Pharmaceutical compounds for treatment of medical disorders

1. A compound of Formula:

or a pharmaceutically acceptable salt thereof;

wherein:

A is selected from A1 and A3;

C5 is selected from:

L is

L3 is —C(O)—;

A1 is selected from:

A3 is selected from:

X 51 , X 52 , and X 53 are independently selected from N, CR 31 , and CR 201 ;

wherein at least one of X 51 , X 52 , and X 53 is selected from CR 201 ;

X 54 , X 55 , and X 56 are independently selected from N, CR 31 , and CR 201 ;

R 201 is selected from aminoalkyl-, alkylaminoalkyl-, heterocycloalkyl-, hydroxyalkyl, -alkyl-O-alkyl, -alkyl-S-alkyl, -alkyl-N(alkyl)-alkyl, -alkyl-NH-alkyl, -aliphatic-O-aliphatic, -aliphatic-S-aliphatic, -aliphatic-N(aliphatic)-aliphatic, -aliphatic-NH-aliphatic, -aliphatic-O-heterocycle, -aliphatic-S-heterocycle, -aliphatic-N(aliphatic)-heterocycle, -aliphatic-NH-heterocycle, -alkyl-NHC(O)haloalkyl, -alkyl-NR 9 C(O)haloalkyl, -alkyl-C(O)NHhaloalkyl, -alkyl-C(O)NR 9 haloalkyl, -alkyl-NHC(O)haloalkyl, -alkyl-NR 9 C(O)aliphatic, -alkyl-C(O)NHaliphatic, -alkyl-NR 9 C(O)aliphatic, -alkyl-NHC(O)aliphatic, -substituted alkyl-N(R 9 )-substituted alkyl, alkyl-heteroaryl, -alkyl-O-haloalkyl, heteroaryl, heterocycle, alkyl-heterocycle, and —N(aliphatic) 2 ;

R 202 is selected from aryl and heteroaryl, wherein the aryl and heteroaryl groups are substituted with R 201 ;

R 5 and R 6 are independently selected from hydrogen, halogen, —CHO, —C(O)NH 2 , —C 2 -C 6 alkanoyl, —C(O)NH(CH 3 ), —COOH, —P(O)(OR 9 ) 2 , —OC(O)R 9 , —C(O)OR 9 , nitro, hydroxyl, phenyl, 5- to 6-membered heteroaryl, cyano, amino, and C 1 -C 6 alkyl;

R 8 and R 8′ are hydrogen;

R 9 and R 10 are independently selected from hydrogen, C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), and —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);

X 11 is N or CR 11 ;

X 12 is N or CR 12 ;

X 13 is N or CR 13 ;

X 14 is N or CR 14 ;

wherein no more than 2 of X 11 , X 12 , X 13 , and X 14 are N;

wherein one of R 12 and R 13 is R 32 and the other is R 31 or R 32 ;

and wherein if there is no R 13 and no R 32 on the A ring then R 12 is R 32 ;

and wherein if there is no R 12 and no R 32 on the A ring then R 13 is R 32 ;

R 31 is independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, —C(O)OR 9 , C 1 -C 6 thioalkyl, —C 0 -C 4 alkylNR 9 R 10 , —C(O)NR 9 R 10 , —SO 2 R 9 , —SO 2 NR 9 R 10 , —OC(O)R 9 , and —C(NR 9 )NR 9 R 10 , each of which R 31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —C(O)NR 9 R 10 , C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, phenyl, and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; each of which phenyl or 4- to 7-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

R 32 is selected from C(O)NR 21 R 71 , —C(O)NR 9 R 71 , —NR 9 C(O)OR 10 , —NR 9 C(O)OR 23 , —NR 9 C(O)R 21 , —NR 9 C(O)NR 9 R 10 , and —NR 9 C(O)NR 10 R 23 ;

or R 32 is selected from NR 72 R 73 , NR 9 SO 2 R 73 , and N(SO 2 R 9 )CH 2 C(O)R 74 ;

