Process for the preparation of macrocyclic metalloprotease inhibitors

A process for the preparation of a compound of formula (X-a):

• or a pharmaceutically acceptable salt form thereof,
• wherein:
• R1 is selected from the group consisting of:
• C1-5 alkyl substituted with 0-5 R1a, —(CH2)r—C3-10 cycloalkyl substituted with 0-5 R1a, and —(CH2)r-aryl substituted with 0-5 R1a;
• R1a is selected independently at each occurrence from the group consisting of:
• hydrogen, —CF3, —CF2CF3, —NR1bR1c, —Si(R1d)3, C1-5 alkyl, C3-10 cycloalkyl, and aryl substituted with 0-5 R1e;
• R1b and R1c are selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R1d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 haloalkyl, and aryl substituted with 0-5 R1e;
• R1e is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR1f, —OH, halo, —NH2, and —(CF2)rCF3;
• R1f is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R3 is selected from the group consisting of:
• —OR4, —NR5R6, —NR6(OR5), C1-5 alkyl substituted with 0-3 R3a, —(CH2)r-aryl substituted with 0-5 R3a, and —(CH2)r-heterocyclic substituted with 0-3 R3a;
• R3a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-5 alkyl, halo, hydroxy, —O—(CH2)r—R3b, —(CH2)r—C(O)R3b, —(CH2)r—SO2NHR3b, —(CH2)r—C(O)NHR3b, —(CH2)r—OC(O)R3b, —(CH2)r—NHSO2R3b, aryl, —(CH2)r—NHC(O)R3b, and —(CH2)r—C(O)OR3b;
• R3b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R4 is selected from the group consisting of:
• hydrogen, C1-C10 alkyl, —(CH2)r—C3-10 cycloalkyl, —(CH2)r-heterocyclic, and —(CH2)r-aryl substituted with 0-5 R4a;
• R4a is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR4b, —OH, halo, —NH2, and —(CF2)rCF3;
• R4b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R5 is selected from the group consisting of:
• C1-C5 alkyl, —(CH2)r—C3-C10 cycloalkyl, —(CHR5aY)n—R9, —(CR7R8)n—O—C(R7R8)r—R9, —(CR7R8)r—R9, and —(CR7R8)rCONR7R8;
• R5a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-10 alkyl substituted with 0-3 R5b, —(CH2)r-aryl substituted with 0-3 R5b, and —(CH2)r—O—(CH2)r-aryl substituted with 0-3 R5b;
• R5b is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR5c, —NHC(O)CH3, -aryl-(CH2)r—NH2, -aryl-(CH2)r-aryl, C1-10 alkyl substituted with 0-3 R5d, and —(CH2)r-aryl substituted with 0-3 R5d;
• R5c is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R5d is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, —O—(CH2)r—R5e, —OH, halo, —NHC(O)CH3, and —C(O)NH2;
• R5e is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R6 is selected from the group consisting of:
• hydrogen, C1-C10 alkyl, —(CH2)r-aryl, —(CH2)r—C(O)R6a, —(CH2)r-heterocyclic and phenyl substituted with 0-5 R6c;
• R6a is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, —O—(CH2)r—R6b, —OH, halo, —NHC(O)CH3, and —C(O)NH2;
• R6b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R6c is selected independently at each occurrence from the group consisting of:
• halogen, NO2, —R6d, and —O—(CH2)r—R6d;
