IP Library › Granted Patent US 9,079,918
Granted Patent B2
US 9,079,918 · App. 14/448,058 · Granted Jul 14, 2015

Macrocycles as factor XIa inhibitors

Inventors: Mimi L. Quan (Yardley, PA); Carl P. Decicco (New Hope, PA); James R. Corte (Lawrenceville, NJ); Cailan Wang (New Hope, PA)
Assignee: Bristol-Myers Squibb Company
C07D498/08C07D487/08
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Quick Facts
Patent No.
US 9,079,918
App. No.
14/448,058
Granted
Jul 14, 2015
Kind
B2
Abstract

The present invention provides compounds of Formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

Claims (104)

1. A compound of Formula (I):

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

ring A is phenyl;

ring B is oxazolyl;

ring C is phenyl;

L 1 is independently selected from the group consisting of: a bond, —CHR 5 —, —CHR 5 CHR 5 —, —CR 5 ═CR 5 —, —C≡C—, —OCH 2 —, —CHR 5 NH—, —CH 2 O—, —SCH 2 —, —SO 2 CH 2 —, —CH 2 NH—, and —CR 5 R 5 —;

L is independently selected from the group consisting of: —C 1-6 alkylene-(aryl)-C 0-4 alkylene-, and —C 1-6 alkylene-(5- to 6-membered heterocycle)-C 0-4 alkylene-; wherein said heterocycle comprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein said alkylene is substituted with 0-2 R 7 and optionally one or more of the carbon atoms of said alkylene may be replaced by O, S, NH, N(C 1-4 alkyl), CO, CONH, NHCO, OCONH, NHCO 2 , SO 2 NH, NHSO 2 , CON(C 1-4 alkyl), or N(C 1-4 alkyl)CO; wherein said aryl and heterocycle are substituted with 0-2 R 7a ;

Y is independently selected from the group consisting of: CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , O, S, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —OCON(C 1-4 alkyl)-, —NHCONH—, —SO 2 NH—, —NHCO 2 —, and —NHSO 2 —;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, OH, C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , CN, NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CO 2 (C 1-4 alkyl), —CO(C 1-4 alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CH 2 NHCO 2 (C 1-4 alkyl), —OCH 2 CO 2 H, —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , and phenyl substituted with 0-2 R a ;

R 2 is independently a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2a ;

R 2a is independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, —CH 2 OH, C 1-4 alkoxy, OH, CF 3 , OCF 3 , CN, NH 2 , CO 2 H, CO 2 (C 1-4 alkyl), COC 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —SO 2 (C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), and —SO 2 N(C 1-4 alkyl) 2 ;

R 3 is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , —CH 2 CO 2 H, and C 3-6 cycloalkyl;

R 4 is independently selected from the group consisting of: H, and C 1-4 alkyl;

R 5 is, independently at each occurrence, selected from the group consisting of: H, halogen, OH, and C 1-4 alkyl;

R 6 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4 alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4 alkyl), —(CH 2 ) 2 CO 2 (C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), —CH 2 NH 2 , —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4 alkyl), —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4 alkyl), —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHSO 2 (C 1-4 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4 alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4 alkyl), —C(O)NH(CH 2 ) 2 O(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4 alkyl), —CON(C 1-4 alkyl) 2 , —CH 2 CONH 2 , and

R 7 and R 7a are, independently at each occurrence, selected from the group consisting of: halogen, OH, NH 2 , CH 2 NH 2 , CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , C 1-4 alkoxy, CH 2 OH, CH 2 O(C 1-4 alkyl), CH 2 O(CH 2 ) 1-4 O(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4 alkyl), CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , —OCO(C 1-4 alkyl), —CON(C 1-4 alkyl)(CH 2 ) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, —(CO) 0-1 (CH 2 ) 0-1 -aryl, and —(CO) 0-1 (CH 2 ) 0-1 -(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein said aryl and heterocycle are substituted with 0-2 R 8 ;

R 8 is, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , C 1-4 alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), CONH 2 , and C 1-4 alkyl;

R 9 is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), O, and S(O) p ;

R a is, independently at each occurrence, selected from the group consisting of: halogen, OH, CF 3 , C 1-4 alkoxy, and C 1-4 alkyl;

p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2.

2. The compound of claim 1 , or a stereoisomer, a tautomer, a

pharmaceutically acceptable salt thereof, wherein:

ring A is phenyl;

and

3. A compound of Formula (II):

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

L 1 is independently selected from the group consisting of: a bond, —CHR 5 CHR 5 —, —CR 5 ═CHR 5 —, —C≡C—, —OCH 2 —, —CHR 5 NH—, —CH 2 O—, —SCH 2 —, —SO 2 CH 2 —, —CH 2 NH—, and —CR 5 R 5 —;

L is independently selected from the group consisting of: —C 1-6 alkylene-(aryl)-C 0-4 alkylene-, and —C 1-6 alkylene-(5- to 6-membered heterocycle)-C 0-4 alkylene-; wherein said heterocycle comprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein said alkylene is substituted with 0-2 R 7 and optionally one or more of the carbon atoms of said alkylene may be replaced by O, S, NH, N(C 1-4 alkyl), CO, CONH, NHCO, OCONH, SO 2 NH, or CON(C 1-4 alkyl); wherein said aryl and heterocycle are substituted with 0-2 R 7a ;

