IP Library Granted Patent US 9,604,994
Granted Patent B2
US 9,604,994 · App. 14/285,007 · Granted Mar 28, 2017

Thienopyrimidine inhibitors of atypical protein kinase C

Inventors: Bruce D Dorsey (Ambler, PA); Keith S. Learn (Perkiomenville, PA); Emma L. Morris (Biggleswade, GB); Gregory R Ott (Media, PA); Jonathan R. A. Roffey (Reading, GB); Christelle N. Soudy (London, GB); Jason C. Wagner (Coatesville, PA)
Assignee: Cancer Research Technology Limited
C07D495/04C07D495/14C07D495/20C07F7/0812
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Quick Facts
Patent No.
US 9,604,994
App. No.
14/285,007
Granted
Mar 28, 2017
Kind
B2
Abstract

The present application provides a compound of formula (I) or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, G, M, Q and X are as defined herein. A compound of formula (I) and its salts have aPKC inhibitory activity, and may be used to treat proliferative disorders.

Claims (51)

1. A compound of formula (I)

or a salt form thereof,

wherein

A is NR 11 , O or S;

M-Q-X is a group of formula

G is a group of formula

R 1 , R 2 , R 11 , and R 17 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 19 , C 2-6 alkenyl optionally substituted by 1-11 R 19 , C 2-6 alkynyl optionally substituted by 1-9 R 19 , C 6-11 aryl optionally substituted by 1-11 R 19 , C 7-16 arylalkyl optionally substituted by 1-19 R 19 , C 3-11 cycloalkyl optionally substituted by 1-21 R 19 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 19 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 19 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 19 , 5-15 membered heteroaryl optionally substituted by 1-15 R 19 , 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 19 , and —OR 20 ;

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 12 , R 13 , R 14 , R 15 , R 16 , and R 18 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 19 , C 2-6 alkenyl optionally substituted by 1-11 R 19 , C 2-6 alkynyl optionally substituted by 1-9 R 19 , C 6-11 aryl optionally substituted by 1-11 R 19 , C 7-16 arylalkyl optionally substituted by 1-19 R 19 , C 3-11 cycloalkyl optionally substituted by 1-21 R 19 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 19 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 19 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 19 , 5-15 membered heteroaryl optionally substituted by 1-15 R 19 , 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 19 , halogen, —CN, —C(═O)R 20 , —C(═O)OR 20 , —C(═O)NR 22 R 23 , —C(═O)C(═O)R 20 , —C(═NR 25 )R 20 , —C(═NR 25 )NR 22 R 23 , —C(═NOH)NR 22 R 23 , —C(═NOR 26 )R 20 , —C(═NNR 22 R 23 )R 20 , —C(═NNR 24 C(═O)R 21 )R 20 , —C(═NNR 24 C(═O)OR 21 )R 20 , —C(═S)NR 22 R 23 , —NO 2 , —NR 22 R 23 , —NR 24 NR 22 R 23 , —N═NR 24 , —NR 24 OR 26 , —NR 24 C(═O)R 20 , —NR 24 C(═O)C(═O)R 20 , —NR 24 C(═O)OR 21 , —NR 24 C(═O)C(═O)OR 21 , —NR 24 C(═O)NR 22 R 23 , —NR 24 C(═O)NR 24 C(═O)R 20 , —NR 24 C(═O)NR 24 C(═O)OR 20 , —NR 24 C(═NR 25 )NR 22 R 23 , —NR 24 C(═O)C(═O)NR 22 R 23 , —NR 24 C(═S)R 20 , —NR 24 C(═S)OR 20 , —NR 24 C(═S)NR 22 R 23 , —NR 24 S(═O) 2 R 21 , —NR 24 S(═O) 2 NR 22 R 23 , —NR 24 P(═O)R 28 R 28 , —NR 24 P(═O)(NR 22 R 23 )(NR 22 R 23 ), —NR 24 P(═O)(OR 20 )(OR 20 ), —NR 24 P(═O)(SR 20 )(SR 20 ), —OR 20 , —OCN, —OC(═O)R 20 , —OC(═O)NR 22 R 23 , —OC(═O)OR 20 , —OC(═NR 25 )NR 22 R 23 , —OS(═O)R 20 , —OS(═O) 2 R 20 , —OS(═O) 2 OR 20 , —OS(═O) 2 NR 22 R 23 , —OP(═O)R 28 R 28 , —OP(═O)(NR 22 R 23 )(NR 22 R 23 ), —OP(═O)(OR 20 )(OR 20 ), —OP(═O)(SR 20 )(SR 20 ), —Si(R 24 ) 3 , —SCN, —S(═O) n R 20 , —S(═O) 2 OR 20 , —SO 3 R 27 , —S(═O) 2 NR 22 R 23 , —S(═O)NR 22 R 23 , —SP(═O)R 28 R 28 , —SP(═O)(NR 22 R 23 )(NR 22 R 23 ), —SP(═O)(OR 20 )(OR 20 ), —SP(═O)(SR 20 )(SR 20 ), —P(═O)R 28 R 28 , —P(═O)(NR 22 R 23 )(NR 22 R 23 ), —P(═O)(OR 20 )(OR 20 ), and —P(═O)(SR 20 )(SR 20 );

