# US 11,078,197 B2 · 5-membered and bicyclic heterocyclic amides as inhibitors of rock

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- Number: US 11,078,197 B2
- Document ID: US11078197B2
- Status: Granted
- Kind: B2
- Application number: 16/629,717
- Filed: 2018-07-11
- Published: 2021-05-20
- Granted: 2021-08-03
- Earliest claimed: 2017-07-12
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Peter W. Glunz; Vladimir Ladziata; Indawati De Lucca; George O. Tora; Tarun Kumar Maishal; Raghuram Tangirala; Kamalraj Thiyagarajan
- Web page: https://patentgrep.com/patent/US11078197B2

## CPC

- C07D 417/12: linked by a chain containing hetero atoms as chain links
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 231/20: One oxygen atom attached in position 3 or 5
- C07D 231/22: with aryl radicals attached to ring nitrogen atoms
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D 495/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically-acceptable salts thereof wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

## Claims

### Claim 1

A compound of Formula (I):
or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
Ring A is selected from a 5-membered heteroaryl comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S, and a bicyclic heteocycle;
R1 is selected from H and C1-4 alkyl;
R1a is C(O)R4; or R1 and R1a are taken together with the nitrogen atom to which they are attached to form a ring of Formula (Ia);
R2 is selected from H, C1-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, —(CR10R10)nC3-10 carbocycle and —(CR10R10)n-4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkenyl, alkynyl, carbocycle, and heterocycle are substituted with 1-4 R7;
R3, at each occurrence, is independently selected from H, halogen, C1-6 alkyl, C2-6 alkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, —CH2OH, —OCH2F, —OCHF2, —OCF3, CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —CO2H, —CH2CO2H, —CO2(C1-4 alkyl), —CO(C1-4 alkyl), —CH2NH2, —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —OCH2CO2H, —NHCO(C1-4 alkyl), —NHCO2(C1-4 alkyl), —NHSO2(C1-4 alkyl), —SO2NH2, —C(═NH)NH2, a carbocycle, and a heterocycle, wherein said alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R4 is selected from —(CR10R10)nC3-10 carbocycle and —(CR10R10)n-4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p; wherein said carbocycle, and heterocycle are substituted with 1-4 R7;
R5 is H; or R2 and R5 are taken together to form ═O; or R2 and R5 are taken together with the carbon atom, to which they are both attached, to form a carbocycle or heterocycle wherein said carbocycle and heterocycle are substituted with 1-4 R7;
R6 is selected from H, C1-4 alkyl, —(CR10R10)nC3-10 carbocycle and —(CR10R10)n-4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkenyl, carbocycle, and heterocycle are substituted with 1-4 R7; provided that R2, R5, and R6 are not all H;
R7, at each occurrence, is independently selected from H, ═O, NO2, halogen, C1-7 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, CN, OH, CHF2, CF3, —(CH2)n—CO2H, —(CH2)n—CO2(C1-4 alkyl), —(CH2)n—NR8R8, —NHCOH, —NHCO(C1-4 alkyl), —NHCOCF3, —NHCO2(C1-4 alkyl), —NHCO2(CH2)2O(C1-4 alkyl), —NHCO2(CH2)3O(C1-4 alkyl), —NHCO2(CH2)2OH, —NHCO2(CH2)2NH2, —NHCO2(CH2)2N(C1-4 alkyl)2, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NR8R8, —NHSO2(C1-4 alkyl), —S(O)p(C1-4 alkyl), —SO2NH2, —SO2NH(C1-4 alkyl), —SO2N(C1-4 alkyl)2, —SO2NH(CH2)2OH, —SO2NH(CH2)2O(C1-4 alkyl), —(CH2)n—CONR8R8, —O(CH2)n-carbocycle, —O(CH2)n-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle, —(CH2)n-carbocycle, and —(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkenyl, alkynyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, —(CH2)n—C(O)C1-4alkyl, —(CH2)n—C(O)carbocycle, —(CH2)n—C(O)heterocycle, —(CH2)n —C(O)NRaRa, —(CH2)n—NRaC(O) C1-4alkyl, —(CH2)n—C(O)OC1-4alkyl, —(CH2)n—C(O)C1-4alkyl, —(CH2)n—C(O)O-carbocycle, —(CH2)n—C(O)O-heterocycle, —(CH2)n—SO2alkyl, —(CH2)n SO2carbocycle, —(CH2)n—SO2heterocycle, —(CH2)n—SO2NRaRa, —(CH2)n-carbocycle, and —(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, ═O, CN, NO2, C1-4 alkyl, C1-4 alkoxy, CO(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), —(CHR10)nNRaRa, S(O)p(C1-4 alkyl), —(CHR10)nCONRaRa, —(CHR10)nNRaCO(C1-4 alkyl), —(CHR10)nOCONRa (CH2)nCO2Ra, S(O)pC1-4alkyl, S(O)pNRaRa, —O(CHR10)ncarbocycle, —O(CHR10)nheterocycle, —O(CHR10)nNRaRa, and —(CR10R10)n-4- to 10-membered heterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 Rb;
R10, at each occurrence, is independently selected from H and C1-4 alkyl;
R11 is independently selected from H and C1-3 alkyl optionally substituted with halogen, C1-4 alkoxy, OH, CN, —CO2H, —CO2(C1-4 alkyl), —CO(C1-4 alkyl), —CONH2, —CONH(C1-4 alkyl), and —CON(C1-4 alkyl)2;
R12 and R13 are independently selected from H, OH, —OC1-3 alkyl substituted with 0-4 Rd, C1-3 alkyl with substituted with 0-4 Rd;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), C1-4 alkylene-CO2(C1-4 alkyl), Rc, CO2Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from ═O, OH, halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, OC(O)C1-4 alkyl, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2H, CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-NH(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, —C1-4 alkylene-O—P(O)(OH)2, —NHCO2(C1-4 alkyl), —Rc, CORc, CO2Rc, and CONHRc, wherein said alkyl and alkoxy are substituted with 0-2 Rd;
Rc, at each occurrence, is independently selected from —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)-5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(O)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from ═O, halogen, OH, C1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, and —NHCO(C1-4 alkyl);
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is independently selected from 0, 1, and 2.

