JPWO2020002701A5

JPWO2020002701A5 -

Info

Publication number: JPWO2020002701A5
Application number: JP2021500159A
Authority: JP
Publication date: 2022-07-11
Anticipated expiration: 2039-07-01

Claims

A pharmaceutical composition comprising a compound having formula (I), or a salt thereof , or a stereoisomer thereof for the prevention or treatment of cancer:

( During the ceremony,
R ¹ is hydrogen; OH; NH ₂ ; SH; F; Cl; Br; I; methyl; optionally substituted alkyl chain; optionally substituted alkenyl chain; optionally substituted. May be alkynyl chain; trihaloalkyl; OR ⁶ ; NR ⁶ R ⁷ ; CN; COR ⁶ ; CONR ⁶ R ⁷ ; CO ₂ R ⁶ ; _C (S) OR ⁶ ; OCOR ⁶ ^; OCO ² R ⁶ ; OC (S) OR ⁶ ; NHCONR ⁶ R ⁷ ; NHCOR ⁶ ; NR ⁶ CO ₂ R ⁷ ; NHCO ₂ R ⁶ ; NHC (S) OR ⁶ ; NO ₂ ; N ₃ ; SR ⁶ ; SO ₃ H; SO ₂ R ⁶ ; SO ₂ NR ⁶ R ⁷ aryl; Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or Het linked, optionally substituted aryl; or if An optionally substituted heterocycle linked by an alkyl, alkenyl or alkynyl chain which may be substituted with.
x is 1, 2, 3, 4 or 5, independent of y and z.
The phenyl ring having the substituent R ¹ is in the para position with respect to the "a" position of the phenyl ring having the substituent R ² .
R ² is hydrogen; OH; NH ₂ ; SH; F; Cl; Br; I; methyl; optionally substituted alkyl chains; optionally substituted alkenyl chains; optionally substituted. May be alkynyl chain; trihaloalkyl; OR ⁶ ; NR ⁶ R ⁷ ; CN; COR ⁶ ; CONR ⁶ R ⁷ ; CO ₂ R ⁶ ; _C (S) OR ⁶ ; OCOR ⁶ ^; OCO ² R ⁶ ; OC (S) OR ⁶ ; NO ₂ ; N ₃ ; NHCONR ⁶ R ⁷ ; NHCOR ⁶ ; NR ⁶ CO ₂ R ⁷ ; NHCO ₂ R ⁶ ; NHC (S) OR ⁶ ; NO ₂ ; SO ₃ H; SO ₂ R ⁶ ; SO ₂ NR ⁶ R ⁷ ; Aryl; Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or Het linked, optionally substituted aryl; or An optionally substituted heterocycle linked by an optionally substituted alkyl, alkenyl or alkynyl chain.
y is 1, 2, 3 or 4 , independent of x and z.
R ³ is hydrogen,
^R4 is hydrogen; OH; NH ₂ ; methyl; optionally substituted alkyl chain; optionally substituted alkenyl chain; optionally substituted alkynyl chain; optionally substituted. Cycloalkyl linked to S via an optionally substituted alkyl chain; optionally substituted to S via an optionally substituted alkenyl chain; optionally substituted. Maybe cycloalkyl; optionally substituted cycloalkyl linked to S via an optionally substituted alkynyl chain; optionally substituted cycloalkenyl; optionally substituted. Cycloalkenyl linked to S via an alkyl chain which may be optionally substituted; optionally substituted to S via an alkenyl chain which may be substituted optionally. Cycloalkenyl which may be optionally substituted Cycloalkenyl linked to S via an alkynyl chain which may be optionally substituted; Cycloalkynyl chain which may be substituted optionally; Cycloalkynyl linked to S via an alkyl chain optionally substituted by; optionally coupled to S via an alkenyl chain optionally substituted by Substitutable cycloalkynyl; optionally substituted cycloalkynyl linked to S via an optionally substituted alkynyl chain; trihaloalkyl; OR ⁶ ; NR ⁶ R ⁷ ; CN; COR ⁶ ; CONR ⁶ R ⁷ ; CO ₂ R ⁶ ; C (S) OR ⁶ ; OCONR ⁶ R ⁷ ; OCOR ⁶ ; OCO ₂ R ⁶ ; OC (S) OR ⁶ ; NO ₂ ; N ₃ ; NHCONR ⁶ R ⁷ ; NHCOR ⁶ ; NR ⁶ CO ₂ R ⁷ ; NHCO ₂ R ⁶ ; NHC (S) OR ⁶ ; NO ₂ ; SO ₃ H; SO ₂ R ⁶ ; SO ₂ NR ⁶ R ⁷ ; Substituentally substituted alkyl, alkenyl, alkynyl chain, aryl or Het-linked, optionally substituted aryl; or optionally substituted alkyl, alkenyl or alkynyl chain. In some cases It is a heterocyclic ring that may be substituted.