any of R 1 and R 2 , R 1 and R 3 , R 1 and R 5 , R 1 and R 11 , R 4 and R 11 , R 6 and R 11 , and R 16 and R 17 can, together with the atoms linking them, form a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R 19 ;

any of R 3 and R 6 , R 7 and R 8 , R 9 and R 1 ° , R 12 and R 13 , and R 14 and R 15 can, together with the atoms linking them, form a C 6-11 aryl optionally substituted by 1-11 R 19 , C 3-11 cycloalkyl optionally substituted by 1-21 R 19 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 19 or a 5-15 membered heteroaryl optionally substituted by 1-15 R 19 ;

R 3 and R 5 or R 4 and R 6 can together form a double bond;

any of R 3 and R 4 , and R 5 and R 6 can together form ═O, ═NR 20 , ═NOR 20 , or ═S;

R 19 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-13 R 39 , C 2-6 alkenyl optionally substituted by 1-11 R 39 , C 2-6 alkynyl optionally substituted by 1-9 R 39 , C 6-11 aryl optionally substituted by 1-11 R 39 , C 7-16 arylalkyl optionally substituted by 1-19 R 39 , C 3-11 cycloalkyl optionally substituted by 1-21 R 39 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 39 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 39 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 39 , 5-15 membered heteroaryl optionally substituted by 1-15 R 39 , 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 39 , halogen, —CN, —C(═O)R 30 , —C(═O)OR 30 , —C(═O)NR 32 R 33 , —C(═O)C(═O)R 30 , —C(═NR 35 )R 30 , —C(═NR 35 )NR 32 R 33 , —C(═NOH)NR 32 R 33 , —C(═NOR 36 )R 30 , —C(═NNR 32 R 33 )R 30 , —C(═NNR 34 C(═O)R 31 )R 30 , —C(═NNR 34 C(═O)OR 31 )R 30 , —C(═S)NR 32 R 33 , —NO 2 , —NR 32 R 33 , —NR 34 NR 32 R 33 , —N═NR 34 , ═NR 30 , NOR 30 , —NR 34 OR 36 , —NR 34 C(═O)R 30 , —NR 34 C(═O)C(═O)R 30 , —NR 34 C(═O)OR 31 , —NR 34 C(═O)C(═O)OR 31 , —NR 34 C(═O)NR 32 R 33 , —NR 34 C(═O)NR 34 C(═O)R 30 , —NR 34 C(═O)NR 34 C(═O)OR 30 , —NR 34 C(═NR 35 )NR 32 R 33 , —NR 34 C(═O)C(═O)NR 32 R 33 , —NR 34 C(═S)R 30 , —NR 34 C(═S)OR 30 , —NR 34 C(═S)NR 32 R 33 , —NR 34 S(═O) 2 R 31 , —NR 34 S(═O) 2 NR 32 R 33 , —NR 34 P(═O)R 38 R 38 , —NR 34 P(═O)(NR 32 R 33 )(NR 32 R 33 ), —NR 34 P(═O)(OR 30 )(OR 30 ), —NR 34 P(═O)(SR 30 )(SR 30 ), —OR 30 , ═O, —OCN, —OC(═O)R 30 , —OC(═O)NR 32 R 33 , —OC(═O)OR 30 , —OC(═NR 35 )NR 32 R 33 , —OS(═O)R 30 , —OS(═O) 2 R 30 , —OS(═O) 2 OR 30 , —OS(═O) 2 NR 32 R 33 , —OP(═O)R 38 R 38 , —OP(═O)(NR 32 R 33 )(NR 32 R 33 ), —OP(═O)(OR 30 )(OR 30 ), —OP(═O)(SR 30 )(SR 30 ), —Si(R 34 ) 3 , —SCN, ═S, —S(═O) n R 30 , —S(═O) 2 OR 30 , —SO 3 R 37 , —S(═O) 2 NR 32 R 33 , —S(═O)NR 32 R 33 , —SP(═O)R 38 R 38 , —SP(═O)(NR 32 R 33 )(NR 32 R 33 ), —SP(═O)(OR 30 )(OR 30 ), —SP(═O)(SR 30 )(SR 30 ), —P(═O)R 38 R 38 , —P(═O)(NR 32 R 33 )(NR 32 R 33 ), —P(═O)(OR 30 )(OR 30 ), and —P(═O)(SR 30 )(SR 30 );

