IP Library › Granted Patent US 8,314,116

Granted Patent B2

US 8,314,116 · App. 12/679,893 · Granted Nov 20, 2012

2-S-benzyl substituted pyrimidines as CRTH2 antagonists

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Quick Facts

Patent No.: US 8,314,116
App. No.: 12/679,893
Granted: Nov 20, 2012
Kind: B2

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Abstract

Provided herein are 2-S-benzyl pyrimidine compounds having CRTH2 (G-protein-coupled chemoattractant receptor, expressed on Th2 cells) antagonistic activity, useful for the prophylaxis and treatment of diseases associated with CRTH2 activity, including the treatment of allergic diseases, eosinophil-related diseases and basophil-related diseases.

Claims (166)

1. A compound having formula I:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

R 1 is —CO 2 H, —C(O)NR 8a R 8b , nitrile or tetrazolyl;

R 4a and R 4b are each independently hydrogen or (C 1 -C 6 )alkyl;

in each instance, independently, W, R 2 , R 3 , R 5 , R 6 , R 8a , R 8b , k and m are selected from (I) or (II) as follows:

(I) W is a single bond, —(CH 2 ) m —, —O—, —S(O) n —, —NR 7 —, —C(O)—, —C(O)O—, —C(O)NR 7 —, —NR 7 C(O)NR 7 — or —NR 7 C(O)O—;

in each instance, independently, R 2 and R 3 are selected from (i) or (ii) as follows:

(i) R 2 and R 3 are each independently (a) hydrogen; (b) F; (c) Br; (d) I; (e) (C 1 -C 6 )alkyl; (f) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di(C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (g) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (h) (C 3 -C 7 )cycloalkyl; (i) —SR 9 ; (j) —NR 10 R 11 ; or (k) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; or

(ii) R 2 and R 3 are each independently (a) hydrogen; (b) Cl; (c) (C 1 -C 6 )alkyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di(C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (f) (C 3 -C 7 )cycloalkyl; (g) —SR 9 ; (h) —NR 12 R 13 ; or (i) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen;

each R 5 is independently (a) hydrogen; (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h) benzyl; (i) benzyloxy; (j) guanidino; (k) heterocyclyl; (l) —NR 14 R 15 ; (m) sulfamoyl; (n) (C 1 -C 6 )alkylsulfonyl; (o) (C 1 -C 6 )alkylaminosulfonyl; (p) di(C 1 -C 6 )alkylaminosulfonyl; (q) —C(O)R 9 ; (r) —C(O)OR 9 ; (s) —C(O)NR 8a R 8b ; (t) —NR 7 C(O)R 9 ; (u) —OC(O)NR 8a R 8b ; (v) —NR 7 C(O)OR 9 ; (w) (C 2 -C 6 )alkenyl; (x) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (y) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; or (z) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

R 6 is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkyl substituted by —C(O)R 6a ; (j) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (k) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (l) aryl; or (m) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

R 6a is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (j) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (k) aryl; or (l) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

each R 7 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

(i) R 8a and R 8b are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

(ii) each R 8a and R 8b , together with the N to which they are bonded, independently may form a 3 to 8 membered saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

each R 9 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; phenyl; or (c) (C 1 -C 6 )alkyl substituted by aryl, alkoxy or mono-, di-, or tri-halogen;

in each instance, independently, R 10 and R 11 are selected from (i) or (ii) as follows:

(i) R 10 and R 11 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

(ii) each R 10 and R 11 , together with the N to which they are bonded, independently may form a 3 to 8 membered saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

in each instance, independently, R 12 and R 13 are selected from (i), (ii), (iii) or (iv) as follows:

(i) R 12 and R 13 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy or alkoxy; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl;

(ii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered saturated ring containing at least one O or S atom, or at least one additional N atom, in the ring;

(iii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered unsaturated ring, optionally containing one or more O or S atom, or one or more additional N atoms, in the ring; or

(iv)R 12 and R 13 , together with the N to which they are bonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring, optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

in each instance, independently, R 14 and R 15 are selected from (i) or (ii) as follows:

