IP Library › Patent Application 14690226

Patent Application

App. No. 14/690,226

Tricyclic Lactams for Use as Anti-Neoplastic and Anti-Proliferative Agents

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US None
App. No.: 14/690,226

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

This invention is in the area of tricyclic lactam compounds and methods for treating selected cancers and hyperproliferative disorders.

Claims (414)

1 . A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

each R 1 is independently aryl, alkyl, cycloalkyl or haloalkyl, wherein each of said alkyl, cycloalkyl and haloalkyl groups optionally includes O or N heteroatoms in place of a carbon in the chain and two R 1 's on adjacent ring atoms or on the same ring atom together with the ring atom(s) to which they are attached optionally form a 3-8-membered cycle;

y is 0, 1, 2, 3 or 4;

R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1 or 2 and n is 0, 1 or 2;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance;

R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 )-(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:

said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *,

n is 0, 1 or 2, and

m is 0, 1 or 2;

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance; and

R 6 is H or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and

R 10 is (i) NHR A , wherein R A is unsubstituted or substituted C 1 -C 8 alkyl, cycloalkylalkyl, or -TT-RR, C 1 -C 8 cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O, and S; TT is an unsubstituted or substituted C 1 -C 8 alkyl or C 3 -C 8 cycloalkyl linker; and RR is a hydroxyl, unsubstituted or substituted C 1 -C 6 alkoxy, amino, unsubstituted or substituted C 1 -C 6 alkylamino, unsubstituted or substituted di-C 1 -C 6 alkylamino, unsubstituted or substituted C 6 -C 10 aryl, unsubstituted or substituted heteroaryl comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S, unsubstituted or substituted C 3 -C 10 carbocycle, or unsubstituted or substituted heterocycle comprising one or two 5- or 6-member rings and 1-4 heteroatoms selected from N, O and S; or (ii) —C(O)—R 12 or —C(O)O—R 13 , wherein R 12 is NHR A or R A and R 13 is R A ;

when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present and are as defined above;

when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present and are as defined above;

or a pharmaceutically acceptable salt thereof.

2 . The method of claim 1 , wherein the compound is selected from the group consisting of:

Structure

Reference

Structure

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

3 . The method of claim 2 , wherein the compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.

4 . The method of claim 2 , wherein the compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.

5 . The method of claim 2 , wherein the compound is selected from the group consisting of Compound AAA through XXX, or its pharmaceutically acceptable salt.

6 . The method of claim 1 , wherein the abnormal T-cell proliferation is T-cell lymphoma.

7 . The method of claim 1 , wherein the abnormal T-cell proliferation is T-cell leukemia.

8 . The method of claim 6 , wherein the abnormal T-cell lymphoma is Hodgkin Lymphoma.

9 . The method of claim 6 , wherein the T-cell lymphoma is Non-Hodgkin Lymphoma.

10 . The method of claim 1 , wherein the compound is conjugated to a targeting agent.

11 . The method of claim 10 , wherein the targeting agent is an antibody or antibody fragment.

12 . The method of claim 1 , wherein the compound is conjugated to a radioisotope.

13 . The method of claim 1 , wherein the host is a human.

14 . The method of claim 6 , wherein the host is a human.

15 . The method of claim 7 , wherein the host is a human.

16 . A method for the treatment of abnormal B-cell proliferation that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

y is 0, 1, 2, 3 or 4;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 ) -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:

n is 0, 1 or 2, and

m is 0, 1 or 2;

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present and are as defined above;

when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present and are as defined above;

or a pharmaceutically acceptable salt thereof.

17 . The method of claim 16 , wherein the compound is selected from the group consisting of:

Structure

Reference

Structure

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

18 . The method of claim 17 , wherein the Compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.

19 . The method of claim 17 , wherein the compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.

20 . The method of claim 17 , wherein the compound is selected from the group consisting of Compound AAA through XXX, or its pharmaceutically acceptable salt.

21 . The method of claim 16 , wherein the compound is conjugated to a targeting agent.

22 . The method of claim 21 , wherein the targeting agent is an antibody or antibody fragment.

23 . The method of claim 16 , wherein the compound is conjugated to a radioisotope.

24 . The method of claim 16 , wherein the host is a human.

25 . A method for the treatment of an autoimmune disease that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

y is 0, 1, 2, 3 or 4;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

n is 0, 1 or 2, and

m is 0, 1 or 2;

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

when compounds comprise a double bond in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present and are as defined above;

when compounds do not comprise a double bond in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present and are as defined above;

or a pharmaceutically acceptable salt thereof.

