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)thiophene-2-carboxylic acid
  • a solution of methyl 5-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)thiophene- 2-carboxylate (about 300 mg, 0.939 mmol) in MeOH (about 10 mL) was added a solution of LiOH-H 2 O (about 394 mg, 9.39 mmol) in H 2 O (about 2 mL). The mixture was stirred at about 20°C for about 12 hours. The mixture was concentrated under reduced pressure to remove the organic solvent.
  • Step 5 Synthesis of tert-butyl N-[[5-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]-2-thienyl]-methyl-oxo-sulfanylidene]carbamate
  • tert-butyl N-[2-amino-4-(4- fluorophenyl)phenyl]carbamate about 65 mg, 0.215 mmol
  • EDCI about 57 mg, 0.297 mmol
  • pyridine about 2 mL
  • Step 6 Synthesis of N-[2-amino-5-(4-fluorophenyl)phenyl]-5-(methylsulfonimidoyl)thiophene-2- carboxamide [0785]
  • N-[2-amino-5-(4-fluorophenyl)phenyl]-5-(methylsulfonimidoyl)thiophene-2- carboxamide [0785]
  • tert-butyl N-[[5-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]-2-thienyl]-methyl-oxo-sulfanylidene]carbamate about 100 mg, 0.170 mmol
  • DCM about 5 mL
  • TFA about 0.26 mL, 3.37 mmol
  • the mixture was stirred at about 20°C for about 12 hours.
  • the combined organic layers were dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 1 Synthesis of tert-butyl N-[[6-[[2-(tert-butoxycarbonylamino)-5-(4- fluorophenyl)phenyl]carbamoyl]pyridazin-3-yl]-methyl-oxo-sulfanylidene]carbamate [0788] To a solution of 6-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)pyridazine-3- carboxylic acid (about 150 mg, 0.498 mmol) in pyridine (about 5 mL) was added tert-butyl N-[2- amino-4-(4-fluorophenyl)phenyl]carbamate (about 100 mg, 0.331 mmol) and 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine;hydrochloride (about 100 mg, 0.522 mmol).
  • the mixture was stirred at about 20°C for about 3 hours.
  • the resultant mixture was extracted with DCM (about 10 mL * 3).
  • the combined organic layers were dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 2 Synthesis of ethyl 4-(N-ethyl-S-methyl-sulfonimidoyl)benzoate
  • Step 3 Synthesis of 4-(N-ethyl-S-methyl-sulfonimidoyl)benzoic acid
  • a mixture of ethyl 4-(N-ethyl-S-methyl-sulfonimidoyl)benzoate (about 400 mg, 1.66 mmol) and LiOH-H 2 O (about 350 mg, 8.34 mmol) in MeOH (about 3 mL) and H 2 O (about 3 mL) was stirred at about 20°C for about 1 hour. The mixture was concentrated under reduced pressure to remove solvent.1N HCl aqueous solution was added to adjust about pH 5.
  • Step 4 Synthesis of tert-butyl N-[2-[[4-(N-ethyl-S-methyl-sulfonimidoyl)benzoyl]amino]-4-(2- thienyl)phenyl]carbamate
  • Step 5 Synthesis of N-[2-amino-5-(2-thienyl)phenyl]-4-(N-ethyl-S-methyl- sulfonimidoyl)benzamide
  • TFA about 3 mL, 38.9 mmol
  • Step 2 Synthesis of methyl 4-[(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)methyl]benzoate
  • Step 3 Synthesis of methyl 4-[1-(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)cyclopropyl]benzoate
  • a mixture of methyl 4-[(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)methyl]benzoate (about 300 mg, 0.916 mmol), tetraoctylammonium;bromide (about 55 mg, 0.100 mmol), NaOH (about 400 mg, 10.0 mmol) and 1,2-dibromoethane (about 1 mL, 11.6 mmol) in 2-methyloxolane (about 5 mL) and H 2 O (0.4 mL) was stirred at about 60°C for about 12 hours.
  • Step 4 Synthesis of 4-[1-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)cyclopropyl]benzoic acid
  • a mixture of methyl 4-[1-(N-tert-butoxycarbonyl-S-methyl- sulfonimidoyl)cyclopropyl]benzoate (about 45 mg, 0.127 mmol) and LiOH-H 2 O (about 30 mg, 0.715 mmol) in H 2 O (about 2 mL) and THF (about 2 mL) was stirred at about 20°C for about 1 hour. The mixture was concentrated under reduced pressure to remove the organic solvent.2N HCl aqueous solution was added to adjust to about pH 5.
