IP Library › Granted Patent US 8,431,695
Granted Patent B2
US 8,431,695 · App. 12/084,411 · Granted Apr 30, 2013

Pyrrolo[2,1-f][1,2,4]triazin-4-ylamines IGF-1R kinase inhibitors for the treatment of cancer and other hyperproliferative diseases

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Quick Facts
Patent No.
US 8,431,695
App. No.
12/084,411
Granted
Apr 30, 2013
Kind
B2
Abstract

This invention relates to novel compounds of formula (I). Formula (I) in which the variable groups are as defined in the specification and claims, to pharmaceutical compositions containing them, and to a method of treatment using them for treatment of cancer.

Claims (525)

1. A compound of formula (I)

wherein

the dotted lines between ring A and the first atoms of groups R 1 and R 4 , respectively, indicate possible double bonds, if required by the structures of R 1 and R 4 ;

the dotted circle in ring A indicates that ring A is aromatic;

the bracket indicates the carbon atoms of ring A to which the pyrrolotriazine may be attached;

R 1 represents H or halogen;

R 2 represents H, or halogen;

R 4 represents

—C(O)—NR 8 R 9 wherein

R 8 represents H or (C 1 -C 3 )alkyl; and

R 9 represents H, (C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl;

—OR 10 wherein

R 10 represents H, (C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl; or

or

R 1 and R 4 may be joined, and taken together with the carbon atoms to which they are attached, form a fused heterocycle having a partial structure selected from the group consisting of

 wherein

R 11 represents H, (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl, pyridyl(C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl;

R 12 represents

H;

(C 1 -C 4 )alkyl;

halogen;

CN; or

NR 12a R 12b wherein

R 12a represents H or (C 1 -C 3 )alkyl; and

R 12b represents H, (C 1 -C 3 )alkyl, benzyl, or —C(O)—(C 1 -C 4 )alkyl;

R 13 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 14 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 15 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 16 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 17 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

L represents

a bond;

(C 1 -C 6 )alkanediyl;

(C 3 -C 5 )alkenediyl;

(C 3 -C 5 )alkynediyl;

a carbonyl group;

R 5 represents

wherein

R 18 represents H or (C 1 -C 3 )alkyl;

R 19 represents

H;

(C 1 -C 3 )alkyl;

(C 3 -C 7 )cycloalkyl;

(CH 2 ) a —OR 20 wherein

 R 20 represents H or (C 1 -C 3 )alkyl; and

 subscript “a” represents 2, 3, or 4;

C(O)—R 21 wherein

 R 21 represents (C 1 -C 3 )alkyl, optionally substituted phenyl, or NR 22 R 23 wherein

 R 22 and R 23 each independently represents H or (C 1 -C 3 )allyl;

 wherein

 R 24 represents H, (C 1 -C 3 )alkyl, or —C(O)—O(C 1 -C 4 )alkyl;

SO 2 R 25 wherein

 R 25 represents (C 1 -C 3 )alkyl or —NR 26 R 27 wherein

 R 26 and R 27 independently represent H or (C 1 -C 3 )alkyl;

wherein

subscript “b” represents 0, 1 or 2;

subscript “c” represents 0, 1, or 2; and

R 28 represents

H;

(C 1 -C 4 )alkyl optionally substituted with OR 29 wherein

R 29 represents H or (C 1 -C 3 )alkyl;

OR 30 wherein

R 30 represents H or (C 1 -C 3 )alkyl;

halogen;

—C(O)—R 31 wherein

R 31 represents (C 1 -C 3 )alkyl;

—NR 32 R 33 wherein R 32 and R 33 independently represent H or (C 1 -C 3 )alkyl, or R 32 and R 33 may be joined and taken together with the N to which they are attached form a pyrrolidine or piperidine ring;

—C(O)—NR 34 R 35 wherein R 34 and R 35 independently represent H or (C 1 -C 3 )alkyl;

 or

—CO 2 R 36 wherein R 36 represents (C 1 -C 4 )alkyl;

wherein

R 37 represents

H;

(C 1 -C 4 )alkyl;

(CH 2 ) d —OR 38 wherein

subscript “d” represents 2, 3, or 4; and

R 38 represents H or (C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) e —C(O)—(CH 2 ) f —NR 39 R 40 wherein

subscript “e” represents 0 or 1;

subscript “f” represents 0, 1, 2, or 3; and

R 39 and R 40 independently represent H or (C 1 -C 3 )alkyl, or R 39 and R 40 may be joined and taken together with the N to which the are attached form a 6-membered heterocycle also containing O, S, or NR 41 wherein R 41 represents H or (C 1 -C 3 )alkyl;

