JPWO2020257752A5

JPWO2020257752A5 -

Info

Publication number: JPWO2020257752A5
Application number: JP2021575472A
Authority: JP
Publication date: 2023-06-28

Claims

A pharmaceutical composition for treating pancreatic cancer in a subject , comprising the following structural formula:

A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof
(In the structural formula above,
the thiazole ring is optionally substituted with -F or -Cl;
Cy is -( _C3 - _C7 ) cycloalkyl, bridged ( _C6 - _C12 ) cycloalkyl, or a 4- to 10-membered heterocyclic ring, each of which is optionally halogen, -OH, (C substituted with one or more groups selected from the group consisting of ₁ - _C4 )alkyl and ( _C1 - _C4 )alkoxy;
^X5 is absent when ^X5 is attached to the nitrogen ring atom of Cy;
X ⁵ is NR ^a or O when X ⁵ is attached to a carbon ring atom of Cy;
X ⁶ is NR ^a or O;
R ¹ is (C ₁ -C ₅ )alkyl optionally substituted with -OH;
R ³ is (C ₁ -C ₅ )alkyl, -CH ₂ -phenyl, -(C ₃ -C ₇ )cycloalkyl, -CH ₂ -(C ₃ -C ₇ )cycloalkyl, -CH ₂ -monocyclic 3- to 7-membered heterocyclic ring, or monocyclic 3- to 7-membered heterocyclic ring represented by R ³ or (C ¹ _-C ₅ )alkyl, —(C ₃ -C ₇ ) cycloalkyl, phenyl, or monocyclic 3- to 7-membered heterocycle optionally is halogen, -OH, ( _C1 - _C4 )alkyl, halomethyl, halomethoxy, -CN, and ( _C1 - _C4 ) substituted with one or more groups selected from the group consisting of alkoxy;
^R2 is ^-NRaC (O)O( _C1 - _C4 )alkyl; ^-NRaC (O) ^NRa ( _C1 - _C4 )alkyl; -NRaC ⁽ O)O( _C2) -NRaC( _O ) ^NRa ( _C2 - _C4 )alkenyl; ^-NRaC (O) ^O- ( _C3 - _C6 )cycloalkyl; -NRaC ⁽ O) ^-NRa- ( _C3 - _C7 )cycloalkyl; ^-NRaC (O)O-phenyl; ^-NRaC (O)NRa ^- phenyl; ^-NRaC (O)O-monocyclic3-7 -NR ^a C(O)NR ^a -monocyclic 3- to 7-membered heterocyclic ring; -NR ^a C(O)O-monocyclic 5- to 6-membered heteroaromatic ring; -NR ^a C(O) NR ^a - is a monocyclic 5-6 membered heteroaromatic ring;
( ^C1 _- _C4 )alkyl and ( _C2 - _C4 )alkenyl in the group represented by R2 are each optionally and independently halogen, _N3 , ^-ORa , ^-NRaR one or more groups selected from the group consisting of ^a , —(C ₃ -C ₆ )cycloalkyl, phenyl, monocyclic 3- to 7-membered heterocyclic ring, and monocyclic 5- to 6-membered heteroaromatic ring; is replaced;
( _C3 - _C7 )cycloalkyl in the group represented by ^R2 ^is optionally selected from the group consisting of halogen, _-CH3 , =O, ^-ORa , and ^-NRaRa1 substituted with one or more groups;
Phenyl in the group represented by ^R2 is optionally substituted with one or more groups selected from the group consisting of halogen, _-CH3 , halomethyl, halomethoxy, -CN, ^-ORa , and _-N3 . has been;
The heterocyclic ring in the group represented by ^R2 is optionally substituted with one or more groups selected from the group consisting of =O, halogen, ^-ORa , _-CH3 , halomethyl and halomethoxy. ;
The heteroaromatic ring ⁱⁿ the group represented by ^R2 is optionally one selected from the group consisting of halogen, -CN, _-CH3 , halomethyl, halomethoxy, ^-ORa , and ^-NRaRa is substituted with the following groups;
each R ^a is independently -H or _-CH3 ).