### Claim 2 (depends on 1)

The compound of claim 1, having Formula (II):
or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein
is selected from
R3, at each occurrence, is independently selected from H, halogen, C1-6 alkyl, C2-6 alkenyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 haloalkyl, —CH2OH, —OCH2F, —OCHF2, —OCF3, CN, —NH2, —NH(C1-4 alkyl), —N(C1-4 alkyl)2, —CO2H, —CH2CO2H, —CO2(C1-4 alkyl), —CO(C1-4 alkyl), —CH2NH2, —CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —OCH2CO2H, —NHCO(C1-4 alkyl), —NHCO2(C1-4 alkyl), —NHSO2(C1-4 alkyl), —SO2NH2, —C(═NH)NH2, a carbocycle, and a heterocycle, wherein said alkyl, alkenyl, alkoxy, alkylthio, haloalkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R4 is selected from C3-10 carbocycle and 4- to 15-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p; wherein said carbocycle, and heterocycle are substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, ═O, NO2, halogen, C1-7 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, CN, OH, CHF2, CF3, —(CH2)n—CO2H, —(CH2)n—CO2(C1-4 alkyl), —(CH2)—NR8R8, —NHCOH, —NHCO(C1-4 alkyl), —NHCOCF3, —NHCO2(C1-4 alkyl), —NHCO2(CH2)2O(C1-4 alkyl), —NHCO2(CH2)3O(C1-4 alkyl), —NHCO2(CH2)2OH, —NHCO2(CH2)2NH2, —NHCO2(CH2)2N(C1-4 alkyl)2, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NR8R8, —NHSO2(C1-4 alkyl), —S(O)p(C1-4 alkyl), —SO2NH2, —SO2NH(C1-4 alkyl), —SO2N(C1-4 alkyl)2, —SO2NH(CH2)2OH, —SO2NH(CH2)2O(C1-4 alkyl), —(CH2)n—CONR8R8, —O(CH2)n-carbocycle, —O(CH2)n-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle, —(CH2)n-carbocycle, and —(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkenyl, alkynyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-6 alkyl, C2-4 alkenyl, C2-4 alkynyl, —(CH2)n—C(O)C1-4alkyl, —(CH2)n—C(O)carbocycle, —(CH2)n—C(O)heterocycle, —(CH2)n—C(O)NRaRa, —(CH2)n—NRaC(O) C1-4alkyl, —(CH2)n—C(O)OC1-4alkyl, —(CH2)n—C(O)C1-4alkyl, —(CH2)n—C(O)O-carbocycle, —(CH2)n—C(O)O-heterocycle, —(CH2)n—SO2alkyl, —(CH2)n SO2carbocycle, —(CH2)n—SO2heterocycle, —(CH2)n—SO2NRaRa, —(CH2)n-carbocycle, and —(CH2)n-heterocycle, wherein said alkyl, alkenyl, alkynyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, ═O, CN, NO2, C1-4 alkyl, C1-4 alkoxy, CO(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), —(CHR10)nNRaRa, S(O)p(C1-4 alkyl), —(CHR10)nCONRaRa, —(CHR10)nNRaCO(C1-4 alkyl), —(CHR10)nOCONRa (CH2)nCO2Ra, S(O)pC1-4alkyl, S(O)pNRaRa, —O(CHR10)ncarbocycle, —O(CHR10)nheterocycle, —O(CHR10)NRaRa, and —(CR10R10)n-4- to 10-membered heterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 Rb;
R10, at each occurrence, is independently selected from H and C1-4 alkyl;
R11 is independently selected from H and C1-3 alkyl optionally substituted with halogen, C1-4 alkoxy, OH, and CN;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), C1-4 alkylene-CO2(C1-4 alkyl), Rc, CO2Rc, and CONHRc; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from ═O, OH, halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, OC(O)C1-4 alkyl, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4alkyl), CO(C1-4haloalkyl), CO2H, CO2(C1-4alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, —NHCO2(C1-4 alkyl), —Rc, CORc, CO2Rc, and CONHRc, wherein said alkyl and alkoxy are substituted with 0-2 Rd;
Rc, at each occurrence, is independently selected from —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-5- to 6-membered heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of: N, NH, N(C1-4 alkyl), O, and S(O)p; wherein each ring moiety is substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from ═O, halogen, OH, C1-4 alkyl, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, C1-4 alkoxy, and —NHCO(C1-4 alkyl);
n, at each occurrence, is independently selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is independently selected from 0, 1, and 2.

