# US 12,760,047 B2 · Phosphorus derivatives as SOS1 inhibitors

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- Number: US 12,760,047 B2
- Document ID: US12760047B2
- Status: Granted
- Kind: B2
- Application number: 18/286,809
- Filed: 2022-04-13
- Published: 2024-07-25
- Granted: 2026-10-13
- Earliest claimed: 2021-04-14
- Assignees: Bayer Aktiengesellschaft
- Applicants: Bayer Aktiengesellschaft
- Inventors: Felix Pape; Steffen Gressies; Timo Stellfeld; Jeremie Xavier G Mortier; Atanas Marinov Kamburov; Benjamin Bader; Keith Graham; Roman Hillig; Jens Schroder; Christoph Philipp Hethey; Matthias Arlt; Gerhard Siemeister; Katrin Nowak-Reppel; Michael Erkelenz
- Web page: https://patentgrep.com/patent/US12760047B2

## CPC

- C07F 9/6584: having one phosphorus atom as ring hetero atom
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61P 35/00: Antineoplastic agents
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F 9/65685: {the ring phosphorus atom being part of a phosphine oxide or thioxide}
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention covers phosphorus derivatives of general formula (I), in which R1, R2, R3, R4, R5, R6, X1, X2, X3, X4 and Y are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, especially diseases associated with SOS1, as a sole agent or in combination with other active ingredients.