A pharmaceutical composition comprising a compound represented by or a pharmaceutically acceptable salt thereof
(In the structural formula above,
the thiazole ring is optionally substituted with -F or -Cl;
Cy is cycloalkyl or a 6-membered monocyclic heterocycle;
X ⁵ and X ⁶ are each independently NR ^a or O;
R ¹ is (C ₁ -C ₅ )alkyl;
R ³ is (C ₁ -C ₅ )alkyl or monocyclic 3-7 membered heterocycle;
^R2 is ^-NRaC (O)O( _C1 - _C4 )alkyl; ^-NRaC (O) ^NRa ( _C1 - _C4 )alkyl; -NRaC ⁽ O)O( _C2) -NRaC( _O ) ^NRa ( _C2 - _C4 )alkenyl; ^-NRaC (O) ^-O ( _C3 - _C6 )cycloalkyl; -NRaC ⁽ O) ^-NRa- ( _C3 - _C6 )cycloalkyl; ^-NRaC (O)O-phenyl; ^-NRaC (O)NRa ^- phenyl; ^-NRaC (O)O-monocyclic3-7 -NR ^a C(O)NR ^a -monocyclic 3- to 7-membered heterocyclic ring; -NR ^a C(O)O-monocyclic 5- to 6-membered heteroaromatic ring; -NR ^a C(O) NR ^a - is a monocyclic 5-6 membered heteroaromatic ring;
( _C1 - _C4 )alkyl and ( _C2 - _C4 )alkenyl in the groups represented by ^R2 are each optionally independently one or more of halogen, _N3 , ^-ORa , - NR ^a R ^a , —(C ₃ -C ₆ )cycloalkyl, phenyl, substituted with a monocyclic 3- to 7-membered heterocyclic ring, or a monocyclic 5- to 6-membered heteroaromatic ring;
-( _C3 - _C6 )cycloalkyl in the group represented by ^R2 is optionally substituted with one or more ^halogen , _-CH3 , ^-ORa , or ^-NRaRa ;
the phenyl in the group represented by ^R2 is optionally substituted with one or more halogen, _-CH3 , halomethyl, halomethoxy, ^-ORa , or _-N3 ;
heterocycles in groups represented by ^R2 are optionally substituted with one or more =O, halogen, _-CH3 , halomethyl, or halomethoxy;
heteroaromatic rings in groups represented by ^R2 are optionally substituted with one or more ^halogen , _-CH3 , halomethyl, halomethoxy, ^-ORa , or ^-NRaRa ;
each R ^a is independently -H or _-CH3 ).

Cy is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;
Azetidinyl, azepanyl, diazaspiro[4.4]nonyl, diazaspiro[3.5]nonyl, diazepanyl, dihydroimidazole, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothienyl, dihydrothiophenyl, dihydrothiopyranyl, hexa hydropyridazinyl, hexahydropyrimidinyl, hydantoinyl, indolinyl, isoindolinyl, morpholinyl, oxiranyl, oxetanyl, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazole, tetrahydroindolyl, tetrahydropyranyl, tetrahydrothienyl, tetrahydropyridinyl le, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, thiomorpholinyl, tropanyl, valerol actamyl;
bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl, bornyl, bornenyl, norbornyl, norbornenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, adamantri;
Azanorbornyl, quinuclidinyl, isoquinuclidinyl, tropanyl, azabicyclo[2.2.1]heptanyl, 2-azabicyclo[3.2.1]octanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.2.2]nonanyl, azabicyclo[3.3. 0]nonanyl, azabicyclo[3.3.1]nonanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.2.1]octanyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydropyrrolo[3,4-c ] pyrrolyl .

Cy is cyclohexyl, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, hexahydropyridazinyl, hexahydropyrimidinyl, valerolactamyl, dihydropyranyl, dihydropyridinyl, dihydropyrimidinyl, dihydrothiopyranyl, tetrahydropyranyl, The pharmaceutical composition according to any one of claims 1 to 3, which is tetrahydropyridinyl, tetrahydropyrimidinyl, or tetrahydrothiopyranyl.

Said compound or a pharmaceutically acceptable salt thereof is a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof
(In the structural formula above,
X ⁷ is NH or O;
R ⁴ is (C ₁ -C ₄ )alkyl, (C ₃ -C ₆ )cycloalkyl, or monocyclic 3-7 membered heterocycle;
(C ₁ -C ₄ )alkyl represented by R ⁴ is optionally halogen, N ₃ , -OR ^a , -NR ^a R ^a , -(C ₃ -C ₆ )cycloalkyl, phenyl, monocyclic 3- substituted with one or more groups selected from the group consisting of a 7-membered heterocyclic ring and a monocyclic 5- to 6-membered heteroaromatic ring;
(C ₃ -C ₆ )cycloalkyl or monocyclic 3- to 7-membered heterocyclic ring represented by R ⁴ , or (C ₃ -C ₆ )cycloalkyl or monocyclic 3- to 7-membered heterocycle in the group represented by R ⁴ the heterocyclic ring is optionally substituted with one or more groups selected from the group consisting of halogen, -OR ^a , =O, and _-CH3 ;
The phenyl in the group represented by ^R4 is optionally substituted with one or more groups selected from the group consisting of halogen, _-CH3 , halomethyl, halomethoxy, ^-ORa , and _-N3 . ;
the heteroaromatic ring in the group represented by ^R4 is optionally substituted with one or more groups selected from the group consisting of halogen and _-CH3 ) ,
A pharmaceutical composition according to any one of claims 1-4 .