R5 is hydrogen; OH; _{NH 2} ^; methyl; optionally substituted alkyl chain; optionally substituted alkenyl chain; optionally substituted alkynyl chain; optionally substituted. Cycloalkyl linked to S via an optionally substituted alkyl chain; optionally substituted to N via an optionally substituted alkenyl chain; optionally substituted. Maybe cycloalkyl; optionally substituted cycloalkyl linked to N via an optionally substituted alkynyl chain; optionally substituted cycloalkenyl; optionally substituted. Cycloalkenyl linked to N via an alkyl chain which may be optionally substituted; optionally substituted to N via an alkenyl chain which may be substituted optionally. Cycloalkenyl which may be optionally substituted Cycloalkenyl linked to N via an alkynyl chain which may be optionally substituted; Cycloalkynyl chain which may be substituted optionally; Cycloalkynyl linked to N via an alkyl chain optionally substituted by; optionally coupled to N via an alkenyl chain optionally substituted by Substitutable cycloalkynyl; optionally substituted cycloalkynyl linked to N via an optionally substituted alkynyl chain; trihaloalkyl; OR ⁶ ; NR ⁶ R ⁷ ; CN; COR ⁶ ; CONR ⁶ R ⁷ ; CO ₂ R ⁶ ; C (S) OR ⁶ ; OCONR ⁶ R ⁷ ; OCOR ⁶ ; OCO ₂ R ⁶ ; OC (S) OR ⁶ ; NO ₂ ; N ₃ ; NHCONR ⁶ R ⁷ ; NHCOR ⁶ ; NR ⁶ CO ₂ R ⁷ ; NHCO ₂ R ⁶ ; NHC (S) OR ⁶ ; NO ₂ ; SO ₃ H; SO ₂ R ⁶ ; SO ₂ NR ⁶ R ⁷ ; Substituentally substituted alkyl, alkenyl, alkynyl chain, aryl or Het-linked, optionally substituted aryl; or optionally substituted alkyl, alkenyl or alkynyl chain. In some cases It is a heterocyclic ring that may be substituted.
R ⁶ and R ⁷ are independent of each other: hydrogen; methyl; optionally substituted alkyl chain; optionally substituted alkenyl chain; optionally substituted alkynyl chain; if. Selected from heterocycles optionally substituted with, and optionally aryls, preferably phenyl or naphthyl.
Each aryl as a group or as part of a group is optionally Het-condensed phenyl, naphthalenyl, anthrasenyl, phenanthrenyl, biphenyl, each substituted OH; F; Cl; Br; I; methyl; optionally. Aryl chains that may be optionally substituted; alkenyl chains that may be optionally substituted; alkynyl chains that may be optionally substituted; cycloalkyls that may be optionally substituted; cycloalkenyls that may be optionally substituted. Cycloalkynyl optionally substituted; OR ⁶ ; NR ⁶ R ⁷ ; CN; COR ⁶ ; CONR ⁶ R ⁷ ; CO ₂ R ⁶ ; C (S) OR ⁶ ; OCOR ⁶ R ⁷ ; OCOR ⁶ ; OCO ₂ R ⁶ ; OC (S) OR ⁶ ; N ₃ ; NHCONR ⁶ R ⁷ ; NHCOR ⁶ ; NR ⁶ CO ₂ R ⁷ ; NHCO ₂ R ⁶ ; NHC (S) OR ⁶ ; NO ₂ ; SR ⁶ ; SO ₃ H; SO ₂ R ⁶ ; SO ₂ NR ⁶ R ⁷ ; aryl; Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or optionally coupled aryl ; And optionally substituted with 1, 2, 3 or 4 substituents selected from optionally substituted heterocycles linked by an optionally substituted alkyl, alkenyl or alkynyl chain. May have been
Each Het as a group or part of a group is a monocyclic ring in which 5, 6 or 7 ring atoms are optionally fused to aryl, or 5 linked to a 4, 5 or 6 membered ring. , 6- or 7-membered ring structure, each ring being saturated, partially unsaturated or completely unsaturated, with at least one of the rings being from nitrogen, oxygen and sulfur. Alkyl containing 1 to 5 heteroatoms, each independently selected, and any one of the rings being optionally substituted with OH; F; Cl; Br; I; methyl; Chain; optionally substituted alkenyl chain; optionally substituted alkynyl chain; optionally substituted cycloalkyl; optionally substituted cycloalkenyl; optionally substituted May be cycloalkynyl; OR ⁶ ; NR ⁶ R ⁷ ; CN; COR ⁶ ; CONR ⁶ R ⁷ ; CO ₂ R ⁶ ; C (S) OR ⁶ ; OCONR ⁶ R ⁷ ; OCOR ⁶ ; OCO ₂ R ⁶ ; OC (S) OR ⁶ ; N ₃ ; NO ₂ ; NHCONR ⁶ R ⁷ ; NHCOR ⁶ ; NR ⁶ CO ₂ R ⁷ ; NHCO ₂ R ⁶ ; NHC (S) OR ⁶ ; NO ₂ ; SR ⁶ ; SO ₃ H; SO ₂ R ⁶ ; SO ₂ NR ⁶ R ⁷ ; aryl; Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or Het linked, optionally substituted aryl; and 1, 2, 3 or 4 substitutions independently selected from the group consisting of optionally substituted alkyl, alkenyl or alkynyl chains linked and optionally substituted heterocycles, respectively. May be optionally substituted with a group ) .