C(O)—OR 42 wherein

R 42 represents H or (C 1 -C 4 )alkyl;

 wherein the N-containing ring is optionally substituted with halogen; and

subscript “h” represents 0 or 1;

subscript “i” represents 0, 1, 2, or 3;

subscript “j” represents 0 or 1;

(CH 2 ) k —C(O)—R 43 wherein

subscript “k” represents 0 or 1; and

R 43 represents (C 1 -C 4 )alkyl optionally substituted with halogen, or (C 3 -C 6 )cycloalkyl optionally substituted with halogen;

(CH 2 ) m —SO 2 R 44 wherein

subscript “m” represents 1, 2, or 3; and

R 44 represents (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or —NR 45 R 46 wherein R 45 and R 46 independently represent H or (C 1 -C 3 )alkyl;

(CH 2 ) n —CN wherein

subscript “n” represents 1, 2, or 3;

 wherein

R 47 represents CN or (C 1 -C 3 )alkyl; or

 wherein

R 48 represents H or (C 1 -C 3 )alkyl;

wherein

subscript “p” represents 0, 1, or 2; and

the ring is optionally substituted on carbon with up to two substituents independently selected from halogen, hydroxyl, and (C 1 -C 3 )alkyl;

R 49 represents

H;

(C 1 -C 4 )alkyl;

(CH 2 ) q —OR 50 wherein

subscript “q” represents 2, 3, or 4; and

R 50 represents H or (C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ), —C(O)—(CH 2 ) s —NR 51 R 52 wherein

subscript “r” represents 0 or 1;

subscript “s” represents 0, 1, 2, or 3; and

R 51 , and R 52 independently represent H or (C 1 -C 3 )alkyl, or R 51 and R 52 may be joined and taken together with the N to which they are attached form a 6-membered heterocycle also containing O, S, or NR 53 wherein R 53 represents H or (C 1 -C 3 )alkyl;

C(O)—(CH 2 ) t —OR 54 wherein

subscript “t” represents 0, 1, 2, or 3; and

R 54 represents H or (C 1 -C 4 )alkyl;

 wherein

R 55 and R 56 independently represent H or (C 1 -C 3 )alkyl;

 wherein

the ring is optionally substituted with halogen;

subscript “u” represents 0 or 1;

subscript “v” represents 0, 1, 2, or 3; and

subscript “w” represents 0 or 1;

(CH 2 ) x —C(O)—R 57 wherein

subscript “x” represents 0 or 1; and

R 57 represents (C 1 -C 4 )alkyl optionally substituted with halogen, or represents (C 3 -C 6 )cycloalkyl optionally substituted with halogen;

 wherein

subscript “y” represents 0 or 1; and

R 58 represents H or (C 1 -C 3 )alkyl;

 or

—SO 2 R 59 wherein

R 59 represents (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or —NR 60 R 61 wherein R 60 and R 61 represent H or (C 1 -C 3 )alkyl;

OR 62 wherein

R 62 represents H or (C 1 -C 3 )alkyl;

halogen;

CN;

 wherein

R 63 represents (C 1 -C 3 )alkyl optionally substituted with hydroxyl or halogen; and subscript “Z” represents 0, 1, or 2;

wherein

subscript “aa” represents 0, 1, or 2;

wherein

R 64 represents

H;

(C 1 -C 3 )alkyl optionally substituted with hydroxyl or halogen;

—C(O)—(CH 2 ) bb —NR 65 R 66 wherein

subscript “bb” represents 0, 1, 2, or 3;

R 65 and R 66 are independently H or (C 1 -C 3 )alkyl, or R 65 and

R 66 may be joined and taken together with the N to which they are attached form a pyrrolidine ring;

—C(O)—(C 1 -C 4 )alkyl;

—C(O)-O(C 1 -C 4 )alkyl;

—SO 2 R 67 wherein

R 67 represents (C 1 -C 3 )alkyl;

wherein

R 68 represents (C 1 -C 3 )alkyl;

—SO 2 R 69 wherein

R 69 represents (C 1 -C 3 )alkyl;

—O—CH 2 -phenyl;

wherein

R 70 represents H or (C 1 -C 3 )alkyl;

wherein

R 71 represents H or (C 1 -C 3 )alkyl;

wherein

R 72 represents H, (C 1 -C 3 )alkyl, or —C(O)O(t-butyl);

wherein

R 73 represents

H

(C 1 -C 3 )alkyl;

wherein

R 78 represents

H

(C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

—SO 2 R 79 wherein R 79 represents H or (C 1 -C 3 )alkyl;

