JPWO2021154665A5

JPWO2021154665A5 -

Info

Publication number: JPWO2021154665A5
Application number: JP2022545918A
Authority: JP
Publication date: 2024-02-02

Claims

Formula (I) below:
[In the formula,
Ar is
And;
W is H, halo, C ₁ -C ₃ alkyl, CN, (C ₁ -C ₄ alkanediyl)OH,
And;
each X is independently N or ^CR2 ;
R ¹ is (C ₁ -C ₅ alkyl),
(C ₂ -C ₅ alkenyl),
(C ₁ -C ₈ alkanediyl) _0-1 (C ₃ -C ₆ cycloalkyl),
(C ₁ -C ₈ alkanediyl) _0-1 (C ₅ -C ₁₀ spiroalkyl),
(C ₂ -C ₈ alkanediyl)OH,
(C ₂ -C ₈ alkanediyl)O(C ₁ -C ₃ alkyl),
(C ₁ -C ₄ alkanediyl) _0-1 (5-6 membered heteroaryl),
(C ₁ -C ₄ alkanediyl) _0-1 phenyl,
(C ₁ -C ₄ alkanediyl)CF ₃ ,
(C ₂ -C ₈ alkanediyl)N[C(=O)](C ₁ -C ₃ alkyl),
or (C ₂ -C ₈ alkanediyl)NR ^x R ^y ;
Each R ² is independently H, O (C ₁ -C ₃ alkyl), S (C ₁ -C ₃ alkyl),
SO ₂ (C ₁ -C ₃ alkyl), C ₁ -C ₃ alkyl, O (C ₃ -C ₄ cycloalkyl),
S (C ₃ -C ₄ cycloalkyl), SO ₂ (C ₃ -C ₄ cycloalkyl),
C ₃ -C ₄ cycloalkyl, Cl, F, CN, or [C(=O)] _0-1 NR ^x R ^y ;
^R3 is H, halo, OH, CN,
_NH2 ,
NH[C(=O)] _0-1 (C ₁ -C ₅ alkyl),
N(C ₁ -C ₅ alkyl) ₂ ,
NH[C(=O)] _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₃ -C ₈ cycloalkyl),
NH[C(=O)] _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₄ -C ₁₀ bicycloalkyl),
NH[C(=O)] _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₅ -C ₁₀ spiroalkyl),
N(C ₃ -C ₆ cycloalkyl) ₂ ,
O(C ₁ -C ₄ alkanediyl) _0-1 (C ₃ -C ₈ cycloalkyl),
O(C ₁ -C ₄ alkanediyl) _0-1 (C ₄ -C ₈ bicycloalkyl),
O(C ₁ -C ₄ alkanediyl) _0-1 (C ₅ -C ₁₀ spiroalkyl),
O(C ₁ -C ₄ alkanediyl) _0-1 (C ₁ -C ₆ alkyl),
N[C ₁ -C ₃ alkyl]C(=O) (C ₁ -C ₆ alkyl),
NH(SO ₂ )(C ₁ -C ₅ alkyl),
NH(SO ₂ )(C ₁ -C ₄ alkanediyl) _0-1 (C ₃ -C ₈ cycloalkyl),
NH(SO ₂ )(C ₁ -C ₄ alkanediyl) _0-1 (C ₄ -C ₁₀ bicycloalkyl),
NH(SO ₂ )(C ₁ -C ₄ alkanediyl) _0-1 (C ₅ -C ₁₀ spiroalkyl),
a 6-membered aromatic or heteroaromatic moiety;
A 5-membered heteroaromatic moiety, or the following structure:
is a part having;
^R4 is _NH2 ,
NH (C ₁ -C ₅ alkyl),
N(C ₁ -C ₅ alkyl) ₂ ,
NH(C ₁ -C ₄ alkanediyl) _0-1 (C ₃ -C ₈ cycloalkyl),
NH(C ₁ -C ₄ alkanediyl) _0-1 (C ₄ -C ₁₀ bicycloalkyl),
NH(C ₁ -C ₄ alkanediyl) _0-1 (C ₅ -C ₁₀ spiroalkyl),
N(C ₃ -C ₆ cycloalkyl) ₂ ,
Or the structure below:
is a part having;
R ⁵ is H, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, C ₃ -C ₆ cycloalkyl,
Halo, O(C ₁ -C ₅ alkyl), (C ₁ -C ₄ alkanediyl)OH,
(C ₁ -C ₄ alkanediyl)O(C ₁ -C ₃ alkyl), phenyl,
NH (C ₁ -C ₅ alkyl), 5- or 6-membered heteroaryl,
And;
R ⁶ is NH ₂ ,
(NH) _0-1 (C ₁ -C ₅ alkyl),
N(C ₁ -C ₅ alkyl) ₂ ,
(NH) _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₃ -C ₈ cycloalkyl),
(NH) _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₄ -C ₁₀ bicycloalkyl),
(NH) _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₅ -C ₁₀ spiroalkyl),
N(C ₃ -C ₆ cycloalkyl) ₂ ,
Or the structure below:
is a part having;
R ^x and R ^y are independently H or C ₁ -C ₃ alkyl, or R ^x and R ^y combine with the nitrogen attached to them to form a 3- to 7-membered heterocycle death;
n is 1, 2, or 3;
p is 0, 1, 2, or 3;
Here, in R ¹ , R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ ,
Alkyl, cycloalkyl, alkanediyl, bicycloalkyl, spiroalkyl, cyclic amine, 6-membered aromatic or heteroaromatic moiety, 5-membered heteroaromatic moiety or the formula:
The part indicated by
OH, halo, CN, (C ₁ -C ₃ alkyl), O (C ₁ -C ₃ alkyl),
C (=O) (C ₁ -C ₃ alkyl), SO ₂ (C ₁ -C ₃ alkyl), NR ^x R ^y ,
(C ₁ -C ₄ alkanediyl)OH, (C ₁ -C ₄ alkanediyl)O(C ₁ -C ₃ alkyl)
May be optionally substituted with one or more substituents selected from;
Alkyl, alkanediyl, cycloalkyl, bicycloalkyl, spiroalkyl, or the formula:
The part indicated by
O, _SO2 , _CF2 , C(=O), NH,
N[C(=O)] _0-1 (C ₁ -C ₃ alkyl),
N[C(=O)] _0-1 (C ₁ -C ₄ alkanediyl) _0-1 CF ₃ ,
or N[C(=O)] _0-1 (C ₁ -C ₄ alkanediyl) _0-1 (C ₃ -C ₅ cycloalkyl)
may have a CH ₂ group substituted with]
A compound having the structure shown in

