Substituted cyanoguanidines as oral anti-virals

Patent metadata

Field	Value
Publication number	US-10112911-B2
Application number	US-201314410952-A
Country	US
Kind code	B2
Filing date	Jun 28, 2013
Priority date	Jun 28, 2012
Publication date	Oct 30, 2018
Grant date	Oct 30, 2018

Abstract

This disclosure relates to: (a) compounds and salts of formula (I), formula (II), formula (III), and formula (IV), that, inter alia, inhibit RSV infection and/or replication; (b) intermediates useful for the preparation of such compounds and salts; (c) compositions comprising such compounds and salts; (d) methods for preparing such intermediates, compounds, salts, and compositions; (e) methods of use of such compounds, salts, and compositions; and (f) kits comprising such compounds, salts, and compositions.

First claim

What is claimed is:

1. A compound having formula (I), or a pharmaceutically acceptable salt thereof,

wherein:
Ar 1 is phenyl or monocyclic heteroaryl having a structure corresponding to a formula selected from the group consisting of:

wherein R 1A is selected from the group consisting of hydrogen; amino; hydroxy; cyano; fluoro; chloro; bromo; iodo; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; C 1 -C 6 alkoxy; haloalkyl; haloalkoxy; oxoalkyl; alkylamino; dialkylamino; alkoxyalkyl; aminoalkyl; N-alkylaminoalkyl; N,N-dialkylaminoalkyl; -L 1 -C(O)—OR 1′ or -L 1 -S(O) 2 R 1′ , wherein L 1 is a bond or alkylene, and R 1′ is hydrogen, C 1 -C 6 alkyl or hydroxyalkyl; -L 2 -O—C(O)—R 2′ , wherein L 2 is a bond or alkylene, and R 2′ is C 1 -C 6 alkyl or hydroxyalkyl; -L 3 -C(O)—NR 3′ R 4′ , wherein L 3 is a bond or alkylene, and R 3′ and R 4′ are each independently selected from the group consisting of hydrogen, alkyl, and hydroxyalkyl; and -L 4 -NR 5′ —C(O)—R 6′ , wherein L 4 is a bond or alkylene, R 5′ is hydrogen or alkyl, and R 6′ is alkyl or hydroxyalkyl; sulfamoyl; N-(alkyl)sulfamoyl; N,N-(dialkyl)sulfamoyl; sulfonamide; alkylthio; and thioalkyl;
R 1B , R 1C , R 1D and R 1E are each independently selected from the group consisting of hydrogen, cyano, halo, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, haloalkoxy, and haloalkyl;
X 1A is CR 1AX or N; X 1B is CR 1BX or N; X 1C is CR 1CX or N; X 1D is CR 1DX or N and X 1E is CR 1EX or N respectively; wherein 1, 2 or 3 of X 1A , X 1B , X 1C , X 1D and X 1E are N; wherein R 1AX is C 1 -C 6 alkyl; and
one of X 1B and X 1D is N, and the other is CR 1BX or CR 1DX , respectively, wherein R 1BX and R 1DX are each hydrogen; and R 1CX and R 1EX are each hydrogen;
Y 1A is CR 1AY , NR 1AY , N, O or S; Y 1B is CR 1BY , NR 1BY , N, O or S; Y 1C is CR 1CY , NR 1CY , N, O or S; and Y 1D is CR 1DY , NR 1DY , N, O or S respectively; wherein 0, 1, 2, 3 or 4 of Y 1A , Y 1B , Y 1C , and Y 1D are NR 1AY , NR 1BY , NR 1CY , or NR 1DY , respectively or N; wherein 0 or 1 of Y 1A , Y 1B , Y 1C and Y 1D is O or S; Y 1E is N or C; wherein 1, 2, 3, or 4 of Y 1A , Y 1B , Y 1C , Y 1D , and Y 1E , is NR 1AY , NR 1BY , NR 1CY , NR 1DY , N, O or S;
R 1AY , R 1BY , R 1CY , and R 1DY are each independently selected from the group consisting of hydrogen; amino; hydroxy; cyano; halo; C 1 -C 6 alkyl; C 2 -C 5 alkenyl; C 2 -C 6 alkynyl; haloalkyl; haloalkoxy; oxoalkyl; alkoxy; alkylamino; dialkylamino; alkoxyalkyl; aminoalkyl; N-alkylaminoalkyl; N,N-dialkylaminoalkyl; -L 1 -C(O)—OR 1′ or -L 1 -S(O) 2 R 1′ , wherein L 1 is a bond or alkylene, and R 1′ is hydrogen, C 1 -C 6 alkyl or hydroxyalkyl; -L 2 -O—C(O)—R 2′ , wherein L 2 is a bond or alkylene, and R 2′ is C 1 -C 6 alkyl or hydroxyalkyl; -L 1 -C(O)—NR 3′ R 4′ , wherein L 3 is a bond or alkylene, and R 3′ and R 4′ are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and hydroxyalkyl; and -L 4 -NR 5′ —C(O)—R 6′ , wherein L 4 is a bond or alkylene, R 5 is hydrogen or C 1 -C 6 alkyl, and R 6′ is C 1 -C 6 alkyl or hydroxyalkyl; sulfamoyl; N-(alkyl)sulfamoyl; N,N-(dialkyl)sulfamoyl; sulfonamide; alkylthio; and thioalkyl;
L A is bond;
R 1 is selected from the group consisting of:

wherein R 2 , and R 3 are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, haloalkyl, alkynyl, oxoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, N-alkylaminoalkyl, N,N-dialkylaminoalkyl, thioalkyl, G 1 , G 2 , and G 2 -alkyl-; wherein
when both R 2 and R 3 are present, one or both of R 2 and R 3 are hydrogen;
G 1 is aryl or heteroaryl, and G 2 is C 3 -C 6 cycloalkyl, wherein the aryl, the heteroaryl and the C 3 -C 6 cycloalkyl are optionally substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —O—R f , —CN, —N(R f )C(O)R f , —CON(R e )(R f ), —C(O)R f , —OC(O)R f , —CO 2 R f , —N(R f )C(O)N(R f ) 2 , —S—R f , —S(O) 2 R f , —S(O)R f , —SO 2 N(R e )(R f ), —N(R e )(R f ), —N(R f )S(O) 2 R f , N(R f )C(O)O(R f ), -L c -O—R f , -L c -CN, -L c -N(R f )C(O)R f , -L 1 -CON(R e )(R f ), -L c -C(O)R f , -L c -OC(O)R f , -L c -CO 2 H, -L c -CO 2 R f , -L c -N(R f )C(O)N(R f ) 2 , -L c -S—R f , -L c -S(O) 2 R f , -L c -S(O)R f , - L c -SO 2 N(R e )(R f ), -L c -N(R e )(R f ), -L c -N(R f )S(O) 2 R f , and -L c -N(R f )C(O)O(R f );
L c , at each occurrence, is independently C 1 -C 6 alkylene or C 3 -C 8 cycloalkyl, wherein L c at each occurrence, is optionally substituted with 1, 2, 3, or 4 halogen or 1 or 2 hydroxy;
R e , at each occurrence, is independently selected form the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 3 -C 8 cycloalkyl, wherein the C 3 -C 8 cycloalkyl is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of halogen, oxo, C 1 -C 3 alkyl, and C 1 -C 3 haloalkyl;
R f , at each occurrence, is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;
Ar 2 is selected from the group consisting of:

wherein for (iii-3), R 4 and R 5 , taken together with the atoms to which they are attached, form a fused phenyl optionally substituted with 1, 2, or 3 C 1 -C 6 alkyl, halo, or haloC 1 -C 6 alkyl; and R 7 is hydrogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl;
wherein for (iii-4), R 6 and R 7 , taken together with the atoms to which they are attached, form a fused phenyl or pyrrolyl;
wherein for (iii-8), R 4 and R 5 , taken together with the atoms to which they are attached, form a fused phenyl, pyridinyl, or pyrazinyl, each optionally substituted with 1, 2, or 3 C 1 -C 6 alkyl, halo, or haloC 1 -C 6 alkyl; and R 6 and R 7 are independently hydrogen, C 1 -C 6 alkyl, or haloC 1 -C 6 alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1A is selected from a group consisting of hydrogen, fluoro, chloro, bromo, iodo, haloalkyl and haloalkoxy; and
R 1B , R 1C , R 1D and R 1E are each independently selected from a group consisting of hydrogen, halo and haloalkyl.

3. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more excipients, and optionally one or more additional therapeutic agents.

4. A compound having formula (I), or a pharmaceutically acceptable salt thereof,

wherein:
Ar 1 is monocyclic heteroaryl having a structure corresponding to a formula selected from the group consisting of:

X 1A is CR 1AX or N; X 1B is CR 1BX or N; X 1C is CR 1CX or N; X 1D is CR 1DX or N; and X 1E is CR 1EX or N; wherein 1, 2 or 3 of X 1A , X 1B , X 1C , X 1D and X 1E are N; wherein
R 1AX is selected from the group consisting of hydrogen; amino; hydroxy; cyano; halo; C 1 -C 6 alkyl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; haloalkyl; haloalkoxy; oxoalkyl; alkoxy; alkylamino; dialkylamino; alkoxyalkyl; aminoalkyl; N-alkylaminoalkyl; N,N-dialkylaminoalkyl; -L 1 -C(O)—OR 1′ or -L 1 -S(O) 2 R 1′ , wherein L 1 is a bond or alkylene

Assignees

• Abbvie Inc
• Abbvie Inc

Inventors

• Gomtsian Artour
• Dekhtyar Tatyana
• Frank Kristine E
• Friedman Michael M
• Josephsohn Nathan
• Molla M-Akhteruzzaman
• Vasudevan Anil
• Ng Iok Chan
• Chafeev Mikhail

Classifications

• A61P31/14

  for RNA viruses · CPC title

• C07D417/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D241/44

  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 carbon atoms of the hetero ring · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/499

  Spiro-condensed pyrazines or piperazines · CPC title