(i) R 14 and R 15 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

(ii) each R 14 and R 15 , together with the N to which they are bonded, independently may form a 3 to 8 membered saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

k is 0, 1 or 2;

each m is independently 1, 2, 3 or 4; and

n is 0, 1 or 2; or

(II) one of R 5 groups and W—R 6 together with the atoms to which they are attached may form a 4 to 8 membered unsaturated ring optionally containing one or more N, O or S atoms in the ring, wherein the ring is optionally substituted with one or more R 5a groups;

R 2 and R 3 are each independently (a) hydrogen; (b) F; (c) Cl; (d) Br; (e) I; (f) (C 1 -C 6 )alkyl; (g) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di(C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 3 -C 7 )cycloalkyl; (j) —SR 9 ; (k) —NR 10 R 11 ; or (l) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen;

the remaining R 5 groups and R 5a are each independently (a) hydrogen; (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) phenyl; (g) phenyloxy; (h) benzyl; (i) benzyloxy; (j) guanidino; (k) heterocyclyl; (l) —NR 14 R 15 ; (m) sulfamoyl; (n) (C 1 -C 6 )alkylsulfonyl; (o) (C 1 -C 6 )alkylaminosulfonyl; (p) di(C 1 -C 6 )alkylaminosulfonyl; (q) —C(O)R 9 ; (r) —C(O)OR 9 ; (s) —C(O)NR 8a R 8b ; (t) —NR 7 C(O)R 9 ; (u) —OC(O)NR 8a R 8b ; (v) —NR 7 C(O)OR 9 ; (w) (C 2 -C 6 )alkenyl; (x) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (y) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; or (z) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

each R 9 is independently (a) hydrogen; (b) (C 1 -C 6 )alkyl; phenyl; or (c) (C 1 -C 6 )alkyl substituted by aryl, alkoxy or mono-, di-, or tri-halogen;

in each instance, independently, R 10 and R 11 are selected from (i) or (ii) as follows:

in each instance, independently, R 14 and R 15 are selected from (i) or (ii) as follows:

(i) R 14 and R 15 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di(C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

k is 0, 1 or 2; and

m is 1, 2, 3 or 4.

2. The compound of claim 1 wherein, in each instance, independently, R 10 and R 11 are selected from (i) or (ii) as follows:

(i) R 10 and R 11 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by unsubstituted phenyl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

in each instance, independently, R 12 and R 13 are selected from (i), (ii), (iii) or (iv) as follows:

(i) R 12 and R 13 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by unsubstituted phenyl, hydroxy, carboxy or alkoxy; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl;

(ii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered saturated ring containing at least one O or S atom, or at least one additional N atom, in the ring;

(iii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered unsaturated ring, optionally containing one or more 0 or S atom, or one or more additional N atoms, in the ring; or

(iv) R 12 and R 13 , together with the N to which they are bonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring, optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring.

3. The compound of claim 1 wherein, in each instance, independently, R 10 and R 11 are selected from (i) or (ii) as follows:

(i) R 10 and R 11 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

in each instance, independently, R 12 and R 13 are selected from (i), (ii), (iii) or (iv) as follows:

(i) R 12 and R 13 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by hydroxy, carboxy or alkoxy; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl;

(ii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered saturated ring containing at least one O or S atom, or at least one additional N atom, in the ring;

(iv) R 12 and R 13 , together with the N to which they are bonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring, optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring.

4. The compound of claim 1 wherein, in each instance, independently, R 10 and R 11 are selected from (i) or (ii) as follows:

(i) R 10 and R 11 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (e) (C 3 -C 7 )cycloalkyl; or

in each instance, independently, R 12 and R 13 are selected from (i), (ii), (iii) or (iv) as follows:

(i) R 12 and R 13 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (e) (C 3 -C 7 )cycloalkyl;

(ii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered saturated ring containing at least one O or S atom, or at least one additional N atom, in the ring;

(iv) R 12 and R 13 , together with the N to which they are bonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring, optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring.

