RU2021107956A

RU2021107956A - COMBINATION THERAPY USING CHEMOKINE RECEPTOR 4 (CCR4) C-C ANTAGONISTS AND ONE OR MORE CHECKPOINT INHIBITORS

Info

Publication number: RU2021107956A
Application number: RU2021107956A
Authority: RU
Inventors: Шицзе ЛИ; Венкат Редди Мали; Раджиндер Сингх; Цзюй Ян; Пэнли Чжан
Original assignee: Кемосентрикс, Инк.
Priority date: 2018-08-29
Filing date: 2019-08-28
Publication date: 2022-09-29

Claims

1. A method of treating cancer in a mammal, comprising administering an effective amount of a C-C chemokine receptor 4 (CCR4) antagonist and one or more immune checkpoint inhibitors.

2. The method of claim 1 wherein said CCR4 antagonist is a selective CCR4 antagonist.

3. The method according to claim 1 or 2, wherein said CCR4 antagonist has the formula:

(I)

or a pharmaceutically acceptable salt thereof, in which

R ¹ is selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, C _3-8 cycloalkyl, halogen, -CN, -SO ₂ Me and -C(O)NH ₂ ;

each R ² is selected from C _1-8 alkyl, C _1-8 haloalkyl, halogen, -CN and C _1-8 alkoxy; or two R ² groups attached to adjacent carbon atoms are optionally connected to form a 5- or 6-membered ring (aliphatic or aromatic, cycloalkyl or heterocycloalkyl);

R ³ is selected from hydrogen, methyl and C _1-4 haloalkyl;

R ⁴ is selected from hydrogen, C _1-8 alkyl, C _1-8 haloalkyl and C _1-8 hydroxyalkyl;

each of the subscripts n is independently an integer from 0 to 3;

B is a bond or C(O);

Q is selected from C, CH, N, O, S, S(O) and SO ₂ ;

W, X, Y, and Z are independently selected from C, CH, and N, but Q and W are not both N;

R ⁵ and R ⁶ are absent or independently selected from H, -OH, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-4 alkoxy-C _1-4 alkyl, -C(O)NR ^a R ^b , C _1-8 alkylene-C(O)NR ^a R ^b , -NH-C _1-4 alkylene-C(O)NR ^a R ^b , -C(O)-C _1-4 alkylene-NR ^a R ^b , -CO ₂ H and acid isosteres, C _1-8 alkylene-CO ₂ H and acid isosteres, -N(R ^a )C(O)NR ^a R ^b , C _1-8 alkylene-N(R ^a )C(O )NR ^a R ^b , -NR ^a R ^b , C _1-8 alkylene-NR ^a R ^b , C _1-8 alkoxy, -C(O)OR ^a , C _1-8 alkylene-C(O)OR ^a , -CN, -C(O)R ^a , -SO ₂ R ^a and -N(R ^a )C(O)R ^b ;

where each R ^a and R ^b is independently selected from hydrogen, C _1-8 alkyl, C _1-8 hydroxyalkyl, C _1-8 haloalkyl and C _1-8 alkoxy; and

R ⁷ is absent or selected from H, C _1-8 alkyl and C _1-8 haloalkyl.

4. The method according to claim 1 or 2, wherein said CCR4 inhibitor has the formula

(Compound 1)

or a pharmaceutically acceptable salt thereof.

5. The method of claim 1 or 2, wherein said CCR4 inhibitor has the formula

(Compound 2)

or a pharmaceutically acceptable salt thereof.

6. The method of claim 1 or 2, wherein said CCR4 inhibitor has the formula

(Compound 3)

or a pharmaceutically acceptable salt thereof.

7. The method of claim 1 or 2, wherein said CCR4 inhibitor has the formula

(Compound 4)

or a pharmaceutically acceptable salt thereof.

8. The method according to any one of paragraphs. 1-7, wherein said one or more immune checkpoint inhibitors is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor or a programmed cell death protein-1 (PD-1) inhibitor.