R 20 , R 21 , R 24 , R 25 , R 26 , R 27 , R 30 , R 31 , R 34 , R 35 , R 36 and R 37 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 49 , C 2-6 alkenyl optionally substituted by 1-11 R 49 , C 2-6 alkynyl optionally substituted by 1-9 R 49 , C 6-11 aryl optionally substituted by 1-11 R 49 , C 7-16 arylalkyl optionally substituted by 1-19 R 49 , C 3-11 cycloalkyl optionally substituted by 1-21 R 49 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 49 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 49 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 49 , 5-15 membered heteroaryl optionally substituted by 1-15 R 49 , and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 49 ;

R 28 and R 38 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-13 R 49 , C 2-6 alkenyl optionally substituted by 1-11 R 49 , C 2-6 alkynyl optionally substituted by 1-9 R 49 , C 6-11 aryl optionally substituted by 1-11 R 49 , C 7-16 arylalkyl optionally substituted by 1-19 R 49 , C 3-11 cycloalkyl optionally substituted by 1-21 R 49 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 49 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 49 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 49 , 5-15 membered heteroaryl optionally substituted by 1-15 R 49 , and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 49 ;

R 22 , R 23 , R 32 and R 33 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 59 , C 2-6 alkenyl optionally substituted by 1-11 R 59 , C 2-6 alkynyl optionally substituted by 1-9 R 59 , C 6-11 aryl optionally substituted by 1-11 R 59 , C 7-16 arylalkyl optionally substituted by 1-19 R 59 , C 3-11 cycloalkyl optionally substituted by 1-21 R 59 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 59 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 59 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 59 , 5-15 membered heteroaryl optionally substituted by 1-15 R 59 , and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 59 ; or any R 22 and R 23 and/or R 32 and R 33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 69 or a 5-15 membered heteroaryl optionally substituted by 1-15 R 69 ;

