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US 2011/0257157 A1Published application
Thiolactams and uses thereof
AssigneeMillennium Pharmaceuticals, Inc.
InventorsIndu T. Bharathan, Matthew Duffey, Amy Elder, Jianping Guo, Gang Li, Dominic Reynolds, Francois Soucy, Tricia J. Vos
Life of this patent
Estimating the term…
Abstract
This invention provides compounds of formula I: wherein R1, R2, R3, R4, R5, and R6 are as described in the specification. The compounds are inhibitors of PLK and are thus useful for treating proliferative, inflammatory, or cardiovascular disorders.
Claims19
1-29. (canceled)
A method for inhibiting PLK activity in a patient comprising administering a composition comprising an amount of a compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is selected from hydrogen, —CN, halogen, optionally substituted C1-6aliphatic, or —YR1a,
- wherein Y is —O—, —S—, or —NR1a, and each occurrence of R1a is independently hydrogen, or optionally substituted C1-6aliphatic;
- R2 is selected from hydrogen, halogen, —ZR2a, or —OR2b,
- wherein Z is an optionally substituted C1-6 alkylene chain, and R2a is —OR2b, —N(R2b)2, —SR2b, —C(O)N(R2b)2, —N(R2b)C(O)R2b, —SO2N(R2b)2, —NR2bSO2R2b, —NR2bC(O)N(R2b)2, or —NR2bSO2N(R2b)2, wherein each occurrence of R2b is independently hydrogen or optionally substituted C1-6alkyl, or two occurrences of R2b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R3 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy;
- R4 is selected from hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH2)xNR4aR4b, —(CH2)xNR4aC(O)R4b, —(CH2)xNR4aS(O)2R4b, —(CH2)xC(O)R4b, —(CH2)xC(O)NR4aR4b, —(CH2)xS(O)2NR4aR4b, or —(CH2)xOR4b,
- wherein
- each occurrence of x is independently 0-6;
- wherein R4a is hydrogen or optionally substituted C1-6aliphatic, and
- R4b is hydrogen, optionally substituted C1-6aliphatic, optionally substituted C3-7-heterocyclyl or C3-7carbocyclyl ring, or is W—R4c, wherein W is an optionally substituted C2-6 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, —OR4d, —N(R4d)2, —SR4d, —C(O)N(R4d)2, —N(R4d)C(O)R4d, —SO2N(R4d)2, —NR4dSO2R4d, —NR4dC(O)N(R4d)2, or —NR4dSO2N(R4d)2, wherein each occurrence of R4d is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R5 is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted C3-7-heterocyclyl ring, or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain or —NR5c,
- wherein when X is an optionally substituted C2-6 alkylene chain R5a is —OR5b, —N(R5b)2, —SR5b, —C(O)N(R5b)2, —N(R5b)C(O)R5b, —SO2N(R5b)2, —NR5bSO2R5b, —NR5bC(O)N(R5b)2, or —NR5bSO2N(R5b)2;
- and
- when X is —NR5c, R5a is hydrogen or optionally substituted C1-6aliphatic, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- wherein each occurrence of R5b and R5c is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R5b, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or
- wherein R4 and R5, taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring;
- and
- R6 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy, effective to inhibit PLK activity in the patient.