## Claims

### Claim 1

A compound of formula (I)
in which
X1 represents CH or N;
X2 represents CRa or N
X3 represents CRa or N
X4 represents CH or N
Y represents O or S;
R1, R2 is independently of each other selected from C1-4 alkyl, ORb or NRcRd, or
R1, R2 together with the phosphorus atom they are attached to form a 4-7 membered heterocycloalkyl in which one or more carbon atom can be replaced by —O—, —NRc—, —S—, —S(O)—, S(O)2— or —S(O)NRf—; and in which each remaining carbon atom can optionally be substituted by one or two —CH3 or by one —CH2—CH3,
R3 is selected from —H, —OH, —CH3, —CN, —NRpRq, or C1-2-alkyl optionally substituted with —OH, —CH3, —CN or halogen
R4 is selected from —H, —F, —Cl, —Br, —OH, —NH2, —N(CH3)H, —CH3 or —CF2H;
R5 represents -A-B-E in which
A represents —CRjRk— or is absent, and
B represents —CRlRm— or is absent, and
E represents —H, —F, —OH, —OCH3, —NH2, —NH—CH3, —N(CH3)2, —N(CH3)—OCH3, —CN, —SO2—CH3, —NH—SO2—CH3, —N(CH3)—SO2—CH3, —NH—C(O)—CH3, —N(CH3)—C(O)—CH3, —S(═NH)(═O)—CH3, —S(═N—CH3)(═O)—CH3, —C(O)—NH2, —C(O)—NH(CH3), —C(O)—N(CH3)2, or
R5 represents —SO2—NRnRo,
R6 is selected from —H, halogen or —CH3;
Ra is selected from —H, halogen, —OH, —OCH3, —CN, cyclopropyl, —NH2, —NH(CH3), —N(CH3)2, or C1-2 alkyl optionally substituted one or more times by halogen, —OH or —OCH3, —CH3, —CF3, —NH2, —NH(CH3), —N(CH3)2, or —CN
Rb is selected from —H (under the condition, that if R1 and R2 are both ORb only one Rb can be —H), —CH3, —CH2—CH3, —CH(CH3)2 or cyclopropyl,
Rc is selected from —CH3, —CH2—CH3, —CH(CH3)2 or cyclopropyl,
Rd is selected from —H, —CH3, —CH2—CH3, —CH(CH3)2 or cyclopropyl,
Re is selected from —H, C1-3-alkyl optionally substituted by one or more —F, cyclopropyl, —C(O)—Rg, —SO2—CH3 or 5 membered heteroaryl optionally substituted by —CH3, halogen, —CF3 or —CF2H
Rf is selected from —H, —CH3, or —CH2—CH3,
Rg is selected from C1-4 alkyl optionally substituted by —OH, —OCH3, —CH3, halogen; or
is selected from 5-membered heteroaryl optionally substituted by —CH3, —CH2CH3, CF2H, CF3 or halogen; or
is selected from NRhRi,
Rh is selected from —H or —CH3, and
Ri is selected from C1-3 alkyl optionally substituted by halogen or from cyclopropyl,
Rj and Rk are independently of each other selected from —H, —F or —CH3, or form together with the carbon atom they are attached to cyclopropyl;
Rl and Rm are independently of each other selected from —H, Deuterium, or —CH3, —CH2—CH3, cyclopropyl;
or form together with the carbon atom they are attached to cyclopropyl; or
Rn and Ro are independently selected from —H or C1-4 alkyl optionally substituted by —OH, —OCH3, or
Rn and Ro form together with the nitrogen atom they are attached to a 4 to 7 membered heterocycloalkyl optionally containing further heteroatoms selected from N or O, in which carbon atoms of this heterocycloalkyl can be optionally substituted by H or C1-4 alkyl and where this C1-4 alkyl can again be substituted by halogen, ═O, —OH, —OCH3, —NH2, —NH—CH3 or —N(CH3)2, and in which nitrogen atoms of this heterocycloalkyl can be optionally substituted by —C(O)-cyclopropyl or —C(O)—C1-4-alkyl, both optionally substituted one or more times with —F;
Rp and Rq are independently selected from —H, —CH3 or —CH2—CH3;
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 of formula (I) in which
X1 represents CH;
X2 represents CRa or N
X3 represents CRa or N
X4 represents CH or N Y represents O;
R1, R2 is independently of each other selected from —CH3, —CH2—CH3 or —CH(CH3)2; or
R1, R2 together with the phosphorus atom they are attached to form
R3 is selected from —CH3, —CHF2, or —CF3;
R4 is selected from —H, —NH2 or —CH3;
R5 is selected from
—Br,
CF2—H, —CF2—F, —CF2—CH3, —CF2—CH2—OH, —CF2—CD2—OH, —CF2—CH2—OCH3, —CF2—CH(CH3)—OH, —CF2—CH(CH2—CH3)—OH, —CF2—C(CH3)2—OH, CF2—C(CH3) 2—OCH3, —CF2—CH(CH(CH3)2)—OH, —CF2—CH(C(CH3)3)—OH, —CF2—C(CH3)(CH2—CH2—CH2—CH3)—OH,
CF2—C(═O)—CH(CH3)2, —CF2—C(═O)—C(CH3)3,
CF2—C(═O)—OH, —CF2—C(═O)—NH2, —CF2—C(═O)—N(CH3)2, —CF2—C(═O)—NH—CH3, —CF2—C(═O)—NH—CH2—CH3, —CF2—C(═O)—NH—cyclopropyl,
CF2—CH2—NH—SO2—CH3, —CF2—CH2—N(CH3)—SO2—CH3, —CF2—CH2—NH—C(═O)—CH3 or —CF2—CH2—N(CH3);
R6 is selected from —H, —CH3, —F or —Cl;
Ra is selected from —H, —CH3, —CH2—CH3, —CF3, —CHF2, —CH2—OH, —CH2—O—CH3, —OH, —OCH3 or cyclopropyl,
Rr is selected from —H, —CH3, —CH(CH3)2, —C(═O)—H, —C(═O)—CH3, —C(═O)—CH2F, —C(═O)—CH(CH3)2, —C(═O)—CH(CH3)—OH, —C(═O)—CH(CH3)—O—CH3,
C(═O)—CH2—CN, —C(═O)—CH2—O—CH3,
—C(═O)—O—C(CH3)3, —C(═O)—O—CH2—CH3,
—C(═O)—NH2, —C(═O)—N(CH3)2, —C(═O)—CH2—CHF2, —C(═O)—NH—cyclopropyl,
—C(═S)—CH3, —SO2—CH3,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein only one of X1, X2, X3 or X4 is N or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein Y represents O or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R1 and R2 are selected from C1-4 alkyl or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R3 is selected from C1-2-alkyl optionally substituted with 1 to 3 —F or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R6 is selected from —F, —Cl, —H or —CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein Ra is selected from —H, —Cl, —CH3, —CF3 or —CF2H or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein Rj and Rk form together with the carbon atom they are attached to cyclopropyl or are selected from either both —F, both —CH3, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein both R1 and R2 are —CH3 or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R5 is —CF3 and R6 is —F or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein X2 is N and X3 is CH or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein Rn and Ro form together with the nitrogen atom they are attached to morpholine or N-acetylpiperazine both optionally substituted with 1 or 2—CH3, —CF3 or —CF2H or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 14 (depends on 1)

The compound according to claim 1, which is 1-acetyl-4-[2-methyl-4-({(1R)-1-[2-methyl-3-(trifluoromethyl)phenyl]ethyl}amino)pyrido[3,4-d]pyrimidin-6-yl]-1,4lambda5-azaphosphinan-4-one according to the formula
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof.

### Claim 15 (depends on 1)

A method for treating a hyperproliferative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1.

### Claim 16 (depends on 15)

The method of claim 15, wherein the hyperproliferative disorder is cancer.

### Claim 17 (depends on 16)

The method of claim 16, wherein the cancer is selected from the group consisting of lung cancer, colorectal cancer, and pancreatic cancer.

### Claim 18 (depends on 15)

The method of claim 15, further comprising administering a second active ingredient, wherein the second active ingredient is an anti-cancer agent.

### Claim 19 (depends on 18)

The method of claim 18, wherein the anti-cancer agent is selected from the group consisting of pemetrexed, osimertinib, and cetuximab.