Aminoquinoline compounds
This invention relates to treating inflammatory and immune diseases with certain aminoquinoline compounds that bind to CXCR3 receptors. The aminoquinoline compounds are covered by the formula (I) shown below. Each variable is defined in the specification.
1. A compound of formula (I):
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, —N═, —N—, —S—, —O—, or a single bond; at most one of X 1 —, X 2 —, X 3 —, and X 4 — being a single bond and at most two of X 1 —, X 2 —, X 3 —, and X 4 — being —N═, —N—, —S—, or —O—;
each of R 1 and R 2 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR b R b ′, —OC(O)—R b , —C(O)—R b , or halogen; or R 1 and R 2 together are C 5 –C 8 heterocycloalkyl;
each of R 3 and R 4 , independently, is H or -A-N(B)-D; at most one of R 3 and R 4 being H; and
each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , NO 2 , CN, C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR c R c ′, —C(O)—OR c , —OC(O)—R c , —C(O)—R c , halogen, or deleted; or R 5 and R 6 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 7 and R 8 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═, —S—, —O—, or a single bond; if R 6 is deleted, X 2 — is —N═, —S—, —O—, or a single bond; if R 7 is deleted, X 3 — is —N═, —S—, —O—, or a single bond; and if R 8 is deleted, X 4 — is —N═, —S—, —O—, or a single bond;
in which A is C 1 –C 12 alkyl optionally containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, C 2 –C 12 alkenyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkynyl optionally containing 1–6 heteroatoms, aryl, heteroaryl, C 1 –C 10 alkylsulfonyl, arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms, C 2 –C 20 arylalkyl optionally containing 1–6 heteroatoms, C 2 –C 20 alkylheteroaryl containing 1–6 heteroatoms, or C 2 –C 20 heteroarylalkyl containing 2–6 heteroatoms; B is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl; or B and A together are heteroaryl; and D is H, aryl, heteroaryl, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, —C(O)—R d , —SO 2 —R d , —C(S)—R d , —C(O)—NR d R d ′, —C(O)—OR d , —OC(O)—R d , —C(O)—SR d , or —SC(O)—R d ; or D and A together are heteroaryl; each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, being H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl; or R d and R d ′ together being C 5 –C 7 heterocycloalkyl;
or a salt thereof.
2. The compound of claim 1 , wherein D is of formula (II),
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═, —CR e —, —N═, —N—, —S—, —O—, or a single bond; at most one of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, being a single bond, and at most two of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, being —N═, —N—, —S—, or —O—;
each of R 1 ′ and R 2 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR f R f ′, —OC(O)—R f , —C(O)—R f , or halogen; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl;
each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , NO 2 , CN, C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR g R g ′, —C(O)—OR g , —OC(O)—R g , —C(O)—R g , halogen, or deleted; or R 3 ′ and R 4 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 4 ′ and R 5 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 5 ′ and R 6 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 3 ′ is deleted, X 1 ′— is —N═, —S—, —O—, or a single bond; if R 4 ′ is deleted, X 2 ′— is —N═, —S—, —O—, or a single bond; if R 5 ′ is deleted, X 3 ′— is —N═, —S—, —O—, or a single bond; and if R 6 ′ is deleted, X 4 ′— is —N═, —S—, —O—, or a single bond;
in which each of R e , R f , R f ′, R g , and R g ′, independently, being H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl.
3. The compound of claim 1 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, —N═, —N—, —S—, or a single bond; each of R 1 and R 2 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, aryl, heteroaryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylamino, diarylamino, —C(O)—NR b R b ′, or —C(O)—R b ; or R 1 and R 2 together are C 5 –C 8 heterocycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NO 2 , —C(O)—NR c R c ′, —C(O)—R c , halogen, or deleted; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═, —S—, or a single bond; if R 6 is deleted, X 2 — is —N═, —S—, or a single bond; if R 7 is deleted, X 3 — is —N═, —S—, or a single bond; and if R 8 is deleted, X 4 — is —N═, —S—, or a single bond; B is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, or heteroaryl; or B and A together are heteroaryl; D is H, aryl, heteroaryl, C 3 –C 8 heterocycloalkyl, or C 1 –C 8 alkyl; or D and A together are heteroaryl; and each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, is H, C 5 –C 8 cycloalkenyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl.