18 more elements
A method for treating a proliferative disorder, a neurodegenerative disorder, an autoimmune disorder, an inflammatory disorder, or an immunologically mediated disorder in a patient, comprising the step of administering to a patient a compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is selected from hydrogen, —CN, halogen, optionally substituted C1-6aliphatic, or —YR1a,
- wherein Y is —O—, —S—, or —NR1a, and each occurrence of R1a is independently hydrogen, or optionally substituted C1-6aliphatic;
- R2 is selected from hydrogen, halogen, —ZR2a, or —OR2b,
- wherein Z is an optionally substituted C1-6 alkylene chain, and R2a is —OR2b, —N(R2b)2, —SR2b, —C(O)N(R2b)2, —N(R2b)C(O)R2b, —SO2N(R2b)2, —NR2bSO2R2b, —NR2bC(O)N(R2b)2, or —NR2bSO2N(R2b)2, wherein each occurrence of R2b is independently hydrogen or optionally substituted C1-6alkyl, or two occurrences of R2b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R3 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy;
- R4 is selected from hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH2)xNR4aR4b, —(CH2)xNR4aC(O)R4b, —(CH2)xNR4aS(O)2R4b, —(CH2)xC(O)R4b, —(CH2)xC(O)NR4aR4b, —(CH2)xS(O)2NR4aR4b, or —(CH2)xOR4b,
- wherein
- each occurrence of x is independently 0-6;
- wherein R4a is hydrogen or optionally substituted C1-6aliphatic, and
- R4b is hydrogen, optionally substituted C1-6aliphatic, optionally substituted C3-7-heterocyclyl or C3-7carbocyclyl ring, or is W—R4c, wherein W is an optionally substituted C2-6 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, —OR4d, —N(R4d)2, —SR4d, —C(O)N(R4d)2, —N(R4d)C(O)R4d, —SO2N(R4d)2, —NR4dSO2R4d, —NR4dC(O)N(R4d)2, or —NR4dSO2N(R4d)2, wherein each occurrence of R4d is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R5 is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted C3-7-heterocyclyl ring, or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain or —NR5c,
- wherein when X is an optionally substituted C2-6 alkylene chain R5a is —OR5b, —N(R5b)2, —SR5b, —C(O)N(R5b)2, —N(R5b)C(O)R5b, —SO2N(R5b)2, —NR5bSO2R5b, —NR5bC(O)N(R5b)2, or —NR5bSO2N(R5b)2;
- and
- when X is —NR5c, R5a is hydrogen or optionally substituted C1-6aliphatic, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- wherein each occurrence of R5b and R5c is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R5b, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or
- wherein R4 and R5, taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring;
- and
- R6 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy.
18 more elements
A method of treating cancer in a patient comprising the step of administering to a patient a compound of formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is selected from hydrogen, —CN, halogen, optionally substituted C1-6aliphatic, or —YR1a,
- wherein Y is —O—, —S—, or —NR1a, and each occurrence of R1a is independently hydrogen, or optionally substituted C1-6aliphatic;
- R2 is selected from hydrogen, halogen, —ZR2a, or —OR2b,
- wherein Z is an optionally substituted C1-6 alkylene chain, and R2a is —OR2b, —N(R2b)2, —SR2b, —C(O)N(R2b)2, —N(R2b)C(O)R2b, —SO2N(R2b)2, —NR2bSO2R2b, —NR2bC(O)N(R2b)2, or NR2bSO2N(R2b)2, wherein each occurrence of R2b is independently hydrogen or optionally substituted C1-6alkyl, or two occurrences of R2b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R3 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy;
- R4 is selected from hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH2)xNR4aR4b, —(CH2)xNR4aC(O)R4b, —(CH2)xNR4aS(O)2R4b, —(CH2)xC(O)R4b, —(CH2)xC(O)NR4aR4b, —(CH2)xS(O)2NR4aR4b, or —(CH2)xOR4b,
- wherein
- each occurrence of x is independently 0-6;
- wherein R4a is hydrogen or optionally substituted C1-6aliphatic, and
- R4b is hydrogen, optionally substituted C1-6aliphatic, optionally substituted C3-7-heterocyclyl or C3-7carbocyclyl ring, or is W—R4c, wherein W is an optionally substituted C2-6 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, —OR4d, —N(R4d)2, —SR4d, —C(O)N(R4d)2, —N(R4d)C(O)R4d, —SO2N(R4d)2, —NR4dSO2R4d, —NR4dC(O)N(R4d)2, or —NR4dSO2N(R4d)2, wherein each occurrence of R4d is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R5 is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted C3-7-heterocyclyl ring, or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain or —NR5c,
- wherein when X is an optionally substituted C2-6 alkylene chain R5a is —OR5b, —N(R5b)2, —SR5b, —C(O)N(R5b)2, —N(R5b)C(O)R5b, —SO2N(R5b)2, —NR5bSO2R5b, —NR5bC(O)N(R5b)2, or —NR5bSO2N(R5b)2;
- and
- when X is —NR5c, R5a is hydrogen or optionally substituted C1-6aliphatic, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- wherein each occurrence of R5b and R5c is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R5b, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or
- wherein R4 and R5, taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring;
- and
- R6 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy.