R 39 , R 49 , R 59 and R 69 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-13 R 79 , C 2-6 alkenyl optionally substituted by 1-11 R 79 , C 2-6 alkynyl optionally substituted by 1-9 R 79 , C 6-11 aryl optionally substituted by 1-11 R 79 , C 7-16 arylalkyl optionally substituted by 1-19 R 79 , C 3-11 cycloalkyl optionally substituted by 1-21 R 79 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 79 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 79 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 79 , 5-15 membered heteroaryl optionally substituted by 1-15 R 79 , 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 79 , halogen, —CN, —C(═O)R 70 , —C(═O)OR 70 , —C(═O)NR 72 R 73 , —C(═O)C(═O)R 70 , —C(═NR 75 )R 70 , —C(═NR 75 )NR 72 R 73 , —C(═NOH)NR 72 R 73 , —C(═NOR 76 )R 70 , —C(═NNR 72 R 73 )R 70 , —C(═NNR 74 C(═O)R 71 )R 70 , —C(═NNR 74 C(═O)OR 71 )R 70 , —C(═S)NR 72 R 73 , —NO 2 , —NR 72 R 73 , —NR 74 NR 72 R 73 , —N═NR 74 , ═NR 70 , ═NOR 70 , —NR 74 OR 76 , —NR 74 C(═O)R 70 , —NR 74 C(═O)C(═O)R 70 , —NR 74 C(═O)OR 71 , —NR 74 C(═O)C(═O)OR 71 , —NR 74 C(═O)NR 72 R 73 , —NR 74 C(═O)NR 74 C(═O)R 70 , —NR 74 C(═O)NR 74 C(═O)OR 70 , —NR 74 C(═NR 75 )NR 72 R 73 , —NR 74 C(═O)C(═O)NR 72 R 73 , —NR 74 C(═S)R 70 , —NR 74 C(═S)OR 70 , —NR 74 C(═S)NR 72 R 73 , —NR 74 S(═O) 2 R 71 , —NR 74 S(═O) 2 NR 72 R 73 , —NR 74 P(═O)R 78 R 78 , —NR 74 P(═O)(NR 72 R 73 )(NR 72 R 73 ), —NR 74 P(═O)(OR 70 )(OR 70 ), —NR 74 P(═O)(SR 70 )(SR 70 ), —OR 70 , ═O, —OCN, —OC(═O)R 70 , —OC(═O)NR 72 R 73 , —OC(═O)OR 70 , —OC(═NR 75 )NR 72 R 73 , —OS(═O)R 70 , —OS(═O) 2 R 70 , —OS(═O) 2 OR 70 , —OS(═O) 2 NR 72 R 73 , —OP(═O)R 78 R 78 , —OP(═O)(NR 72 R 73 )(NR 72 R 73 ), —OP(═O)(OR 70 )(OR 70 ), —OP(═O)(SR 70 )(SR 70 ), —Si(R 74 ) 3 , —SCN, ═S, —S(═O) n R 70 , —S(═O) 2 OR 70 , —SO 3 R 77 , —S(═O) 2 NR 72 R 73 , —S(═O)NR 72 R 73 , —SP(═O)R 78 R 78 , —SP(═O)(NR 72 R 73 )(NR 72 R 73 ), —SP(═O)(OR 70 )(OR 70 ), —SP(═O)(SR 70 )(SR 70 ), —P(═O)R 78 R 78 , —P(═O)(NR 72 R 73 )(NR 72 R 73 ), —P(═O)(OR 70 )(OR 70 ), and —P(═O)(SR 70 )(SR 70 );

R 70 , R 71 , R 74 , R 75 , R 76 and R 77 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 89 , C 2-6 alkenyl optionally substituted by 1-11 R 89 , C 2-6 alkynyl optionally substituted by 1-9 R 89 , C 6-11 aryl optionally substituted by 1-11 R 89 , C 7-16 arylalkyl optionally substituted by 1-19 R 89 , C 3-11 cycloalkyl optionally substituted by 1-21 R 89 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 89 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 89 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 89 , 5-15 membered heteroaryl optionally substituted by 1-15 R 89 , and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 89 ;

R 72 and R 73 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-13 R 99 , C 2-6 alkenyl optionally substituted by 1-11 R 99 , C 2-6 alkynyl optionally substituted by 1-9 R 99 , C 6-11 aryl optionally substituted by 1-11 R 99 , C 7-16 arylalkyl optionally substituted by 1-19 R 99 , C 3-11 cycloalkyl optionally substituted by 1-21 R 99 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 99 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 99 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 99 , 5-15 membered heteroaryl optionally substituted by 1-15 R 99 , and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 99 ; or any R 72 and R 73 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 109 or a 5-15 membered heteroaryl optionally substituted by 1-15 R 109 ;

R 78 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-13 R 89 , C 2-6 alkenyl optionally substituted by 1-11 R 89 , C 2-6 alkynyl optionally substituted by 1-9 R 89 , C 6-11 aryl optionally substituted by 1-11 R 89 , C 7-16 arylalkyl optionally substituted by 1-19 R 89 , C 3-11 cycloalkyl optionally substituted by 1-21 R 89 , C 4-17 cycloalkylalkyl optionally substituted by 1-32 R 89 , 3-15 membered heterocycloalkyl optionally substituted by 1-28 R 89 , 4-21 membered heterocycloalkylalkyl optionally substituted by 1-40 R 89 , 5-15 membered heteroaryl optionally substituted by 1-15 R 89 , and 6-21 membered heteroarylalkyl optionally substituted by 1-27 R 89 ;

