# US 7,608,632 B2 · Sulfonamide inhibitors of aspartyl protease

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- Number: US 7,608,632 B2
- Document ID: US7608632B2
- Status: Granted
- Kind: B2
- Application number: 11/408,287
- Filed: 2006-04-19
- Published: 2006-08-24
- Granted: 2009-10-27
- Earliest claimed: 1992-09-08
- Assignees: Vertex Pharmaceuticals Incorporated
- Inventors: Roger D. Tung; Mark A. Murcko; Govinda R. Bhisetti
- Web page: https://patentgrep.com/patent/US7608632B2

## CPC

- C07D 207/26: 2-Pyrrolidones
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- C07C 307/06: having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
- C07C 311/13: the carbon skeleton containing six-membered aromatic rings
- C07C 311/18: to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C 311/29: having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/39: having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
- C07C 311/46: Y being a hydrogen or a carbon atom
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 213/30: Oxygen atoms
- C07D 213/78: Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 215/38: Nitrogen atoms (nitro radicals C07D215/18)
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 239/22: with hetero atoms directly attached to ring carbon atoms
- C07D 263/24: with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
- C07D 271/08: 1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
- C07D 277/36: Sulfur atoms
- C07D 307/12: Radicals substituted by oxygen atoms
- C07D 307/20: Oxygen atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07K 5/06139: {with the first amino acid being heterocyclic}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07C 2601/02: with a three-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

## Claims

### Claim 1

A compound of formula I:
wherein:
A is selected from the group consisting of —R1—C1-C6 alkyl substituted with one or more groups selected from the group consisting of —O-HetA;
each R1 is independently selected from the group consisting of —C(O);
each HetA is independently selected from the group consisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; and C6-C10 aryl; and wherein any member of said HetA may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —R2—OH, —CN, —CO2R2, —C(O)—N(R2)(R2), —S(O)2—N(R2)(R2), —N(R2)—C(O)—R2, —C(O)—R2, —S(O)n—R2, —OCF3, —S(O)n—Ar, methylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Ar and —O—Ar;
each R2 is independently selected from the group consisting of H and C1-C3 alkyl;
B, when present, is —N(R2)—C(R3)(R3)—C(O)—;
x is 0;
each R3 is independently selected from the group consisting of H, Het, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl and C5-C6 cycloalkenyl, wherein any member of said R3, except H, may be optionally substituted with one or more substituents selected from the group consisting of —OR2, —C(O)—NH—R2, —S(O)n—N(R2)(R2), Het, —CN, —SR2, —CO2R2, NR2—C(O)—R2;
each n is independently 1 or 2;
D is C1-C4 alkyl substituted with Ar;
D′ is C1-C4 alkyl, which may be optionally substituted with one or more groups selected from C3-C6 cycloalkyl, —OR2, —R3, —O—Ar and Ar; C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, —OR2, —R3, —O—Ar and Ar; C3-C6 cycloalkyl, which may be optionally substituted with or fused with Ar; and C5-C6 cycloalkenyl, which may be optionally substituted with or fused with Ar;
each Ar is independently selected from the group consisting of phenyl; and 3-6 membered carbocyclic ring, wherein said carbocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —N(R2)—C(O)—R2, C1-C3 alkyl substituted with —OH and optionally substituted with Ar, —CN, —CO2R2, —C(O)—N(R2)(R2), halo and —CF3;
E is Het; and
each Het is independently selected from the group consisting of 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), and O wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —R2—OH, —CN, —CO2R2, —C(O)—N(R2)(R2), —S(O)2—N(R2)(R2), —N(R2)—C(O)—R2, —C(O)—R2, —S(O)n—R2, —OCF3, —S(O)n—Ar, methylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Ar and —O—Ar.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein said compound has the structure of formula XXII:
and A, D′ and E are defined as in claim 1.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein:
A is —R1—C1-C6 alkyl substituted with one or more groups selected from —O-HetA;
each R1 is —C(O)—;
each HetA is independently selected from the group consisting of C3-C7 cycloalkyl; C5-C7 cycloalkenyl; C6-C10 aryl; wherein any member of said HetA may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR2, —R2, —N(R2)2, —R2—OH, —CN, —CO2R2, —C(O)—N(R2)2 and —S(O)2—N(R2)2;
each R2 is independently selected from the group consisting of H and C1-C3 alkyl;
B, when present, is —NH—CH(R3)—C(O)—;
x is 0;
R3 is selected from the group consisting of Ret, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl and C5-C6 cycloalkenyl, wherein any member of said R3 may be optionally substituted with one or more substituents selected from the group consisting of —OR2, —C(O)—NH—R2, —S(O)—N(R2)2, Het and —CN;
n is 1 or 2;
D is C1-C4 alkyl substituted with Ar;
D′ is C1-C4 alkyl, which may be optionally substituted with C3-C6 cycloalkyl or Ar; C2-C4 alkenyl, which may be optionally substituted with C3-C6 cycloalkyl or Ar; C3-C6 cycloalkyl, which may be optionally substituted or fused with Ar; and C5-C6 cycloalkenyl, which may be optionally substituted or fused with Ar;
Ar is selected from the group consisting of phenyl; 3-6 membered carbocyclic ring, wherein said carbocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, —OR2, —R2, —N(R2)2, —N(R2)—C(O)R2, C1-C3 alkyl substituted with —OH and optionally substituted with Ar, —CN, —CO2R2, —C(O)—N(R2)2, halo and —CF3;
E is Het;
each Het is independently selected from the group consisting of 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), and O wherein said heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —R2—OH, —CN, —CO2R2, —C(O)—N(R2)(R2), —S(O)2—N(R2)(R2), —N(R2)—C(O)—R2, —C(O)—R2, —S(O)—R2, —OCF3, —S(O)n—Ar, methylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Ar and —O—Ar.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein said compound has a molecular weight less than or equal to about 700 g/mol.

### Claim 5 (depends on 4)

A compound according to claim 4, wherein said compound has a molecular weight less than or equal to about 600 g/mol.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant or vehicle.