—C(O)—(C 1 -C 3 )alkyl;

—C(O)-(optionally substituted phenyl);

 wherein R 80 represents H or (C 1 -C 3 )alkyl;

—(CH 2 ) ee —C(O)—(CH 2 ) ff —NR 81 R 82 wherein

subscript “ee” represents 0 or 1;

subscript “ff” represents 0, 1, 2, or 3; and

R 81 and R 82 independently represent H or (C 1 -C 3 )alkyl

wherein

R 83 represents H or (C 1 -C 3 )alkyl;

wherein

R 85 represents H, (C 1 -C 3 )alkyl, or —(CH 2 ) ii —C(O)—(CH 2 ) jj —NR 86 R 87 wherein

subscript “ii” represents 0 or 1;

subscript “jj” represents 0, 1, 2, or 3; and

R 86 and R 87 independently represent H or (C 1 -C 3 )alkyl;

wherein

R 88 represents H, (C 1 -C 3 )alkyl, or —(CH 2 ) kk —C(O)—(CH 2 ) mm —NR 89 R 90 wherein

subscript “kk” represents 0 or 1;

subscript “mm” represents 0, 1, 2, or 3; and

R 89 and R 90 independently represent H or (C 1 -C 3 )alkyl;

wherein subscript “nn” represents 0 or 1;

wherein

subscript “oo” represents 0, 1, or 2; and

R 91 represents (C 1 -C 3 )alkyl;

wherein R 92 represents H or (C 1 -C 3 )alkyl;

wherein

R 93 represents

H;

(CH 2 ) pp —OR 94 wherein

subscript “pp” represents 2 or 3; and

R 94 represents H or (C 1 -C 3 )alkyl;

(CH 2 ) qq —C(O)—(CH 2 ) rr —NR 95 R 96 wherein

subscript “qq” represents 0 or 1;

subscript “rr” represents 0 or 1; and

R 95 and R 96 independently represent H or (C 1 -C3)alkyl;

C(O)—R 97 wherein

R 97 represents H or (C 1 -C 3 )alkyl;

—SO 2 R 98 wherein

R 98 represents H or (C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) ss —CH(OR 99 )—(CH 2 ) tt R 100 wherein

subscript “ss” represents 0 or 1;

subscript “tt” represents 1, 2, or 3; and

R 99 and R 100 each independently represents H or (C 1 -C 3 )alkyl;

wherein

R 101 represents

H;

(C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) uu —OR 102 wherein

subscript “uu” represents 2 or 3; and

R 102 represents H or (C 1 -C 3 )alkyl;

SO 2 R 103 wherein

R 103 represents (C 1 -C 3 )alkyl;

(CH 2 ) v v —C(O)—(CH 2 ) w w —NR 104 R 105 wherein

subscript “v v” represents 0 or 1;

subscript “w w” represents 0 or 1; and

R 104 and R 105 independently represent H or (C 1 -C 3 )alkyl;

—C(O)O(t-butyl);

C(O)—R 106 wherein

R 106 represents (C 1 -C 3 )alkyl optionally substituted with

OR 107 wherein

 R 107 represents H or (C 1 -C 3 )alkyl;

R 6 represents H or (C 1 -C 3 )alkyl; and

R 7 represents H, CN, or (C 1 -C 3 )alkyl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of formula (I) of claim 1

wherein

the dotted lines between ring A and the first atoms of groups R 1 and R 4 , respectively, indicate possible double bonds, if required by the structures of R 1 and R 4 ;

the dotted circle in ring A indicates that ring A is aromatic;

the bracket indicates the carbon atoms of ring A to which the pyrrolotriazine may be attached;

R 1 represents H or halogen;

R 2 represents H or halogen;

R 4 represents

—OR 10 wherein

R 10 represents H, (C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl; or

or

R 1 and R 4 may be joined, and taken together with the carbon atoms to which they are attached, form a fused heterocycle having a partial structure selected from the group consisting of

 wherein

R 11 represents H, (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl, pyridyl(C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl;

R 12 represents

H;

(C 1 -C 4 )alkyl;

halogen;

CN; or

NR 12a R 12b wherein

R 12a represents H or (C 1 -C 3 )alkyl; and

R 12b represents H, (C 1 -C 3 )alkyl, benzyl, or —C(O)—(C 1 -C 4 )alkyl;