18 more elements
A process for preparing a compound of formula I:
- or a salt thereof, wherein
- R1 is selected from hydrogen, —CN, halogen, optionally substituted C1-6aliphatic, or —YR1a,
- wherein Y is —O—, —S—, or —NR1a, and each occurrence of R1a is independently hydrogen, or optionally substituted C1-6aliphatic;
- R2 is selected from hydrogen, halogen, —ZR2a, or —OR2b,
- wherein Z is an optionally substituted C1-6 alkylene chain, and R2a is —OR2b, —N(R2b)2, —SR2b, —C(O)N(R2b)2, —N(R2b)C(O)R2b, —SO2N(R2b)2, —NR2bSO2R2b, —NR2bC(O)N(R2b)2, or —NR2bSO2N(R2b)2, wherein each occurrence of R2b is independently hydrogen or optionally substituted C1-6alkyl, or two occurrences of R2b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R3 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy;
- R4 is selected from hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH2)xNR4aR4b, —(CH2)xNR4aC(O)R4b, —(CH2)xNR4aS(O)2R4b, —(CH2)xC(O)R4b, —(CH2)xC(O)NR4aR4b, —(CH2)xS(O)2NR4aR4b, or —(CH2)xOR4b,
- wherein
- each occurrence of x is independently 0-6;
- wherein R4a is hydrogen or optionally substituted C1-6aliphatic, and
- R4b is hydrogen, optionally substituted C1-6aliphatic, optionally substituted C3-7-heterocyclyl or C3-7carbocyclyl ring, or is W—R4c, wherein W is an optionally substituted C2-6 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, —OR4d, —N(R4d)2, —SR4d, —C(O)N(R4d)2, —N(R4d)C(O)R4d, —SO2N(R4d)2, —NR4dSO2R4d, —NR4dC(O)N(R4d)2, or —NR4dSO2N(R4d)2, wherein each occurrence of R4d is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R5 is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted C3-7-heterocyclyl ring, or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain or —NR5c,
- wherein when X is an optionally substituted C2-6 alkylene chain R5a is —OR5b, —N(R5b)2, —SR5b, —C(O)N(R5b)2, —N(R5b)C(O)R5b, —SO2N(R5b)2, —NR5bSO2R5b, —NR5bC(O)N(R5b)2, or —NR5bSO2N(R5b)2;
- and
- when X is —NR5c, R5a is hydrogen or optionally substituted C1-6aliphatic, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- wherein each occurrence of R5b and R5c is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R5b, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or
- wherein R4 and R5, taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring;
- and
- R6 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy,
- the process comprising the steps of:
- (a-1) treating a compound of formula II:
- wherein variables R1 and R2 are as described above, with a compound of formula III:
- wherein variables R3, R4, R5 and R6 are as described above;
- to form a compound of formula IV:
- wherein variables R1, R2, R3, R4, R5 and R6 are as described above;
- and
- (a-2) thionating the compound of formula IV to form the compound of formula I.