or R 32 is selected from —OC(O)(CH 2 ) 1-4 R 21 , —OC(O)NR 21 R 22 , —OC(O)(C 1-6 alkyl or C 3-6 cycloalkyl)(aryl), —OC(O)(C 1-6 alkyl or C 3-6 cycloalkyl)(heteroaryl), —OC(O)(C 1-6 alkyl or C 3-6 cycloalkyl)(heterocycle), —OC(O)(heteroaryl), —OC(O)(aryl), —OC(O)(C 1-6 alkyl or C 3-6 cycloalkyl), —OC(O)NR 9 (CH 2 ) 1-4 P(O)(OR 21 )(OR 22 ), —C(O)(C 1-6 alkyl or C 3-6 cycloalkyl)(aryl), —C(O)(C 1-6 alkyl or C 3-6 cycloalkyl)(heteroaryl), —C(O)(C 1-6 alkyl or C 3-6 cycloalkyl)(heterocycle), —C(O)(heteroaryl), —C(O)(heterocycle), —C(O)(aryl), —C(O)(C 1-6 alkyl or C 3-6 cycloalkyl), —C(O)(CH 2 )S(O)R 21 , O-heteroalkyl, and O-heteroaliphatic;

or R 32 is selected from —O(CH 2 ) 1-4 R 23a , —OC 2 -C 4 alkenylR 23a , —OC 2 -C 4 alkynylR 23 , —O(CH 2 ) 1-4 paracyclophane, —O(CH 2 ) 1-4 P(O)R 23b R 23b , —O(CH 2 ) 1-4 S(O)NR 21 R 22 , —O(CH 2 ) 1-4 SO 2 NR 21 R 22 , —O(C 3 -C 7 cycloalkyl), —O(aryl), —O(heteroaryl), and —O residue of a carbohydrate;

or R 32 is selected from R 48 , S(O)═NHR 21 , S(O)═N(R 21 )R 21 , SF 5 , S═NHR 21 , S═N(R 21 )R 21 , JC(R 9 )═NR 21 , and SO 2 OR 21 ;

or R 32 is selected from —O(CH 2 ) 1-4 S(O)NR 24 R 30 and —O(CH 2 ) 1-4 SO 2 NR 24 R 30 ;

R 11 and R 14 are independently selected from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR 9 ) 2 , —(PO)(OR 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl(aryl), C 2 -C 6 alkenyl(cycloalkyl), C 2 -C 6 alkenyl(heterocycle), C 2 -C 6 alkenyl(heteroaryl), C 2 -C 6 alkynyl(aryl), C 2 -C 6 alkynyl(cycloalkyl), C 2 -C 6 alkynyl(heterocycle), C 2 -C 6 alkynyl(heteroaryl), C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —C 0 -C 4 alkyl(mono- and di-C 1 -C 6 alkylamino), —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C 0 -C 4 alkoxy(C 3 -C 7 cycloalkyl), C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;

B is selected from:

wherein R 25 , R 26 , and R 27 are independently selected from halogen and C 1 -C 6 alkyl optionally substituted with one or more halogen atoms; and R 28 is C 1 -C 6 alkyl or cyclopropyl; or

B is

wherein R 26 is halogen or C 1 -C 6 alkyl optionally substituted with one or more halogen atoms, and R 27 is C 1 -C 6 alkyl or cyclopropyl;

J is independently selected from a covalent bond, C 1 -C 4 alkylene, —OC 1 -C 4 alkylene, C 2 -C 4 alkenylene, and C 2 -C 4 alkynylene;

R 21 and R 22 are independently selected from hydrogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl, —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl, —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl, (4- to 8-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;

or R 21 and R 22 can be taken together to form a carbocyclic or heterocyclic ring;

R 23 is independently selected at each occurrence from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (aryl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, (4- to 8-membered heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;

R 23a is independently selected at each occurrence from C 3 -C 7 cycloalkyl;

R 23b is independently selected at each occurrence from hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, —O(CH 2 ) 2-4 O(CH 2 ) 8-18 , —OC(R 23c ) 2 OC(O)OR 23 d, —OC(R 23c ) 2 OC(O)R 23d , an N-linked amino acid, or an N-linked amino acid ester;

R 23c is independently selected at each occurrence from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (aryl)C 0 -C 4 alkyl, (aryl)C 2 -C 8 alkenyl- or (aryl)C 2 -C 8 alkynyl; or two R 23c groups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, or a 3-6 membered carbocyclic ring;

R 23d is independently selected at each occurrence from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (aryl)C 0 -C 4 alkyl, (aryl)C 2 -C 8 alkenyl, or (aryl)C 2 -C 8 alkynyl;

