Heterocyclic antiestrogens

Patent metadata

Field	Value
Publication number	US-10865199-B2
Application number	US-201615770824-A
Country	US
Kind code	B2
Filing date	Oct 26, 2016
Priority date	Oct 27, 2015
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

Abstract

The present invention provides novel heterocyclic compounds as anticancer agents, especially as estrogen receptor (ER) antagonists/degraders and process for their preparation.

First claim

The invention claimed is:

1. A compound of Formula I

or salts or stereoisomers thereof wherein,
R 1 is mono or di-substitution on ring A and is selected from a group consisting of, —OR 3 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 3 ) 2 ,—NR 3 SO 2 R 3 , —NR 3 CHO, —NR 3 COR 3 , —OC(O)R 3 , —OC(O)N(R 3 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 3 wherein R 3 at each occurrence is selected from hydrogen, C 1-6 linear, branched or cyclic alkyl and C 1-6 linear, branched or cyclic haloalkyl;
R 2 is mono or di-substitution and is a halogen;
R 4 is selected from hydrogen and —C 1-5 alkyl;
L is selected from C 1-7 linear or branched alkyl;
R 7 and R 8 are absent or independently selected from hydrogen and C 1-5 alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 5 membered ring optionally containing 1 to 2 additional heteroatoms selected from oxygen, nitrogen or sulfur; and the ring is optionally substituted with one or more group selected from halogen, —OR 6 , —N(R 6 ) 2 and R 6 wherein R 6 , at each occurrence is selected from a group comprising hydrogen, C 1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR 5 —, —S—, —SO—,—S(O) 2 —, —CR 5 ═CR 5 —, —C≡C—, —NR 5 CO—, —CONR 5 —, —NR 5 CONR 5 —, NR 5 C(O)O— and —OC(O)O—;
optionally, R 6 is further substituted with one or more groups selected from a group comprising halogen, —OR 12 , —N(R 12 ) 2 , and —COOR 12 , —CON(R 12 ) 2 or —CON(R 12 )OH; wherein R 12 at each occurrence is selected from hydrogen or C 1-6 linear, branched or cyclic alkyl;
is a double or a triple bond;
R 13 is selected from a group comprising —R 14 , —OR 14 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 14 ) 2 , —NR 14 SO 2 R 14 , —NR 14 CHO, —NR 14 COR 14 , —OC(O)R 14 , —OC(O)N(R 14 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 14 wherein R 14 at each occurrence is selected from hydrogen, and C 1-6 linear, branched or cyclic alkyl; and
X is oxygen.

2. The compound of claim 1 wherein, R 1 is selected from OH, OR 3 and —OC(O)R 3
R 4 is C 1-5 alkyl;
L is selected from C 1-4 alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4-5 membered ring optionally containing 1 or 2 additional nitrogen atoms and the ring is optionally substituted with one or more group selected from halogen, —OR 6 , —N(R 6 ) 2 and R 6 ; wherein R 6, at each occurrence is selected from hydrogen and C 1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals selected from —O—, —NR 5 —, —S— and —CR 5 ═CR 5 —;
optionally, R 6 is further substituted with one or more groups selected from halogen, —OR 12 and —N(R 12 ) 2 ;
is a double or a triple bond; and
R 7 and R 8 are hydrogen or absent;
R 13 is a group selected from hydrogen, halogen and —C 1-6 haloalkyl; and
X is oxygen.

3. The compound of claim 1 wherein R 2 is substituted at position 3 of ring C and R 1 is substituted at position 7 of the ring A.

