JPWO2021021761A5

JPWO2021021761A5 -

Info

Publication number: JPWO2021021761A5
Application number: JP2022506188A
Authority: JP
Publication date: 2023-08-04

Claims

compounds of formula (I)

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
During the ceremony,
R ¹ and R ² are independently hydrogen, C ₁ -C ₆ alkyl, halo, or C ₁ -C ₆ haloalkyl;
provided that if X is sulfur, then R ¹ and R ² are both not hydrogen, and if X is sulfur or a bond, provided that R ¹ and R ² are not halo;
or R ¹ and R ² together with the carbon atom to which they are attached;

and
X is CR ³ R ⁴ or sulfur;
R ³ and R ⁴ are independently hydrogen, C ₁ -C ₆ alkyl, halo, or C ₁ -C ₆ haloalkyl;
or R ¹ and R ³ together with the carbon atom to which they are attached are moieties

forming;
R ⁵ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl;
Z is CH or nitrogen;
n is 0 or 1;
R ⁶ is hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
R ⁷ is C ₁ -C ₆ alkyl-OH, —(CR ⁸ R ⁹ ) _m —(5- to 10-membered monocyclic or fused bicyclic heteroaryl), —(CR ⁸ R ⁹ ) _m —( 4-10 membered monocyclic or fused bicyclic heterocyclyl), —(CR ⁸ R ⁹ ) _m —(C ₆ -C ₁₀ aryl), or —(CR ⁸ R ⁹ ) _m —(C ₃ -C _{6 )} cycloalkyl),
each heteroaryl, heterocyclyl, aryl, or cycloalkyl group is optionally substituted with 1-5 R ¹⁰ groups;
Alternatively, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached are a 5- to 10-membered monocyclic or fused bicyclic heteroaryl, or a 4- to 10-membered monocyclic or fused bicyclic forming a cyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1 to 2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; the heterocyclyl is optionally substituted with 1-5 R ¹⁰ groups;
m is 0 or 1;
R ⁸ and R ⁹ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Each R ¹⁰ is independently C ₁ -C ₆ alkyl, C _{1 -C} ₆ haloalkyl, C ₁ -C ₆ alkyl-OH, —CN, C ₁ -C ₆ alkyl-CN, —O(C ₁ - C ₆ alkyl), —O(C ₁ -C ₆ haloalkyl), halo, hydroxy, oxo, —CO ₂ H, —C(O)NH(C ₁ -C ₆ alkyl), —C(O)N(C ₁ -C ₆ alkyl) ₂ , —C(O)NH(C ₁ -C ₆ haloalkyl), —C(O)O(C ₁ -C ₆ alkyl), —SO ₂ —(C ₁ -C ₆ alkyl) , —SO ₂ —NH(C ₁ -C ₆ alkyl), —SO ₂ —N(C ₁ -C ₆ alkyl) ₂ , —C(O)(C ₁ -C ₆ alkyl), —(C ₁ -C ₆ alkylene)—C(O)N(C ₁ -C ₆ alkyl) ₂ , —(C ₁ -C ₆ alkylene)—C(O)NH(C ₁ _{-C 6} alkyl), C ₃ -C ₆ cycloalkyl , 5-6 membered heterocyclyl, 5-6 membered heteroaryl, —(C ₁ -C ₆ alkylene)-(5-6 membered heterocyclyl), —(C ₁ -C ₆ alkylene)-(5-6 membered heteroaryl) , —C(O)—(5- to 6-membered heterocyclyl), —C(O)-(5- to 6-membered heteroaryl), or C ₆ -C ₁₀ aryl;
each cycloalkyl, heterocyclyl, heteroaryl, or aryl group is optionally substituted with 1-5 R ¹¹ groups;
or two R ¹⁰ groups attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a spiro C ₃ -C ₆ cycloalkyl or spiro 4-6 membered heterocyclyl; , each optionally substituted by 1 to 5 R ¹¹ groups;
each R ¹¹ is independently C ₁ -C ₆ alkyl, hydroxy, oxo, or —C(O)(C ₁ -C ₆ alkyl);
R ¹² is hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
Alternatively, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, optionally contain 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen forming a 4- to 10-membered monocyclic or fused bicyclic heterocyclyl, wherein R ¹² is attached to the 4- to 10-membered monocyclic or fused bicyclic heterocyclyl to form a 7- to 14-membered fused dicyclic C ₁ -C ₆ alkylene forming a cyclic or tricyclic heterocyclyl, each heterocyclyl optionally substituted by 1 to 5 R ¹⁰ groups;
each R ¹³ is independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OH, or C ₁ -C ₃ haloalkyl;
A compound, or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