R 79 , R 89 , R 99 and R 109 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-13 halogen, C 2-6 alkenyl, C 2-6 alkynyl, C 6-11 aryl, C 7-16 arylalkyl, C 3-11 cycloalkyl, C 4-17 cycloalkylalkyl, 3-15 membered heterocycloalkyl, 4-21 membered heterocycloalkylalkyl, 5-15 membered heteroaryl, 6-21 membered heteroarylalkyl, halogen, —CN, —C(═O)R 110 , —C(═O)OR 110 , —C(═O)NR 110 R 110 , —C(═O)C(═O)R 110 , —C(═NR 110 )R 110 , —C(═NR 110 )NR 110 R 110 , —C(═NOH)NR 110 R 110 , —C(═NOR 110 )R 110 , —C(═NNR 110 R 110 )R 110 , —C(═NNR 110 C(═O)R 110 )R 110 , —C(═NNR 110 C(═O)OR 110 )R 110 , —C(═S)NR 110 R 110 ), —NO 2 , —NR 110 R 110 , —NR 110 NR 110 R 110 , —N═NR 110 , ═NR 110 , ═NOR 110 , —NR 110 OR 110 , —NR 110 C(═O)R 110 , —NR 110 C(═O)C(═O)R 110 , —NR 110 C(═O)OR 110 , —NR 110 C(═O)C(═O)OR 110 , —NR 110 C(═O)NR 110 R 110 , —NR 110 C(═O)NR 110 C(═O)R 110 , —NR 110 C(═O)NR 110 C(═O)OR 110 , —NR 110 C(═NR 110 )NR 110 R 110 , —NR 110 C(═O)C(═O)NR 110 R 110 , —NR 110 C(═S)R 110 , —NR 110 C(═S)OR 110 , —NR 110 C(═S)NR 110 R 110 , —NR 110 S(═O) 2 R 110 , —NR 110 S(═O) 2 NR 110 R 110 , —NR 110 P(═O)R 111 R 111 , —NR 110 P(═O)(NR 110 R 110 )(NR 110 R 110 ), —NR 110 P(═O)(OR 110 )(OR 110 ), —NR 110 P(═O)(SR 110 )(SR 110 ), —OR 110 , ═O, —OCN, —OC(═O)R 110 , —OC(═O)NR 110 R 110 , —OC(═O)OR 110 , —OC(═NR 110 )NR 110 R 110 , —OS(═O)R 110 , —OS(═O) 2 R 110 , —OS(═O) 2 OR 110 , —OS(═O) 2 NR 110 R 110 , —OP(═O)R 111 R 111 , —OP(═O)(NR 110 R 110 )(NR 110 R 110 ), —OP(═O)(OR 110 )(OR 110 ), —OP(═O)(SR 110 )(SR 110 ), —Si(R 110 ) 3 , —SCN, ═S, —S(═O) n R 110 , —S(═O) 2 OR 110 , —SO 3 R 110 , —S(═O) 2 NR 110 ,R 110 , —S(═O)NR 110 R 110 , —SP(═O)R 111 R 111 , —SP(═O)(NR 110 R 110 )(NR 110 R 110 ), —SP(═O)(OR 110 )(OR 110 ), —SP(═O)(SR 110 )(SR 110 ), —P(═O)R 111 R 111 , —P(═O)(NR 110 R 110 )(NR 110 R 110 ), —P(═O)(OR 110 )(OR 110 ), and —P(═O)(SR 110 )(SR 110 );

R 110 at each occurrence is independently chosen from H, C 1-6 alkyl and C 1-6 -haloalkyl;

R 111 at each occurrence is independently chosen from C 1-6 alkyl and C 1-6 -haloalkyl; and

n at each occurrence is independently chosen from 0, 1, and 2.

2. A compound as defined in claim 1 , wherein A is NR 11 .

3. A compound as defined in claim 1 , wherein G is a group of formula

4. A compound as defined in claim 3 , wherein G is a group of formula

and the compound of formula (I) is a compound of formula (Ic)