Y is independently selected from the group consisting of: CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , O, S, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —OCON(C 1-4 alkyl)-, —NHCONH—, and —SO 2 NH—;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-6 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, OH, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , CN, NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , CO 2 (C 1-4 alkyl), CO(C 1-4 alkyl), —OCH 2 CO 2 H, —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4 alkyl), —CH 2 NHCO 2 (C 1-4 alkyl), —SO 2 NH 2 , and —C(═NH)NH 2 ;

R 2 is independently a 5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2a ;

R 2a is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, —CH 2 OH, C 1-4 alkoxy, OH, CF 3 , OCF 3 , CN, NH 2 , CO 2 H, CO 2 (C 1-4 alkyl), COC 1-4 alkyl, —CONH 2 , —CONH(C 1-4 alkyl), and —CON(C 1-4 alkyl) 2 ;

R 3 is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , and —CH 2 CO 2 H;

R 4 is independently selected from the group consisting of: H and C 1-4 alkyl;

R 5 is, independently at each occurrence, selected from the group consisting of: H, halogen, OH, and C 1-4 alkyl;

R 6 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4 alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4 alkyl), —(CH 2 ) 2 CO 2 (C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), —CH 2 NH 2 , —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4 alkyl), —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4 alkyl), —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHSO 2 (C 1-4 alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4 alkyl), —C(O)NH(CH 2 ) 2 O(C 1-4 alkyl), CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , —CH 2 CONH 2 , and

R 7 and R 7a are, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , N(C 1-4 alkyl) 2 , C 1-4 alkoxy, CH 2 OH, CH 2 O(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4 alkyl), CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , —OCO(C 1-4 alkyl), —CON(C 1-4 alkyl)(CH 2 ) 2 N(C 1-4 alkyl) 2 , C 1-4 alkyl, and —(CO) 0-1 -(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4 alkyl), O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R 8 ;

R 8 is, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , C 1-4 alkoxy, and C 1-4 alkyl; and

p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2.

4. The compound of claim 3 , having Formula (II), a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L 1 is independently selected from the group consisting of: a bond, —CH 2 CH 2 —, —CH═CH—, —C(Me)═CH—, —C≡C—, and —CH 2 NH—;

L is independently selected from the group consisting of: —(CH 2 ) 1-2 -(phenylene)-(CH 2 ) 0-3 —, —CH 2 O(CH 2 ) 1-4 -(phenylene)-(CH 2 ) 0-3 —, —(CH 2 ) 1-2 -(phenylene)-CONH(CH 2 ) 0-2 —, —(CH 2 ) 1-2 -phenylene-CON(C 1-4 alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 1-2 -(pyridinylene)-(CH 2 ) 0-3 —, —CH 2 -pyrimidinylene-(CH 2 ) 0-3 —,

wherein each ring moiety is substituted with 0-2 R 7a ;

Y is independently selected from the group consisting of: CH 2 , CH(C 1-4 alkyl), C(C 1-4 alkyl) 2 , O, S, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—;

R 1 is, independently at each occurrence, selected from: halogen, CN, OH, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CO(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —C(═NH)NH 2 , —C(O)NH 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4 alkyl), and —SO 2 NH 2 ;

R 3 is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4 alkyl), —C(O)NH 2 , —C(O)NH(C 1-4 alkyl), —C(O)N(C 1-4 alkyl) 2 , and —CH 2 CO 2 H; and

R 6 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4 alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4 alkyl), —(CH 2 ) 2 CO 2 (C 1-4 alkyl), NH 2 , —CH 2 NH 2 , —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4 alkyl), —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4 alkyl), —NHC(O)NH(C 1-4 alkyl), —NHC(O)N(C 1-4 alkyl) 2 , —NHSO 2 (C 1-4 alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4 alkyl), CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , and

5. The compound of claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L 1 is independently selected from the group consisting of: a bond, —CH 2 CH 2 — and —CH═CH—;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, CN, C 1-4 alkyl, OH, C 1-4 alkoxy, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , CO(C 1-4 alkyl), NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4 alkyl), and —C(═NH)NH 2 ;

R 3 is independently selected from the group consisting of: H, halogen, CN, CF 3 , CO 2 H, CO 2 (C 1-4 alkyl), and C 1-4 alkyl; and

R 6 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4 alkyl), —CH 2 CO 2 H, —CH 2 CO 2 (C 1-4 alkyl), NH 2 , —CH 2 NH 2 , —NHCO(C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —CH 2 NHCO 2 (C 1-4 alkyl), —CONH 2 , —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 CH 2 CO 2 H, —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), and