R ¹ and R ² are independently hydrogen, C ₁ -C ₃ alkyl, halo, or C ₁ -C ₃ haloalkyl ;
R ¹ and R ² are independently hydrogen, —CH ₃ , fluoro, or —CF ₃ ;
R ¹ and R ² , together with the carbon atom to which they are attached, form the group

2. The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms :

3. The compound of claim 1 or 2 , or a tautomer thereof, or ^a pharmaceutically acceptable salt thereof , wherein X is sulfur or X is CR3R4 ^.

R ³ and R ⁴ are independently hydrogen, halo, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl ;
3. The compound of claim 1 or 2, wherein R ³ and R ⁴ are independently hydrogen, fluoro, —CH ₃ , or —CF ₃ , or a tautomer thereof, or a pharmaceutically acceptable compound thereof. Salt to be served.

R ¹ and R ³ together with the carbon atom to which they are attached are moieties

3. The compound of claim 1 or 2 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms :

R ² is hydrogen, C ₁ -C ₃ alkyl, halo, or C ₁ -C ₃ haloalkyl;
R ⁴ is hydrogen, C ₁ -C ₃ alkyl, halo, or C ₁ -C ₃ haloalkyl;
each R ¹³ is independently hydrogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ alkyl-OH, or C ₁ -C ₂ haloalkyl ;
or R ² is hydrogen, —CH ₃ , fluoro, or —CF ₃ ;
R ⁴ is hydrogen, —CH ₃ , fluoro, or —CF ₃ ;
each R ¹³ is independently hydrogen, —CH ₃ , —CH ₂ OH, or —CF ₃ ;
or R ² and R ⁴ are each hydrogen;
6. The compound of Claim 5 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R13 ^is hydrogen .

R ⁵ is C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, or C ₃ -C ₄ cycloalkyl ;
7. The compound of any one of claims 1 to 6 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein R ⁵ is -CH ₃ , -CHF ₂ , or cyclopropyl .

8. A compound according to any one of Claims 1 to 7 , wherein Z is CH or Z is nitrogen, or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

9. The compound according to any one of claims 1 to 8 , wherein n is 0, or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

9. The compound according to any one of claims 1 to 8 , wherein n is 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

11. Any one of claims 1 to 10 , wherein R ⁶ is hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl , or R ⁶ is hydrogen or -CH ₃ A compound, or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

R ⁷ is C ₁ -C ₃ alkyl-OH, —(CR ⁸ R ⁹ ) _m —(5- to 6-membered monocyclic heteroaryl), —(CR ⁸ R ⁹ ) _m —(8- to 10-membered fused bicyclic heteroaryl), —(CR ⁸ R ⁹ ) _m —(4- to 6-membered monocyclic heterocyclyl), —(CR ⁸ R ⁹ ) _m —(8- to 10-membered fused bicyclic heterocyclyl) , —(CR ⁸ R ⁹ ) _m —(C ₆ -C ₁₀ aryl), or —(CR ⁸ R ⁹ ) _m —(C ₃ -C ₆ cycloalkyl),
each heteroaryl, heterocyclyl, aryl, or cycloalkyl group is optionally substituted with 1 to 5 R ¹⁰ groups;
Or ^R7 is

A compound according to any one of claims 1 to 11 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , selected from the group consisting of :

13. The compound of claim 12 , wherein m is 0 or 1 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

R ⁸ and R ⁹ are independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl , or
^13. The compound of Claim 12 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R8 and R9 ^are independently hydrogen, -CH3 _, or -CF3 _.

