# US 10,865,199 B2 · Heterocyclic antiestrogens

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- Number: US 10,865,199 B2
- Document ID: US10865199B2
- Status: Granted
- Kind: B2
- Application number: 15/770,824
- Filed: 2016-10-26
- Published: 2018-12-13
- Granted: 2020-12-15
- Earliest claimed: 2015-10-27
- Assignees: Sun Pharma Advanced Research Company Ltd.
- Applicants: Sun Pharma Advanced Research Company Limited
- Inventors: Ranjan Kumar Pal; Amit Pravinbhai Sedani; Kaushikkumar Dhanjibhai Prajapati; Dijixa Pinakin Rana; Sandeep Pankajbhai Pathak; Japan Nitinkumar Desai; Jayraj Dilipbhai Aradhye; Bhavesh Mohanbhai Panchal; Indraneel Ghosh; Trinadha Rao Chitturi
- Web page: https://patentgrep.com/patent/US10865199B2

## CPC

- C07D 405/10: linked by a carbon chain containing aromatic rings
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/12: with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D 311/60: with aryl radicals attached in position 2
- C07D 335/06: Benzothiopyrans; Hydrogenated benzothiopyrans
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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

## Claims

### Claim 1

A compound of Formula I
or salts or stereoisomers thereof wherein,
R1 is mono or di-substitution on ring A and is selected from a group consisting of, —OR3, halogen, —C1-6 haloalkyl, —OC1-6 haloalkyl, —CN, —N(R3)2,—NR3SO2R3, —NR3CHO, —NR3COR3, —OC(O)R3, —OC(O)N(R3)2, —OP(O)(OH)2 and —OC(O)OR3 wherein R3 at each occurrence is selected from hydrogen, C1-6 linear, branched or cyclic alkyl and C1-6 linear, branched or cyclic haloalkyl;
R2 is mono or di-substitution and is a halogen;
R4 is selected from hydrogen and —C1-5 alkyl;
L is selected from C1-7 linear or branched alkyl;
R7 and R8 are absent or independently selected from hydrogen and C1-5 alkyl;
R9 and R10 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, —OR6, —N(R6)2 and R6 wherein R6, at each occurrence is selected from a group comprising hydrogen, C1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR5—, —S—, —SO—,—S(O)2—, —CR5═CR5—, —C≡C—, —NR5CO—, —CONR5—, —NR5CONR5—, NR5C(O)O— and —OC(O)O—;
optionally, R6 is further substituted with one or more groups selected from a group comprising halogen, —OR12, —N(R12)2, and —COOR12, —CON(R12)2 or —CON(R12)OH; wherein R12 at each occurrence is selected from hydrogen or C1-6 linear, branched or cyclic alkyl;
is a double or a triple bond;
R13 is selected from a group comprising —R14, —OR14, halogen, —C1-6 haloalkyl, —OC1-6 haloalkyl, —CN, —N(R14)2, —NR14SO2R14, —NR14CHO, —NR14COR14, —OC(O)R14, —OC(O)N(R14)2, —OP(O)(OH)2 and —OC(O)OR14 wherein R14 at each occurrence is selected from hydrogen, and C1-6 linear, branched or cyclic alkyl; and
X is oxygen.

### Claim 2 (depends on 1)

The compound of claim 1 wherein, R1 is selected from OH, OR3 and —OC(O)R3
R4 is C1-5 alkyl;
L is selected from C1-4 alkyl;
R9 and R10 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, —OR6, —N(R6)2 and R6; wherein R6, at each occurrence is selected from hydrogen and C1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals selected from —O—, —NR5—, —S— and —CR5═CR5—;
optionally, R6 is further substituted with one or more groups selected from halogen, —OR12 and —N(R12)2;
is a double or a triple bond; and
R7 and R8 are hydrogen or absent;
R13 is a group selected from hydrogen, halogen and —C1-6 haloalkyl; and
X is oxygen.

### Claim 3 (depends on 1)

The compound of claim 1 wherein R2 is substituted at position 3 of ring C and R1 is substituted at position 7 of the ring A.

### Claim 4

A compound of Formula I
or salts or stereoisomers thereof wherein,
R1 is mono or di-substitution on ring A and is selected from a group consisting of —OR3, halogen, —C1-6 haloalkyl, —OC1-6 haloalkyl, —CN, —N(R3)2, —NR3SO2R3, —NR3CHO, —NR3COR3, —OC(O)R3, —OC(O)N(R3)2, —OP(O)(OH)2 and —OC(O)OR3 wherein R3 at each occurrence is selected from hydrogen, and C1-6 linear or branched alkyl;
R2 is mono or di-substitution and is a halogen;
R4 is —C1-5 alkyl;
L is selected from C1-4 linear or branched alkyl;
R7 and R8 are independently selected from hydrogen and C1-5 alkyl;
R9 and R10 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, —OR6, —N(R6)2 and R6 wherein R6, at each occurrence is selected from a group comprising hydrogen, C1-20 linear, branched or cyclic alkyl optionally interrupted with one or more radicals independently selected from —O—, —NR5—, —S—, —SO—, —S(O)2—, —CR5═CR5—, —C≡C—, —NR5CO—, —CONR5—, —NR5CONR5—, —NR5C(O)O— and —OC(O)O—;
optionally, R6 is further substituted with one or more groups selected from a group comprising halogen, —OR12, —N(R12)2, and —COOR12, —CON(R12)2 or —CON(R12)OH; wherein R12 at each occurrence is selected from hydrogen or C1-6 linear, branched or cyclic alkyl;
is a double bond;
R13 is selected from a group consisting of hydrogen, halogen, —C1-6 haloalkyl and —C1-6 alkyl; and
X is oxygen.

### Claim 5 (depends on 4)

The compound of claim 4 wherein, R1 is selected from OH, —OR3, —OC1-6 haloalkyl and —OC(O)R3, wherein R3 is C1-6 linear or branched alkyl;
R9 and R10 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(R6)2 and R6; wherein R6, at each occurrence is independently selected from hydrogen and C1-15 linear or branched alkyl;
optionally, R6 is further substituted with one or more groups selected from halogen and —OR12; wherein R12 is hydrogen;
R7 and R8 are hydrogen; and
R13 is a group selected from hydrogen and halogen.

### Claim 6 (depends on 4)

The compound of claim 4 wherein R2 is substituted at position 3 of ring C and R1 is substituted at position 7 of the ring A.

### Claim 7 (depends on 4)

The compound of claim 4, wherein
R1 is a monosubstitution and is —OH;
R2 is a di-substitution;
R4 is methyl;
R9 and R10 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(R6)2 and R6;
wherein R6, at each occurrence is selected from hydrogen and C1-10 linear or branched alkyl;
optionally, R6 is further substituted with one or more groups selected from halogen and —OR12; wherein R12 is hydrogen.

### Claim 8 (depends on 4)

The compound of claim 4, wherein
R1 is a monosubstitution and is —OH;
R2 is a di-substitution;
R7 and R8 are hydrogen;
R13 is hydrogen;
R4 is methyl;
L is C1-3 linear alkyl; and
R9 and R10 together with the nitrogen atom to which they are attached forms a 4-5 membered ring wherein the ring is substituted with R6; wherein R6, is selected from C1-3 linear alkyl and wherein R6 is further substituted with halogen.

### Claim 9 (depends on 8)

The compound of claim 8 wherein R2 is fluoro.