6. The compound of claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof, wherein:

L is independently selected from the group consisting of: —CH 2 -phenylene-(CH 2 ) 0-3 —, —CH 2 O(CH 2 ) 2-4 -phenylene-(CH 2 ) 0-1 —, —CH 2 -phenylene-CONH(CH 2 ) 0-2 —, —CH 2 -phenylene-CON(C 1-4 alkyl)(CH 2 ) 0-2 —, —CH 2 -pyridinylene-(CH 2 ) 0-3 —, —CH 2 -pyrimidinylene-(CH 2 ) 0-2 —,

wherein each ring moiety is substituted with 0-1 R 7a ;

Y is independently selected from the group consisting of: CH 2 , O, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—; and

L 1 is independently selected from the group consisting of: a bond and —CH═CH—;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, OH, C 1-4 alkoxy, CO(C 1-4 alkyl), CN, CH 2 F, CHF 2 , OCHF 2 , NH 2 , N(C 1-4 alkyl) 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4 alkyl), and —C(═NH)NH 2 ;

R 3 is independently selected from the group consisting of: H, halogen, C 1-4 alkyl, and CN;

R 6 is, independently at each occurrence, selected from the group consisting of: halogen, NH 2 , CO 2 H, CO 2 (C 1-4 alkyl), CONH 2 , CONH(C 1-4 alkyl), CON(C 1-4 alkyl) 2 , —NHCO 2 (C 1-4 alkyl), —CH 2 NHCO 2 (C 1-4 alkyl), —NHCO 2 CH 2 CO 2 H, —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), and

and

R 7a is independently selected from the group consisting of: halogen, C 1-4 alkyl, and N(C 1-4 alkyl) 2 .

7. The compound of claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R 7a ;

Y is independently selected from the group consisting of: CH 2 , O, NH, N(C 1-4 alkyl), N(CO 2 (C 1-4 alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—;

L 1 is independently selected from the group consisting of: a bond and —CH═CH—;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, OH, C 1-4 alkoxy, CO(C 1-4 alkyl), CN, CH 2 F, CHF 2 , OCHF 2 , NH 2 , N(C 1-4 alkyl) 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4 alkyl), and —C(═NH)NH 2 ;

R 2 is independently a 5-membered heterocycle selected from: triazolyl and tetrazolyl;

R 3 is independently selected from the group consisting of: H, halogen, C 1-4 alkyl, and CN;

R 6a is independently selected from the group consisting of: H, halogen, NH 2 , CO 2 H, CONH 2 , CO 2 (C 1-4 alkyl), —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 CH 2 CO 2 H, —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), and

and

R 7a is independently selected from the group consisting of: halogen, C 1-4 alkyl, and N(C 1-4 alkyl) 2 .

8. The compound of claim 3 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R 7a ;

Y is independently selected from the group consisting of: CH 2 , O, NH, —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4 alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—;

L 1 is independently selected from the group consisting of: a bond and —CH═CH—;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, OH, C 1-4 alkoxy, CO(C 1-4 alkyl), CN, CH 2 F, CHF 2 , OCHF 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4 alkyl), and —C(═NH)NH 2 ;

R 3 is independently selected from the group consisting of: H, halogen, C 1-4 alkyl, and CN;

R 6a is independently selected from the group consisting of: H, halogen, NH 2 , CO 2 H, CONH 2 , —NHCO 2 (C 1-4 alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4 alkyl), —NHCO 2 CH 2 CH(C 1-4 alkyl)O(C 1-4 alkyl), and

and

R 7a is independently selected from the group consisting of: halogen, C 1-4 alkyl, and N(C 1-4 alkyl) 2 .

9. The compound of claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L-Y is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R 7a ;

L 1 is independently selected from the group consisting of: a bond and —CH═CH—;

R 1 is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4 alkyl, C 1-4 alkoxy, CO(C 1-4 alkyl), CN, CHF 2 , and OCHF 2 ;

R 2 is independently a 5-membered heterocycle selected from: pyrazolyl, imidazolyl, triazolyl, and tetrazolyl;

R 3 is independently selected from the group consisting of: H and halogen;

R 6a is independently selected from the group consisting of: H, halogen, NH(C 1-4 alkyl), and NHCO 2 (C 1-4 alkyl); and

R 7a is independently selected from the group consisting of: halogen, C 1-4 alkyl, N(C 1-4 alkyl) 2 .

10. The compound of claim 9 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L-Y is independently selected from the group consisting of:

wherein each ring moiety is substituted with 0-1 R 7a ;

R 2 is independently triazolyl or tetrazolyl; and

R 6a is independently selected from the group consisting of: H, halogen, and NHCO 2 (C 1-4 alkyl).

11. The compound of claim 9 or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:

L-Y is independently selected from the group consisting of:

R 1 is independently selected from the group consisting of: F, Cl, Me, OMe, COMe, CN, CHF 2 , and OCHF 2 ;

R 2 is tetrazolyl;

R 3 is independently selected from the group consisting of: H and Cl; and

R 6a is independently selected from the group consisting of: H, F, and NHCO 2 Me.

12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of claim 1 .

Continuity (4)
Division 13577666
Provisional Application 61303423 · Feb 11, 2010
Provisional Application 61405338 · Oct 21, 2010
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