R ⁶ and R ⁷ together with the nitrogen atom to which they are attached are 5- to 10-membered monocyclic or fused bicyclic heteroaryl or 4- to 10-membered monocyclic or fused bicyclic forming the formula heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, each heteroaryl or heterocyclyl is optionally substituted by 1 to 5 R ¹⁰ groups ;
Alternatively, R ⁶ and R ⁷ together with the nitrogen atom to which they are attached are 5- to 6-membered monocyclic heteroaryl, 8- to 10-membered fused bicyclic heteroaryl, 4- to 6-membered forming a monocyclic heterocyclyl or an 8- to 10-membered fused bicyclic heterocyclyl, wherein each heteroaryl or heterocyclyl is optionally selected from the group consisting of nitrogen, sulfur, and oxygen. containing an additional heteroatom, each heteroaryl or heterocyclyl optionally substituted by 1 to 5 R ¹⁰ groups;
or R6 ^and R7 ^together with the nitrogen atom to which they are attached,

or
Alternatively, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, optionally contain 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen forming a 4- to 10-membered monocyclic or fused bicyclic heterocyclyl, wherein R ¹² is attached to the 4- to 10-membered monocyclic or fused bicyclic heterocyclyl to form a 7- to 18-membered fused dicyclic C ₁ -C ₆ alkylene forming a cyclic or tricyclic heterocyclyl , each heterocyclyl optionally substituted with 1 to 5 R ¹⁰ groups;
Alternatively, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, optionally contain 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen C ₁ forming a 4-6 membered monocyclic heterocyclyl and R ¹² is attached to the 4-6 membered monocyclic heterocyclyl to form a 7-11 membered fused bicyclic heterocyclyl -C ₃ alkylene, each heterocyclyl optionally substituted with 1 to 5 R ¹⁰ groups, or
Alternatively, R ⁶ and R ⁷ , together with the nitrogen atom to which they are attached, optionally contain 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen forming an 8-10 membered fused bicyclic heterocyclyl and R ¹² is attached to the 8-10 membered fused bicyclic heterocyclyl to form an 11-15 membered fused tricyclic heterocyclyl C ₁ -C ₃ alkylene, each heterocyclyl optionally substituted with 1 to 5 R ¹⁰ groups, or
or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic heterocyclyl and R 12 is a 5- to 6-membered ^monocyclic heterocyclyl Combined with:

or a tautomer thereof, or a pharmaceutically acceptable salt thereof , according to any one of claims 1 to 10 , wherein -CH ₂ - is formed .

Each R ¹⁰ , if present, is independently C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl-OH, —CN, C ₁ -C ₃ alkyl-CN, —O (C ₁ -C ₃ alkyl), —O(C ₁ -C ₃ haloalkyl), halo, hydroxy, oxo, —CO ₂ H, —C(O)NH(C ₁ -C ₃ alkyl), —C(O )NH(C ₁ -C ₃ haloalkyl), —C(O)O(C ₁ -C ₃ alkyl), —SO ₂ —(C ₁ -C ₃ alkyl), —SO ₂ —NH(C ₁ -C ₃ alkyl), —SO ₂ —N(C ₁ -C ₃ alkyl) ₂ , —C(O)(C ₁ -C ₃ alkyl), —(C ₁ -C ₃ alkylene) —C(O)N(C ₁ -C ₃ alkyl) ₂ , —(C ₁ -C ₃ alkylene)-C(O)NH(C ₁ -C ₃ alkyl), C ₃ -C ₆ cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered hetero Aryl, —(C ₁ -C ₃ alkylene)-(5- to 6-membered heterocyclyl), —(C _1-3 alkylene)-(5- to 6-membered heteroaryl ₎ , —C(O)-(5- to 6-membered heterocyclyl), —C(O)—(5- to 6-membered heteroaryl), or C ₆ -C ₁₀ aryl;
each cycloalkyl, heterocyclyl, heteroaryl, or aryl group is optionally substituted with 1-5 R ¹¹ groups;
or two R ¹⁰ groups attached to the same carbon atom, taken together with the carbon atom to which they are attached, form a spiro C ₃ -C ₆ cycloalkyl or spiro 4-6 membered heterocyclyl; , each optionally substituted by 1 to 5 R ¹¹ groups , or
or each R ¹⁰ is independently -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CF ₃ , -CHF ₂ , -CH ₂ CF ₃ , -CH ₂ OH, -CN, —CH ₂ CN, —OCH ₃ , —OCF ₃ , bromo, fluoro, hydroxy, oxo, —CO ₂ H, —C(O)NH(CH ₃ ), —C(O)N(CH ₃ ) ₂ , — C(O)NH(CF3 ₎ _, -C(O)OCH3 , -SO2CH3 _, -SO2NH ₍ CH3 ) _, -SO2N ( _CH3 ) ₂ , _-C (O ₎ _CH3 , —(CH ₂ )—C(O)N(CH ₃ ) ₂ , —(CH ₂ )—C(O)NH(CH ₃ ),