26 . The method of claim 25 , wherein the compound is selected from the group consisting of:

Structure

Reference

Structure

AAA

BBB

CCC

DDD

EEE

FFF

GGG

HHH

III

JJJ

KKK

LLL

MMM

NNN

OOO

PPP

QQQ

RRR

SSS

TTT

UUU

VVV

WWW

XXX

27 . The method of claim 26 , wherein the compound is selected from the group consisting of Compound A through Compound Z, or its pharmaceutically acceptable salt.

28 . The method of claim 26 , wherein the compound is selected from the group consisting of Compound AA through ZZ, or its pharmaceutically acceptable salt.

29 . The method of claim 26 , wherein the compound is selected from the group consisting of Compound AAA through XXX, or its pharmaceutically acceptable salt.

30 . The method of claim 25 , wherein the autoimmune disease is arthritis.

31 . The method of claim 25 , wherein the autoimmune disease is psoriasis.

32 . The method of claim 25 , wherein the autoimmune disease is Crohn's disease.

33 . The method of claim 25 , wherein the autoimmune disease is lupus.

34 . The method of claim 25 , wherein the compound is conjugated to a targeting agent.

35 . The method of claim 34 , wherein the targeting agent is an antibody or antibody fragment.

36 . The method of claim 25 , wherein the compound is conjugated to a radioisotope.

37 . The method of claim 30 , wherein the host is a human.

38 . The method of claim 31 , wherein the host is a human.

39 . The method of claim 32 , wherein the host is a human.

40 . The method of claim 1 , wherein the compound is administered in combination therapy with a second active agent.

41 . The method of claim 16 , wherein the compound is administered in combination therapy with a second active agent.

42 . The method of claim 25 , wherein the compound is administered in combination therapy with a second active agent.

43 . A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula VI to a host in need thereof:

wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , Z, m, n, and y are as defined in claim 1 ;

each R 14 is independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

or two R 14 groups bonded to the same carbon can form an exocyclic double bond;

or two R 14 groups bonded to the same carbon can form a carbonyl group; and

when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R 14 groups are present as allowed for in Formula VI above; or

when the compound of Formula VI does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R 14 groups are present as allowed for in Formula VI above;

or a pharmaceutically acceptable salt thereof.

44 . The method of claim 1 , wherein the compound is selected from the group consisting of:

45 . The method of claim 43 , wherein the compound is selected from the group consisting of:

46 . A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula I, II, III, IV, or V to a host in need thereof:

wherein:

Z is —(CH 2 ) x — wherein x is 1, 2, 3 or 4 or —O—(CH 2 ) z — wherein z is 2, 3 or 4;

each X is independently CH or N;

each X′ is independently CH or N;

X″ is independently CH 2 , S or NH, arranged such that the moiety is a stable 5-membered ring;

R, R 8 , and R 11 are independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

y is 0, 1, 2, 3 or 4;

R 2 is -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -C(O)—O-alkyl; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring and wherein m is 0, 1, or 2 and n is 0, 1 or 2;

wherein heterocyclo may be optionally independently substituted with 1 to 3 R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 3 and R 4 at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring; or R 3 and R 4 together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance, and wherein two R x groups bound to the same or adjacent atom may optionally combine to form a ring;

R 5 and R 5 * at each occurrence is:

(i) hydrogen or

R x at each occurrence is independently, halo, cyano, nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, -(alkylene) m -OR 5 , -(alkylene) m -O-alkylene-OR 5 , -(alkylene) m -S(O) n —R 5 , -(alkylene) m -NR 3 R 4 , -(alkylene) m -CN, -(alkylene) m -C(O)—R 5 , -(alkylene) m -C(S)—R 5 , -(alkylene) m -C(O)—OR 5 , -(alkylene) m -O—C(O)—R 5 , -(alkylene) m -C(S)—OR 5 , -(alkylene) m -C(O)-(alkylene) m -NR 3 R 4 , -(alkylene) m -C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(S)—NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—R 5 , -(alkylene) m -N(R 3 )—C(S)—R 5 , -(alkylene) m -O—C(O)—NR 3 R 4 , -(alkylene) m -O—C(S)—NR 3 R 4 , -(alkylene) m -SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—SO 2 —R 5 , -(alkylene) m -N(R 3 )—SO 2 —NR 3 R 4 , -(alkylene) m -N(R 3 )—C(O)—OR 5 , -(alkylene) m -N(R 3 )—C(S)—OR 5 , or -(alkylene) m -N(R 3 )—SO 2 —R 5 ; wherein:

said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups, any of which, other than heterocyclo, may be further independently substituted with one or more -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, and