4. A compound of Formula I

or salts or stereoisomers thereof wherein,
R 1 is mono or di-substitution on ring A and is selected from a group consisting of —OR 3 , halogen, —C 1-6 haloalkyl, —OC 1-6 haloalkyl, —CN, —N(R 3 ) 2 , —NR 3 SO 2 R 3 , —NR 3 CHO, —NR 3 COR 3 , —OC(O)R 3 , —OC(O)N(R 3 ) 2 , —OP(O)(OH) 2 and —OC(O)OR 3 wherein R 3 at each occurrence is selected from hydrogen, and C 1-6 linear or branched alkyl;
R 2 is mono or di-substitution and is a halogen;
R 4 is —C 1-5 alkyl;
L is selected from C 1-4 linear or branched alkyl;
R 7 and R 8 are independently selected from hydrogen and C 1-5 alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 5 membered ring optionally containing 1 to 2 additional heteroatoms selected from oxygen, nitrogen or sulfur; and the ring is optionally substituted with one or more group selected from halogen, —OR 6 , —N(R 6 ) 2 and R 6 wherein R 6 , at each occurrence is selected from a group comprising hydrogen, C 1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR 5 —, —S—, —SO—, —S(O) 2 —, —CR 5 ═CR 5 —, —C≡C—, —NR 5 CO—, —CONR 5 —, —NR 5 CONR 5 —, —NR 5 C(O)O— and —OC(O)O—;
optionally, R 6 is further substituted with one or more groups selected from a group comprising halogen, —OR 12 , —N(R 12 ) 2 , and —COOR 12 , —CON(R 12 ) 2 or —CON(R 12 )OH; wherein R 12 at each occurrence is selected from hydrogen or C 1-6 linear, branched or cyclic alkyl;
is a double bond;
R 13 is selected from a group consisting of hydrogen, halogen, —C 1-6 haloalkyl and —C 1-6 alkyl; and
X is oxygen.

5. The compound of claim 4 wherein, R 1 is selected from OH, —OR 3 , —OC 1-6 haloalkyl and —OC(O)R 3 , wherein R 3 is C 1-6 linear or branched alkyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 5 membered ring optionally containing 1 additional heteroatom selected from oxygen, nitrogen and sulfur and the ring is optionally substituted with one or more groups selected from halogen, —N(R 6 ) 2 and R 6 ; wherein R 6 , at each occurrence is independently selected from hydrogen and C 1-15 linear or branched alkyl;
optionally, R 6 is further substituted with one or more groups selected from halogen and —OR 12 ; wherein R 12 is hydrogen;
R 7 and R 8 are hydrogen; and
R 13 is a group selected from hydrogen and halogen.

6. The compound of claim 4 wherein R 2 is substituted at position 3 of ring C and R 1 is substituted at position 7 of the ring A.

7. The compound of claim 4 , wherein
R 1 is a monosubstitution and is —OH;
R 2 is a di-substitution;
R 4 is methyl;
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4 to 5 membered ring optionally containing 1 additional nitrogen atom and the ring is optionally substituted with one or more groups selected from halogen, —N(R 6 ) 2 and R 6 ;
wherein R 6 , at each occurrence is selected from hydrogen and C 1-10 linear or branched alkyl;
optionally, R 6 is further substituted with one or more groups selected from halogen and —OR 12 ; wherein R 12 is hydrogen.

8. The compound of claim 4 , wherein
R 1 is a monosubstitution and is —OH;
R 2 is a di-substitution;
R 7 and R 8 are hydrogen;
R 13 is hydrogen;
R 4 is methyl;
L is C 1-3 linear alkyl; and
R 9 and R 10 together with the nitrogen atom to which they are attached forms a 4-5 membered ring wherein the ring is substituted with R 6 ; wherein R 6 , is selected from C 1-3 linear alkyl and wherein R 6 is further substituted with halogen.

9. The compound of claim 8 wherein R 2 is fluoro.

Assignees

• Sun Pharma Advanced Res Co Ltd

Inventors

• Pal Ranjan Kumar
• Sedani Amit Pravinbhai
• Prajapati Kaushikkumar Dhanjibhai
• Rana Dijixa Pinakin
• Pathak Sandeep Pankajbhai
• Desai Japan Nitinkumar
• Aradhye Jayraj Dilipbhai
• Panchal Bhavesh Mohanbhai
• Ghosh Indraneel
• Chitturi Trinadha Rao

Classifications

• A61K31/47

  Quinolines; Isoquinolines · CPC title

• A61K31/382

  having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496) · CPC title

• A61K31/352

  condensed with carbocyclic rings, e.g. methantheline  {(cannabinoids A61K31/658)} · CPC title

• C07D405/10 Primary

  linked by a carbon chain containing aromatic rings · CPC title

• C07D335/06

  Benzothiopyrans; Hydrogenated benzothiopyrans · CPC title