4. The compound of claim 3 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, or —N═; each of R 1 and R 2 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; or R 1 and R 2 together are C 5 –C 8 heterocycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, halogen, or deleted; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═; if R 6 is deleted, X 2 — is —N═; if R 7 is deleted, X 3 — is —N═; and if R 8 is deleted, X 4 — is —N═; A is C 1 –C 12 alkyl optionally containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, C 2 –C 12 alkenyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkynyl optionally containing 1–6 heteroatoms, aryl, C 1 –C 10 alkylsulfonyl, arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms, or C 2 –C 20 arylalkyl optionally containing 1–6 heteroatoms; D is H, aryl, heteroaryl, C 3 –C 8 heterocycloalkyl, or C 1 –C 8 alkyl; and each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, is H, aryl, or heteroaryl.
5. The compound of claim 4 , wherein A is arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 arylalkyl, or C 1 –C 12 alkyl optionally containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl; or A and B together are heteroaryl.
6. The compound of claim 5 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, or halogen; and B is H or B and A together are heteroaryl.
7. The compound of claim 6 , wherein the compound is
8. The compound of claim 4 , wherein D is of formula (II),
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═, —CR e —, or —N═; at most two of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′— being —N═;
each of R 1 ′ and R 2 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl; and
each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, or halogen; or R 4 ′ and R 5 ′ together are C 5 –C 7 heterocycloalkyl
in which R e is H, aryl, or heteroaryl.
9. The compound of claim 8 , wherein A is C 1 –C 12 alkyl containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
10. The compound of claim 8 , wherein A is C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms.
11. The compound of claim 8 , wherein A is aryl, or A and B together are heteroaryl.
12. The compound of claim 9 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, C 1 –C 6 alkylthio, or halogen; B is H; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, C 1 –C 6 alkylthio, or halogen.
13. The compound of claim 12 , wherein the compound is one
14. The compound of claim 10 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, or halogen; B is H; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, or halogen.
15. The compound of claim 14 , wherein the compound is one
16. The compound of claim 11 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H or C 1 –C 8 alkyl; B is H; or B and A together are heteroaryl; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H or C 1 –C 8 alkyl.
17. The compound of claim 16 , wherein the compound is compound 36.
18. A compound of formula (I):
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, CR a , —N═, —N—, —S—, —O—, or a single bond; at most one of X 1 —, X 2 —, X 3 —, and X 4 — being a single bond and at most two of X 1 —, X 2 —, X 3 —, and X 4 — being —N═, —N—, —S—, or —O—;
R 1 is C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR b R b ′, —OC(O)—R b , —C(O)—R b , or halogen; R 2 is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR b R b ′, —OC(O)—R b , —C(O)—R b , or halogen; or R 1 and R 2 together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl;
each of R 3 and R 4 , independently, is H or -A-N(B)-D; at most one of R 3 and R 4 being H; and
each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , NO 2 , CN, C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR c R c ′, —C(O)—OR c , —OC(O)—R c , —C(O)—R c , or deleted; or R 5 and R 6 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 7 and R 8 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═, —S—, —O—, or a single bond; if R 6 is deleted, X 2 — is —N═, —S—, —O—, or a single bond; if R 7 is deleted, X 3 — is —N═, —S—, —O—, or a single bond; and if R 8 is deleted, X 4 — is —N═, —S—, —O—, or a single bond; and further provided that not all of R 5 , R 6 , R 7 , and R 8 are H;
in which A is C 1 –C 12 alkyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkenyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkynyl optionally containing 1–6 heteroatoms, aryl, heteroaryl, C 1 –C 10 alkylsulfonyl, arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms, C 2 –C 20 arylalkyl optionally containing 1–6 heteroatoms, C 2 –C 20 alkylheteroaryl containing 1–6 heteroatoms, or C 2 –C 20 heteroarylalkyl containing 1–6 heteroatoms; B is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl; or B and A together are heteroaryl; and D is H, aryl, heteroaryl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, —C(O)—R d , —SO 2 —R d , —C(S)—R d , —C(O)—NR d R d ′, —C(O)—OR d , —OC(O)—R d , —C(O)—SR d , or —SC(O)—R d ; or D and A together are heteroaryl; each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, being H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl; or R d and R d ′ together being C 5 –C 7 heterocycloalkyl;
or a salt thereof.