or
or two R ¹⁰ groups attached to the same carbon atom , together with the carbon atom to which they are attached,

and
A compound according to any one of claims 12 to 15, ^or a tautomer thereof, or a pharmaceutical permissible salt.

each R ¹¹ , if present, is independently C ₁ -C ₃ alkyl, hydroxy, oxo, or —C(O)(C ₁ -C ₃ alkyl);
17. The compound of claim 16 , or a tautomer thereof, or a compound thereof, wherein each R ¹¹ is independently -CH ₃ , hydroxy, oxo, or -C(O)CH ₃ A pharmaceutically acceptable salt of

R ¹² is hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl ;
R ¹² is hydrogen, —CH ₃ , or —CF ₃ ;
^18. A compound according to any one of claims 1 to 17 , or a pharmaceutically acceptable salt thereof, wherein R12 is hydrogen.

or a tautomer thereof , or a pharmaceutically acceptable salt thereof .

compounds of formula (II)

or a tautomer thereof, or a pharmaceutically acceptable salt thereof,
During the ceremony,
R ²¹ and R ²² are independently hydrogen, C ₁ -C ₆ alkyl, halo, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl;
provided that when Y is sulfur or a bond, R ²¹ and R ²² are not halo;
or R ²¹ and R ²² together with the carbon atom to which they are attached;

and
Y is CR ²³ R ²⁴ , sulfur, or a bond;
R ²³ and R ²⁴ are independently hydrogen, halo, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
or R ²¹ and R ²³ together with the carbon atom to which they are attached are moieties

forming;
R ²⁵ is C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, or C ₃ -C ₆ cycloalkyl;
W is CH or nitrogen;

teeth,

is selected from the group consisting of
wherein a nitrogen atom, if not substituted by ^R26 , is bonded to hydrogen if necessary to satisfy valences;
Each R ²⁶ is independently C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C ₆ alkyl-OH, C ₁ -C ₆ alkyl-CN, —(CR ²⁸ R ²⁹ ) _p — (4- to 6-membered heterocyclyl), —(CR ²⁸ R ²⁹ ) _p —(5- to 6-membered heteroaryl), —(CR ²⁸ R ²⁹ ) _p —(C ₆ -C ₁₀ aryl), or —(CR ²⁸ R ²⁹ ) _p- ( _C3 - _C6 cycloalkyl),
each cycloalkyl, heterocyclyl, heteroaryl, or aryl group is optionally substituted with 1-5 R ²⁷ groups;
Each R ²⁷ is independently C ₁ -C ₆ alkyl, C 1 -C ₆ alkyl-OH, C ₁ _-C ₆ haloalkyl, C ₁ -C ₆ alkyl-CN, —CN, halo, hydroxy, —O —(C ₁ -C ₆ alkyl), —O(C ₁ -C ₆ haloalkyl), oxo, —C(O)NH ₂ , —C(O)NH(C ₁ -C ₆ alkyl), —C(O ) N(C ₁ -C ₆ alkyl) ₂ , —C(O)NH(C ₁ -C ₆ haloalkyl), —CO ₂ H, —C(O)O(C ₁ -C ₆ alkyl), —SO ₂ —(C ₁ -C ₆ alkyl), —SO ₂ —NH(C ₁ -C ₆ alkyl), —SO ₂ —N(C ₁ -C ₆ alkyl) ₂ , —C(O)(C ₁ -C ₆ alkyl), —(C ₁ -C ₆ alkylene)-C(O)N(C ₁ -C ₆ alkyl) ₂ , or —(C ₁ -C ₆ alkylene)-C(O)NH(C ₁ -C ₆ alkyl);
p is 0 or 1;
R ²⁸ and R ²⁹ are independently hydrogen, C ₁ -C ₆ alkyl, or C ₁ -C ₆ haloalkyl;
each R ³⁰ is independently hydrogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, or C ₁ -C ₃ alkyl-OH;
A compound, or a tautomer thereof, or a pharmaceutically acceptable salt thereof .