X ⁷ is NH or O;
R ³ is (C ₁ -C ₅ )alkyl;
R ⁴ is (C ₁ -C ₄ )alkyl, and the (C ₁ -C ₄ )alkyl represented by R ⁴ is optionally one or more halogens, —OR ^a , —NR ^a R ^a , — ( _C3 - _C6 )cycloalkyl, phenyl (optionally substituted with one or more halogen, _-CH3 , halomethyl, halomethoxy, ^ORa , or _N3 ), monocyclic 3-7 membered hetero substituted with a ring (optionally substituted with =O, halogen, or _CH3 ) or a monocyclic 5-6 membered heteroaromatic ring (optionally substituted with halogen or _-CH3 ) 6. The pharmaceutical composition of claim 5, wherein

or a pharmaceutically acceptable salt thereof, the pharmaceutical composition according to any one of claims 1-6,

or a pharmaceutically acceptable salt thereof .

or a pharmaceutically acceptable salt thereof .

or a pharmaceutically acceptable salt thereof .

or a pharmaceutically acceptable salt thereof .

or a pharmaceutically acceptable salt thereof .

The pharmaceutical composition according to any one of claims 1-6, wherein Cy is azetidinyl or pyrrolidinyl and said nitrogen ring atom is attached to said thiazole ring.

Cy is 1,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[4.4]nonyl, 2,7-diazaspiro[3.5]nonyl, 1,4-diazepanyl, 2,5-diazabicyclo[2.2.1]heptanyl , 3,8-diazabicyclo[3.2.1]octanyl, octahydropyrrolo[3,4-b]pyrrolyl, or octahydropyrrolo[3,4-c]pyrrolyl, wherein the two nitrogen ring atoms are the thiazole ring and said -X ⁵ C(O)X ⁶ R ³ moieties , respectively.

R ⁴ is -(C ₁ -C ₃ )alkyl, (C ₃ -C ₆ )cycloalkyl, or monocyclic 3- to 7-membered heterocyclic ring, wherein -(C ₁ -C ₃ )alkyl is optionally (i) phenyl optionally substituted with one or more halogen or _-CH3 ; (ii) monocyclic 5-6 membered heteroaromatic optionally substituted with one or more halogen or _-CH3 or (iii) optionally substituted with a monocyclic 3- to 7-membered heterocyclic ring optionally substituted with one or more groups selected from the group consisting of halogen and _-CH3 , claims 5 and 7- 15. The pharmaceutical composition according to any one of 14.

R ⁴ is -(C ₁ -C ₃ )alkyl, -CHR ^a -phenyl, -CHR ^a -5- to 6-membered heteroaromatic ring, or -CHR ^a -3- to 7-membered monocyclic heterocyclic ring; Phenyl, a 5- to 6-membered heteroaromatic ring, or a 3- to 7-membered monocyclic heterocyclic ring in the group represented by ⁴ is optionally one or more groups selected from the group consisting of halogen and _-CH3 The pharmaceutical composition according to any one of claims 5 and 7-14, which is substituted with

^R4 is -( _C1 - _C3 )alkyl, which is optionally (i) phenyl optionally substituted with one or more halogen, _-CH3 , halomethyl, halomethoxy, ^ORa , or _N3 ; (ii) a monocyclic 5-6 membered heteroaromatic ring optionally substituted with one or more halogen or _-CH3 ; or (iii) optionally substituted with one or more =O or _-CH3 The pharmaceutical composition according to any one of claims 5 to 14, substituted with a monocyclic 3- to 7-membered heterocyclic ring.