26 more elements
A process for preparing a compound of formula IA:
- or a salt thereof, wherein
- R1 is optionally substituted C1-4aliphatic, halogen, —CN, or —OMe;
- R3 is methyl or CF3;
- and
- R5 is an optionally substituted C3-7-heterocyclyl ring or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain, and R5a is —N(R5b)2, wherein each occurrence of R5b is independently hydrogen or C1-6alkyl, or two occurrences of R5b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring,
- the process comprising the steps of:
- (b-1) treating a compound of formula II:
- wherein R1 is as described above and R2 is H, with a compound of formula III:
- wherein variables R3 and R5 are as described above and R4 and R6 are each H;
- to form a compound of formula IV,
- wherein variables R1, R3, and R5 are as described above, and R2, R4 and R6 are each H;
- and
- (b-2) thionating the compound of formula IV to form the compound of formula I-A.
10 more elements
A process for preparing a compound of formula I-B:
- or a salt thereof;
- wherein
- R1 is optionally substituted C1-4aliphatic, halogen, —CN, or —OMe;
- R3 is methyl or CF3;
- and
- R4 is —NR4aR4b, wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring, or wherein R4a is hydrogen or C1-4alkyl, and R4b is an optionally substituted C3-7-heterocyclyl ring or is W—R4c, wherein W is an optionally substituted C2-4 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, or —N(R4d)2, wherein each occurrence of R4d is independently hydrogen or C1-6alkyl, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring.
- the process comprising the steps of:
- (d-1) treating a compound of formula II wherein R1 is as described generally and in subsets herein as for compounds of formula and R2 is H;
- with an compound of formula III, wherein variables R3 and R4 are as described generally and in subsets herein as for compounds of formula I-B and R5 and R6 are each H;
- to form a compound of formula IV, wherein variables R1, R3, and R4 are as described generally and in subsets herein as for compounds of formula I-B, and R2, R5 and R6 are each H;
- and
- (d-2) thionating the compound of formula IV to form the compound of formula I-B.
9 more elements
A process for preparing a compound of formula III:
- wherein R4 and R6 are each H, R3 is methyl, R5 is X—R5a, wherein X is an optionally substituted C3 alkylene chain, and R5a is —N(Me)2,
- the process comprising the steps of:
- (e-1) treating a compound of formula V:
- with a compound of formula VI:
- in the presence of Pd(PPh3)2Cl2, CuI, and triethylamine to give a compound of formula VII:
- (e-2) hydrogenating the compound of formula VII with hydrogen and Pd(OH)2 in the presence of a suitable solvent, such as isopropyl alcohol, followed by treatment with HCl to give a compound of formula VIII:
- (e-3) treating the compound of formula VIII with a compound of formula IX:
- in the presence of acetic acid and acetonitrile to give the compound of formula III.
5 more elements
A compound of formula III:
- or a salt thereof, wherein
- R3 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy;
- R4 is selected from hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH2)xNR4aR4b, —(CH2)xNR4aC(O)R4b, —(CH2)xNR4aS(O)2R4b, —(CH2)xC(O)R4b, —(CH2)xC(O)NR4aR4b, —(CH2)xS(O)2NR4aR4b, or —(CH2)xOR4b,
- wherein
- each occurrence of x is independently 0-6;
- wherein R4a is hydrogen or optionally substituted C1-6aliphatic, and
- R4b is hydrogen, optionally substituted C1-6aliphatic, optionally substituted C3-7-heterocyclyl or C3-7carbocyclyl ring, or is W—R4c, wherein W is an optionally substituted C2-6 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, —OR4d, —N(R4d)2, —SR4d, —C(O)N(R4d)2, —N(R4d)C(O)R4d, —SO2N(R4d)2, —NR4dSO2R4d, —NR4dC(O)N(R4d)2, or —NR4dSO2N(R4d)2, wherein each occurrence of R4d is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R5 is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted C3-7-heterocyclyl ring, or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain or —NR5c,
- wherein when X is an optionally substituted C2-6 alkylene chain R5a is —OR5b, —N(R5)2, —SR5b, —C(O)N(R5b)2, —N(R5b)C(O)R5b, —SO2N(R5b)2, —NR5bSO2R5b, —NR5bC(O)N(R5b)2, or —NR5bSO2N(R5b)2;
- and
- when X is —NR5c, R5a is hydrogen or optionally substituted C1-6aliphatic, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- wherein each occurrence of R5b and R5c is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R5b, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or
- wherein R4 and R5, taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring;
- and
- R6 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy,
- provided that:
- i) at least one of R3, R4, R5 and R6 is other than H;
- ii) when R3, R5 and R6 are H, then R4 is other than morpholinyl, —C(O)NH2, —OMe, or —O-n-butyl;
- iii) when R4, R5 and R6 are H, then R3 is other than chloro or —OMe;
- and
- iv) the compound of formula III is other than:
- or a salt thereof.
