ASH1L inhibitors and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-11147885-B2
Application number	US-202016854527-A
Country	US
Kind code	B2
Filing date	Apr 21, 2020
Priority date	Nov 10, 2017
Publication date	Oct 19, 2021
Grant date	Oct 19, 2021

Abstract

Provided herein are small molecules that bind to ASH1L and inhibit ASH1L activity, and methods of use thereof for the treatment of disease, including acute leukemia, solid cancers and other diseases dependent on activity of ASH1L.

First claim

The invention claimed is:

1. A compound comprising the structure of:

wherein X, when present, is CH or N;
wherein R 1 is selected from H, alkyl, substituted alkyl, branched alkyl, a substituted branched alkyl, alkoxy, amine, substituted amine, thioalkyl, ketone, amide, a substituted amide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, a carbocyclic ring, s substituted carobocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof;
wherein R 2 , R 3 , R 4 , R 5 , and R 7 , when present, are independently selected from H, halogen, CH 3 , OH, SH, NH 2 , CN, CF 3 , CCl 3 , —CH 2 —CH 3 , —CH 2 —OH, —CH 2 NH 2 , —C(O)NH 2 , CH 3 SH, CH 2 C 1 , CH 2 Br, CH 2 F, CHF 2 , CH 2 CN, CH 2 CF 3 , CH 2 Cl 3 , alkyl, haloalkyl, and alcohol; and
wherein R 6 is selected from H, alkyl, substituted alkyl, hydroxy, alkoxy, amine, substituted amine, alkylamine, substituted alkylamine, thioalkyl, halogen, ketone, amide, substituted amide, alkylamide, substituted alkylamide, cyano, sulfonyl, carboxy, dialkylphosphine oxide, a carbocyclic ring, a substituted carbocyclic ring, an aromatic ring, a substituted aromatic ring, a heterocyclic aromatic ring, a substituted heterocyclic aromatic ring, a substituted or non-substituted heterocyclic non-aromatic ring, carbocyclic or heterocyclic aromatic ring fused to another aromatic ring, a hydrogen bond donor, a hydrogen bond acceptor, and combinations thereof;
or a salt thereof.

2. The compound of claim 1 , wherein said compound is selected from Compounds 21-85.

3. The compound of claim 1 , wherein R 1 , R 2-5 , R 6 , R 7 , and X, when present, are independently selected from the R 1 , R 2-5 , R 6 , R 7 , and X, groups of compounds 21-85, in any combination.

4. A pharmaceutical composition comprising a compound of claim 1 .

5. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is formulated for oral administration.

6. The pharmaceutical composition of claim 4 , wherein the pharmaceutical composition is formulated for injection.

7. A method of inhibiting ASH1L, comprising contacting ASH1L with an effective amount of a compound of claim 1 .

8. The method of claim 7 , wherein ASH1L activity is inhibited by binding of the compound or pharmaceutical composition to ASH1L.

9. A method of treating leukemia, hematologic malignancy, or a solid tumor cancer, comprising administering to a subject the pharmaceutical composition of claim 4 in an amount effective to inhibit the activity of ASH1L.

10. The method of claim 9 , wherein the solid tumor cancer is selected from breast cancer, prostate cancer, ovarian cancer, liver cancer or thyroid cancer.

11. The method of claim 10 , wherein the leukemia is selected from AML, ALL, Mixed Lineage Leukemia or a leukemia with Partial Tandem Duplication of MLL.

12. The method of claim 9 , wherein the pharmaceutical composition is co-administered with an additional therapeutic.

13. The method of claim 9 , wherein the subject is a human.

14. A compound of claim 1 , comprising the structure of:

wherein X, when present, is CH or N;
wherein R 2 -R 5 , when present, are independently selected from: H, halogen, OH, CH 3 , NH 2 , CH 2 CH 3 ;
wherein R 7 , when present, is H or halogen; and
wherein R 1 and R 6 are independently selected from one of Formulas (a-q):