• R6d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• alternatively, R5 and R6 combine to form a 3- to 8- membered heterocyclic ring containing 1 to 3 additional heteroatoms selected from —O—, —NR6—, —S(O)p-, and —C(O)—, optionally fused to a phenyl ring;
• R7 and R8 may be H or R5a;
• alternatively, R7 and R8 combine to form 3- to 7- membered heterocyclic ring substituted with 1-3 R7a, containing 1-3 additional heteroatoms selected from —O—, —S(O)p-, and —NR6—, optionally fused to an aryl ring substituted with 0-3 R7c;
• R7a is selected independently at each occurrence from the group consisiting of:
• hydrogen, C1-5 alkyl, C3-5 cycloalkyl, hydroxy, halo, —OR7b, —NHC(O)CH3, —C(O)NH2, and aryl;
• R7b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R7c is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, C3-5 cycloalkyl, hydroxy, halo, —O(CH2)r—R7d, —NHC(O)CH3, —C(O)NH2, and aryl;
• R7d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R9 is selected from the group consisting of:
• hydrogen, C1-5 alkyl, —C(O)OC1-5 alkyl, —(CH2)r-aryl substituted with 0-3 R9a, and a 5- or 6- membered heterocyclic ring containing from 0 to 2 N, O or S(O)p, and substituted with 0-3 R9a;
• R9a is selected from the group consisting of:
• —OH, —O—(CH2)r—R9b, —C(O)OR9b, NHR10 and aryl;
• R9b is selected from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R10 is independently at each occurrence H or C1-10 alkyl substituted with 0-3 R10a;
• R10a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-C10 alkyl substituted with 0-3 R10b, and —(CH2)r-aryl substituted with 0-3 R10b;
• R10b is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR10c, —NHC(O)CH3, —(CH2)r—C(O)NH2, -aryl-NH2, and —SO2NH2;
• R10c is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R11 is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-C10 alkyl substituted with 0-3 R11a, and —(CH2)r-aryl substituted with 0-3 R11a;
• R11a is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR11b, —NHC(O)CH3, —(CH2)r—C(O)NH2, -aryl-NH2, and —SO2NH2;
• R11b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• n is selected from 1, 2 and 3;
• p is selected independently at each occurrence from 0, 1 and 2;
• r is selected independently at each occurrence from 0, 1, 2, and 3;
• Y is selected from the group consisting of:
• —CONR10—, —NR10CO—, —SO2NR10—, —NR10SO2—, and a 5 membered heterocyclic ring;
• and
• z is selected from 1, 2, 3, 4 and 5;
• the process comprising:
• cyclizing a compound of formula (VIII-a):
• or a salt form thereof;
• wherein:
• R2 is selected from the group consisting of:
• C1-10 alkyl, C3-10 cycloalkyl, and —(CH2)r-phenyl substituted with 0-3 R2a;
• R2a is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR2b, —OH, halo, —NH2, and —(CF2)rCF3;
• R2b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• to form a compound of formula (IX-a):
• contacting the compound of formula (IX-a) with an oxidizing agent to form a compound of formula (X-a) or a pharmaceutically acceptable salt form thereof.