9. The method of claim 8 wherein said PD-1 inhibitor is a small molecule PD-1/PD-L1 inhibitor.

10. The method of claim 9 wherein said small molecule PD-1/PD-L1 inhibitor is selected from the group consisting of

or

.

11. The method of claim 9 wherein said PD-1 inhibitor is a compound having formula (II)

(II)

or a pharmaceutically acceptable salt thereof; where:

R ¹ is selected from the group consisting of halogen, C _5-8 cycloalkyl, C _6-10 aryl and thienyl, where C _6-10 aryl and thienyl are optionally substituted with 1-5 R ^x substituents;

each R ^{x is} independently selected from the group consisting of halogen, -CN, -R ^c , -CO ₂ R ^a , -CONR ^a R ^b , -C(O)R ^a , -OC(O)NR ^a R ^b , - NR ^b C(O)R ^a , -NR ^b C(O) ₂ R ^c , -NR ^a -C(O)NR ^a R ^b , -NR ^a R ^b , -OR ^a , -OX ¹ -OR ^a , -OX ¹ -CO ₂ R ^a , -OX ¹ -CONR ^a R ^b , -X ¹ -OR ^a , -X ¹ -NR ^a R ^b , -X ¹ -CO ₂ R ^a , -X ¹ -CONR ^a R ^b , -SF ₅ and -S(O) ₂ NR ^a R ^b , where each X ¹ is C _1-4 alkylene; each R ^a and R ^b is independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or when attached to the same nitrogen atom, they can combine with this nitrogen atom to form a five- or six-membered ring, having 0 to 2 additional heteroatoms as ring members selected from N, O and S and optionally substituted with an oxo group; each R ^c is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, C _2-8 alkynyl, and C _1-8 haloalkyl; and, optionally, when two R ^x substituents are located on adjacent atoms, they combine to form a fused five-, six-, or seven-membered carbocyclic or heterocyclic ring, optionally substituted with 1-3 substituents independently selected from halo, oxo, C _{1- 8} haloalkyl and C _1-8 alkyl;

each R ^2a , R ^2b and R ^2c is independently selected from the group consisting of H, halogen, -CN, -R ^d , -CO ₂ R ^e , -CONR ^e R ^f , -C(O)R ^e , -OC( O)NR ^e R ^f , -NR ^f C(O)R ^e , -NR ^f C(O) ₂ R ^d ,
-NR ^e -C(O)NR ^e R ^f , -NR ^e R ^f , -OR ^e , -OX ² -OR ^e , -OX ² -NR ^e R ^f , -OX ² -CO ₂ R ^e ,
-OX ² -CONR ^e R ^f , -X ² -OR ^e , -X ² -NR ^e R ^f , -X ² -CO ₂ R ^e , -X ² -CONR ^e R ^f , -SF ₅ , -S( O) ₂ NR ^e R ^f , C _6-10 aryl and C _5-10 heteroaryl, where each X ² is C _1-4 alkylene; each R ^e and R ^{f is} independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or when attached to the same nitrogen atom, they can combine with this nitrogen atom to form a five- or six-membered ring, having 0 to 2 additional heteroatoms as ring members selected from N, O and S and optionally substituted with an oxo group; each R ^d is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl and C _1-8 haloalkyl;

R ³ is selected from the group consisting of -NR ^g R ^h and C _4-12 heterocyclyl, where C _4-12 heterocyclyl is optionally substituted with 1-6 R ^y ;

each R ^y is independently selected from the group consisting of halogen, -CN, -R ⁱ , -CO ₂ R ^j , -CONR ^j R ^k , -CONHC _1-6 alkyl-OH, -C(O)R ^j , -OC (O)NR ^j R ^k , -NR ^j C(O)R ^k , -NR ^j C(O) ₂ R ^k , CONOH, PO ₃ H ₂ , -NR ^j -C _1-6 alkyl-C(O) ₂ R ^k , -NR ^j C(O)NR ^j R ^k , -NR ^j R ^k , -OR ^j , -S(O) ₂ NR ^j R ^k , -OC _1-6 alkyl-OR ^j , -OC _{1 -6} alkyl-NR ^j R ^k , -OC _1-6 alkyl-CO ₂ R ^j , -OC _1-6 alkyl-CONR ^j R ^k , -C _1-6 alkyl-OR ^j , -C _1-6 alkyl- NR ^j R ^k , -C _1-6 alkyl-CO ₂ R ^j , -C _1-6 alkyl-CONR ^j R ^k and SF ₅ ,