  • Step 5 Synthesis of tert-butyl N-[[1-[4-[[2-(tert-butoxycarbonylamino)-5-(2- thienyl)phenyl]carbamoyl]phenyl]cyclopropyl]-methyl-oxo-sulfanylidene]carbamate
  • tert-butyl N-[2-amino-4-(2- thienyl)phenyl]carbamate about 40 mg, 0.138 mmol
  • EDCI about 30 mg, 0.156 mmol
  • Step 6 Synthesis of N-[2-amino-5-(2-thienyl)phenyl]-4-[1- (methylsulfonimidoyl)cyclopropyl]benzamide
  • Step 1 Synthesis of 4-(5-methyl-2-thienyl)-2-nitro-aniline [0801] To a mixture of 4,4,5,5-tetramethyl-2-(5-methyl-2-thienyl)-1,3,2-dioxaborolane (750 mg, 3.35 mmol) and 4-bromo-2-nitro-aniline (about 550 mg, 2.53 mmol) in EtOH (about 2 mL), H 2 O (2 mL) and dioxane (about 6 mL) were added Pd(dppf)Cl 2 -DCM (about 210 mg, 0.258 mmol) and K 2 CO 3 (about 1.05 g, 7.60 mmol). The mixture was stirred at about 100°C for about 12 hours.
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[4-(5-methyl-2-thienyl)-2-nitro- phenyl]carbamate
  • a mixture of 4-(5-methyl-2-thienyl)-2-nitro-aniline (about 590 mg, 2.52 mmol), TEA (about 1.05 mL, 7.56 mmol), DMAP (about 61 mg, 0.499 mmol) and (Boc) 2 O (1.65 g, 7.56 mmol) in DCM (10 mL) was stirred at about 20°C for about 12 hours. The mixture was concentrated under reduced pressure. The residue was triturated in MeOH (about 40 mL). The mixture was filtered.
  • Step 3 Synthesis of tert-butyl N-[4-(5-methyl-2-thienyl)-2-nitro-phenyl]carbamate [0803] A mixture of tert-butyl N-tert-butoxycarbonyl-N-[4-(5-methyl-2-thienyl)-2-nitro- phenyl]carbamate (about 670 mg, 1.54 mmol), DCM (about 10 mL) and TFA (about 0.18 mL, 2.31 mmol) was stirred at about 20°C for about 1 hour. The resulting mixture was quenched by addition of saturated NaHCO 3 aqueous solution (about 20 mL) and extracted with DCM (about 50 mL * 3).
  • Step 4 Synthesis of tert-butyl N-[2-amino-4-(5-methyl-2-thienyl)phenyl]carbamate [0804] To a solution of tert-butyl N-[4-(5-methyl-2-thienyl)-2-nitro-phenyl]carbamate (about 520 mg, 1.56 mmol) in THF (about 10 mL) was added Pd/C (about 200 mg, 10 wt% Pd with 50 wt% water). The suspension was degassed and purged with hydrogen for about 3 times. The mixture was stirred under hydrogen (in balloon) at about 20°C for about 12 hours.
  • Step 5 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(5-methyl-2- thienyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate [0805] To a mixture of 4-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzoic acid (about 100 mg, 0.334 mmol) and tert-butyl N-[2-amino-4-(5-methyl-2-thienyl)phenyl]carbamate (about 123 mg, 0.404 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1- amine;hydrochloride (about 97 mg, 0.506 mmol) in pyridine (about 4 mL) was stirred at about 50°C for about 1 hour.
  • Step 6 Synthesis of N-[2-amino-5-(5-methyl-2-thienyl)phenyl]-4- (methylsulfonimidoyl)benzamide
  • tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(5-methyl-2- thienyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate about 120 mg, 0.205 mmol
  • DCM (2 mL)
  • TFA about 2 mL, 25.9 mmol
  • the mixture was purified by preparative HPLC (Instrument: Gilson GX-281 Liquid Handler, Gilson 322 Pump, Gilson 156 UV Detector; Column: 2_Phenomenex Gemini C1875 * 40 mm * 3 ⁇ m; Mobile phase A: water (10 mmol NH 4 HCO 3 )-ACN; Mobile phase B: MeCN; Gradient: B from 33% to 63% in 7.8 min, hold 100% B for 2 min; Flow Rate: 30 mL/min; Column Temperature: 30 o C; Wavelength: 220 nm, 254 nm) to give N-[2- amino-5-(5-methyl-2-thienyl)phenyl]-4-(methylsulfonimidoyl)benzamide (about 32.1 mg).
  • Step 1 Synthesis of 4-(5-chloro-2-thienyl)-2-nitro-aniline [0807]
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[4-(5-chloro-2-thienyl)-2-nitro- phenyl]carbamate
  • 4-(5-chloro-2-thienyl)-2-nitro-aniline about 700 mg, 2.75 mmol
  • THF about 10 mL
  • 4-(5-chloro-2-thienyl)-2-nitro-aniline about 700 mg, 2.75 mmol
  • N,N-diethylethanamine about 1.2 mL, 8.24 mmol
  • N,N-dimethylpyridin-4-amine about 34 mg, 0.278 mmol.
