Claims for Patent: 10,030,005

Summary for Patent: 10,030,005

Title:	Inhibitors of RET
Abstract:	Described herein are compounds that inhibit wild-type RET and its resistant mutants, pharmaceutical compositions including such compounds, and methods of using such compounds and compositions.
Inventor(s):	Jason D. Brubaker, Joseph L. Kim, Kevin J. Wilson, Douglas Wilson, Lucian V. DiPietro
Assignee:	Rigel Pharmaceuticals Inc
Application Number:	US15/340,428
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 10,030,005
Patent Claims:	1. A compound having the formula (A): or a pharmaceutically acceptable salt thereof, wherein: ring A is an aryl or heteroaryl ring; each of X1 and X2 is independently selected from N and C(R6); each of Y1 and Y2 is independently selected from —CH2— and —O—, wherein no more than one of Y1 or Y2 is —O—; each R1 and each R7 is independently selected from selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halo, C1-C6 heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, heterocyclylalkyl, nitro, cyano, —C(O)R, —OC(O)R, —C(O)OR, -(C1-C6 alkylene)-C(O)R, —SR, —S(O)2R, —S(O)2—N(R)(R), -(C1-C6 alkylene)-S(O)2R, -(C1-C6 alkylene)-S(O)2—N(R)(R), —N(R)(R), —C(O)—N(R)(R), —N(R)—C(O)R, —N(R)—C(O)OR, —(C1-C6 alkylene)-N(R)—C(O)R, —N(R)S(O)2R, and —P(O)(R)(R), wherein each of alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, aryl, heteroaryl, aryloxy, aralkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra, or two R1 or two R7 are taken together with the carbon atoms to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb; each of R2, R3a, R3b, R4, R8a, and R8b is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, hydroxyl, C1-C6 heteroalkyl, and —N(R)(R), wherein each alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of Ra; each of R5 and R9 is independently selected from hydrogen, C1-C6 alkyl, and C1-C6 heteroalkyl, wherein each alkyl and heteroalkyl is independently substituted with 0-5 occurrences of Ra; each R6 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, C1-C6 heteroalkyl, and —N(R)(R), wherein each alkyl, alkoxy, and heteroalkyl is independently substituted with 0-5 occurrences of Ra; each R is independently selected from hydrogen, hydroxyl, halo, thiol, C1-C6 alkyl, C1-C6 thioalkyl, C1-C6 alkoxy, C1-C6 heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, wherein each alkyl, thioalkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl is independently substituted with 0-5 occurrences of Ra, or 2 R together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring independently substituted with 0-5 occurrences of Rb; each Ra and each Rb is independently selected from C1-C6 alkyl, halo, hydroxyl, C1-C6 heteroalkyl, C1-C6 alkoxy, cycloalkyl, heterocyclyl, and cyano, wherein each alkyl, heteroalkyl, alkoxy, cycloalkyl, and heterocyclyl is independently substituted with 0-5 occurrences of R′; each R′ is independently selected from C1-C6 alkyl, C1-C6 heteroalkyl, halo, hydroxyl, cycloalkyl, and cyano, or 2 R′ together with the atom(s) to which they are attached form a cycloalkyl or heterocyclyl ring; represents a single or double bond; m is 0, 1, or 2; n is 0, 1, 2, or 3; and each o is 0 when is a double bond; and each o is 1 when is a single bond. 2. The compound of claim 1 having the formula (I): or a pharmaceutically acceptable salt thereof, wherein; represents a single or double bond. 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: m is 1; R1 is located at the 5-position; and R1 is C1-C4 alkyl optionally substituted with 0-3 occurrences of Ra. 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, hydroxyl, halo, and C1-C4 alkoxy. 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each of R3a, R3b, R8a, and R8b is independently selected from hydrogen and C1-C4 alkyl optionally substituted with 0-3 occurrences of Ra. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein at least one pair of R3a and R3b or R8a and R8b is simultaneously hydrogen. 7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, C1-C4 alkyl, and C1-C4 alkoxy, wherein each alkyl portion of R4 is optionally substituted with 0-3 occurrences of Ra. 8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is hydrogen or C1-C4 alkyl optionally substituted with 0-3 occurrences of Ra. 9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R6 is independently selected from hydrogen, halo, and C1-C4 alkyl optionally substituted with 0-3 occurrences of Ra. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein ring A is a 6-membered monocyclic heteroaryl comprising at least one nitrogen ring atom. 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: n is 1; and R7 is pyrazol-1-yl optionally substituted with 0-3 occurrences of Ra. 13. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R9 is hydrogen. 14. A compound having the formula (II): or a pharmaceutically acceptable salt thereof, wherein: X1 is selected from N, CH, and C(halo); X2 is selected from N and CH; X3 is selected from N and CH; R12 is selected from hydrogen, hydroxyl, halo, and O—C1-C4 alkyl; each of R13a, R13b, R18a, and R18b is independently selected from hydrogen and C1-C4 alkyl; R14 is selected from hydrogen, C1-C4 alkyl and O—C1-C4 alkyl; R15 is selected from hydrogen and C1-C4 alkyl; R16 is selected from hydrogen and C1-C4 alkyl; R17b is selected from hydrogen and halo; and each of R17a and R17c is independently selected from hydrogen and C1-C4 alkyl. 15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein: X1 is selected from N, CH, and C(Cl); R12 is selected from hydrogen, hydroxyl, fluoro, and —O—CH3; each of R13a, R13b, R18a, and R18b is independently selected from hydrogen, methyl, and ethyl, wherein at least one pair of R13a and R13b or R18a and R18b is simultaneously hydrogen; R14 is selected from hydrogen, —CH3, —CH2CH3, —OCH3, and —OCH2CH3; R15 is selected from hydrogen and —CH3; R16 is selected from hydrogen and —CH3; R17b is selected from hydrogen, chloro, and fluoro; R17a and R17c are simultaneously hydrogen or —CH3, wherein when R17a and R17c are simultaneously —CH3, R17b is hydrogen. 16. A pharmaceutical composition comprising: a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 17. A method for treating a subject suffering from non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 18. A method for treating a subject suffering from papillary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 19. A method for treating a subject suffering from medullary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 20. A method for treating a subject suffering from colorectal cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 21. A method for treating a subject suffering from multiple endocrine neoplasia, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. 22. A compound selected from: TABLE 1 Exemplary Compounds of the Invention. Compound Structure 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 and pharmaceutically acceptable salts thereof. 23. A compound selected from: and pharmaceutically acceptable salts thereof. 24. A pharmaceutical composition comprising: a compound of claim 23 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 25. A method for treating a subject suffering from non-small cell lung cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof. 26. A method for treating a subject suffering from papillary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof. 27. A method for treating a subject suffering from medullary thyroid cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof. 28. A method for treating a subject suffering from colorectal cancer, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof. 29. A method for treating a subject suffering from multiple endocrine neoplasia, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 23 or a pharmaceutically acceptable salt thereof. 30. A compound