A compound of formula (III):

• wherein:
• R2 is —CH(CH3)2;
• G is —OCH2OCH3;
• and
• z is 2.

A compound of formula (IV):

• wherein:
• R1 is —CH2CH(CH3)2
• R2 is —CH(CH3)2;
• G is —OCH2OCH3;
• and
• z is 2.

A compound of formula (IV-a):

• wherein:
• R1 is —CH2CH(CH3)2;
• R2 is —CH(CH3)2;
• R12 is selected independently at each occurrence from C1-6 alkyl or phenyl;
• G is —OCH2OCH3 or —O-t-butyldimethylsilyl;
• and
• z is 2.

A compound of formula (V):

• or a form thereof;
• wherein:
• R1 is —CH2CH(CH3)2;
• R2 is —CH(CH3)2;
• G is —OCH2OCH3 or —O-t-butyldimethylsilyl;
• and
• z is 2.

A compound of formula (VII):

• or a salt form thereof;
• wherein:
• D is P1—NR11—CH2CH2CH2—;
• G is selected from the group consisting:
• halogen, —OP or —OH;
• P is a suitable oxygen protecting group;
• P1 is a suitable nitrogen protecting group;
• R1 is selected from the group consisting of:
• C1-5 alkyl substituted with 0-5 R1a, —(CH2)r—C3-10 cycloalkyl substituted with 0-5 R1a, and —(CH2)r-aryl substituted with 0-5 R1a;
• R1a is selected independently at each occurrence from the group consisting of:
• hydrogen, —CF3, —CF2CF3, —NR1bR1c, —Si(R1d)3, C1-5 alkyl, C3-10 cycloalkyl, and aryl substituted with 0-5 R1e;
• R1b and R1c are selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R1d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 haloalkyl, and aryl substituted with 0-5 R1e;
• R1e is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR1f, —OH, halo, —NH2, and —(CF2)rCF3;
• R1f is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R2 is selected from the group consisting of:
• C1-10 alkyl, C3-10 cycloalkyl, and —(CH2)r-phenyl substituted with 0-3 R2a;
• R2a is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR2b, —OH, halo, —NH2, and —(CF2)rCF3;
• R2b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R3 is selected from the group consisting of:
• —OR4, —NR5R6, —NR6(OR5), C1-5 alkyl substituted with 0-3 R3a, —(CH2)r-aryl substituted with 0-5 R3a, and —(CH2)r-heterocyclic substituted with 0-3 R3a;
• R3a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-5 alkyl, halo, hydroxy, —O—(CH2)r—R3b, —(CH2)r—C(O)R3b, —(CH2)r—SO2NHR3b, —(CH2)r—C(O)NHR3b, —(CH2)r—OC(O)R3b, —(CH2)r—NHSO2R3b, aryl, —(CH2)r—NHC(O)R3b, and —(CH2)r—C(O)OR3b;
• R3b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R4 is selected from the group consisting of:
• hydrogen, C1-C10 alkyl, —(CH2)r—C3-10 cycloalkyl, —(CH2)r-heterocyclic, and —(CH2)r-aryl substituted with 0-5 R4a;
• R4a is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR4b, —OH, halo, —NH2, and —(CF2)rCF3;
• R4b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R5 is selected from the group consisting of:
• C1-5 alkyl, —(CH2)r—C3-10 cycloalkyl, —(CHR5aY)n—R9, —(CR7R8)n—O—C(R7R8)r—R9, —(CR7R8)r—R9, and —(CR7R8)rCONR7R8;
• R5a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-10 alkyl substituted with 0-3 R5b, —(CH2)r-aryl substituted with 0-3 R5b, and —(CH2)r—O—(CH2)r-aryl substituted with 0-3 R5b;
• R5b is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR5c, —NHC(O)CH3, -aryl-(CH2)r—NH2, -aryl-(CH2)r-aryl, C1-10 alkyl substituted with 0-3 R5d, and —(CH2)r-aryl substituted with 0-3 R5d;