19. The compound of claim 18 , wherein D is of formula (II),
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 ′, X 2 ′, X 3 ′, and X 4 ′, independently, is —C═, —CR e —, —N═, —N—, —S—, —O—, or a single bond; at most one of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, being a single bond, and at most two of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, being —N═, —N—, —S—, or —O—;
each of R 1 ′ and R 2 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR f R f ′, —OC(O)—R f , —C(O)—R f , or halogen; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl;
each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , NO 2 , CN, C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR g R g ′, —OC(O)—R g , —C(O)R g , or deleted; or R 3 ′ and R 4 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 4 ′ and R 5 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 5 ′ and R 6 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 3 ′ is deleted, X 1 ′— is —N═, —S—, —O—, or a single bond; if R 4 ′ is deleted, X 2 ′— is —N═, —S—, —O—, or a single bond; if R 5 ′ is deleted, X 3 ′— is —N═, —S—, —O—, or a single bond; if R 6 ′ is deleted, X 4 ′— is —N═, —S—, —O—, or a single bond; and further provided that not all of R 3 ′, R 4 ′, R 5 ′, and R 6 ′ are H;
in which each of R e , R f , R f ′, R g , and R g ′, independently, being H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl.
20. The compound of claim 18 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, —N═, —N—, —S—, or a single bond; R 1 is C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, heteroaryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylamino, diarylamino, —C(O)—NR b R b ′, or —C(O)—R b ; R 2 is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, aryl, heteroaryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylamino, diarylamino, —C(O)—NR b R b ′, or —C(O)—R b ; or R 1 and R 2 together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NO 2 , —C(O)—NR c R c ′, —C(O)—R c , or deleted; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═, —S—, or a single bond; if R 6 is deleted, X 2 — is —N═, —S—, or a single bond; if R 7 is deleted, X 3 — is —N═, —S—, or a single bond; and if R 8 is deleted, X 4 — is —N═, —S—, or a single bond; B is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, or heteroaryl; or B and A together are heteroaryl; D is H, aryl, heteroaryl, C 3 –C 8 heterocycloalkyl, or —C(O)—R d ; or D and A together are heteroaryl; and each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, is H, C 5 –C 8 cycloalkenyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl.
21. The compound of claim 20 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, or —N═; R 1 is C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; R 2 is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; or R 1 and R 2 together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, or deleted; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═; if R 6 is deleted, X 2 — is —N═; if R 7 is deleted, X 3 — is —N═; and if R 8 is deleted, X 4 — is —N═; A is C 1 –C 12 alkyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkenyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkynyl optionally containing 1–6 heteroatoms, aryl, C 1 –C 10 alkylsulfonyl, arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms, or C 2 –C 20 arylalkyl optionally containing 1–6 heteroatoms; D is H, aryl, heteroaryl, C 3 –C 8 heterocycloalkyl, or —C(O)—R d ; and each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, is H, aryl, or heteroaryl.
22. The compound of claim 21 , wherein A is C 1 –C 12 alkyl.
23. The compound of claim 22 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; R 1 and R 2 together are C 5 –C 8 cycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H or C 1 –C 8 alkyl; B is H; and D is H, heteroaryl, or —C(O)—R d .
24. The compound of claim 23 , wherein the compound is
25. The compound of claim 21 , wherein D is of formula (II),
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═, —CR e —, or —N═; at most two of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′— being —N═;
each of R 1 ′ and R 2 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl; and
each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, or arylthio; or R 4 ′ and R 5 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl
in which R e is H, aryl, or heteroaryl.
26. The compound of claim 25 , wherein A is C 1 –C 12 alkyl.
27. The compound of claim 25 , wherein A is C 1 –C 12 alkyl containing 1–6 heteroatoms and optionally substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
28. The compound of claim 26 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; R 1 and R 2 together are C 5 –C 8 cycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, or halogen; B is H; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, or C 1 –C 6 alkoxy.
29. The compound of claim 28 , wherein the compound is one
30. The compound of claim 27 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; R 1 and R 2 together are C 5 –C 8 cycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H or C 1 –C 8 alkyl; B is H; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H or C 1 –C 8 alkyl.
