Cycloalkenyl hydroxamic acid derivatives and their use as histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-9914717-B2
Application number	US-201314654296-A
Country	US
Kind code	B2
Filing date	Dec 19, 2013
Priority date	Dec 20, 2012
Publication date	Mar 13, 2018
Grant date	Mar 13, 2018

Abstract

The present invention provides compounds of formula (I) or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein W, X, n, s, t, and Ra are as described herein. The present invention relates generally to selective inhibitors of histone deacetylase and to methods of making and using them.

First claim

What is claimed:

1. A compound of formula I:

or a pharmaceutically acceptable salt or tautomer thereof, wherein:
n is 0, 1, 2, 3, 4, or 5;
t is 0, 1, 2, 3, 4, or 5, provided that at least one of n and t is not 0;
s is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
X is O;
W is CR e ;
R e is hydrogen, OH, C 1 -C 4 alkyl, or halogen;
z is 0, 1, or 2;
each R a is independently selected from halogen, CN, CF 3 , OR f , OCF 3 , C(O)R g , C 1 -C 8 alkoxyl, NR h R i , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, unsubstituted (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 1 ;
or R e is attached to R a to form a fused ring, wherein said fused ring is selected from C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3 to 10-membered, saturated or unsaturated heterocyclic ring, 6 to 10-membered aromatic ring, and 3 to 10-membered heteroaromatic ring, wherein said fused ring is unsubstituted or substituted with one or more R 2 ;
each R g is selected from hydrogen, OR L , NR m R o , CF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 3 ;
each one of R f , R h , R i , R j , R L , R m , and R o is independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C(O)R p , S(O) z R jj , (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 4 ;
each one of R p and R jj is independently selected from OR q , NR r R u , CF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 5 ;
each one of R q , R r , and R u is independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 6 ;
each one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 is independently selected from halogen, CF 3 , OCF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OC 1 —C 8 alkyl, NH 2 , NHC 1 —C 8 alkyl, N(C 1 -C 8 alkyl) 2 , C(O)NR v R y , C(O)R aa , C(O)OR bb , and (CH 2 ) k -6 to 10-membered aromatic ring, wherein said aromatic ring is unsubstituted or substituted with one or more R 7 ;
each one of R v , R y , R aa , and R bb is independently selected from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, aromatic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 7 ;
each R 7 is independently selected from halogen, CF 3 , OCF 3 , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OC 1 —C 8 alkyl, NH 2 , NHC 1 —C 8 alkyl, and N(C 1 -C 8 alkyl) 2 ; and
k is 0, 1, 2, or 3.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein n is 0, 1, or 2, and t is 0, 1, 2, or 3, provided that at least one of n and t is not 0.

3. The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt or tautomer thereof, wherein:
R cc is selected from hydrogen, halogen, CN, CF 3 , OR f , OCF 3 , C(O)R g , C 1 -C 8 alkoxyl, NR h R i , SR j , C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (CH 2 ) k —C 3 -C 8 cycloalkyl, (CH 2 ) k —C 4 -C 8 cycloalkenyl, (CH 2 ) k -3 to 10-membered, saturated or unsaturated heterocyclic ring, unsubstituted (CH 2 ) k -6 to 10-membered aromatic ring, and (CH 2 ) k -3 to 10-membered heteroaromatic ring, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclic ring, and heteroaromatic ring are independently unsubstituted or substituted with one or more R 1 ; and
t′ is 0, 1, or 2;
or R cc is attached to R e to form a fused ring, wherein said fused ring is selected from C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3 to 10-membered, saturated or unsaturated heterocyclic ring, 6 to 10-membered aromatic ring, and 3 to 10-membered heteroaromatic ring, further wherein said fused ring is unsubstituted or substituted with one or more R 2 .

4. The compound of claim 3 , or a pharmaceutically acceptable salt or tautomer thereof, wherein
R cc is attached to R e to form a fused ring, wherein said fused ring is selected from C 3 -C 8 cycloalkyl, C 4 -C 8 cycloalkenyl, 3 to 10-membered, saturated or unsaturated heterocyclic ring, 6 to 10-membered aromatic ring, and 3 to 10-membered heteroaromatic ring, further wherein said fused ring is unsubstituted or substituted with one or more R 2 .

5. The compound of claim 1 , wherein the compound is of the formula:
or a pharmaceutically acceptable salt or tautomer thereof.

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

7. A method of treating a disease, disorder, or condition in a subject in need thereof comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, wherein the disease, disorder, or condition is leukemia, lymphoma, multiple myeloma, melanoma, breast cancer, ovarian cancer, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, rheumatoid arthritis, lupus, coeliac disease, scleroderma, psoriasis, inflammatory bowel diseases, arthritis, type I diabetes, or organ transplant rejection.

8. A kit containing one or more compounds of claim 1 , or a pharmaceutically acceptable salt or tauto

Assignees

• Broad Inst Inc

Inventors

• Holson Edward
• Lazzaro Fanny
• Olson David
• Wagner Florence Fevrier
• Weiwer Michel

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07C323/61

  having the sulfur atom of at least one of the thio groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton · CPC title