wherein each J, J 1 , J 2 , J 3 , and J 4 , when present, are independently selected from the group consisting of: a covalent bond, H, alkyl 1-15 , alkenyl 1-6 , alkynyl 1-6 , (CH 2 ) 0-6 C(S)NH 2 , (CH 2 ) 0-6 C(O)NH 2 , O, S, NH, (CH 2 ) 0-6 C(O)NH(CH 2 ) 1-6 , (CH 2 ) 0-6 NHC(O)(CH 2 ) 1-6 , alkylsulfonyl, sulfonamide, alkyl sulfonamide, (CH 2 ) 0-6 C(S)NH(CH 2 ) 1-6 , (CH 2 ) 0-6 O(CH 2 ) 1-6 , (CH 2 ) 0-6 OH, (CH 2 ) 0-6 S(CH 2 ) 1-6 , (CH 2 ) 0-6 SH, (CH 2 ) 0-6 NH(CH 2 ) 1-6 , (CH 2 ) 0-6 N(CH 2 ) 1-6 (CH 2 ) 1-6 , (CH 2 ) 0-6 NH 2 , (CH 2 ) 0-6 SO 2 (CH 2 ) 1-6 , (CH 2 ) 0-6 NHSO 2 (CH 2 ) 1-6 , (CH 2 ) 0-6 SO 2 NH 2 , halogen, haloalkyl, dihaloalkyl, trihaloalkyl, alkyl with 1-3 halogens at two or more positons along its length, (CH 2 ) 1-4 SP(Ph) 2 ═S, (CH 2 ) 0-6 NH(CH 2 ) 1-5 OH, (CH 2 ) 0-6 NH(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 NH(CH 2 ) 1-5 SH, (CH 2 ) 0-6 O(CH 2 ) 1-5 OH, (CH 2 ) 0-6 O(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 O(CH 2 ) 1-5 SH, (CH 2 ) 0-6 S(CH 2 ) 1-5 OH, (CH 2 ) 0-6 S(CH 2 ) 1- 5 NH 2 , (CH 2 ) 0-6 S(CH 2 ) 1-5 SH, (CH 2 ) 0-6 O(CH 2 ) 1-6 NH(CH 2 ) 1-5 OH, (CH 2 ) 0-6 O(CH 2 ) 1-6 NH(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 O(CH 2 ) 1-6 NH(CH 2 ) 1-5 SH, (CH 2 ) 0-6 O(CH 2 ) 1-6 O(CH 2 ) 1-5 OH, (CH 2 ) 0-6 O(CH 2 ) 1-6 O(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 O(CH 2 ) 1-6 O(CH 2 ) 1-5 SH, (CH 2 ) 0-6 O(CH 2 ) 1-6 S(CH 2 ) 1-5 OH, (CH 2 ) 0-6 O(CH 2 ) 1-6 S(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 O(CH 2 ) 1-6 S(CH 2 ) 1-5 SH, (CH 2 ) 0-6 S(CH 2 ) 1-6 NH(CH 2 ) 1-5 OH, (CH 2 ) 0-6 S(CH 2 ) 1-6 NH(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 S(CH 2 ) 1-6 NH(CH 2 ) 1-5 SH, (CH 2 ) 0-6 S(CH 2 ) 1-6 O(CH 2 ) 1- 5 OH, (CH 2 ) 0-6 S(CH 2 ) 1-6 O(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 S(CH 2 ) 1-6 O(CH 2 ) 1-5 SH, (CH 2 ) 0-6 S(CH 2 ) 1-6 S(CH 2 ) 1-5 OH, (CH 2 ) 0-6 S(CH 2 ) 1-6 S(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 S(CH 2 ) 1-6 S(CH 2 ) 1-5 SH, (CH 2 ) 0-6 NH(CH 2 ) 1- 6 NH(CH 2 ) 1-5 OH, (CH 2 ) 0-6 NH(CH 2 ) 1-6 NH(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 NH(CH 2 ) 1-6 NH(CH 2 ) 1-5 SH, (CH 2 ) 0-6 NH(CH 2 ) 1-6 O(CH 2 ) 1-5 OH, (CH 2 ) 0-6 NH(CH 2 ) 1-6 O(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 NH(CH 2 ) 1-6 O(CH 2 ) 1-5 SH, (CH 2 ) 0-6 NH(CH 2 ) 1-6 S(CH 2 ) 1-5 OH, (CH 2 ) 0-6 NH(CH 2 ) 1-6 S(CH 2 ) 1-5 NH 2 , (CH 2 ) 0-6 NH(CH 2 ) 1- 6 S(CH 2 ) 1-5 SH, (CH 2 ) 0-3 C(O)O(CH 2 ) 0-3 , (CH 2 ) 0-3 C(S)O(CH 2 ) 0-3 , (CH 2 ) 0-3 C(O)S(CH 2 ) 0-3 , (CH 2 ) 0-3 C(S)S(CH 2 ) 0-3 , (CH 2 ) 0-3 C(O)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 C(S)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(O)(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(S)(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(O)(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(S)(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(O)(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(S)(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(O)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(S)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(O)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(S)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(O)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(S)NH(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(O)O(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(S)O(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(O)O(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(S)O(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(O)O(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(S)O(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(O)S(CH 2 ) 0-3 , (CH 2 ) 0-3 NHC(S)S(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(O)S(CH 2 ) 0-3 , (CH 2 ) 0-3 OC(S)S(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(O)S(CH 2 ) 0-3 , (CH 2 ) 0-3 SC(S)S(CH 2 ) 0-3 , (CH 2 O) 1-6 , and trimethyl methane;
wherein each Q, Q 1 , and Q 2 , when present, is independently selected from the group consisting of: furan, benzofuran, isobenzofuran, pyrrole, indole, isoindole, thiophene, benzothiophene, benzo[c]thiophene, imidazole, benzimidazole, purine, pyrazole, indazole, oxazole, benzooxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, benzene, napthalene, pyridine, quinolone, isoquinoline,

Assignees

• Univ Michigan Regents

Inventors

• Grembecka Jolanta
• Klossowski Szymon
• Deng Jing
• Cierpicki Tomasz
• Li Hao
• Miao Hongzhi
• Purohit Trupta
• Kim Eungi

Classifications

• A61K31/454 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K38/45

  Transferases (2) · CPC title

• C12Y203/02

  Aminoacyltransferases (2.3.2) · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title