  • the mixture was stirred at about 25°C for about 12 hours.
  • the reaction mixture was diluted with water (about 20 mL) and extracted with EtOAc (about 30 mL * 2).
  • the combined organic layers were washed with brine (about 30 mL), dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • Step 3 Synthesis of tert-butyl N-[4-(5-chloro-2-thienyl)-2-nitro-phenyl]carbamate [0809] To a solution of tert-butyl N-tert-butoxycarbonyl-N-[4-(5-chloro-2-thienyl)-2-nitro- phenyl]carbamate (about 920 mg, 2.02 mmol) in DCM (about 10 mL) was added 2,2,2- trifluoroacetic acid (about 0.2 mL, 3.03 mmol). The mixture was stirred at about 20°C for about 12 hours.
  • the resultant mixture was dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash chromatography (ISCO®; about 12 g SepaFlash® Silica Flash Column, Petroleum Ether/EtOAc with EtOAc from 0 ⁇ 15%, 60 mL/min, 254 nm) to afford tert-butyl N-[4-(5-chloro-2-thienyl)-2- nitro-phenyl]carbamate (about 561 mg).
  • Step 4 Synthesis of tert-butyl N-[2-amino-4-(5-chloro-2-thienyl)phenyl]carbamate [0810] To a solution of tert-butyl N-[4-(5-chloro-2-thienyl)-2-nitro-phenyl]carbamate (about 523 mg, 1.47 mmol) in EtOH (about 6 mL) was added Iron (about 412 mg, 7.38 mmol) and ammonia;hydrochloride (about 394 mg, 7.37 mmol). The mixture was stirred at about 80°C for about 1 hour.
  • the reaction mixture was filtered .
  • the filtrate was diluted with H 2 O (about 30 mL) and extracted with EtOAc (about 40 mL * 2).
  • the combined organic layers were washed with brine (about 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the residue was purified by flash chromatography (ISCO®; about 12 g SepaFlash® Silica Flash Column, Petroleum Ether/EtOAc with EtOAc from 0 ⁇ 15%, 60 mL/min, 254 nm) to afford tert-butyl N-[2-amino-4-(5-chloro-2-thienyl)phenyl]carbamate (about 270 mg).
  • Step 5 Synthesis of tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(5-chloro-2- thienyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate [0811] To a solution of tert-butyl N-[2-amino-4-(5-chloro-2-thienyl)phenyl]carbamate (about 221 mg, 0.680 mmol) and 4-(N-tert-butoxycarbonyl-S-methyl-sulfonimidoyl)benzoic acid (about 170 mg, 0.568 mmol) in pyridine (about 6 mL) was added 3- (ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (about 130 mg, 0.837 mmol).
  • the mixture was stirred at about 50°C for about 1 hour.
  • the reaction mixture was diluted with NH 4 Cl (about 30 mL) and extracted with EtOAc (about 40 mL * 2).
  • the combined organic layers were washed with brine (about 40 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 6 Synthesis of N-[2-amino-5-(5-chloro-2-thienyl)phenyl]-4- (methylsulfonimidoyl)benzamide
  • tert-butyl N-[[4-[[2-(tert-butoxycarbonylamino)-5-(5-chloro-2- thienyl)phenyl]carbamoyl]phenyl]-methyl-oxo-sulfanylidene]carbamate about 240 mg, 0.396 mmol
  • DCM about 10 mL
  • TFA about 0.3 mL, 3.96 mmol
  • the resultant mixture was dried over Na 2 SO 4 and filtered.
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by flash chromatography (ISCO®; about 12 g SepaFlash® Silica Flash Column, Petroleum Ether/EtOAc with EtOAc from 0 ⁇ 100%, 40 mL/min, 254 nm) to give the desired product, but impure.
  • the resulting mixture was stirred at about 100°C for about 12 hours under N2.
  • the resulting mixture was quenched by addition of water (about 100 mL) and extracted with EtOAc (about 100 mL * 3).
  • the combined organic layer was washed with saturated NH4Cl aqueous solution (about 100 mL * 2), brine (about 100 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • Step 2 Synthesis of tert-butyl N-tert-butoxycarbonyl-N-[2-nitro-4-(p-tolyl)phenyl]carbamate
  • Step 3 Synthesis of tert-butyl N-[2-nitro-4-(p-tolyl)phenyl]carbamate
  • Step 4 Synthesis of tert-butyl N-[2-amino-4-(p-tolyl)phenyl]carbamate

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