^R4 is (i) -( _C1 - _C3 )alkyl; (ii) _-CH2 -phenyl optionally substituted with halogen, _-CH3 , halomethyl, halomethoxy, ^ORa , or _N3 ; iii) -CH( _CH3 )-phenyl optionally substituted with halogen, _-CH3 , halomethyl, halomethoxy, ^ORa , or _N3 ; (iv) - optionally substituted with halogen or _-CH3 or (v) _-CH2-3- to 7-membered monocyclic heterocyclic ring _optionally substituted with =O or _-CH3 . pharmaceutical composition .

R ³ is (C ₁ -C ₄ )alkyl, -(C ₄ -C ₆ )cycloalkyl, -CH ₂ -phenyl, -CH ₂ -monocyclic 4- to 6-membered heterocyclic ring, or monocyclic 4- to 6-membered ring A phenyl or monocyclic 4- to 6-membered heterocyclic ring which is heterocyclic and is represented by R ³ or in a group represented by R ³ is optionally selected from the group consisting of halogen, -OR ^a and -CH ₃ The pharmaceutical composition of any one of claims 1, 3-5, and 7-18, substituted with one or more selected groups.

or a pharmaceutically acceptable salt thereof .

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof .

or a pharmaceutically acceptable salt thereof.

or a pharmaceutically acceptable salt thereof .

^R3 is isopropyl, t-butyl, cyclobutyl, cyclopentyl, benzyl, oxetanyl, tetrahydro-2H-pyranyl, or

The pharmaceutical composition according to any one of claims 1 to 24, which is

26. The pharmaceutical composition according to any one of claims 1-25, wherein ^R1 is t-butyl.

27. The pharmaceutical composition according to any one of claims 1-26, wherein ^R3 is isopropyl or oxetanyl.

28. The pharmaceutical composition of Claim 27, wherein ^R3 is isopropyl.

^R4 is

The pharmaceutical composition according to any one of claims 5 to 28, which is

^R4 is

30. The pharmaceutical composition according to claim 29, which is

^R4 is

30. The pharmaceutical composition according to claim 29, which is

^R4 is

30. The pharmaceutical composition according to claim 29, which is

^R4 is

30. The pharmaceutical composition according to claim 29, which is

^R4 is

30. The pharmaceutical composition according to claim 29, which is

35. The medicament of any one of claims 1-34, wherein the subject is further co-administered with an effective amount of a DNA repair inhibitor, a DNA damage response (DDR) inhibitor, a DNA damaging agent, or an immunomodulatory agent. composition .

36. The medicament of claim 35, wherein said DNA damaging agent is selected from the group consisting of exposure to DNA damaging chemicals; exposure to chemotherapeutic agents; exposure to radiotherapy; and exposure to ionizing or ultraviolet radiation. composition .

37. The pharmaceutical composition of claim 35 or 36, wherein the subject has been determined to have increased levels and/or activity of DNA damaging processes or DNA editing enzymes.

38. The pharmaceutical composition of Claim 37, wherein said immunomodulatory agent is selected from the group consisting of immune checkpoint regulators, Toll-like receptor (TLR) agonists, cell-based therapies, cytokines, and cancer vaccines.

Said DNA editing enzymes are activation-induced cytidine deaminase (AID or AICDA), APOBEC2, APOBEC3A, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, APOBEC3H, APOBEC4, type 1 topoisomerase, type 2 topoisomerase, recombinant activating gene 1 (RAG 1) , and recombination activation gene 2 ( RAG2 ).

The pharmaceutical composition according to any one of claims 1-39, wherein said subject is a mammal.

The pharmaceutical composition according to any one of claims 1-40, wherein said subject is a human.

42. The pharmaceutical composition of any one of claims 1-41, wherein the pharmaceutical composition is administered such that the compound is administered at a dose ranging from about 50 mg/ ^m2 to about 500 mg/ ^m2 . .

The pharmaceutical composition contains the compound at about 3±2 mg/m ² , 3±1.8 mg/m ² , 3±1.6 mg/m ² , 3±1.5 mg/m ² , 3±1.4 mg/m ^{2 .} , 3±1.3 mg/m ² , 3±1.2 mg/m ² , 3±1.1 mg/m ² , 3±1 mg/m ² , 3±0.9 mg/m ² , 3±0.8 mg/m ² , 3 ±0.7 mg/ ^m2 , 3±0.6 mg/ ^m2 , 3±0.5 mg/ ^m2 , 3±0.4 mg/ ^m2 , 3±0.3 mg/ ^m2 , 3±0.2 mg/ ^m2 , or 3± 42. The pharmaceutical composition according to any one of claims 1-41, administered to give a dose of 0.1 mg/ ^m2 .