wherein heterocycle may be further independently substituted with one to three substitutions selected from -(alkylene) m -CN, -(alkylene) m -OR 5 *, -(alkylene) m -S(O) n —R 5 *, -(alkylene) m -NR 3 *R 4 *, -(alkylene) m -C(O)—R 5 *, -(alkylene) m -C(═S)R 5 *, -(alkylene) m -C(═O)OR 5 *, -(alkylene) m -OC(═O)R 5 *, -(alkylene) m -C(S)—OR 5 *, -(alkylene) m -C(O)—NR 3 *R 4 *, -(alkylene) m -C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(S)—NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—R 5 *, -(alkylene) m -N(R 3 *)—C(S)—R 5 *, -(alkylene) m -O—C(O)—NR 3 *R 4 *, -(alkylene) m -O—C(S)—NR 3 *R 4 *, -(alkylene) m -SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—SO 2 —R 5 *, -(alkylene) m -N(R 3 *)—SO 2 —NR 3 *R 4 *, -(alkylene) m -N(R 3 *)—C(O)—OR 5 *, -(alkylene) m -N(R 3 *)—C(S)—OR 5 *, or -(alkylene) m -N(R 3 *)—SO 2 —R 5 *;

n is 0, 1 or 2, and

m is 0, 1; or 2 and

R 3 * and R 4 * at each occurrence are independently:

(i) hydrogen or

(ii) alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, arylalkyl, or heteroarylalkyl any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valance; or R 3 * and R 4 * together with the nitrogen atom to which they are attached may combine to form a heterocyclo ring optionally independently substituted with one or more R x groups as allowed by valance;

R 6 is H, absent, or lower alkyl, -(alkylene)m-heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring; and

when the compound of Formula I, II, III, IV, or V has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R 8 groups are present as allowed for in Formula I, II, III, IV, or V above; or

when the compound of Formula I, II, III, IV, or V does not include a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, four R 8 groups are present as allowed for in Formula I, II, III, IV, or V above;

wherein each heteroaryl is an aryl ring system that contains one or more heteroatoms selected from the group O, N and S, wherein the ring nitrogen and sulfur atom(s) are optionally oxidized, and nitrogen atom(s) are optionally quarternized;

wherein each aryl is a carbocyclic aromatic system containing one or two rings, wherein such rings may be attached together in a fused manner, and wherein each aryl may have 1 or more R x substituents;

wherein each heterocyclo is a saturated or partially saturated heteroatom-containing ring radical, where the heteroatoms may be selected from nitrogen, sulfur and oxygen, wherein each heterocyclo is a monocyclic 6-8 membered ring or a 5-16 membered bicyclic ring system, and wherein each heterocyclo may have 1 to 3 R x substituents;

or a pharmaceutically acceptable salt thereof.

47 . A method for the treatment of abnormal T-cell proliferation that comprises administering an effective amount of a compound of Formula VI to a host in need thereof:

wherein R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R x , Z, m, n, and y are as defined in claim 46 ;

each R 14 is independently H, C 1 -C 3 alkyl (including methyl) or haloalkyl, cycloalkyl or cycloalkyl containing one or more heteroatoms selected from N, O or S; -(alkylene) m -C 3 -C 8 cycloalkyl, -(alkylene) m -aryl, -(alkylene) m -heterocyclo, -(alkylene) m -heteroaryl, -(alkylene) m -NR 3 R 4 , -(alkylene) m -C(O)—NR 3 R 4 ; -(alkylene) m -O—R 5 , -(alkylene) m -S(O) n —R 5 , or -(alkylene) m -S(O) n —NR 3 R 4 any of which, other than heterocyclo, may be optionally independently substituted with one or more R x groups as allowed by valence, and wherein two R x groups bound to the same or adjacent atoms may optionally combine to form a ring;

or two R 14 groups bonded to the same carbon can form an exocyclic double bond;

or two R 14 groups bonded to the same carbon can form a carbonyl group; and

when the compound of Formula VI has a double bond, as indicated by the (----), in the 6-membered ring fused to the pyrimidine ring, two R 14 groups are present as allowed for in Formula VI above; or

or a pharmaceutically acceptable salt thereof.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 7, 2016

From: GASTON, RICKY D.; GADWOOD, ROBERT C.

To: KALEXSYN, INC.

Reel/Frame 038836/0306 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 7, 2016

From: KALEXSYN, INC.

To: G1 THERAPEUTICS, INC.

Reel/Frame 038836/0418 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 7, 2016

From: STRUM, JAY COPELAND; BISI, JOHN EMERSON; ROBERTS, PATRICK JOSEPH

To: G1 THERAPEUTICS, INC.

Reel/Frame 038836/0516 →