### Claim 3 (depends on 2)

The compound of claim 2, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
is selected from
R3, at each occurrence, is independently selected from H, C1-4 alkyl, a carbocycle, and a heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R4 is selected from
R7, at each occurrence, is independently selected from H, ═O, NO2, halogen, C1-4 alkyl, C1-4 alkoxy, CN, OH, CF3, —(CH2)n—CO2H, —(CH2)n—CO2(C1-4 alkyl), —(CH2)n—NR8R8, —NHCO(C1-4 alkyl), —NHCOCF3, —NHCO2(C1-4 alkyl), —NHCO2(CH2)2O(C1-4 alkyl), —NHCO2(CH2)3O(C1-4alkyl), —NHCO2(CH2)2OH, —NHCO2(CH2)2NH2, —NHCO2(CH2)2N(C1-4 alkyl)2, —NHCO2CH2CO2H, —CH2NHCO2(C1-4 alkyl), —NHC(O)NR8R8, —NHSO2(C1-4 alkyl), —S(O)2(C1-4alkyl), —SO2NH2, —SO2NH(C1-4 alkyl), —SO2N(C1-4alkyl)2, —SO2NH(CH2)2OH, —SO2NH(CH2O(C1 alkyl), —(CH2)n—CONR8R8, —O(CH2)n-carbocycle, —O(CH2)n-heterocycle, —NHCO-carbocycle, —NHCO-heterocycle, —SO2N(C1-4alkyl)2-carbocycle, —SO2N(C1-4alkyl)-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, (CH2)n-carbocycle, and —(CH2)-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, C(O)C1-4alkyl, C(O)carbocycle, C(O)heterocycle, —(CH2)n—C(O)NRaRa, C(O)OC1-4alkyl, C(O)O-carbocycle, C(O)O-heterocycle, SO2alkyl, SO2carbocycle, SO2heterocycle, SO2NRaRa, —(CH2)n-carbocycle, and —(CH2)n-heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, ═O, CN, NO2, CHF2, CF3, C1-4 alkyl, C1-4 alkoxy, CH2OH, C2H, CO2(C1-4alkyl), CONH2, —(CH2)nNRaRa, —(CH2)nCONRaRa, —(CH2)nNHCO(C1-4 alkyl), —S(O)2(C1-4 alkyl), —S(O)2(C1-4 alkyl), —O(CH2)nheterocycle, —O(CH2)2-4NRaRa, and —(CH2)n-4- to 10-membered heterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H and C1-4 alkyl; alternatively, Ra and Ra are taken together with the nitrogen atom to which they are attached to form a 4- to 10-membered heterocycle, wherein said alkyl, alkylene, and heterocycle are substituted with 0-4 Rb; and
Rb, at each occurrence, is independently selected from ═O, halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4alkyl)2, —CONH—C1-4alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4alkyl)2, and —NHCO2(C1-4 alkyl).