5. A compound as defined in claim 1 , wherein R 1 , R 2 , and R 11 are independently chosen from H and C 1-6 alkyl optionally substituted by 1-3 R 19 ; R 3 , R 4 , R 5 , and R 6 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , halogen, —CN, —C(═O)R 20 , —C(═O)OR 20 , —C(═O)NR 22 R 23 , —NO 2 , —NR 22 R 23 , —NR 24 C(═O)R 20 , —NR 24 S(═O) 2 R 21 , —OR 20 , —OC(═O)R 20 , —S(═O) n R 20 , and —S(═O) 2 NR 22 R 23 ; alternatively, R 3 and R 6 can, together with the atoms linking them, form a C 6-10 aryl optionally substituted by 1-3 R 19 , C 3-10 cycloalkyl optionally substituted by 1-3 R 19 , 3-10 membered heterocycloalkyl optionally substituted by 1-3 R 19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R 19 ; alternatively R 3 and R 5 or R 4 and R 6 can together form a double bond; and alternatively any of R 1 and R 2 , R 1 and R 3 , R 1 and R 5 , R 1 and R 11 , R 4 and R 11 , and R 6 and R 11 can, together with the atoms linking them, form a 5-15 membered heterocycloalkyl optionally substituted by 1-3 R 19 or a 5-15 membered heteroaryl optionally substituted by 1-3 R 19 .

6. A compound as defined in claim 1 , wherein R 1 , R 4 , R 5 , R 6, and R 11 are independently chosen from H and C 1-6 alkyl optionally substituted by 1-3 R 19 ; R 2 is chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 7-11 arylalkyl optionally substituted by 1-3 R 19 , and 6-10 membered heteroarylalkyl optionally substituted by 1-3 R 19 ; R 3 is chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 7-11 arylalkyl optionally substituted by 1-9 R 19 , C 6-7 cycloalkylalkyl optionally substituted by 1-6 R 19 , and 6-11 membered heteroarylalkyl optionally substituted by 1-7 R 19 ; and alternatively any of R 1 and R 2 , R 1 and R 3 , R 1 and R 5 , R 1 and R 11 , and R 4 and R 11 can, together with the atoms linking them, form a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R 19 .

7. A compound as defined in claim 1 , wherein R 7 , R 8 , R 9 , and R 10 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 2-6 alkynyl optionally substituted by 1-3 R 19 , C 6-10 aryl optionally substituted by 1-3 R 19 , C 3-7 cycloalkyl optionally substituted by 1-3 R 19 , 3-7 membered heterocycloalkyl optionally substituted by 1-3 R 19 , 5-6 membered heteroaryl optionally substituted by 1-3 R 19 , halogen, —CN, —C(═O)R 20 , —C(═O)NR 22 R 23 , —NO 2 , —NR 22 R 23 , —NR 24 S(═O) 2 R 21 , —OR 20 , —S(═O) n R 20 , and —S(═O) 2 NR 22 R 23 ; alternatively, either or both of R 7 and R 8 , and/or R 9 and R 10 , can, together with the atoms linking them, form a C 3-7 cycloalkyl optionally substituted by 1-3 R 19 , or a 3-7 membered heterocycloalkyl optionally substituted by 1-3 R 19 .

8. A compound as defined in claim 1 , wherein R 7 , R 8 , R 9 , and R 10 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 2-6 alkenyl optionally substituted by 1-3 R 19 , C 2-6 alkynyl optionally substituted by 1-3 R 19 , C 6-10 aryl optionally substituted by 1-3 R 19 , C 7-11 arylalkyl optionally substituted by 1-3 R 19 , C 3-10 cycloalkyl optionally substituted by 1-3 R 19 , 3-10 membered heterocycloalkyl optionally substituted by 1-3 R 19 , 5-10 membered heteroaryl optionally substituted by 1-3 R 19 , 6-11 membered heteroarylalkyl optionally substituted by 1-3 R 19 , halogen, —CN, —C(═O)R 20 , —C(═O)NR 22 R 23 , —NR 22 R 23 , —NR 24 C(═O)R 20 , and —OR 20 ; alternatively, either or both of R 7 and R 8 , and/or R 9 and R 1 ° , can, together with the atoms linking them, form a C 6-10 aryl optionally substituted by 1-3 R 19 , C 3-10 cycloalkyl optionally substituted by 1-3 R 19 , 3-10 membered heterocycloalkyl optionally substituted by 1-3 R 19 or a 5-10 membered heteroaryl optionally substituted by 1-3 R 19 .