R ²¹ and R ²² are independently hydrogen, C ₁ -C ₃ alkyl, halo, C ₁ -C ₃ haloalkyl, or C ₃ -C ₅ cycloalkyl ;
R ²¹ and R ²² are independently hydrogen, —CH ₃ , fluoro, —CF ₃ , or cyclobutyl;
R ²¹ and R ²² together with the carbon atom to which they are attached,

21. The compound of claim 20 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms :

22. The compound of claim 20 or 21 , wherein Y is sulfur, Y is CR23R24 ^, or Y is a bond, or a tautomer ^thereof , or a pharmaceutically acceptable salt.

R ²³ and R ²⁴ are independently hydrogen, halo, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl ;
22. The compound of claim 20 or 21 , or a tautomer thereof, or a pharmaceutically acceptable compound thereof, wherein R ²³ and R ²⁴ are independently hydrogen, fluoro, -CH ₃ , or -CF ₃ Salt to be served.

R ²¹ and R ²³ together with the carbon atom to which they are attached are moieties

22. A compound according to claim 20 or 21 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, which forms

R ²² is hydrogen, C ₁ -C ₃ alkyl, halo, or C ₁ -C ₃ haloalkyl;
R ²⁴ is hydrogen, C ₁ -C ₃ alkyl, halo, or C ₁ -C ₃ haloalkyl;
each R ³⁰ is independently hydrogen, C ₁ -C ₂ alkyl, C ₁ -C ₂ haloalkyl, or C ₁ -C ₂ alkyl-OH ;
or R ²² is hydrogen, —CH ₃ , F, or —CF ₃ ;
R ²⁴ is hydrogen, —CH ₃ , F, or —CF ₃ ;
each R ³⁰ is independently hydrogen, —CH ₃ , —CF ₃ , or —CH ₂ OH;
or R ²² and R ²⁴ are each hydrogen;
25. The compound of Claim 24 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein each R30 ^is hydrogen .

R ²⁵ is C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, or C ₃ -C ₄ cycloalkyl ;
26. The compound of any one of claims 20 to 25 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein R ²⁵ is -CH ₃ , -CF ₃ , or cyclopropyl .

27. The compound of any one of claims 20-26 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein W is CH.

27. The compound of any one of claims 20-26 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein W is nitrogen.

Each R ²⁶ , if present, is independently C ₁ -C ₃ alkyl, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl-OH, C ₁ -C ₃ alkyl-CN, —(CR ²⁸ R ²⁹ ) _p -(4- to 6-membered heterocyclyl), -(CR ²⁸ R ²⁹ ) _p -(5- to 6-membered heteroaryl), -(CR ²⁸ R ²⁹ ) _p -(C ₆ -C ₁₀ aryl), or - (CR ²⁸ R ²⁹ ) _p -(C ₃ -C ₆ cycloalkyl),
each heterocyclyl, heteroaryl, aryl, or cycloalkyl group is optionally substituted with 1 to 5 R ²⁷ groups;
or each R ²⁶ is independently -CH ₃ , -CF ₃ , -CH ₂ OH, -CH ₂ CN,

or a tautomer thereof , or a pharmaceutically acceptable salt thereof , according to any one of claims 20 to 28 .