### Claim 4 (depends on 3)

The compound of claim 3, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
R3, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, C3-6 cycloalkyl, and a heterocycle, wherein said alkyl, phenyl, cycloalkyl, and heterocycle are substituted with 0-4 R9;
R4 is selected from
R7, at each occurrence, is independently selected from H, halogen, C1-7 alkyl, C1-7 alkoxy, —NR8R8, C3-6 cycloalkyl, phenyl, and —(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkoxy, cycloalkyl phneyl, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-heterocycle, wherein said alkyl, cycloalkyl, phenyl, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
R9, at each occurrence, is independently selected from F, Cl, OH, ═O, CN, C1-4 alkyl, C1-4 alkoxy, —(CH2)nNRaRa, —(CH2)nCONRaRa, C3-6 cycloalkyl, and a 4- to 10-membered heterocycle, wherein said alkyl, alkoxy, cycloalkyl, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), and C1-4 alkylene-CO2(C1-4 alkyl); and
Rb, at each occurrence, is independently selected from halogen, OH, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, and —NHCO2(C1-4 alkyl).

### Claim 5 (depends on 4)

The compound of claim 4, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
R3, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl, C3-6 cycloalkyl, and a heterocycle, wherein said alkyl, phenyl, cycloalkyl, and heterocycle are substituted with 0-4 R9;
R4 is selected from
R7, at each occurrence, is independently selected from H, halogen, CN, C1-7 alkyl, C1-7 alkoxy, —NR8R8, C3-6 cycloalkyl, phenyl, and —(CH2)-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkoxy, cycloalkyl phneyl, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-heterocycle, wherein said alkyl, cycloalkyl, phenyl, and heterocycle are substituted with 0-4 R9;
alternatively, R8 and R8 are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from
R9, at each occurrence, is independently selected from F, Cl, OH, ═O, CN, C1-4 alkyl, C1-4 alkoxy, —(CH2)nNRaRa, —(CH2)nCONRaRa, C3-6 cycloalkyl, and a 4- to 10-membered heterocycle, wherein said alkyl, alkoxy, cycloalkyl, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), and C1-4 alkylene-CO2(C1-4 alkyl); and
Rb, at each occurrence, is independently selected from halogen, OH, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, and —NHCO2(C1-4 alkyl).

### Claim 6 (depends on 2)

The compound of claim 2, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
is selected from
R3, at each occurrence, is independently selected from H and C1-4 alkyl;
R4 is selected from
R7, at each occurrence, is independently selected from H, halogen, CN, C1-4 alkyl, C1-4 alkoxy, —NR8R8, C3-6 cycloalkyl, phenyl, and —(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkoxy, cycloalkyl phneyl, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)n-phenyl, and —(CH2)n-heterocycle, wherein said alkyl, phenyl, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from F, Cl, OH, ═O, CN, C1-4 alkyl, C1-4 alkoxy, —(CH2)nNRaRa, —(CH2)nCONRaRa, C3-6 cycloalkyl, and a 4- to 10-membered heterocycle, wherein said alkyl, alkoxy, cycloalkyl, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), and C1-4 alkylene-CO2(C1-4 alkyl); and
Rb, at each occurrence, is independently selected from halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, and N(C1-4 alkyl)2.

### Claim 7 (depends on 6)

The compound of claim 6, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
R4 is selected from
R7, at each occurrence, is independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, —NR8R8, C3-6 cycloalkyl, phenyl, and —(CH2)n-heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NR8, O, and S(O)p, wherein said alkyl, alkoxy, cycloalkyl phneyl, and heterocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)n—C3-6 cycloalkyl, —(CH2)n-phenyl, and —(CH2)n-heterocycle, wherein said alkyl, cycloalkyl, phenyl, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from F, Cl, OH, ═O, CN, C1-4 alkyl, C1-4 alkoxy, —(CH2)nNRaRa, —(CH2)nCONRaRa, C3-6 cycloalkyl, and a 4- to 10-membered heterocycle, wherein said alkyl, alkoxy, cycloalkyl, and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, —(CH2)nOH, CO(C1-4 alkyl), COCF3, CO2(C1-4 alkyl), —CONH2, —CONH—C1-4 alkylene-CO2(C1-4 alkyl), and C1-4 alkylene-CO2(C1-4 alkyl); and
Rb, at each occurrence, is independently selected from halogen, C1-4 alkyl, C1-4 alkoxy, OCF3, NH2, NO2, N(C1-4 alkyl)2, CO(C1-4 alkyl), CO(C1-4 haloalkyl), CO2(C1-4 alkyl), CONH2, —CONH(C1-4 alkyl), —CON(C1-4 alkyl)2, —CONH—C1-4 alkylene-O(C1-4 alkyl), —CONH—C1-4 alkylene-N(C1-4 alkyl)2, and —NHCO2(C1-4 alkyl).