31. A pharmaceutical composition comprising a compound of formula (I):
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, —N═, —N—, —S—, —O—, or a single bond; at most one of X 1 —, X 2 —, X 3 —, and X 4 — being a single bond and at most two of X 1 —, X 2 —, X 3 —, and X 4 — being —N═, —N—, —S—, or —O—;
each of R 1 and R 2 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR b R b ′, —C(O)—OR b , —OC(O)—R b , —C(O)—R b , or halogen; or R 1 and R 2 together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl;
each of R 3 and R 4 , independently, is H or -A-N(B)-D; and
each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , NO 2 , CN, C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR c R c ′, —C(O)—OR c , —OC(O)—R c , —C(O)—R c , halogen, or deleted; or R 5 and R 6 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 7 and R 8 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═, —S—, —O—, or a single bond; if R 6 is deleted, X 2 — is —N═, —S—, —O—, or a single bond; if R 7 is deleted, X 3 — is —N═, —S—, —O—, or a single bond; and if R 8 is deleted, X 4 — is —N═, —S—, —O—, or a single bond;
in which A is C 1 –C 12 alkyl optionally containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, C 2 –C 12 alkenyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkynyl optionally containing 1–6 heteroatoms, aryl, heteroaryl, C 1 –C 10 alkylsulfonyl, arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms, C 2 –C 20 arylalkyl optionally containing 1–6 heteroatoms, C 2 –C 20 alkylheteroaryl containing 1–6 heteroatoms, or C 2 –C 20 heteroarylalkyl containing 2–6 heteroatoms; B is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl; or B and A together are C 5 –C 7 heterocycloalkyl or heteroaryl; and D is H, aryl, heteroaryl, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, —C(O)—R d , —SO 2 —R d , —C(S)—R d , —C(O)—NR d R d ′, —C(O)—OR d , —OC(O)—R d , —C(O)—SR d , or —SC(O)—R d ; or D and A together are C 5 –C 7 heterocycloalkyl or heteroaryl; each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, being H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl; or R d and R d ′ together being C 5 –C 7 heterocycloalkyl; or a salt thereof; and
a pharmaceutically acceptable carrier.
32. The composition of claim 31 , wherein D is of formula (II),
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═, —CR e —, —N═, —N—, —S—, —O—, or a single bond; at most one of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, being a single bond, and at most two of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, being —N═, —N—, —S—, or —O—;
each of R 1 ′ and R 2 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR f R f ′, —C(O)—OR f , —OC(O)—R f , —C(O)—R f , or halogen; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl;
each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, heteroaryl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NH 2 , NO 2 , CN, C 1 –C 6 alkylamino, C 1 –C 12 dialkylamino, arylamino, diarylamino, —C(O)—NR g R g ′, —C(O)—OR g , —OC(O)—R g , C(O)R g , halogen, or deleted; or R 3 ′ and R 4 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 4 ′ and R 5 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; or R 5 ′ and R 6 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 3 ′ is deleted, X 1 ′— is —N═, —S—, —O—, or a single bond; if R 4 ′ is deleted, X 2 ′— is —N═, —S—, —O—, or a single bond; if R 5 ′ is deleted, X 3 ′— is —N═, —S—, —O—, or a single bond; and if R 6 ′ is deleted, X 4 ′— is —N═, —S—, —O—, or a single bond;
in which each of R e , R f , R f ′, R g , and R g ′, independently, being H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl.
33. The composition of claim 31 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, —N═, —N—, —S—, or a single bond; each of R 1 and R 2 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, aryl, heteroaryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylamino, diarylamino, —C(O)—NR b R b ′, or —C(O)—R b ; or R 1 and R 2 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 cycloalkyl, C 5 –C 8 cycloalkenyl, C 3 –C 8 heterocycloalkyl, C 5 –C 8 heterocycloalkenyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, NO 2 , —C(O)—NR c R c ′, —C(O)—R c , halogen, or deleted; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═, —S—, or a single bond; if R 6 is deleted, X 2 — is —N═, —S—, or a single bond; if R 7 is deleted, X 3 — is —N═, —S—, or a single bond; and if R 8 is deleted, X 4 — is —N═, —S—, or a single bond; B is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, or heteroaryl; or B and A together are C 5 –C 7 heterocycloalkyl or heteroaryl; D is H, aryl, heteroaryl, C 1 –C 8 alkyl, C 3 –C 8 heterocycloalkyl, or —C(O)—R d ; or D and A together are C 5 –C 7 heterocycloalkyl or heteroaryl; and each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, being H, C 5 –C 8 cycloalkenyl, C 5 –C 8 heterocycloalkenyl, aryl, or heteroaryl.