R 14 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 15 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 16 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 17 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

L represents

a bond;

—(C 1 -C 6 )alkanediyl;

a carbonyl group;

R 5 represents

 wherein

R 18 represents H or (C 1 -C 3 )alkyl;

R 19 represents

H;

(C 1 -C 3 )alkyl;

(C 3 -C 7 )cycloalkyl;

(CH 2 ), —OR 20 wherein

R 20 represents H or (C 1 -C 3 )alkyl; and

subscript “a” represents 2, 3, or 4;

C(O)—R 21 wherein

R 21 represents (C 1 -C 3 )alkyl, optionally substituted phenyl, or NR 22 R 23 wherein

R 22 and R 23 each independently represents H or (C 1 -C 3 )alkyl;

SO 2 R 25 wherein

R 25 represents (C 1 -C 3 )alkyl or —NR 26 R 27 wherein

 R 26 and R 27 independently represent H or (C 1 -C 3 )alkyl;

wherein

subscript “b” represents 0, 1 or 2;

subscript “c” represents 0, 1, or 2; and

R 28 represents

H;

(C 1 -C 4 )alkyl optionally substituted with OR 29 wherein

R 29 represents H or (C 1 -C 3 )alkyl;

OR 30 wherein

—R 30 represents H or (C 1 -C 3 )alkyl;

halogen;

—C(O)—R 31 wherein

R 31 represents (C 1 -C 3 )alkyl;

—C(O)—NR 34 R 35 wherein R 34 and R 35 independently represent H or (C 1 -C 3 )alkyl; or

—CO 2 R 36 wherein R 36 represents (C 1 -C 4 )alkyl;

wherein

R 37 represents

H;

(C 1 -C 4 )alkyl;

(CH 2 ) d —OR 38 wherein

subscript “d” represents 2, 3, or 4; and

R 38 represents H or (C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) e —C(O)—(CH 2 ) f —NR 39 R 40 wherein

subscript “e” represents 0 or 1;

subscript “f” represents 0, 1, 2, or 3; and

R 39 and R 40 independently represent H or (C 1 -C 3 )alkyl, or R 39 and R 40 may be joined and taken together with the N to which they are attached form a 6-membered heterocycle also containing O, S, or NR 41 wherein R 41 represents H or (C 1 -C 3 )alkyl;

 wherein the N-containing ring is optionally substituted with halogen; and

subscript “h” represents 0 or 1;

subscript “i” represents 0, 1, 2, or 3;

subscript “j” represents 0 or 1; or

(CH 2 ) m —SO 2 R 44 wherein

subscript “m” represents 1, 2, or 3; and

R 44 represents (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or —NR 45 R 46 wherein R 45 and R 46 independently represent H or (C 1 -C 3 )alkyl;

wherein

subscript “p” represents 0, 1, or 2; and

the ring is optionally substituted on carbon with up to two substituents independently selected from halogen, hydroxyl, and (C 1 -C 3 )alkyl;

R 49 represents

H;

(C 1 -C 4 )alkyl;

(CH 2 ) q —OR 50 wherein

subscript “q” represents 2, 3, or 4; and

R 50 represents H or (C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) r —C(O)—(CH 2 ) s —NR 51 R 52 wherein

subscript “r” represents 0 or 1;

subscript “s” represents 0, 1, 2, or 3; and

R 51 and R 52 independently represent H or (C 1 -C 3 )alkyl, or R 51 and R 52 may be joined and taken together with the N to which they are attached form a 6-membered heterocycle also containing O, S, or NR 53 wherein R 53 represents H or (C 1 -C 3 )alkyl;

C(O)—(CH 2 ) t —OR 54 wherein

subscript “t” represents 0, 1, 2, or 3; and

R 54 represents H or (C 1 -C 4 )alkyl;

 wherein

R 55 and R 56 independently represent H or (C 1 -C 3 )alkyl;

 wherein

the ring is optionally substituted with halogen;

subscript “u” represents 0 or 1;

subscript “v” represents 0, 1, 2, or 3; and

subscript “w” represents 0 or 1;

(CH 2 ) x —C(O)—R 57 wherein

subscript “x” represents 0 or 1; and

R 57 represents (C 1 -C 4 )alkyl optionally substituted with halogen, or represents (C 3 -C 6 )cycloalkylv optionally substituted with halogen;

 or

—SO 2 R 59 wherein

R 59 represents (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or —NR 60 R 61 wherein R 60 and R 61 represent H or (C 1 -C 3 )alkyl;

