# US 11,304,929 B2 · Tosylacetate based compounds and derivatives thereof as PHGDH inhibitors

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- Number: US 11,304,929 B2
- Document ID: US11304929B2
- Status: Granted
- Kind: B2
- Application number: 16/493,346
- Filed: 2018-03-13
- Published: 2022-01-13
- Granted: 2022-04-19
- Earliest claimed: 2017-03-14
- Assignees: Boehringer Ingelheim International GmbH
- Applicants: Boehringer Ingelheim International GmbH
- Inventors: Harald Weinstabl; Georg Dahmann; Matthias Treu; Bernd Wellenzohn; Stephan Karl Zahn
- Web page: https://patentgrep.com/patent/US11304929B2

## CPC

- A61K 31/404: Indoles, e.g. pindolol
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2018: {Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 209/60: Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
- C07D 231/14: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention encompasses compounds of formula (I), wherein the groups R1 to R, A1 to A4 and n have the meanings given in the claims and specification, their use as inhibitors of PHGDH, pharmaceutical compositions which contain compounds of this kind and their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases.

## Claims

### Claim 1

A compound of formula (I), or a salt thereof,
wherein
n is 1 or 2;
A1, A2, A3 and A4 are independently selected from —N═ and —CR13═ and wherein none, one or two independently selected A1, A2, A3 and A4 can be —N═;
R13 is hydrogen, halogen, —C1-3alkyl, —O—C1-3alkyl;
R1 is selected from the group consisting of hydrogen, —C1-3alkyl and —C1-3 alkyl-OH;
R2 is
wherein
X is —N═ or —CR7—;
R7 is selected from hydrogen, halogen, —C1-3alkyl and —O—C1-3 alkyl;
R4 is selected from the group consisting of hydrogen, halogen, —C1-3haloalkyl, —C1-3alkyl;
R5 is selected from the group consisting of hydrogen, halogen, —C1-3haloalkyl, —C1-3alkyl;
or R4 and R5 taken together form a ring selected from a 5 or 6 membered heteroaryl, a 5 or 6 membered heterocyclyl and phenyl;
E is selected from a bond, —C1-3alkylene-, —C1-3haloalkylene-, —C2-3alkynylene, 5 or 6 membered -heteroarylene- and 5 or 6 membered -heterocyclylene-;
R6 is selected from hydrogen, halogen, —C1-3alkyl, which —C1-3alkyl is optionally substituted with one group selected from —NH2, —N(C1-3alkyl)2 and 5 or 6 membered heterocycloalkyl;
or R2 is
wherein
R8 is selected from indolyl or phenyl, each of which group is optionally substituted with one, two or three substituents independently selected from halogen, —C1-3haloalkyl, —C1-3alkyl, —O—C1-3alkyl;
R3 is
and z is 1 or 2;
or R3 is —C(R9R10)—COO—R11 and
R9 and R10 are the same or different, independently selected from hydrogen, —C1-3alkyl, —C1-3alkyl-O—C1-3alkyl;
or R9 and R10 taken together form a —C3-5cycloalkyl or a 6 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with —C(O)—C1-3alkyl;
R11 is selected from the group consisting of hydrogen, —C3-6cycloalkyl, 4-6 membered heterocycloalkyl and —C1-5alkyl, which —C1-5alkyl group is optionally and independently substituted with one or two the same or different substituents, selected from R12;
R12 is selected from the group consisting of —C3-6cycloalkyl, halogen, —OH, —O—C1-4alkyl, —O—C1-4alkyl-O—C1-4alkyl, —O—C1-4alkyl-OH, —OC(O)—C1-4alkyl, —NHCOO—C1-4alkyl, —SO2—C1-3alkyl, —N(C1-3alkyl)2, 5 or 6 membered heteroaryl and phenyl, which phenyl group is optionally substituted with —C1-3haloalkyl, or R12 is a 4 to 6 membered heterocycloalkyl, which heterocycloalkyl is optionally substituted with halogen or —C1-3alkyl.

### Claim 2 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein each of A1, A2, A3 and A4 is —CH═.

### Claim 3 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R1 is selected from among hydrogen, —CH3 and —CH2OH.

### Claim 4 (depends on 3)

The compound according to claim 3, or a salt thereof, wherein R1 is selected from among —CH3 and —CH2OH.

### Claim 5 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein X is —CR7— and
R7 is selected from hydrogen and —O—C1-3alkyl.

### Claim 6 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R2 is
and
R8 is selected from
indolyl and phenyl, wherein the phenyl is optionally substituted with —F, —Cl, —O—CH3, —CH3.

### Claim 7 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R4 is selected from among hydrogen, —F and —Cl.

### Claim 8 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R5 is selected from among hydrogen, —F, —Cl, —CF3.

### Claim 9 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein E is a bond and R6 is selected from hydrogen, —C1-3alkyl and halogen; or
E is a 5 membered -heteroarylene- and R6 is —C1-3alkyl substituted with a 6 membered heterocycloalkyl; or
E is a 6 membered -heterocycloalkylene- and R6 is —C1-3alkyl,
E is —C2-3alkynylene- and R6 is hydrogen.

### Claim 10 (depends on 9)

The compound according to claim 9, or a salt thereof, wherein E is a bond and R6 is —C1-3alkyl.

### Claim 11 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R3 is selected from the group consisting of —C(R9R10)—COO—R11,
z is 1 or 2;
m is 1, 2, 3 or 4;
R9 and R10 are the same or different, independently selected from hydrogen, —C1-3alkyl, —C1-3alkyl-O—C1-3alkyl;
R11 is selected from the group consisting of hydrogen, 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, or —C1-5alkyl linear or branched, optionally substituted with 1 or 2 the same or different substituents, independently selected from R12;
R12 is selected from the group consisting of cycloalkyl, heterocycloalkyl, halogen, OH, —O—C1-4alkyl, —O—C1-4alkyl-O—C1-4alkyl, —OC(O)—C1-4alkyl, —NHCOO—C1-4alkyl, —SO2—C1-3alkyl, —N(C1-3alkyl)2,
five and six membered aryl and heteroaryl.

### Claim 12 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R11 is H or —C1-5alkyl.

### Claim 13 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R9 and R10 are the same or different, independently selected from hydrogen and —C1-3alkyl.

### Claim 14 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R2 is
R7 is hydrogen;
R4 is selected from the group consisting of —F, —Cl, Br and —C1-3alkyl;
R5 is selected from the group consisting of —F, —Cl and Br;
E is a bond and R6 is —C1-3alkyl.

### Claim 15 (depends on 1)

The compound according to claim 1, or a salt thereof, wherein R3 is selected from

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.