JPWO2021003417A5

JPWO2021003417A5 -

Info

Publication number: JPWO2021003417A5
Application number: JP2021578010A
Authority: JP
Publication date: 2023-08-07

Claims

The following structural formula:
[In the formula,
X ¹ is -N- and X ² is -C(R ⁹ )-, or X ¹ is -C(R ⁹ )- and X ² is -N-;
R ⁹ is —H, halo, hydroxy, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy, — C(O)NR ²⁰ R ²¹ or —NR ²⁰ R ²¹ ;
R ²⁰ and R ²¹ are each independently —H or (C ₁ -C ₆ )alkyl;
R ¹ is halo, —CN, —C(O)NR ¹⁰ R ¹¹ , —C(O)(C ₁ -C ₆ )alkyl, —OR ¹² or —NR ¹⁰ R ¹¹ ;
R ¹⁰ and R ¹¹ are each independently —H or (C ₁ -C ₆ )alkyl;
R ¹² is —H or (C ₁ -C ₆ )alkyl;
R ² is -NR ¹³ R ¹⁴ ;
R ¹³ and R ¹⁴ are each independently —H or (C ₁ -C ₆ )alkyl, or together with the N to which they are attached optionally with 1 or more R ³⁰ forming optionally substituted ( _C3 - _C7 )heterocyclyl;
R ³⁰ is independently for each occurrence halo, oxo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or ( C ₁ -C ₆ ) haloalkoxy;
R ³ is —H, halo, cyano or (C ₁ -C ₆ )alkyl;
R ⁴ is -H, (C ₁ -C ₆ )alkyl, hydroxy(C ₁ -C ₆ )alkyl or -C(O)(C ₁ -C ₆ )alkyl;
R ⁵ is -H;
R ⁶ is —H, halo, (C ₁ -C ₆ ⁾ alkoxy, (C ₁ -C ₆ )haloalkoxy or (C ₃ ^-C ₇ )cycloalkoxy; (C ₆ )aryl or (C ₅ -C ₆ )heteroaryl optionally substituted with 1 or more R ⁴⁰ , or 1 or more R ⁵⁰ together with intervening atoms; forming (C ₅ -C ₈ )carbocyclyl or (C ₅ -C ₈ )heterocyclyl optionally substituted with
R ⁴⁰ is independently for each occurrence halo, hydroxy, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or ( C ₁ -C ₆ ) haloalkoxy;
R ⁵⁰ is independently for each occurrence halo, oxo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or ( C ₁ -C ₆ ) haloalkoxy;
R ⁷ is halo, hydroxy, cyano, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy, —C(O ) NR ¹⁷ R ¹⁸ or -NR ¹⁷ R ¹⁸ ;
R ¹⁷ and R ¹⁸ are each independently —H or (C ₁ -C ₆ )alkyl;
R ⁸ is independently for each occurrence halo, oxo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ ) is haloalkoxy;
m is 0 or 1 with the proviso that R ⁹ is halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ ) is haloalkoxy, then m is 0;
n is 0, 1 or 2]
or a pharmaceutically acceptable salt thereof.

(i) X ¹ is -N- and X ² is -C(R ⁹ )-;
(ii) X ¹ is -C(R ⁹ )- and X ² is -N-, and/or
(iii) R ⁹ is -H, or
(iv) R ²⁰ and R ²¹ are each —H, and/or
(v) R ¹ is halo or -CN, or
(vi) R ¹ is chloro, bromo or -CN, or
(vii) R ¹ is chloro;
optionally, R ² is —N(CH ₃ ) ₂ , 1-piperidinyl-2-one, 1-pyrrolidinyl-2-one, 1-imidazolidinyl-2-one, 1-pyrrolidinyl, or 1-piperidinyl;
A compound according to claim 1, or a pharmaceutically acceptable salt thereof.

R ¹³ and R ¹⁴ are
(i) each independently selected from (C ₁ -C ₆ )alkyl;
(ii) together with the N to which they are attached form a ( _C3 - _C7 )heterocyclyl optionally substituted with one or more ^R30 ,
(iii) together with the N to which they are attached form ( _C3 - _C7 )heterocyclyl substituted with one oxo and optionally substituted with one or more ^R30 , or
(iv) together with the N to which they are attached form a piperidinone, pyrrolidinone or imidazolidinone optionally substituted with one or more R ³⁰ ;
Optionally, R ³⁰ is independently for each occurrence halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is (C ₁ -C ₆ )haloalkoxy.