9. A compound as defined in claim 1 , wherein R 12 , R 13 , R 14, and R 15 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 2-6 alkenyl optionally substituted by 1-3 R 19 , C 2-6 alkynyl optionally substituted by 1-3 R 19 , C 6-10 aryl optionally substituted by 1-3 R 19 , C 3-7 cycloalkyl optionally substituted by 1-3 R 19 , 3-7 membered heterocycloalkyl optionally substituted by 1-3 R 19 , 5-6 membered heteroaryl optionally substituted by 1-3 R 19 , halogen, —CN, —C(═O)R 20 , —C(═O)OR 20 , —C(═O)NR 22 R 23 , —NO 2 , —NR 22 R 23 , —NR 24 C(═O)R 20 , —NR 24 C(═O)OR 21 , —NR 24 C(═O)NR 22 R 23 , —NR 24 S(═O) 2 R 21 , —NR 24 S(═O) 2 NR 22 R 23 , —OR 20 , —OC(═O)R 20 , —OC(═O)NR 22 R 23 , —OC(═O)OR 20 , —S(═O) n R 20 , —S(═O) 2 OR 20 , —SO 3 R 27 , —S(═O) 2 NR 22 R 23 , —S(═O)NR 22 R 23 , —P(═O)R 28 R 28 , —P(═O)(NR 22 R 23 )(NR 22 R 23 ), and —P(═O)(OR 20 )(OR 20 ); alternatively, either or both of R 12 and R 13 , and/or R 14 and R 15 , can, together with the atoms linking them, form a C 6-10 aryl optionally substituted by 1-3 R 19 , C 3-7 cycloalkyl optionally substituted by 1-3 R 19 , 3-7 membered heterocycloalkyl optionally substituted by 1-3 R 19 or a 5-6 membered heteroaryl optionally substituted by 1-3 R 19 .

10. A compound as defined in claim 1 , wherein R 12 , R 13 , and R 14 are H;

R 15 is chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 2-6 alkenyl optionally substituted by 1-3 R 19 , C 2-6 alkynyl optionally substituted by 1-3 R 19 , C 6-10 aryl optionally substituted by 1-3 R 19 , C 3-7 cycloalkyl optionally substituted by 1-3 R 19 , 3-7 membered heterocycloalkyl optionally substituted by 1-3 R 19 , 5-6 membered heteroaryl optionally substituted by 1-3 R 19 , halogen, , —CN, —C(═O)R 20 , —C(═O)NR 22 R 23 , —NO 2 , —NR 22 R 23 , —NR 24 C(═O)R 20 , —NR 24 S(═O) 2 R 21 , —OR 20 , —S(═O) n R 20 , —S(═O) 2 NR 22 R 23 .

11. A compound as defined in claim 1 , wherein R 17 is H; and R 16 and R 18 are independently chosen from H and C 1-6 alkyl.

12. A compound as defined in claim 1 , wherein R 19 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-3 R 39 , C 6-10 aryl optionally substituted by 1-3 R 39 , C 7-11 arylalkyl optionally substituted by 1-3 R 39 , C 3-6 cycloalkyl optionally substituted by 1-3 R 39 , 3-6 membered heterocycloalkyl optionally substituted by 1-3 R 39 , 5-6 membered heteroaryl optionally substituted by 1-3 R 39 , halogen, —CN, —C(═O)R 30 , —C(═O)NR 32 R 33 , —NR 32 R 33 , —NR 34 C(═O)R 30 , —NR 34 S(═O) 2 R 31 , —OR 30 , ═O, —S(═O) n R 30 , and —S(═O) 2 NR 32 R 33 .

13. A compound as defined in claim 1 , wherein R 20 , R 21 , R 24 , R 25 , R 26 , R 27 , R 30 , R 31 , R 34 , R 35 , R 36 and R 37 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 49 , phenyl optionally substituted by 1-3 R 49 , benzyl optionally substituted by 1-3 R 49 , C 3-6 cycloalkyl optionally substituted by 1-3 R 49 , 3-6 membered heterocycloalkyl optionally substituted by 1-3 R 49 , and 5-6 membered heteroaryl optionally substituted by 1-3 R 49 .

14. A compound as defined in claim 1 , wherein R 22 , R 23 , R 32 and R 33 at each occurrence is independently chosen from H, C 1-6 alkyl, C 6-10 aryl, C 7-11 arylalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, and 5-10 membered heteroaryl.