5. The compound of claim 1 wherein R 1 is —CO 2 H.

6. The compound of claim 1 wherein R 4a and R 4b are each independently hydrogen.

7. A compound having formula II:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

X is a single bond, —O(CH 2 ) p — or —NR 9 (CH 2 ) p —;

in each instance, independently, R 2 and R 3 are selected from (i) and (ii) as follows:

(i) R 2 and R 3 are each independently (a) hydrogen; (b) F; (c) Br; (d) (e) (C 1 -C 6 )alkyl; (f) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di(C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (g) (C 1 -C 6 )alkyl substituted by mono-, di-, tri-halogen; (h) (C 3 -C 7 )cycloalkyl; (i) —SR 9 ; (j) —NR 10 R 11 ; or (k) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and

R 4a and R 4b are each independently hydrogen or (C 1 -C 6 )alkyl;

R 6 is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkyl substituted by —C(O)R 6a ; (j) (C 1 -C 6 )alkoxy substituted by mono-, di- or tri-halogen; (k) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (l) aryl; or (m) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k)-NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 ) alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

R 6a is (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) (C 2 -C 6 )alkenyl; (d) (C 2 -C 6 )alkynyl; (e) (C 3 -C 7 )cycloalkyl; (f) (C 1 -C 6 )alkyl substituted by aryl or heteroaryl; (g) (C 2 -C 4 )alkenyl substituted by aryl or heteroaryl; (h) (C 1 -C 6 )alkynyl; substituted by mono-, di-, or tri-halogen; (i) (C 1 -C 6 )alkoxy substituted by mono-, di-, or tri-halogen; (j) (C 1 -C 6 )alkylthio substituted by mono-, di-, or tri-halogen; (k) aryl; or (l) heteroaryl; wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) guanidino; (f) heterocyclyl; (g) phenyl; (h) phenyloxy; (i) benzyl; (j) benzyloxy; (k) —NR 8a R 8b ; (l) —C(O)R 9 ; (m) —C(O)NR 8a R 8b ; (n) —OC(O)NR 8a R 8b ; (o) —C(O)OR 9 ; (p) —NR 7 C(O)OR 9 ; (q) —NR 7 C(O)R 9 ; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

in each instance, independently, R 8a and R 8b are selected from (i) and (ii) as follows:

(i) R 8a and R 8b are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di(C 1 -C 6 )alkyl)carbamoyl, (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; and

(ii) each R 8a and R 8b , together with the N to which they are bonded, independently form a 3 to 8 membered saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

each R 9 is independently hydrogen or (C 1 -C 6 )alkyl;

in each instance, independently, R 10 and R 11 are selected from (i) and (ii) as follows:

(i) R 10 and R 11 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy, alkoxy, carbamoyl, (C 1 -C 6 )alkylcarbamoyl, di((C 1 -C 6 )alkyl)carbamoyl; (C 3 -C 7 )cycloalkylcarbamoyl or (C 3 -C 7 )heterocyclylcarbamoyl; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; and

(ii) each R 10 and R 11 , together with the N to which they are bonded, independently form a 3 to 8 membered saturated or unsaturated ring optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

in each instance, independently, R 12 and R 13 are selected from (i), (ii), (iii) and (iv) as follows:

(ii) R 12 and R 13 , together with the N to which they are bonded, form a 5 membered saturated ring containing at least one O or S atom, or at least one additional N atom, in the ring;

(iv) R 12 and R 13 , together with the N to which they are bonded, form a 3, 4, 6, 7 or 8 membered saturated or unsaturated ring, optionally containing one or more O or S atoms, or one or more additional N atoms, in the ring;

k is 0, 1 or 2; and

each p is independently 1, 2, 3, 4, 5 or 6.