Formula (Ia) below:
The compound according to claim 1, having a structure represented by:

The following formula (Ib):
The compound according to claim 1, having a structure represented by:

R ³ is
The compound according to claim 3, which is

R ¹ is
And;
^5. A compound according to claim 4, wherein R5 is H or Me.

The following formula (Ic):
The compound according to claim 1, having a structure represented by:

R ⁴ is
7. The compound according to claim 6.

R ¹ is
And;
8. A compound according to claim 7, wherein ^R5 is H or Me.

The following formula (Id):
[In the formula,
W is
]
A compound having the structure shown in

A pharmaceutical composition for treating cancer, comprising an anti -cancer immunotherapeutic agent and a compound according to any one of claims 1 to 9 .

The pharmaceutical composition according to claim 10, wherein the anti-cancer immunotherapeutic agent is an antagonist anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibody.

The pharmaceutical composition according to claim 10 , wherein the anti-cancer immunotherapeutic agent is ipilimumab, nivolumab, or pembrolizumab.

The cancer is lung cancer (including non-small cell lung cancer), pancreatic cancer, kidney cancer, head and neck cancer, lymphoma (including Hodgkin lymphoma), skin cancer (including melanoma and Merkel skin cancer), urothelial cancer 13. The pharmaceutical composition according to any one of claims 10 to 12 , which is cancer of the stomach (including bladder cancer), gastric cancer, hepatocellular carcinoma, or colorectal cancer.

The following formula (Ie):
[In the formula,
^R1 is
And;
R ⁵ is H or Me;
R ⁷ is H, C ₁ -C ₅ alkyl, or C ₃ -C ₆ cycloalkyl; where the cycloalkyl group is CH substituted with O, NH, or N(C ₁ -C ₃ )alkyl. You may have _two groups as appropriate]
A compound having the structure shown in