where the C _1-6 alkyl portion of R ^y is optionally further substituted with OH, SO ₂ NH ₂ , CONH ₂ , CONOH, PO ₃ H ₂ , COO-C _1-8 alkyl or CO ₂ H, where each R ^j and R ^k is independently selected from hydrogen, C _1-8 alkyl optionally substituted with 1 to 2 substituents selected from OH, SO ₂ NH ₂ , CONH ₂ , CONOH, PO ₃ H ₂ , COO-C _1-8 alkyl or CO ₂ H, and C _{1 -8} haloalkyl optionally substituted with 1-2 substituents selected from OH, SO ₂ NH ₂ , CONH ₂ , CONOH, PO ₃ H ₂ , COO-C _1-8 alkyl or CO ₂ H, or when attached to the same atom nitrogen R ^j and R ^k can combine with this nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O and S, and optionally substituted with an oxo group; each R ⁱ is independently selected from the group consisting of -OH, C _1-8 alkyl, C _2-8 alkenyl and C _1-8 haloalkyl, each of which may be optionally substituted with OH, SO ₂ NH ₂ , CONH ₂ , CONOH, PO ₃ H ₂ , COO-C _1-8 alkyl or CO ₂ H;

R ^g is selected from the group consisting of H, C _1-8 haloalkyl and C _1-8 alkyl;

R ^h is selected from -C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 alkyl-COOH, C _1-8 alkyl-OH, C _1-8 alkyl-CONH ₂ , C _1-8 alkyl-SO ₂ NH ₂ , C _1-8 alkyl-PO ₃ H ₂ , C _1-8 alkyl-CONOH, C _1-8 alkyl-NR ^h1 R ^h2 , -C(O)-C _1-8 alkyl, -C(O) -C _1-8 alkyl-OH, -C(O)-C _1-8 alkyl-COOH, C _3-10 cycloalkyl, -C _3-10 cycloalkyl-COOH, -C _3-10 cycloalkyl-OH, C _{4- 8} heterocyclyl, -C _4-8 heterocyclyl-COOH, -C _4-8 heterocyclyl-OH, -C _1-8 alkyl-C _4-8 heterocyclyl, -C _1-8 alkyl-C _3-10 cycloalkyl, C _{5- 10} heteroaryl, -C _1-8 alkyl-C _5-10 heteroaryl, C ₁₀ carbocyclyl, -C _1-8 alkyl-C _6-10 aryl, -C _1-8 alkyl-(C=O)-C _6-10 aryl, -C _1-8 alkyl-NH(C=O)-C _1-8 alkenyl, -C _1-8 alkyl-NH(C=O)-C _1-8 alkyl, -C _1-8 alkyl-NH (C=O)-C _1-8 alkynyl, -C _1-8 alkyl-(C=O)-NH-C _1-8 alkyl-COOH and -C _1-8 alkyl-(C=O)-NH- C _1-8 alkyl-OH, optionally substituted with CO ₂ H; or

R ^h combined with the N to which it is attached is a mono-, di- or tripeptide containing 1-3 natural amino acids and 0-2 non-natural amino acids, while

unnatural amino acids have an alpha carbon substituent selected from C _2-4 hydroxyalkyl, C _1-3 alkyl guanidinyl and C _1-4 alkyl heteroaryl,

the alpha carbon of each natural or non-natural amino acid is optionally further substituted with a methyl group, and

the terminal fragment of a mono-, di-, or tripeptide is selected from the group consisting of C(O)OH, C(O)OC _1-6 alkyl and PO ₃ H ₂ where