The cancers are basal cell cancer, melanoma, medulloblastoma, stellate cell tumor, lung cancer, prostate cancer, pancreatic cancer, colorectal cancer, breast cancer, ovarian cancer, cervical cancer, rhabdomyosarcoma, neuroblastoma, digestion. The pharmaceutical composition according to claim 1, which is selected from tube tumor, leukemia, rhabdomyosarcoma and osteosarcoma.

The pharmaceutical composition according to claim 1 or 2, wherein R ² is hydrogen; OH; NH ₂ ; SH; F; Cl; Br; I; or methyl.

^R4 may be aryl; Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or Het linked, optionally substituted aryl; or optionally substituted. The pharmaceutical composition according to claim 3, wherein the heterocycle is optionally substituted with a good alkyl, alkenyl or alkynyl chain.

R ¹ is hydrogen, F; Cl; Br; I; methyl; optionally substituted alkyl chain; OR ⁶ ; aryl; or Het.
^R2 is F; Cl; Br; or I,
R ⁵ is hydrogen; methyl; optionally substituted alkyl chain; optionally substituted cycloalkyl linked to N via optionally substituted alkyl chain; optionally substituted cycloalkyl; aryl. Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or optionally substituted aryl linked by aryl or Het; or optionally substituted alkyl, alkenyl or The pharmaceutical composition according to claim 4, which is a heterocycle linked by an alkynyl chain and optionally substituted.

The pharmaceutical composition according to claim 5, wherein R ¹ is OR ⁶ .

The pharmaceutical composition according to claim 6, wherein R ² is F.

^R4 may be aryl; Het; optionally substituted alkyl, alkenyl, alkynyl chain, aryl or Het linked, optionally substituted aryl; or optionally substituted. The pharmaceutical composition of claim 7, wherein the heterocycle is optionally substituted with a good alkyl, alkenyl or alkynyl chain.

The pharmaceutical composition according to claim 7, wherein R ⁵ is H.

The compound of the formula (I) is
4,5-Dichloro-N- (1- (3-fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) thiophene-2-sulfonamide ;
N- (1- (3-Fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) -3,5-dimethylisoxazole-4 -Sulfonamide;
N- (1- (3-Fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) benzo [d] [1,3] dioxol- 5-Sulfonamide;
N- (1- (3-Fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) -5- (pyridin-2-yl) thiophene -2-Sulfonamide;
N- (1- (3-Fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) benzofuran-2-sulfonamide;
-4,5-Dichloro-N- (cyanomethyl) -N- (1- (3-fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) ) Thiophene-2-sulfonamide;
Ethyl N- (benzo [d] [1,3] dioxol-5-ylsulfonyl) -N- (1- (3-fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) glycinate;
N- (1- (3-Fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) -N- (2-morpholino-2-oxoethyl) ) Benzo [d] [1,3] dioxol-5-sulfonamide;
2-((4,5-Dichloro-N- (1- (3-fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) thiophene) ) -2-Sulfonamide) Acetamide;
Ethyl N- (1- (3-fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) -N-((5- (pyridin-) The pharmaceutical composition according to any one of claims 1 to 9, which is selected from 2-yl) thiophene-2-yl) sulfonyl) glycinate.

N- (1- (3-Fluoro-2'-methoxy- [1,1'-biphenyl] -4-yl) -2-oxopiperidine-3-yl) -5- (pyridin-2-yl) thiophene- The pharmaceutical composition according to any one of claims 1 to 10, which is 2-sulfonamide.

The compound of the formula (I) is a chemotherapeutic agent, a metabolic antagonist, a spindle poisonous plant alkaloid, a cytotoxic / antitumor antibiotic, a topoisomerase inhibitor, an antibody, a photosensitizer, a kinase inhibitor, and a pathway specific. Any of claims 2-11, which is used in combination with an additional compound selected from a target inhibitor, an antihormonal agent, an aromatase inhibitor, an antiandrogen substance, a ribozyme, a vaccine, an antiangiogenic agent, an antiviral agent or a combination thereof. The pharmaceutical composition according to item 1.

The pharmaceutical composition according to any one of claims 2 to 12, wherein the compound of the formula (I) is contained in the pharmaceutical composition .

Any one of claims 2-13, wherein the compound of formula (I) is administered by the oral, rectal, nasal, ocular, topical, vaginal, parenteral, transdermal, intraperitoneal, intrapulmonary or intranasal route. The pharmaceutical composition according to the section.

Any one of claims 2-14, wherein the compound of formula (I) is used in the prevention or treatment of cancer in combination with surgical therapy, radiation therapy, immunotherapy, epigenetic therapy or a combination thereof. The pharmaceutical composition according to the section.