### Claim 8 (depends on 1)

The compound of claim 1, having Formula (III):
or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
is selected from
R2 is selected from C1-4 alkyl, —(CH2)0-1-phenyl and —(CH2) 4-6-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from N, O, and S(O)p, wherein said alkyl, phenyl, and heteroaryl are substituted with 1-4 R7;
R3, at each occurrence, is independently selected from H, C1-4 alkyl, and cyclopropyl; and
R7, at each occurrence, is independently selected from H, C1-4 alkyl, 1-4 alkoxy, CN, OH, CHF2, and CF3.

### Claim 9 (depends on 1)

The compound of claim 1, having Formula (IV):
or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
is selected from
R3, at each occurrence, is independently selected from H, C1-4 alkyl, and cyclopropyl; and
R6 is selected from C1-4 alkyl, —(CH2)0-1-phenyl and —(CH2) 4-6-membered heteroaryl comprising carbon atoms and 1-2 heteroatoms selected from N, O, and S(O)p.

### Claim 10 (depends on 3)

The compound of claim 3, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
R3 is C1-4 alkoxy;
R4 is selected from
R7, at each occurrence, is independently selected from H, halogen, C1-4 alkyl, C1-4 alkoxy, CN, and OH, wherein said alkyl and alkoxy are substituted with 0-4 R9;
R8 is selected from 6-membered aryl and 6-membered heterocycle, wherein said aryl and heterocyle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, CN, CHF2, and CF3.

### Claim 11 (depends on 2)

The compound of claim 2, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
is selected from
R3, at each occurrence, is independently selected from H, halogen, C1-6 alkyl, C1-4 alkoxy, a carbocycle, and a heterocycle, wherein said alkyl, alkoxy, carbocycle, and heterocycle are substituted with 0-4 R9;
R4 is selected from
R7, at each occurrence, is independently selected from H, C1-3 alkyl, C1-4 alkoxy, NHR8, and a carbocycle, wherein said alkyl, alkoxy, and carbocycle are substituted with 0-4 R9;
R8, at each occurrence, is independently selected from H, C1-6 alkyl, a carbocycle, and a heterocycle, wherein said alkyl, carbocycle, and heterocycle are substituted with 0-4 R9;
R9, at each occurrence, is independently selected from halogen, OH, CN, C1-4 alkyl, S(O)pC1-4alkyl, -4- to 10-membered heterocycle, wherein said alkyl and heterocycle are substituted with 0-4 Rb;
Ra, at each occurrence, is independently selected from H and C1-4 alkyl substituted with 0-4 Rb;
Rb, at each occurrence, is independently selected from halogen and C1-4 alkyl substituted with 0-2 Rd;
Rd is halogen; and
p, at each occurrence, is independently selected from 0, 1, and 2.

### Claim 12 (depends on 8)

The compound of claim 8, or a stereoisomer, an enantiomer, a diastereoisomer, a tautomer, a pharmaceutically-acceptable salt thereof, wherein:
R2 is C1-4 alkyl substituted with 1-4 R7;
R7, at each occurrence, is independently selected from H, OH, CHF2, and CF3.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

### Claim 14 (depends on 1)

A method prophylaxis and/or treatment of a disorder associated with aberrant Rho kinase activity, comprising administrating to a patient in need thereof a therapeutically effective amount of a compound according to claim 1.

### Claim 15 (depends on 14)

The method according to claim 14, wherein said disorder is selected from the group consisting of a cardiovascular disorder, a smooth muscle related disorder, a fibrotic disease, an inflammatory disease, neuropathic disorders, oncologic disorders, and an autoimmune disorder.

### Claim 16 (depends on 15)

The method according to claim 15, wherein said cardiovascular disorder is selected from the group consisting of angina, atherosclerosis, stroke, cerebrovascular disease, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stenosis, vasospasm, hypertension and pulmonary hypertension.