R ^h1 and R ^h2 are each independently selected from the group consisting of H, C _1-6 alkyl and C _1-4 hydroxyalkyl;

The C _1-8 alkyl portions of R ^h are optionally further substituted with 1-3 substituents independently selected from OH, COOH, SO ₂ NH ₂ , CONH ₂ , CONOH, COO-C _1-8 alkyl, PO ₃ H ₂ and C _5-6 heteroaryl optionally substituted with 1-2 C _1-3 alkyl substituents,

The C ₁₀ carbocyclyl, C _5-10 heteroaryl, and C _6-10 aryl portions of R ^h are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) ₂ , COOH, SO ₂ NH ₂ , CONH ₂ , CONOH, PO ₃ H ₂ , COO-C _1-8 alkyl, C _1-4 alkyl, C _1-4 alkyl-OH, C _1-4 alkyl-SO ₂ NH ₂ , C _1-4 alkyl CONH ₂ , C _1-4 alkyl- CONOH, C _1-4 alkyl-PO ₃ H ₂ , C _1-4 alkyl-COOH and phenyl, and

C _4-8 heterocyclyl and C _3-10 cycloalkyl portions of R ^h are optionally substituted with 1-4 R ^w substituents;

each R ^w substituent is independently selected from C _1-4 alkyl, C _1-4 alkyl-OH, C _1-4 alkyl-COOH, C _1-4 alkyl-SO ₂ NH ₂ , C _1-4 alkyl CONH ₂ , C _{1 -4} alkyl-CONOH, C _1-4 alkyl-PO ₃ H, OH, COO-C _1-8 alkyl, COOH, SO ₂ NH ₂ , CONH ₂ , CONOH, PO ₃ H ₂ and oxo groups;

R ⁴ is selected from the group consisting of OC _1-8 alkyl, OC _1-8 haloalkyl, OC _1-8 alkyl-R ^z , C _6-10 aryl, C _5-10 heteroaryl, -OC _1-4 alkyl-C _{6 -10} aryl and -OC _1-4 alkyl-C _5-10 heteroaryl, where C _6-10 aryl and C _5-10 heteroaryl are optionally substituted with 1-5 R ^z ;

each R ^{z is} independently selected from the group consisting of halogen, -CN, -R ^m , -CO ₂ R ⁿ , -CONR ⁿ R ^p , -C(O)R ⁿ , -OC(O)NR ⁿ R ^p , - NR ⁿ C(O)R ^p , -NR ⁿ C(O) ₂ R ^m , -NR ^n- C(O)NR ⁿ R ^p ,
-NR ⁿ R ^p , -OR ⁿ , -OX ³ -OR ⁿ , -OX ³ -NR ⁿ R ^p , -OX ³ -CO ₂ R ⁿ , -OX ³ -CONR ⁿ R ^p ,
-X ³ -OR ⁿ , -X ³ -NR ⁿ R ^p , -X ³ -CO ₂ R ⁿ , -X ³ -CONR ⁿ R ^p , -SF ₅ , -S(O) ₂ R ⁿ R ^p , - S(O) ₂ NR ⁿ R ^p , and a 3-7 membered carbocyclic or 4-7 membered heterocyclic ring, wherein the 3-7 membered carbocyclic or 4-7 membered heterocyclic ring is optionally substituted with 1-5 R ^t , where each R ^t is independently selected from the group consisting of C _1-8 alkyl, C _1-8 haloalkyl, -CO ₂ R ⁿ , -CONR ⁿ R ^p , -C(O)R ⁿ , -OC(O)NR ⁿ R ^p , -NR ⁿ C(O)R ^p , -NR ⁿ C(O) ₂ R ^m , -NR ^n- C(O)NR ⁿ R ^p , -NR ⁿ R ^p , -OR ⁿ , -OX ³ -OR ⁿ , -OX ³ -NR ⁿ R ^p , -OX ³ -CO ₂ R ⁿ , -OX ³ -CONR ⁿ R ^p , -X ³ -OR ⁿ , -X ³ -NR ⁿ R ^p ,
-X ³ -CO ₂ R ⁿ , -X ³ -CONR ⁿ R ^p , -SF ₅ and -S(O) ₂ NR ⁿ R ^p ;