42. The pharmaceutical composition of any one of claims 1-41, wherein the pharmaceutical composition is administered such that the compound is administered at a dose of about 3 mg/ ^m2 .

The pharmaceutical composition contains about 120±100 mg ^/ m ² , 120±90 mg/m 2 , 120±80 mg/m ² , 120±70 mg/m ² , 120±60 mg/m ² , 120±50 mg/m ² , 120±45 mg/m ² , 120±40 mg/m ² , 120±35 mg/m ² , 120±30 mg/m ² , 120±25 mg/m ² , 120 ±20 mg/ ^m2 , 120±15 mg/ ^m2 , 120±10 mg/ ^m2 , 120±9 mg/ ^m2 , 120±8 mg/ ^m2 , 120±7 mg/ ^m2 , 120±6 mg/ ^m2 , 120±5 mg/ ^m2 , 120±4 mg/ ^m2 , 120±3 mg/ ^m2 , 120±2 mg / ^m2 , or 120±1 mg/ ^m2 42. The pharmaceutical composition according to any one of claims 1-41, which is administered to

42. The pharmaceutical composition of any one of claims 1-41, wherein the pharmaceutical composition is administered such that the compound is administered at a dose of about 120 mg/ ^m2 .

The pharmaceutical composition contains about 240±100 mg/m ² , 240±90 mg/m ² , 240±80 mg/m ² , 240±70 mg/m ² , 240±60 mg/m ² , 240±50 mg/ ^m2 , 240±45 mg/ ^m2 , 240±40 mg/ ^m2 , 240±35 mg/ ^m2 , 240±30 mg/ ^m2 , 240±25 mg/ ^m2 , 240 ±20 mg/ ^m2 , 240±15 mg/ ^m2 , 240±10 mg/ ^m2 , 240±9 mg/ ^m2 , 240±8 mg/ ^m2 , 240±7 mg/ ^m2 , 240±6 mg/ ^m2 , 240±5 mg/ ^m2 , 240±4 mg/ ^m2 , 240±3 mg/ ^m2 , 240±2 mg / ^m2 , or 240±1 mg/ ^m2 42. The pharmaceutical composition according to any one of claims 1-41, which is administered to

42. The pharmaceutical composition of any one of claims 1-41, wherein the pharmaceutical composition is administered such that the compound is administered at a dose of about 240 mg/ ^m2 .

42. The pharmaceutical composition according to any one of claims 1-41, wherein a 14-day drug holiday follows after said pharmaceutical composition is administered.

42. The pharmaceutical composition according to any one of claims 1-41, wherein a 21-day drug holiday follows after said pharmaceutical composition is administered.

42. The pharmaceutical composition of any one of claims 1-41, wherein said pharmaceutical composition is administered at about 240 mg/m 2 of said compound ^followed by a 14-day drug holiday.

42. The pharmaceutical composition of any one of claims 1-41, wherein said pharmaceutical composition is administered at about 240 mg/m ² of said compound followed by a 21 day drug holiday.

42. The pharmaceutical composition of any one of claims 1-41, wherein said pharmaceutical composition is administered at about 120 mg/m 2 of said compound ^followed by a 14-day drug holiday.

42. The pharmaceutical composition of any one of claims 1-41, wherein said pharmaceutical composition is administered at about 120 mg/m 2 of said compound ^followed by a 21 day drug holiday.

42. The pharmaceutical composition according to any one of claims 1-41, wherein said compound is compound 67A or a pharmaceutically acceptable salt thereof.

42. The pharmaceutical composition of any one of claims 1-41, wherein said pharmaceutical composition is administered at a dose ranging from about 50 mg/day to about 500 mg/day of said compound.

57. The pharmaceutical composition according to any one of claims 1-56, wherein said pharmaceutical composition is administered once a day.

57. The pharmaceutical composition according to any one of claims 1-56, wherein said pharmaceutical composition is administered once every two days.

58. The pharmaceutical composition according to any one of claims 1-57, wherein said pharmaceutical composition is administered once daily for 4 weeks.

58. The pharmaceutical composition according to any one of claims 1-57, wherein said pharmaceutical composition is administered once daily for 4 weeks followed by 1 drug holiday.

The compound is Compound 67A:

or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition for the treatment of pancreatic cancer in a subject , comprising compound 67A:

or a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof.

Compound 67A for the manufacture of a medicament for treating pancreatic cancer in a subject:

or use of a composition comprising a pharmaceutically acceptable salt thereof.

or use of a pharmaceutically acceptable salt thereof.