OR 62 wherein

R 62 represents H or (C 1 -C 3 )alkyl;

halogen;

CN;

 wherein

R 63 represents (C 1 -C 3 )alkyl optionally substituted with hydroxyl or halogen; and subscript “z” represents 0, 1, or 2;

 wherein

subscript “aa” represents 0, 1, or 2;

 wherein

R 64 represents

H;

(C 1 -C 3 )alkyl optionally substituted with hydroxyl or halogen;

—C(O)—(CH 2 ) bb —NR 65 R 66 wherein

subscript “bb” represents 0, 1, 2, or 3;

R 65 and R 66 are independently H or (C 1 -C 3 )alkyl, or R 65 and

R 66 may be joined and taken together with the N to which they are attached form a pyrrolidine ring;

—C(O)—(C 1 -C 4 )alkyl;

—C(O)—O(C 1 -C 4 )alkyl;

wherein

R 78 represents

H

(C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

—SO 2 R 79 wherein R 79 represents H or (C 1 -C 3 )alkyl;

—C(O)—(C 1 -C 3 )alkyl;

—(CH 2 ) ee —C(O)—(CH 2 ) ff —NR 81 R 82 wherein

subscript “ee” represents 0 or 1;

subscript “ff” represents 0, 1, 2, or 3; and

R 81 and R 82 independently represent H or (C 1 -C 3 )alkyl;

wherein

R 85 represents H, (C 1 -C 3 )alkyl, or —(CH 2 ) ii —C(O)—(CH 2 ) jj —NR 86 R 87 wherein

subscript “ii” represents 0 or 1;

subscript “jj” represents 0, 1, 2, or 3; and

R 86 and R 87 independently represent H or (C 1 -C 3 )alkyl;

wherein

R 93 represents

H;

(CH 2 ) pp —OR 94 wherein

subscript “pp” represents 2 or 3; and

R 94 represents H or (C 1 -C 3 )alkyl;

(CH 2 ) qq —C(O)—(CH 2 ) rr —NR 95 R 96 wherein

subscript “qq” represents 0 or 1;

subscript “rr” represents 0 or 1; and

R 95 and R 96 independently represent H or (C 1 -C 3 )alkyl;

C(O)—R 97 wherein

R 97 represents H or (C 1 -C 3 )alkyl;

—SO 2 R 98 wherein

R 98 represents H or (C 1 -C 3 )alkyl;

wherein

R 101 represents

H;

(C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) uu —OR 102 wherein

subscript “uu” represents 2 or 3; and

R 102 represents H or (C 1 -C 3 )alkyl;

SO 2 R 103 wherein

R 103 represents (C 1 -C 3 )alkyl;

(CH 2 ) v v —C(O)—(CH 2 ) w w —NR 104 R 105 wherein

subscript “v v” represents 0 or 1;

subscript “w w” represents 0 or 1; and

R 104 and R 105 independently represent H or (C 1 -C 3 )alkyl;

C(O)—R 106 wherein

R 106 represents (C 1 -C 3 )alkyl optionally substituted with OR 107 wherein

 R 107 represents H or (C 1 -C 3 )alkyl;

R 6 represents H or (C 1 -C 3 )alkyl; and

R 7 represents H, CN, or (C 1 -C 3 )alkyl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound of formula (I) of claim 1

wherein

the dotted lines between ring A and the first atoms of groups R 1 and R 4 , respectively, indicate possible double bonds, if required by the structures of R 1 and R 4 ;

the dotted circle in ring A indicates that ring A is aromatic;

the bracket indicates the carbon atoms of ring A to which the pyrrolotriazine may be attached;

R 1 represents H or halogen;

R 2 represents H or halogen;

R 4 represents

—OR 10 wherein

R 10 represents H, (C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl; or

or

R 1 and R 4 may be joined, and taken together with the carbon atoms to which they are attached, form a fused heterocycle having a partial structure selected from the group consisting of

 wherein

R 11 represents H, (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 3 )alkyl, pyridyl(C 1 -C 3 )alkyl, optionally substituted phenyl, or optionally substituted benzyl;

R 12 represents

H;

(C 1 -C 4 )alkyl;

halogen;

CN; or

NR 12a R 12b wherein

R 12a represents H or (C 1 -C 3 )alkyl; and

R 12b represents H, (C 1 -C 3 )alkyl, benzyl, or —C(O)—(C 1 -C 4 )alkyl;