R 24 and R 30 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycle, or a 6- to 10-membered bicyclic heterocycle group having fused, spiro, or bridged rings;

R 48 is selected from halogen, hydroxyl, nitro, cyano, amino, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 thioalkyl, C 1 -C 6 alkoxy, -JC 3 -C 7 cycloalkyl, —B(OH) 2 , -JC(O)NR 9 R 23 , -JOSO 2 OR 21 , —C(O)(CH 2 ) 1-4 S(O)R 21 , —O(CH 2 ) 1-4 S(O)NR 21 R 22 , -JOP(O)(OR 21 )(OR 22 ), -JP(O)(OR 21 )(OR 22 ), -JOP(O)(OR 21 )R 22 , -JOP(O)R 21 R 22 , -JP(O)R 21 R 22 , -JSP(O)(OR 21 )(OR 22 ), -JSP(O)(OR 21 )(R 22 ), -JSP(O)(R 21 )(R 22 ), -JNR 9 P(O)(NHR 21 )(NHR 22 ), -JNR 9 P(O)(OR 21 )(NHR 22 ), -JNR 9 P(O)(OR 21 )(OR 22 ), -JC(S)R 21 , -JNR 21 SO 2 R 22 , -JNR 9 S(O)NR 10 R 22 , -JNR 9 SO 2 NR 1 OR 22 , -JSO 2 NR 9 COR 22 , -JSO 2 NR 9 CONR 21 R 22 , -JNR 21 SO 2 R 22 , -JC(O)NR 21 SO 2 R 22 , -JC(NH 2 )═NR 22 , -JCH(NH 2 )NR 9 S(O) 2 R 22 , -JOC(O)NR 21 R 22 , -JNR 21 C(O)OR 22 , -JNR 21 OC(O)R 22 , —(CH 2 ) 1-4 C(O)NR 21 R 22 , -JC(O)NR 24 R 30 , -JNR 9 C(O)R 21 , -JC(O)R 21 , -JNR 9 C(O)NR 10 R 22 , —CCR 21 , —(CH 2 ) 1-4 OC(O)R 21 , -JC(O)OR 23 , and R 103 ; each of which R 48 may be optionally substituted with one or more substituents selected from halogen, hydroxyl, nitro, cyano, amino, oxo, —B(OH) 2 , —Si(CH 3 ) 3 , —COOH, —CONR 9 R 10 , —P(O)(OH) 2 , C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 6 alkoxy, —C 0 -C 4 alkyl(mono- and di-C 1 -C 4 alkylNR 9 R 10 ), C 1 -C 6 alkyl ester, C 1 -C 4 alkylamino, C 1 -C 4 hydroxylalkyl, —OC(O)R 9 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 9 C(O)OR 10 , C 1 -C 6 haloalkyl, S(O)═NHR 21 , SF 5 , JC(R 9 )═NR 21 , SO 2 OR 21 , and C 1 -C 6 haloalkoxy;

R 103 is C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, fluorine, chlorine, or bromine;

R 71 is independently selected at each occurrence from hydroxyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl, —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl, —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S;

R 72 is independently selected at each occurrence from aryl, heterocycle, alkynyl, hydroxyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (aryl)C 0 -C 4 alkyl, (heterocycle)C 0 -C 4 alkyl, (heteroaryl)C 0 -C 4 alkyl, —C 1 -C 6 alkylOC(O)OC 1 -C 6 alkyl, —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl, —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl, —S(O)(O)(alkyl), —S(O)(alkyl), —S(O)(O)(heteroalkyl), —S(O)(heteroalkyl), —S(O)(O)(aryl), —S(O)(aryl), —S(O)(O)(heteroaryl), and —S(O)(heteroaryl);

R 73 is independently selected at each occurrence from hydrogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl, —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl, —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S; and

R 74 is proline substituted with a —C(O)NR 9 R 10 .

2. The compound of claim 1 , wherein B1 is selected from:

3. The compound of claim 1 , wherein R 201 is selected from —(CH 2 ) m —O-heterocycle, —(CH 2 ) m —NH-heterocycle, and —(CH 2 ) m —NR 9 -heterocycle; and wherein m is 0, 1, 2, or 3.

4. The compound of claim 1 , wherein C5 is selected from:

5. The compound of claim 1 , wherein A is A3 and A3 is selected from:

6. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. The compound of claim 1 , wherein the compound is

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein B is