where each X ³ is C _1-4 alkylene; each R ⁿ and R ^p is independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or when attached to the same nitrogen atom, they can combine with this nitrogen atom to form a five- or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O and S and optionally substituted with an oxo group; each R ^m is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl and C _1-8 haloalkyl; and, optionally, when two R ^z substituents are on adjacent atoms, they combine to form a fused five- or six-membered carbocyclic or heterocyclic ring, optionally substituted with an oxo group;

n is 0, 1, 2 or 3;

each R ⁵ is independently selected from the group consisting of halogen, -CN, -R ^q , -CO ₂ R ^r , -CONR ^r R ^s , -C(O)R ^r , -OC(O)NR ^r R ^s , - NR ^r C(O)R ^s , -NR ^r C(O) ₂ R ^q , -NR ^r -C(O)NR ^r R ^s , -NR ^r R ^s , -OR ^r , -OX ⁴ -OR ^r , -OX ⁴ -NR ^r R ^s , -OX ⁴ -CO ₂ R ^r , -OX ⁴ -CONR ^r R ^s , -X ⁴ -OR ^r , -X ⁴ -NR ^r R ^s , -X ⁴ -CO ₂ R ^r , -X ⁴ -CONR ^r R ^s , -SF ₅ , -S(O) ₂ NR ^r R ^s , where each X ⁴ is C _1-4 alkylene; each R ^r and R ^s is independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or, when attached to the same nitrogen atom, can combine with this nitrogen atom to form a five- or six-membered ring having from 0 up to 2 additional heteroatoms as ring members selected from N, O and S and optionally substituted with oxo; each R ^q is independently selected from the group consisting of C _1-8 alkyl and C _1-8 haloalkyl;

R ^6a is selected from the group consisting of H, C _1-4 alkyl and C _1-4 haloalkyl;

each R ^6b is independently selected from the group consisting of F, C _1-4 alkyl, OR ^u , C _1-4 haloalkyl, NR ^u R ^v , where each R ^u and R ^v are independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or when attached to the same nitrogen atom, they can combine with this nitrogen atom to form a five- or six-membered ring having 0 to 2 additional heteroatoms as ring members selected from N, O and S , and optionally substituted with an oxo group; and

m is 0, 1, 2, 3, or 4.

12. The method of claim 8, wherein said PD-1 inhibitor is an anti-PD-1 antibody.

13. The method of claim 12 wherein said anti-PD-1 antibody is selected from the group consisting of Nivolumab, Pembrolizumab, and Pidilizumab.

14. The method of claim 8, wherein said CTLA-4 inhibitor is an anti-CTLA-4 antibody.

15. The method of claim 14, wherein said anti-CTLA-4 antibody is selected from the group consisting of Ipilimumab, Tremelimumab, AGEN1884, and AGEN2041.

16. The method according to any one of paragraphs. 1-7, wherein said one or more immune checkpoint inhibitors are a cytotoxic T-lymphocyte associated protein 4 (CTLA-4) inhibitor and a programmed cell death protein-1 (PD-1) inhibitor.

17. The method of claim 16 wherein said PD-1 inhibitor is an anti-PD-1 antibody and said CTLA-4 inhibitor is an anti-CTLA-4 antibody.

18. The method of claim 17 wherein said anti-PD-1 inhibitor is selected from the group consisting of Nivolumab, Pembrolizumab and Pidilizumab and said CTLA-4 inhibitor is selected from the group consisting of Ipilimumab, Tremelimumab, AGEN1884 and AGEN2041.

19. The method according to any one of paragraphs. 1-15, wherein said cancer is a solid cancer.

20. The method of claim 19 wherein said cancer is colon cancer.

21. The method of claim 19 wherein said cancer is pancreatic cancer.