• R5c is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R5d is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, —O—(CH2)r—R5e, —OH, halo, —NHC(O)CH3, and —C(O)NH2;
• R5e is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R6 is selected from the group consisting of:
• hydrogen, C1-C10 alkyl, —(CH2)r-aryl, —(CH2)r—C(O)R6a, —(CH2)r-heterocyclic, and phenyl substituted with 0-5 R6c;
• R6a is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, —O—(CH2)r—R6b, —OH, halo, —NHC(O)CH3, and —C(O)NH2;
• R6b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R6c is selected independently at each occurrence from the group consisting of:
• halogen, NO2, —R6d, and —O—(CH2)r—R6d;
• R6d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• alternatively, R5 and R6 combine to form a 3- to 8- membered heterocyclic ring containing 1 to 3 additional heteroatoms selected from —O—, —NR6—, —S(O)p-, and —C(O)—, optionally fused to a phenyl ring;
• R7 and R8 may be H or R5a;
• alternatively, R7 and R8 combine to form 3 to 7 membered heterocyclic ring substituted with 1-3 R7a, containing 1-3 additional heteroatoms selected from —O—, —S(O)p-, and —NR6—, optionally fused to an aryl ring substituted with 0-3 R7c;
• R7a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-5 alkyl, C3-5 cycloalkyl, hydroxy, halo, —OR7b, —NHC(O)CH3, —C(O)NH2, and aryl;
• R7b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R7c is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, C3-5 cycloalkyl, hydroxy, halo, —O(CH2)r—R7d, —NHC(O)CH3, —C(O)NH2, and aryl;
• R7d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R9 is selected from the group consisting of:
• hydrogen, C1-5 alkyl, —C(O)OC1-5 alkyl, —(CH2)r-aryl substituted with 0-3 R9a, and a 5 or 6 membered heterocyclic ring containing from 0 to 2 N, O or S(O)p, and substituted with 0-3 R9a;
• R9a is selected from the group consisting of:
• —OH, —O—(CH2)r—R9b, —C(O)OR9b, —NHR10 and aryl;
• R9b is selected from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R10 is independently at each occurrence H or C1-10 alkyl substituted with 0-3 R1a;
• R10a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-C10 alkyl substituted with 0-3 R10b, and —(CH2)r-aryl substituted with 0-3 R10b;
• R10b is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR10c, —NHC(O)CH3, —(CH2)r—C(O)NH2, -aryl-NH2, and —SO2NH2;
• R10c is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R11 is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-C10 alkyl substituted with 0-3 R11a, and —(CH2)r-aryl substituted with 0-3 R11a;
• R11a is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR11b, —NHC(O)CH3, —(CH2)r—C(O)NH2, -aryl-NH2, and —SO2NH2;
• R11 bis selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• n is selected from 1, 2 and 3;
• p is selected independently at each occurrence from 0, 1 and 2;
• r is selected independently at each occurrence from 0, 1, 2, and 3;
• Y is selected from the group consisting of:
• —CONR10—, —NR10CO—, —SO2NR10—, —NR10SO2—, and a 5 membered heterocyclic ring;
• and
• z is selected from 1, 2, 3, 4 and 5.