30. The compound of claim 29 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein p is 0 or 1 .

R ²⁸ and R ²⁹ are independently hydrogen, C ₁ -C ₃ alkyl, or C ₁ -C ₃ haloalkyl , or
^31. The compound of Claim 30 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , wherein R28 and R29 ^are independently hydrogen, -CH3 _, or -CF3 _.

Each R ²⁷ , if present, is independently C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyl-OH, C ₁ -C ₃ haloalkyl, C ₁ -C ₃ alkyl-CN, —CN, halo, hydroxy, —O—(C ₁ -C ₃ alkyl), —O(C ₁ -C ₃ haloalkyl), oxo, —C(O)NH ₂ , —C(O)NH(C ₁ -C ₃ alkyl), —C(O)NH(C ₁ -C ₃ haloalkyl), —C(O)N(C ₁ -C ₃ alkyl) ₂ , —CO ₂ H, —C(O)O(C ₁ -C ₃ alkyl) , —SO ₂ —(C ₁ -C ₃ alkyl), —SO ₂ —NH(C ₁ -C ₃ alkyl), —SO ₂ —N(C ₁ -C ₃ alkyl) ₂ , —C(O)(C ₁ -C ₃ alkyl), -(C ₁ -C ₃ alkylene)-C(O)N(C ₁ -C ₃ alkyl) ₂ , or -(C ₁ -C ₃ alkylene)-C(O)NH(C ₁ -C ₃ alkyl) , or
Each R ²⁷ is independently —CH ₃ , —CH ₂ OH, —CF ₃ , —CH ₂ CN, —CN, F, Cl, hydroxy, —OCH ₃ , —OCF ₃ , oxo, —C(O )NH ₂ , —C(O)NH(CH ₃ ), —C(O)NH(CF ₃ ), —C(O)N(CH ₃ ) ₂ , —CO ₂ H, —C(O)OCH ₃ , —SO ₂ —(CH ₃ ), —SO ₂ —NH(CH ₃ ), —SO ₂ —N(CH ₃ ) ₂ , —C(O)(CH ₃ ), —(CH ₂ )—C(O )N(CH ₃ ) ₂ , or —(CH ₂ )—C( O )NH(CH ₃ ), or a tautomer thereof, or pharmaceutically acceptable salts thereof .

Formula (II-A)

has
21. The compound of claim 20 , wherein ^R21 , ^R22 , and ^R25 are as defined in the compound of formula (II), or a tautomer thereof, or a pharmaceutically acceptable salt.

or a tautomer thereof , or a pharmaceutically acceptable salt thereof .

35. A pharmaceutical composition comprising a compound according to any one of claims 1-34 , or a tautomer thereof, or a pharmaceutically acceptable salt thereof , and a pharmaceutically acceptable excipient.

A method of modulating the activity of an immune cell in vitro or ex vivo , comprising contacting said immune cell with an amount of a Cbl-b inhibitor effective to modulate the activity of said immune cell, said Cbl- The b inhibitor is a compound according to any one of claims 1 to 34 ,
said immune cells comprise T cells, B cells, or natural killer (NK) cells;
said immune cells are or are isolated from a blood sample from a mammalian subject;
said immune cells are tumor infiltrating lymphocytes (TILs) isolated or isolated from a tumor from a mammalian subject with cancer;
said immune cells comprise T cells, and modulating the activity of said T cells is one of: increased T cell activation, increased T cell proliferation, decreased T cell depletion, and decreased T cell tolerance; or contains multiple or
wherein the increased T cell activation comprises increased production of cytokines and/or said cytokines are one or more selected from the group consisting of IL-2, IFN-γ, TNFα and GM-CSF including and/or
increased T cell activation comprises increased cell surface expression of one or more T cell activation markers and/or said T cell activation markers are selected from the group consisting of CD25, CD69 and CTLA4 and/or
said T cells were or have been in contact with an anti-CD3 antibody, alone or in combination with an anti-CD28 antibody, and/or
further comprising culturing said immune cells with IL-2 alone or in combination with anti-CD3 and/or anti-CD28 antibodies, and/or
said immune cells comprise NK cells, and modulating NK cell activity comprises increasing NK cell activation, and/or
increased NK cell activation comprises increased production of cytokines, and/or
said cytokine comprises one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β;
said immune cells comprise B cells, wherein modulating B cell activity comprises increasing B cell activation, optionally increasing B cell activation comprises increasing expression of CD69, and /or
said immune cells are human immune cells, and/or
said immune cell comprises a recombinant chimeric receptor, said recombinant chimeric receptor optionally being a chimeric antigen receptor;
Method.