R 14 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

R 15 represents H, (C 1 -C 3 )alkyl, or optionally substituted benzyl;

L represents

a bond; or

(C 1 -C 6 )alkanediyl;

R 5 represents

 wherein

R 18 represents H or (C 1 -C 3 )alkyl;

R 19 represents

H;

(C 1 -C 3 )alkyl;

(C 3 -C 7 )cycloalkyl;

(CH 2 ) a —OR 20 wherein

R 20 represents H or (C 1 -C 3 )alkyl; and

subscript “a” represents 2, 3, or 4;

C(O)—R 21 wherein

R 21 represents (C 1 -C 3 )alkyl, optionally substituted phenyl, or NR 22 R 23 wherein

R 22 and R 23 each independently represents H or (C 1 -C 3 )alkyl;

SO 2 R 25 wherein

R 25 represents (C 1 -C 3 )alkyl or —NR 26 R 27 wherein

 R 26 and R 27 independently represent H or (C 1 -C 3 )alkyl;

wherein

subscript “b” represents 0, 1 or 2;

subscript “c” represents 0, 1, or 2; and

R 28 represents

H;

(C 1 -C 4 )alkyl optionally substituted with OR 29 wherein

R 29 represents H or (C 1 -C 3 )alkyl;

OR 30 wherein

R 30 represents H or (C 1 -C 3 )alkyl;

halogen;

—C(O)—R 31 wherein

R 31 represents (C 1 -C 3 )alkyl;

—C(O)—NR 34 R 35 wherein R 34 and R 35 independently represent H or

(C 1 -C 3 )alkyl; or

—CO 2 R 36 wherein R 36 represents (C 1 -C 4 )alkyl;

wherein

subscript “p” represents 0, 1, or 2; and

the ring is optionally substituted on carbon with up to two substituents independently selected from halogen, hydroxyl, and (C 1 -C 3 )alkyl;

R 49 represents

H;

(C 1 -C 4 )alkyl;

(CH 2 ) q —OR 50 wherein

subscript “q” represents 2, 3, or 4; and

R 50 represents H or (C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) r —C(O)—(CH 2 ) s —NR 51 R 52 wherein

subscript “r” represents 0 or 1;

subscript “s” represents 0, 1, 2, or 3; and

R 51 and R 52 independently represent H or (C 1 -C 3 )alkyl, or R 51 and R 52 may be joined and taken together with the N to which they are attached form a 6-membered heterocycle also containing O, S, or NR 53 wherein R 53 represents H or (C 1 -C 3 )alkyl;

 wherein

R 55 and R 56 independently represent H or (C 1 -C 3 )alkyl;

 wherein

the ring is optionally substituted with halogen;

subscript “u” represents 0 or 1;

subscript “v” represents 0, 1, 2, or 3; and

subscript “w” represents 0 or 1; or

—SO 2 R 59 wherein

R 59 represents (C 1 -C 3 )alkyl, (C 3 -C 6 )cycloalkyl, or —NR 60 R 61 wherein R 60 and R 61 represent H or (C 1 -C 3 )alkyl;

wherein

R 85 represents H, (C 1 -C 3 )alkyl, or —(CH 2 ) ii —C(O)—(CH 2 ) jj —NR 86 R 87 wherein

subscript “ii” represents 0 or 1;

subscript “jj” represents 0, 1, 2, or 3; and

R 86 and R 87 independently represent H or (C 1 -C 3 )alkyl;

wherein

R 101 represents

H;

(C 1 -C 3 )alkyl;

(C 3 -C 6 )cycloalkyl;

(CH 2 ) uu —OR 102 wherein

subscript “uu” represents 2 or 3; and

R 102 represents H or (C 1 -C 3 )alkyl;

SO 2 R 103 wherein

R 103 represents (C 1 -C 3 )alkyl;

(CH 2 ) v v —C(O)—(CH 2 ) w w —NR 104 R 105 wherein

subscript “v v” represents 0 or 1;

subscript “w w” represents 0 or 1; and

R 104 and R 105 independently represent H or (C 1 -C 3 )alkyl;

C(O)—R 106 wherein

R 106 represents (C 1 -C 3 )alkyl optionally substituted with OR 107 wherein

 R 107 represents H or (C 1 -C 3 )alkyl;

R 6 represents H or (C 1 -C 3 )alkyl; and

R 7 represents H, CN, or (C 1 -C 3 )alkyl;

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 plus a pharmaceutically acceptable carrier.

5. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 2 plus a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 3 plus a pharmaceutically acceptable carrier.