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Heterocyclic compounds as ccr5 antagonists

Heterocyclic compounds as ccr5 antagonists description/claims

The human immunodeficiency virus (“HIV”) is the causative agent for acquired immunodeficiency syndrome (“AIDS”), a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections, and its precursor AIDS-related complex (“ARC”), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.

In addition to CD4, HIV requires a co-receptor for entry into target cells. The chemokine receptors function together with CD4 as co-receptors for HIV. The chemokine receptors CXCR4 and CCR5 have been identified as the main co-receptors for HIV-1. CCR5 acts as a major co-receptor for fusion and entry of macrophage-tropic HIV into host cells. These chemokine receptors are thought to play an essential role in the establishment and dissemination of an HIV infection. Therefore, CCR5 antagonists are thought to be useful as therapeutic agents active against HIV.

We have now discovered a series of small molecule nonpeptide compounds that are useful as inhibitors of HIV replication.

The present invention features compounds that are useful in the inhibition of HIV replication, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as pharmaceutically acceptable salts or pharmaceutical composition ingredients. The present invention further features methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV as monotherapy or in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. The present invention also features pharmaceutical compositions, comprising the above-mentioned compounds that are suitable for the prevention or treatment of CCR5-related diseases and conditions. The present invention further features processes for making the above-mentioned compounds.

The present invention includes compounds of formula (I)

and pharmaceutically acceptable derivatives thereof, wherein:

X is a C1-5 alkylene chain, wherein said X is optionally substituted by one or more ═O, ═S, —S(O)t—, alkyl, or halogen and wherein said C1-5 alkylene chain may optionally have 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen;

Ring A is a saturated, partially saturated or aromatic 3-7 monocyclic or 8-10 membered bicyclic ring having one ring nitrogen and 0-4 additional heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen;

Ring B has an oxygen atom in addition to the depicted nitrogen;

R1 is alkyl optionally substituted by one or more R7, alkenyl optionally substituted by one or more R7, alkynyl optionally substituted by one or more R7, cycloalkyl optionally substituted by one or more R8, heterocyclyl optionally substituted by one or more R8, heteroaryl optionally substituted by one or more R6, or aryl optionally substituted by one or more R6; or R1 and X taken together form a saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen that is fused to Ring A;

each R2 is independently selected from —OR0, —C(O)—R0, —S(O)2—R0, —C(O)—N(R0)2, —S(O)2—N(R0)2, —(CH2)a—N(R0)(—Vb—R+), —(CH2)a—(—Vb—R+), halogen, alkyl optionally substituted by one or more R7, alkenyl optionally substituted by one or more R7, alkynyl optionally substituted by one or more R7, aryl optionally substituted by one or more R6, heteroaryl optionally substituted by one or more R6, cycloalkyl optionally substituted by one or more R8, or heterocyclyl optionally substituted by one or more R8; and two adjacent R2s on Ring A are optionally taken together to form a fused, saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen; or two geminal R2s are optionally taken together to form a spiro, saturated, partially saturated or aromatic 5-6 membered ring having 0-3 heteroatoms selected from oxygen, phosphorus, sulfur, or nitrogen, said fused or spiro ring being optionally substituted by one or more R8;

each a independently is 0-3;

each b independently is 0 or 1;

V is —C(O)—, —C(O)O—, —S(O)2—, or —C(O)—N(R0)—;

R+ is alkyl, cycloalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, or heterocyclyl, wherein said R+ is optionally substituted by one or more R8;

m is 0 or 1;

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