34. The composition of claim 33 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═, —CR a —, or —N═; each of R 1 and R 2 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; or R 1 and R 2 together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, halogen, or deleted; or R 6 and R 7 together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl; provided that if R 5 is deleted, X 1 — is —N═; if R 6 is deleted, X 2 — is —N═; if R 7 is deleted, X 3 — is —N═; and if R 8 is deleted, X 4 — is —N═; A is C 1 –C 12 alkyl optionally containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl, C 2 –C 12 alkenyl optionally containing 1–6 heteroatoms, C 2 –C 12 alkynyl optionally containing 1–6 heteroatoms, aryl, C 1 –C 10 alkylsulfonyl, arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms, or C 2 –C 20 arylalkyl optionally containing 1–6 heteroatoms; D is H, aryl, heteroaryl, C 1 –C 8 alkyl, C 3 –C 8 heterocycloalkyl, or —C(O)—R d ; and each of R a , R b , R b ′, R c , R c ′, R d , and R d ′, independently, being H, aryl, or heteroaryl.
35. The composition of claim 34 , wherein A is arylsulfonyl, C 1 –C 10 alkylcarbonyl containing 1–6 heteroatoms, C 2 –C 20 arylalkyl, or C 1 –C 12 alkyl optionally containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl or A and B together are heteroaryl.
36. The composition of claim 35 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; or R 1 and R 2 together are C 5 –C 8 cycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, or halogen; and B is H or B and A together are heteroaryl.
37. The composition of claim 34 , wherein D is of formula (II),
wherein
each is a single bond or a double bond; provided that if one is a double bond, its neighboring is not a double bond;
each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═, —CR e —, or —N═; at most two of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′— being —N═;
each of R 1 ′ and R 2 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, aryl, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, or C 1 –C 6 alkylthio; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl or C 5 –C 8 heterocycloalkyl; and
each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 2 –C 8 alkenyl, C 2 –C 8 alkynyl, C 3 –C 8 heterocycloalkyl, OH, C 1 –C 6 alkoxy, aryloxy, heteroaryloxy, C 1 –C 6 alkylthio, arylthio, or halogen; or R 4 ′ and R 5 ′ together are C 5 –C 7 cycloalkyl or C 5 –C 7 heterocycloalkyl in which R e is H, aryl, or heteroaryl.
38. The composition of claim 37 , wherein A is C 1 –C 12 alkyl containing 1–6 heteroatoms and substituted with sulfonyl, C 1 –C 6 alkylsulfonyl, arylsulfonyl, or heteroarylsulfonyl.
39. The composition of claim 37 , wherein A is C 2 –C 20 alkylaryl optionally containing 1–6 heteroatoms.
40. The composition of claim 37 , wherein A is aryl, or A and B together are heteroaryl.
41. The composition of claim 38 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; or R 1 and R 2 together are C 5 –C 8 cycloalkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, C 1 –C 6 alkylthio, or halogen; B is H; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; or R 1 ′ and R 2 ′ together are C 5 –C 8 cycloalkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy,aryloxy, C 1 –C 6 alkylthio, or halogen.
42. The composition of claim 39 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, or halogen; B is H; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H, C 1 –C 8 alkyl, C 1 –C 6 alkoxy, aryloxy, or halogen.
43. The composition of claim 40 , wherein each of X 1 —, X 2 —, X 3 —, and X 4 —, independently, is —C═; each of R 1 and R 2 , independently, is H or C 1 –C 8 alkyl; each of R 5 , R 6 , R 7 , and R 8 , independently, is H or C 1 –C 8 alkyl; B is H; or B and A together are heteroaryl; each of X 1 ′—, X 2 ′—, X 3 ′—, and X 4 ′—, independently, is —C═; each of R 1 ′ and R 2 ′, independently, is H or C 1 –C 8 alkyl; each of R 3 ′, R 4 ′, R 5 ′, and R 6 ′, independently, is H or C 1 –C 8 alkyl.
44. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier.
45. A compound selected from the group consisting of
or a salt thereof.
46. A pharmaceutical composition comprising a compound of claim 45 and a pharmaceutically acceptable carrier.