A method of producing modified immune cells, comprising culturing a cell population containing immune cells in the presence of an amount of a Cbl-b inhibitor effective to modulate the activity of said immune cells, thereby producing said modified immune cells. A method comprising generating immune cells, wherein said Cbl-b inhibitor is a compound according to any one of claims 1-34 .

further comprising culturing said immune cells with an anti-CD3 antibody alone or in combination with an anti-CD28 antibody;
further comprising culturing said immune cells with IL-2 alone or in combination with anti-CD3 and/or anti-CD28 antibodies;
38. The method of claim 37 , further comprising collecting said modified immune cells .

a tumor wherein said immune cells are or are isolated from a blood sample from a mammalian subject or wherein said immune cells are or are isolated from a tumor from a mammalian subject having cancer are infiltrating lymphocytes (TILs), or
the immune cells are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells;
the modified immune cells are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells;
said immune cells are tumor infiltrating lymphocytes (TILs);
said immune cells are human immune cells;
said immune cells or said modified immune cells comprise a recombinant chimeric receptor;
wherein said recombinant chimeric receptor is a chimeric antigen receptor;
39. A method according to claim 37 or 38 .

Use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity, said Cbl-b inhibitor comprising any one of claims 1-34 Use, which is a compound according to .

Use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer, wherein said Cbl-b inhibitor is a compound according to any one of claims 1-34 .

A Cbl-b inhibitor for use in treating or preventing a disease or condition associated with Cbl-b activity, said Cbl-b inhibitor according to any one of claims 1-34 . A Cbl-b inhibitor, which is a compound of

A Cbl-b inhibitor for use in treating cancer, wherein said Cbl-b inhibitor is a compound according to any one of claims 1-34 . .

35. A composition comprising a compound according to any one of claims 1-34 for use in treating cancer in combination with an effective amount of an additional therapeutic agent .

the composition and the additional therapeutic agent are administered sequentially, in any order;
45. The composition of claim 44 , wherein said composition and said additional therapeutic agent are administered simultaneously .

the additional therapeutic agent comprises an immune checkpoint inhibitor;
46. The composition of claim 44 or 45 , wherein said additional therapeutic agent comprises an anti-neoplastic agent .

The immune checkpoint inhibitor is PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of , TIM3 (CD366), and VISTA;
said immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152);
said at least one inhibitory checkpoint molecule comprises PD-1, and optionally said immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, semiplimab, and biosimilars thereof;
said at least one inhibitory checkpoint molecule comprises PD-L1, and optionally said immune checkpoint inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof;
said at least one inhibitory checkpoint molecule comprises CTLA-4, and optionally said immune checkpoint inhibitor is selected from the group consisting of ipilimumab, tremelimumab, and biosimilars thereof;
said immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof, optionally said antibody or fragment is a human or humanized antibody or fragment;
or the antineoplastic agent is classified in the group consisting of cytotoxic antibiotics, plant alkaloids, antimetabolites, alkylating agents, and other antineoplastic agents;
said antineoplastic agent comprises a cytotoxic antibiotic, optionally said cytotoxic antibiotic is ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, aclarubicin , epirubicin, daunorubicin, doxorubicin, and dactinomycin; or
The antineoplastic agent comprises a plant alkaloid, optionally wherein the plant alkaloid is trabectedin, cabazitaxel, paclitaxel, polygumex, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, bintaforide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine or is selected from the group consisting of
wherein said antineoplastic agent comprises an antimetabolite, optionally said antimetabolite is a pyrimidine analogue, a purine analogue, or a folic acid analogue, optionally said antimetabolite is floxyuridine, triflu selected from the group consisting of lysine, tegafur, fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nerarabine, clofarabine, fludarabine, cladribine, thioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate or
said antineoplastic agent comprises an alkylating agent, optionally wherein said alkylating agent is dacarbazine, temozolomide, pipobroman, mitobronitol, etogluside, uracil mustard, lanimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, selected from the group consisting of carbocone, triaziquone, thiotepa, mannosulphan, treosulfan, busulfan, bendamustine, prednimastine, trophosphamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide;
said antineoplastic agents comprise other antineoplastic agents selected from the group consisting of platinum compounds, protein kinase inhibitors, and other agents;
said antineoplastic agent comprises a platinum compound, optionally said platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatylene;
the anti-neoplastic agent comprises a protein kinase inhibitor;
47. The composition of claim 46 , wherein said antineoplastic agent comprises other agents .