21 more elements
A compound of formula IV:
- or a salt thereof, wherein
- R1 is selected from hydrogen, —CN, halogen, optionally substituted C1-6aliphatic, or —YR1a,
- wherein Y is —O—, —S—, or —NR1a, and each occurrence of R1a is independently hydrogen, or optionally substituted C1-6aliphatic;
- R2 is selected from hydrogen, halogen, —ZR2a, or —OR2b,
- wherein Z is an optionally substituted C1-6 alkylene chain, and R2a is —OR2b, —N(R2b)2, —SR2b, —C(O)N(R2b)2, —N(R2b)C(O)R2b, —SO2N(R2b)2, —NR2bSO2R2b, —NR2bC(O)N(R2b)2, or NR2bSO2N(R2b)2, wherein each occurrence of R2b is independently hydrogen or optionally substituted C1-6alkyl, or two occurrences of R2b, taken together with a nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R3 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy;
- R4 is selected from hydrogen, optionally substituted C1-6aliphatic, an optionally substituted 3-7-membered heterocyclyl ring, —(CH2)xNR4aR4b, —(CH2)xNR4aC(O)R4b, —(CH2)xNR4aS(O)2R4b, —(CH2)xC(O)R4b, —(CH2)xC(O)NR4aR4b, —(CH2)xS(O)2NR4aR4b, or —(CH2)xOR4b,
- wherein
- each occurrence of x is independently 0-6;
- wherein R4a is hydrogen or optionally substituted C1-6aliphatic, and
- R4b is hydrogen, optionally substituted C1-6aliphatic, optionally substituted C3-7-heterocyclyl or C3-7carbocyclyl ring, or is W—R4c, wherein W is an optionally substituted C2-6 alkylene chain, and R4c is an optionally substituted C3-7-heterocyclyl ring, —OR4d, —N(R4d)2, —SR4d, —C(O)N(R4d)2, —N(R4d)C(O)R4d, —SO2N(R4d)2, —NR4dSO2R4d, —NR4dC(O)N(R4d)2, or —NR4dSO2N(R4d)2, wherein each occurrence of R4d is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R4d, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or wherein R4a and R4b, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- R5 is hydrogen, optionally substituted C1-6aliphatic, an optionally substituted C3-7-heterocyclyl ring, or is X—R5a, wherein X is an optionally substituted C2-6 alkylene chain or —NR5c,
- wherein when X is an optionally substituted C2-6 alkylene chain R5a is —OR5b, —N(R5b)2, —SR5b, —C(O)N(R5b)2, —N(R5b)C(O)R5b, —SO2N(R5b)2, —NR5bSO2R5b, —NR5bC(O)N(R5b)2, or —NR5bSO2N(R5b)2;
- and
- when X is —NR5c, R5a is hydrogen or optionally substituted C1-6aliphatic, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- wherein each occurrence of R5b and R5c is independently hydrogen or optionally substituted C1-6aliphatic, or two occurrences of R5b, or R5a and R5c, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-7-membered heterocyclyl ring;
- or
- wherein R4 and R5, taken together, form an optionally substituted 5-7-membered cycloaliphatic or heterocyclyl ring;
- and
- R6 is selected from hydrogen, halogen, optionally substituted C1-4alkyl, or optionally substituted C1-4alkoxy.
18 more elements
Dependencies are inferred from the claim text.