15. A compound as defined in claim 1 , wherein R 39 , R 49 , R 59 and R 69 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-3 R 79 , C 2-16 alkenyl optionally substituted by 1-3 R 79 , C 2-6 alkynyl optionally substituted by 1-3 R 79 , C 6-10 aryl optionally substituted by 1-3 R 79 , C 7-11 arylalkyl optionally substituted by 1-3 R 79 , C 3-10 cycloalkyl optionally substituted by 1-3 R 79 , 3-10 membered heterocycloalkyl optionally substituted by 1-3 R 79 , 5-10 membered heteroaryl optionally substituted by 1-3 R 79 , halogen, —CN, —C(═O)R 70 , —C(═O)OR 70 , —C(═O)NR 72 R 73 , —NO 2 , —NR 72 R 73 , —NR 74 C(═O)R 70 , —NR 74 C(═O)NR 72 R 73 , —NR 74 S(═O) 2 R 71 , —OR 70 , ═O, —S(═O) n R 70 , and —S(═O) 2 NR 72 R 73 .

16. A compound as defined in claim 1 , wherein R 70 , R 71 , R 74 , R 75 , R 76 and R 77 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 89 , C 6-10 aryl optionally substituted by 1-3 R 89 , C 7-11 arylalkyl optionally substituted by 1-3 R 89 , C 3-10 cycloalkyl optionally substituted by 1-3 R 89 , 3-10 membered heterocycloalkyl optionally substituted by 1-3 R 89 , and 5-10 membered heteroaryl optionally substituted by 1-3 R 89 .

17. A compound as defined in claim 1 , wherein R 72 and R 73 at each occurrence is independently chosen from H, C 1-6 alkyl, phenyl, benzyl, C 5-6 cycloalkyl, 5-6 membered heterocycloalkyl, and 5-6 membered heteroaryl; alternatively, any R 72 and R 73 may form, together with the nitrogen atom to which they are attached, a 5-6 membered heterocycloalkyl or a 5-6 membered heteroaryl.

18. A compound as defined in claim 1 , wherein R 78 at each occurrence is independently chosen from C 1-6 alkyl, phenyl, benzyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, and 5-6 membered heteroaryl.

19. A compound as defined in claim 1 , wherein R 79 , R 89 , R 99 and R 109 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-3 halogen, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 7-11 arylalkyl, C 3-10 cycloalkyl, 3-10 membered heterocycloalkyl, 5-10 membered heteroaryl, halogen, —CN, —C(═O)R 110 , —C(═O)OR 110 , —C(═O)NR 110 R 110 , —NO 2 , —NR 110 R 110 , —NR 110 OR 110 , —NR 110 C(═O)R 110 , —NR 110 C(═O)NR 110 R 110 , —NR 110 S(═O) 2 R 110 , —NR 110 S(═O) 2 NR 110 R 110 , —OR 110 , ═O, —OCN, —OC(═O)R 110 , —S(═O) n R 110 , —S(═O) 2 NR 110 R 110 , and —S(═O)NR 110 R 110 .

20. A compound as defined in claim 1 , wherein R 110 at each occurrence is independently chosen from H, C 1-6 alkyl and C 1-6 -haloalkyl; and R 111 at each occurrence is independently chosen from C 1-6 alkyl and C 1-6 -haloalkyl.

21. A pharmaceutical composition comprising a compound as defined in claim 1 or a salt thereof and a pharmaceutically acceptable excipient.

22. The compound as defined in claim 1 , wherein MQX is

23. The compound as defined in claim 22 , wherein R 8 is a pyrazolyl.

24. The compound as defined in claim 22 , wherein G is

25. The compound as defined in claim 2 , wherein MQX is

26. The compound as defined in claim 2 , wherein G is

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 15, 2024
From: VARIAN BIOPHARMACEUTICALS, INC.
To: WINDTREE THERAPEUTICS, INC.
Reel/Frame 069171/0875 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 13, 2017
From: IGNYTA, INC.
To: CANCER RESEARCH TECHNOLOGY LIMITED
Reel/Frame 040964/0825 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 17, 2015
From: CEPHALON, INC.
To: IGNYTA, INC.
Reel/Frame 035186/0151 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 21, 2014
From: DORSEY, BRUCE D.; LEARN, KEITH S.; MORRIS, EMMA L.; OTT, GREGORY R.; ROFFEY, JONATHAN R.A.; SOUDY, CHRISTELLE N.; WAGNER, JASON C.
To: CANCER RESEARCH TECHNOLOGY LIMITED; CEPHALON, INC.
Reel/Frame 033349/0530 →
Continuity (3)
Continuation PCTUS2012065831 · Nov 19, 2012
Provisional Application 61563310 · Nov 23, 2011
Related Publication 20140323435A1 · Oct 30, 2014