A composition comprising a compound according to any one of claims 1-34 for use in the treatment of cancer in combination with an effective amount of radiotherapy .

whether the radiation therapy is external beam radiation therapy;
49. The composition of claim 48 , wherein said radiotherapy is internal radiotherapy .

A composition for administration by enteral administration, optionally wherein said enteral administration is oral administration,
wherein said composition is formulated to be administered by parenteral administration, optionally said parenteral administration is intratumoral injection or said parenteral administration consists of intravenous, intraperitoneal and subcutaneous through a path selected from the group,
50. The composition of any one of claims 44-49 .

whether said cancer is a blood cancer;
the hematologic cancer is lymphoma, leukemia, or myeloma;
whether the cancer is a non-hematologic cancer;
wherein said non-hematological cancer is carcinoma, sarcoma, or melanoma;
A composition according to any one of claims 44-50 .

A method of generating an expanded population of tumor-infiltrating lymphocytes (TILs), comprising:
(a ) obtaining a biological sample comprising TILs from an individual treated according to the composition of any one of claims 44-51 ;
(b) culturing said TILs in a cell culture medium comprising at least one T cell growth factor to produce an expanded population of TILs.

53. The method of claim 52 , wherein said at least one T cell growth factor comprises IL-2.

the cell culture medium further comprises an anti-CD3 antibody or both an anti-CD3 antibody and an anti-CD28 antibody;
said cell culture medium further comprises said Cbl-b inhibitor;
wherein said cell culture medium further comprises irradiated feeder cells;
54. A method according to claim 52 or 53 .

55. A composition comprising said expanded population of TILs produced by the method of any one of claims 52-54 and a physiologically acceptable buffer.

A method of generating an expanded population of tumor-infiltrating lymphocytes (TILs), comprising:
(a) obtaining a biological sample comprising TILs from an individual with cancer who has received or has received an effective amount of a Cbl-b inhibitor which is a compound according to any one of claims 1-34 ; and,
(b) culturing said TILs in a cell culture medium comprising at least one T cell growth factor to produce an expanded population of TILs.

said cancer in said mammalian subject is a non-hematologic cancer, optionally said non-hematologic cancer is sarcoma, carcinoma, or melanoma;
wherein said mammalian subject with cancer is a human;
37. The method of claim 36 .

36. A pharmaceutical composition according to claim 35 for use in generating a population of tumor infiltrating lymphocytes (TIL).

37. Use of the cells of claim 36 in the manufacture of a medicament for treating or preventing diseases or conditions associated with Cbl-b activity.

37. Use of cells according to claim 36 in the manufacture of a medicament for treating cancer.

37. A composition comprising the cells of claim 36 for use in treating or preventing diseases or conditions associated with Cbl-b activity.

37. A composition comprising the cells of claim 36 for use in treating cancer.

Use of the cells of claim 37 in the manufacture of a medicament for treating or preventing diseases or conditions associated with Cbl-b activity.

38. Use of cells according to claim 37 in the manufacture of a medicament for treating cancer.

38. A composition comprising the cells of claim 37 for use in treating or preventing diseases or conditions associated with Cbl-b activity.

38. A composition comprising the cells of claim 37 for use in treating cancer.