^R3 is
(i) halo, cyano or (C ₁ -C ₆ )alkyl;
(ii) chloro or methyl;
(iii) is H, halo or (C ₁ -C ₆ )alkyl, or
(iv) A compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, which is H, chloro or methyl.

A compound according to any one of claims 1 to 4, wherein R ⁴ is -H, -CH ₃ , 2-hydroxyethyl or -C(O)CH ₃ .

The following structural formula:
6. The compound of claim 5, represented by or a pharmaceutically acceptable salt thereof.

(i) R ⁵ is —H and R ⁶ is halo, (C ₁ -C ₆ )alkoxy, (C ₁ -C ₆ )haloalkoxy or (C ₃ -C ₇ )cycloalkoxy, for example R ⁶ is (C ₁ -C ₆ )alkoxy or (C ₃ -C ₇ )cycloalkoxy, for example R ⁶ is methoxy, ethoxy or isopropyloxy, for example R ⁶ is methoxy, or
(ii) R ⁵ and R ⁶ together with their intervening atoms are optionally substituted with one or more R ⁴⁰ (C ₆ )aryl or (C ₅ -C ₆ ) heteroaryl, or (C ₅ -C ₈ )carbocyclyl or (C ₅ -C ₈ )heterocyclyl optionally substituted with one or more R ⁵⁰ , for example, R ⁵ and R ^7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein 6 together with their intervening atoms form ( _C6 )aryl.

(i) R ⁷ is halo, cyano, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ )haloalkoxy, or
(ii) R ¹⁷ and R ¹⁸ are each —H, and/or
(iii) R ⁹ is -H and m is 1, or
(iv) m is 0 and/or
(v) R ⁸ is independently for each occurrence halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ ) is haloalkoxy and/or
(vi) a compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein n is 0;

The following structural formula:
(i)
(ii)
(iii)
(iv)
(v)
(vi)
or
(vii)
[In the formula,
Z is -N(R ⁶⁰ )- or -C(R ⁶⁰ ) ₂ -;
R ³⁰ is independently for each occurrence halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ )halo is alkoxy;
R ⁶⁰ is independently for each occurrence hydrogen, halo, hydroxy, (C ₁ -C ₆ )alkyl, (C ₁ -C ₆ )haloalkyl, (C ₁ -C ₆ )alkoxy or (C ₁ -C ₆ ) is haloalkoxy;
p is 0, 1, 2, 3, 4 or 5];
For example the structure:
or represented by a pharmaceutically acceptable salt thereof,
Optionally, in (i)-(vii), the compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is -CH ₃ .

The following structural formula:
(i)
(ii)
(iii)
(iv)
(v)
(vi)
or
(vii)
3. The compound of claim 1, represented by or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

11. A pharmaceutical combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of one or more other therapeutic agents in some cases
(i) said one or more other therapeutic agents are independently selected from anticancer agents, antiallergic agents, antiemetic agents, analgesics, immunomodulatory agents or cytoprotective agents;
(ii) a pharmaceutical combination wherein said one or more other therapeutic agents is a proteasome inhibitor, eg, said proteasome inhibitor is bortezomib.

11. A therapeutically effective amount of a compound according to any one of claims 1 to 10, or 11. A method according to any one of claims 1 to 10, comprising administering to said subject a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 11 or a pharmaceutical combination according to claim 12. A compound or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to claim 11 or the pharmaceutical combination according to claim 12,
said TNK1-mediated disease, disorder or condition is a cancer, gastrointestinal disorder, SIRS, MODS, sepsis, an autoimmune disorder, a microbiome disease, disorder or condition, or a disease, disorder or condition resulting from trauma or intestinal injury. e.g., said TNK1-mediated disease, disorder or condition is cancer, e.g., cancer is
(i) including solid tumors;
(ii) pancreatic cancer
(iii) prostate cancer
(iv) non-solid tumors
(v) blood cancer
(vi) acute leukemia
(vii) the acute leukemia is acute myelogenous leukemia or acute lymphocytic leukemia;
(viii) chronic leukemia,
(ix) chronic leukemia that is chronic myelogenous leukemia or chronic lymphocytic leukemia,
(x) including lymphoma;
(xi) Hodgkin's lymphoma,
(xii) non-Hodgkin's lymphoma, or
(xiii) multiple myeloma;
a compound or a pharmaceutically acceptable salt thereof, for example, wherein said cancer is associated with a TNK1 mutation, for example, lung cancer wherein said cancer is Hodgkin's lymphoma, colorectal cancer, lung cancer, or non-small cell lung cancer; Pharmaceutical composition or pharmaceutical combination.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, for use in a method of treating a TNK1-mediated disease, disorder or condition in a subject with a TNK1 mutation in a subject with a TNK1 mutation. , the pharmaceutical composition according to claim 11 or the pharmaceutical combination according to claim 12,
determining whether said subject has a TNK1 mutation; and, if said subject is determined to have said TNK1 mutation, a therapeutically effective amount of a compound of any one of claims 1-10 or administering to said subject a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 11, or a pharmaceutical combination according to claim 12, wherein said TNK1-mediated disease, disorder or condition is cancer , gastrointestinal disorders, SIRS, MODS, sepsis, autoimmune disorders, microbiome diseases, disorders or conditions, or diseases, disorders or conditions resulting from trauma or intestinal injury, and optionally
(i) said TNK1 mutation is a C-terminal truncation mutation, and/or
(ii) A compound or a pharmaceutically acceptable salt, pharmaceutical composition or combination thereof, wherein said TNK1-mediated disease, disorder or condition is a cancer selected from colorectal cancer, Hodgkin's lymphoma or lung cancer.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in a method of improving intestinal barrier function in a subject in need thereof; A pharmaceutical composition according to claim 11 or a pharmaceutical combination according to claim 12, wherein a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, claim A compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a pharmaceutical combination, comprising administering the pharmaceutical composition of claim 11 or the pharmaceutical combination of claim 12 to said subject.

11. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in a method of treating a disease, disorder or condition in a subject that would benefit from improved intestinal barrier function. A pharmaceutical composition according to claim 11 or a pharmaceutical combination according to claim 12, wherein a therapeutically effective amount of a compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, administering the pharmaceutical composition of claim 11 or the pharmaceutical combination of claim 12 to said subject,
optionally, said disease, disorder or condition is cancer, gastrointestinal disorder, systemic inflammatory response syndrome (SIRS), multiple organ dysfunction syndrome (MODS), sepsis, autoimmune disorder, microbiome disease, disorder or condition; or a disease, disorder or condition resulting from trauma or intestinal injury, such as
(i) said gastrointestinal disorder is multiple intestinal neoplasms, ischemia/reperfusion injury, colitis, infectious diarrhea, celiac disease or inflammatory bowel disease (IBD), or
(ii) the autoimmune disorder is fibrosis, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, Graves' disease, Hashimoto's thyroiditis, severe A compound or a pharmaceutically acceptable salt thereof that is myasthenia, IBD, polymyositis, dermatomyositis, inflammatory myositis, ankylosing spondylitis, ulcerative colitis, psoriasis, vasculitis, Sjögren's disease or transplant rejection , a pharmaceutical composition or a pharmaceutical combination.

treatment further comprises administering to said subject one or more additional therapeutic agents; optionally
(i) said treatment comprises administering one or more standard therapeutic agents to said subject;
(ii) said treatment comprises administering a proteasome inhibitor to said subject;
(iii) the treatment wherein the proteasome inhibitor is bortezomib, N-5-benzyloxycarbonyl-Ile-Glu(O-tert-butyl)-Ala-leucinal, carfilzomib, ixazomib, marizomib (NPI-0052), delanzomib (CEP-18770), or O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(2R)-2- administering to said subject a proteasome inhibitor selected from methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912);
(iv) said treatment comprises administering to said subject a proteasome inhibitor, wherein said proteasome inhibitor is bortezomib;
(v) said treatment comprises administering an immune checkpoint inhibitor to said subject, or
(vi) said treatment comprises administering to said subject an immune checkpoint inhibitor selected from a PD-1 inhibitor, a PD-L1 inhibitor or a CTLA-4 inhibitor;
A compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition or a pharmaceutical combination for use according to any one of claims 13-16.

Use in a method of inhibiting TNK1 activity in a cell, comprising:
(i) contacting said cell with a compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, a pharmaceutical composition of claim 11 or a pharmaceutical combination of claim 12; optionally said cell is in a human,
(ii) a TNK1-mediated disease, disorder selected from cancer, gastrointestinal disorders, SIRS, MODS, sepsis, autoimmune disorders, microbiome diseases, disorders or conditions, or diseases, disorders or conditions resulting from trauma or intestinal injury; or a therapeutically effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, a pharmaceutical composition according to claim 11, or a pharmaceutical composition according to claim 12, in a symptomatic subject. administering to said subject a pharmaceutical combination of
A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, optionally wherein said TNK1 has a mutation, e.g. said mutation is a truncating mutation; 13. A pharmaceutical composition according to Claim 12 or a pharmaceutical combination according to Claim 12.