8. The compound of claim 7 , wherein R 2 is halogen.

9. The compound of claim 7 , wherein R 4a and R 4b are each independently hydrogen.

10. The compound of claim 7 , wherein

R 6 is aryl or heteroaryl, wherein said aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of (a) halogen; (b) cyano; (c) nitro; (d) hydroxy; (e) —NR 14 R 15 ; (f) —C(O)R 9 ; (g) —C(O)NR 8a R 8b ; (h) —NR 7 C(O)R 9 ; (i) —OC(O)NR 8a R 8b ; (j) —NR 7 C(O)OR 9 ; (k) —C(O)OR 9 ; (l) guanidino; (m) heterocyclyl; (n) phenyl; (o) phenyloxy; (p) benzyl; (q) benzyloxy; (r) sulfamoyl; (s) (C 1 -C 6 )alkylsulfonyl; (t) (C 1 -C 6 )alkylaminosulfonyl; (u) di(C 1 -C 6 )alkylaminosulfonyl; (v) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (w) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (x) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen;

each R 7 is independently hydrogen or (C 1 -C 6 )alkyl;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

(i) R 8a and R 8b are each independently selected from hydrogen or (C 1 -C 6 )alkyl; or

in each instance, independently, R 14 and R 15 are selected from (i) or (ii) as follows:

(i) R 14 and R 15 are each independently selected from (a) hydrogen; (b) (C 1 -C 6 )alkyl; (c) phenyl; (d) (C 1 -C 6 )alkyl substituted by aryl, hydroxy, carboxy or alkoxy; (e) (C 1 -C 6 )alkyl substituted by mono-, di-, or tri-halogen; or (f) (C 3 -C 7 )cycloalkyl; or

11. The compound of claim 7 , having formula III:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein R 9 is hydrogen.

12. The compound of claim 11 , wherein

each R 7 is independently hydrogen or (C 1 -C 6 )alkyl;

in each instance, independently, R 8a and R 8b are selected from (i) or (ii) as follows:

(i) R 8a and R 8b are each independently selected from hydrogen or (C 1 -C 6 )alkyl; or

in each instance, independently, R 14 and R 15 are selected from (i) or (ii) as follows:

13. The compound of claim 7 wherein R 2 and R 3 are each —N(CH 3 ) 2 .

14. The compound of claim 7 , having formula IV:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, wherein

R 2 is halogen;

each R 16 is independently (a) hydrogen (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) —NR 8a R 8b ; (g) —C(O)R 9 ; (h) —C(O)NR 8a R 8b ; (i) —NR 7 C(O)R 9 ; (j) —OC(O)NR 8a R 8b ; (k) —NR 7 C(O)OR 9 ; (l) —C(O)OR 9 ; (m) guanidino; (n) heterocyclyl; (o) phenyl; (p) phenyloxy; (q) benzyl; (r) benzyloxy; (s) sulfamoyl; (t) (C 1 -C 6 )alkylsulfonyl; (u) (C 1 -C 6 )alkylaminosulfonyl; (v) di(C 1 -C 6 )alkylaminosulfonyl; (w) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (x) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; and (y) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen; and

q is 0, 1, 2, 3, 4 or 5.

15. The compound of claim 14 , wherein

each R 16 is independently (a) hydrogen (b) halogen; (c) cyano; (d) nitro; (e) hydroxy; (f) —NH 2 ; (g) —NH(C 1 -C 6 )alkyl; (h) —N((C 1 -C 6 )alkyl) 2 ; (i) —NHC(O)(C 1 -C 6 )alkyl; (j) —C(O)(C 1 -C 6 )alkyl; (k) —CO 2 H; (l) —C(O)O(C 1 -C 6 )alkyl; (m) phenyl; (n) phenyloxy; (o) benzyl; (p) benzyloxy; (q) sulfamoyl; (r) (C 1 -C 6 )alkylsulfonyl; (s) (C 1 -C 6 )alkylaminosulfonyl; (t) di(C 1 -C 6 )alkylaminosulfonyl; (u) (C 1 -C 6 )alkyl optionally substituted by mono-, di-, or tri-halogen; (v) (C 1 -C 6 )alkoxy optionally substituted by mono-, di-, or tri-halogen; or (w) (C 1 -C 6 )alkylthio optionally substituted by mono-, di-, or tri-halogen.

16. The compound of claim 7 , having formula V:

or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

17. The compound of claim 16 wherein R 2 is halogen.

18. The compound of claim 16 wherein

R 2 is halogen; and

R 3 is —N(CH 3 ) 2 .

19. The compound of claim 16 wherein R 2 and R 3 are each independently —N(CH 3 ) 2 .

20. The compound of claim 1 , having the formula