A compound of formula (IX-a):

• or a salt form thereof;
• wherein:
• R1 is selected from the group consisting of:
• C1-5 alkyl substituted with 0-5 R1a, —(CH2)r—C3-10 cycloalkyl substituted with 0-5 R1a, and —(CH2)r-aryl substituted with 0-5 R1a;
• R1a is selected independently at each occurrence from the group consisting of:
• hydrogen, —CF3, —CF2CF3, —NR1bR1c, —Si(R1d)3, C1-5 alkyl, C3-10 cycloalkyl, and aryl substituted with 0-5 R1e;
• R1b and R1c are selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R1d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 haloalkyl, and aryl substituted with 0-5 R1e;
• R1e is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR1f, —OH, halo, —NH2, and —(CF2)rCF3;
• R1f is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R2 is selected from the group consisting of:
• C1-10 alkyl, C3-10 cycloalkyl, and —(CH2)r-phenyl substituted with 0-3 R2a;
• R2a is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR2b, —OH, halo, —NH2, and —(CF2)rCF3;
• R2b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R3 is selected from the group consisting of:
• —OR4, —NR5R6, —NR6(OR5), C1-5 alkyl substituted with 0-3 R3a, —(CH2)r-aryl substituted with 0-5 R3a, and —(CH2)r-heterocyclic substituted with 0-3 R3a;
• R3a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-5 alkyl, halo, hydroxy, —O—(CH2)r—R3b, —(CH2)r—C(O)R3b, —(CH2)r—SO2NHR3b, —(CH2)r—C(O)NHR3b, —(CH2)r—OC(O)R3b, —(CH2)r—NHSO2R3b, aryl, —(CH2)r—NHC(O)R3b, and —(CH2)r—C(O)OR3b;
• R3b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R4 is selected from the group consisting of:
• hydrogen, C1-C10 alkyl, —(CH2)r—C3-10 cycloalkyl, —(CH2)r-heterocyclic, and —(CH2)r-aryl substituted with 0-5 R4a;
• R4a is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, —(CH2)r—OR4b, —OH, halo, —NH2, and —(CF2)rCF3;
• R4b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R5 is selected from the group consisting of:
• C1-5 alkyl, —(CH2)r—C3-C10 cycloalkyl, —(CHR5aY)n—R9, —(CR7R8)n—O—C(R7R8)r—R9, —(CR7R8)r—R9, and —(CR7R8)rCONR7R8;
• R5a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-10 alkyl substituted with 0-3 R5b, —(CH2)r-aryl substituted with 0-3 R5b, and —(CH2)r—O—(CH2)r-aryl substituted with 0-3 R5b;
• R5b is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR5c, —NHC(O)CH3, -aryl-(CH2)r—NH2, -aryl-(CH2)r-aryl, C1-10 alkyl substituted with 0-3 R5d, and —(CH2)r-aryl substituted with 0-3 R5d;
• R5c is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R5d is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, —O—(CH2)r—R5e, —OH, halo, —NHC(O)CH3, and —C(O)NH2;
• R5e is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R6 is selected from the group consisting of:
• hydrogen, C1-C10 alkyl, —(CH2)r-aryl, —(CH2)r—C(O)R6a, —(CH2)r-heterocyclic, and phenyl substituted with 0-5 R6c;
• R6a is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, —O—(CH2)r—R6b, —OH, halo, —NHC(O)CH3, and —C(O)NH2;
• R6b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• R6c is selected independently at each occurrence from the group consisting of:
• halogen, NO2, —R6d, and —O—(CH2)r—R6d;
• R6d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C3-5 cycloalkyl and phenyl;
• alternatively, R5 and R6 combine to form a 3 to 8 membered heterocyclic ring containing 1 to 3 additional heteroatoms selected from —O—, —NR6—, —S(O)p-, and —C(O)—, optionally fused to a phenyl ring;
• R7 and R8 may be H or R5a;
• alternatively, R7 and R8 combine to form 3 to 7 membered heterocyclic ring substituted with 1-3 R7a, containing 1-3 additional heteroatoms selected from —O—, —S(O)p-, and —NR6—, optionally fused to an aryl ring substituted with 0-3 R7c;
• R7a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-5 alkyl, C3-5 cycloalkyl, hydroxy, halo, —OR7b, —NHC(O)CH3, —C(O)NH2, and aryl;
• R7b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R7c is selected independently at each occurrence from the group consisting of;
• hydrogen, C1-5 alkyl, C3-5 cycloalkyl, hydroxy, halo, —O(CH2)r—R7d, —NHC(O)CH3, —C(O)NH2, and aryl;
• R7d is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R9 is selected from the group consisting of:
• hydrogen, C1-5 alkyl, —C(O)OC1-5 alkyl, —(CH2)r-aryl substituted with 0-3 R9a, and a 5 or 6 membered heterocyclic ring containing from 0 to 2 N, O or S(O)p, and substituted with 0-3 R9a;
• R9a is selected from the group consisting of:
• —OH, —O—(CH2)r—R9b, —C(O)OR9b, —NHR10 and aryl;
• R9b is selected from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R10 is independently at each occurrence H or C1-10 alkyl substituted with 0-3 R10a;
• R10a is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-C10 alkyl substituted with 0-3 R10b, and —(CH2)r-aryl substituted with 0-3 R10b;
• R10b is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR10c, —NHC(O)CH3, —(CH2)r—C(O)NH2, -aryl-NH2, and —SO2NH2;
• R10c is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• R11 is selected independently at each occurrence from the group consisting of:
• hydrogen, C1-C10 alkyl substituted with 0-3 R11a, and —(CH2)r-aryl substituted with 0-3 R11a;
• R11a is selected independently at each occurrence from the group consisting of:
• hydrogen, halo, hydroxy, —OR11b, —NHC(O)CH3, —(CH2)r—C(O)NH2, -aryl-NH2, and —SO2NH2;
• R11b is selected independently at each occurrence from the group consisting of:
• C1-5 alkyl, C1-5 cycloalkyl and phenyl;
• n is selected from 1, 2 and 3;
• p is selected independently at each occurrence from 0, 1 and 2;
• r is selected independently at each occurrence from 0, 1, 2, and 3;
• Y is selected from the group consisting of:
• —CONR10—, —NR10CO—, —SO2NR10—, —NR10SO2—, and a 5- membered heterocyclic ring;
• and
• z is selected from 1, 2, 3, 4 and 5.