IP Library › Granted Patent US 11,370,794

Granted Patent B2

US 11,370,794 · App. 16/348,816 · Granted Jun 28, 2022

Toll-like receptor antagonist compounds and methods of use

Inventors: Albert Frederick Candia, III (San Mateo, CA); Richard Thomas Beresis (San Francisco, CA); Robert L. Coffman (Portola Valley, CA)

Assignee: DYNAVAX TECHNOLOGIES CORPORATION

C07D487/04 A61K45/06 C07D231/56 C07D235/18 C07D519/00

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Quick Facts

Patent No.: US 11,370,794
App. No.: 16/348,816
Granted: Jun 28, 2022
Kind: B2

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Abstract

The invention relates to compounds of formula (I): or a salt or solvate thereof, wherein the variables are as described herein. Compounds of formula (I), and pharmaceutical compositions thereof, are antagonists of toll-like receptors such as TLR7, TLR8, and/or TLR9. In certain embodiments, compounds of the invention are useful for inhibiting immune response and treating diseases associated with undesirable immune response.

Claims (656)

1. A compound of formula (I):

or a salt or solvate thereof, wherein:

A 1 is C or N;

A 2 is CR 2 , N, or NR 2a ;

A 3 is CR 30 , N, or NR 3a ;

A 4 is N or CR 4 ;

A 5 is N or CR 5 ;

provided that two, three or four of A 1 , A 2 , A 3 , A 4 , and A 5 are N; wherein the dashed lines indicate partial or delocalized bonds in an aromatic ring;

i and j are independently 0, 1, or 2;

R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 2 , R 3 , R 30 , R 4 , and R 5 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 2a and R 3a is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl, and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 6 , where present, is independently C 1 -C 6 alkyl optionally substituted by R 10A ;

n is 0, 1, 2, 3, or 4;

U is a bond or methylene optionally substituted by R 10 ;

V is a bond or C 1 -C 2 alkylene optionally substituted by R 10 ;

W is a bond or C 1 -C 4 alkylene optionally substituted by one or both of R W1 and R W2 ;

X is CR X1 R X2 —;

Y is CR Y1 R Y2 —;

R 7 is hydrogen, C 1 -C 6 alkyl, or taken together with R 8 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R X1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

R 8 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , C 6 -C 14 aryl, 5-10-membered heteroaryl, or taken together with R 7 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R X1 , R X2 or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R 10 , where present, to form a C 1 -C 6 alkylene, or taken together with R 9 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by 10° or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R 9 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , or taken together with R 8 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R Y2 , R 8 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R W1 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 , or R Y1 to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R W2 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R W2 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R W1 , R X1 ; R X2 ; R Y1 ; R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R X1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R Y1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R X2 is hydrogen or C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R X1 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R 8 to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

R Y1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 , or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 ; R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R Y2 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y1 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R 8 to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

each R 10 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, halogen, —CN, —OR 11 , —SR 11 , —NR 12 R 13 , —NO 2 , —C═NH(OR 11 ), —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —C(O)NR 12 R 13 , —NR 11 C(O)R 12 , —NR 11 C(O)OR 12 , —NR 11 C(O)NR 12 R 13 , —S(O)R 11 , —S(O) 2 R 11 , —NR 11 S(O)R 12 , —NR 11 S(O) 2 R 12 , —S(O)NR 12 R 13 , —S(O) 2 NR 12 R 13 , or —P(O)(OR 12 ) (OR 13 ); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl and C 6 -C 14 aryl of R 10 are independently optionally substituted by halogen, —CN, oxo, —OR 14 , —SR 14 , —NR 14 R 15 , —C(O)R 14 , —C(O)OR 14 , —S(O)R 14 , —S(O) 2 R 14 , —P(O)(OR 14 )(OR 15 ), 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen, or taken together with R 8 to form a C 1 -C 6 alkylene;

each R 10A is independently oxo or R 10 ;

R 11 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, or 3-6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, and 3-6-membered heterocyclyl of R 11 are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17 , —P(O)(OR 16 )(OR 17 ), or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

R 12 and R 13 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, or 3-6 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl, and 3-6 membered heterocyclyl of R 12 and R 13 are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17 or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

or R 12 and R 13 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 16 , —NR 16 R 17 , or C 1 -C 6 alkyl optionally substituted by halogen, oxo, or —OH;

R 14 and R 15 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;

or R 14 and R 15 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, or C 1 -C 6 alkyl optionally substituted by halogen or oxo; and

R 16 and R 17 are each independently hydrogen, C 1 -C 6 alkyl optionally substituted by halogen or oxo, C 2 -C 6 alkenyl optionally substituted by halogen or oxo, or C 2 -C 6 alkynyl optionally substituted by halogen or oxo;

or R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, or C 1 -C 6 alkyl optionally substituted by oxo or halogen;

provided that when R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , and the 5-10-membered heteroaryl is a fused ring heteroaryl comprising an aryl moiety fused to a heterocycle containing the nitrogen atom to which R 8 and R 9 are attached, the aryl moiety is not adjacent to the nitrogen atom to which R 8 and R 9 are attached;

and provided that the compounds is not a compound selected from the group consisting of:

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)piperidine-4-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-morpholinoethyl)piperidine-4-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-morpholinopropyl)piperidine-4-carboxamide;

N-(2-(diethylamino)ethyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(dimethylamino)ethyl)piperidine-4-carboxamide;

N-(3-(diethylamino)propyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(2-(diethylamino)ethyl)-1-(2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(3-(diethylamino)propyl)-1-(2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(dimethylamino)ethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(2-methylpiperidin-1-yl)ethyl)piperidine-4-carboxamide;

N-(2-(butyl(ethyl)amino)ethyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(2-(azepan-1-yl)ethyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(pyrrolidin-1-yl)propyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(piperidin-1-yl)propyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-morpholinoethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-((1-ethylpyrrolidin-2-yl)methyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-morpholinopropyl)piperidine-4-carboxamide;

N-(2-(diethylamino)ethyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(dimethylamino)ethyl)piperidine-4-carboxamide;

N-(3-(diethylamino)propyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(4-ethylpiperazin-1-yl)ethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(2-methylpiperidin-1-yl)ethyl)piperidine-4-carboxamide;

N-(2-(butyl(ethyl)amino)ethyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(2-(azepan-1-yl)ethyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(pyrrolidin-1-yl)propyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(2-methylpiperidin-1-yl)propyl)piperidine-4-carboxamide;

N-(3-(azepan-1-yl)propyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(piperidin-1-yl)propyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-morpholinoethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-((1-ethylpyrrolidin-2-yl)methyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)piperidine-3-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(pyrrolidin-1-yl)propyl)piperidine-3-carboxamide;

(1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(pyrrolidin-1-yl)propyl)piperidine-3-carboxamide;

N-(3-(azepan-1-yl)propyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(diethylamino)propyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)piperidine-3-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(pyrrolidin-1-yl)ethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-morpholinoethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(dimethylamino)ethyl)piperidine-3-carboxamide;

(1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-ethylpiperazin-1-yl)methanone,

(1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-3-yl)(4-ethylpiperazin-1-yl)methanone,

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-morpholinoethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-morpholinopropyl)piperidine-3-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(diethylamino)ethyl)piperidine-3-carboxamide;

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-ethylpiperazin-1-yl)methanone;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-morpholinoethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(4-methylpiperazin-1-yl)propyl)piperidine-3-carboxamide;

N-(2-(dimethylamino)ethyl)-1-(2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide;

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone;

N-(2-(diethylamino)ethyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide;

(1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-3-yl)(4-methylpiperazin-1-yl)methanone;

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-propylpiperazin-1-yl)methanone;

(1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-methylpiperazin-1-yl)methanone;

N-(3-(diethylamino)propyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide;

(1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-ethylpiperazin-1-yl)methanone;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(4-ethylpiperazin-1-yl)ethyl)piperidine-3-carboxamide;

(1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-3-yl)(4-propylpiperazin-1-yl)methanone;

(1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-propylpiperazin-1-yl)methanone;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(dimethylamino)ethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-3-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-3-carboxamide;

1-(2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-3-carboxamide;

1-(2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-3-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-3-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-3-carboxamide;

1-(2-(4-methoxyphenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-3-ylmethyl)piperidine-4-carboxamide;

1-(2-(4-chlorophenyl)-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(pyridin-2-ylmethyl)piperidine-4-carboxamide;

N-(2-(1H-indol-3-yl)ethyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide;

N-(2-(1H-indol-3-yl)ethyl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide; and

N-(5-chloropyridin-2-yl)-1-(3,4-dimethyl-2-phenyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide; or a salt or solvate thereof.

2. The compound of claim 1 , or a salt or solvate thereof, wherein at least one applies:

(a) A 1 is N, A 2 is CR 2 and A 3 is N;

(b) A 1 is C, A 2 is CR 2 or NR 2a and A 3 is NH;

(d) A 4 is N and A 5 is CR 5 ;

(e) A 4 is CR 4 and A 5 is CR 5 .

3. The compound of claim 1 , or a salt or solvate thereof, wherein at least one applies:

(a) R 2a is C 1 -C 6 alkyl;

(b) R 4 is hydrogen;

4. The compound of claim 1 , or a salt or solvate thereof, wherein the compound is at least one of the following:

(a) the compound of formula (Ia):

(b) the compound of formula (II):

(d) the compound of formula (III):

and

(e) the compound of formula (IIIa):

5. The compound of claim 1 , or a salt or solvate thereof, wherein i is 2 and j is 1 or 2; or wherein i is 1 and j is 2; or wherein i is 1 and j is 1; or wherein i is 1 and j is 0; or wherein i is 0 and j is 0.

6. The compound of claim 1 , or a salt or solvate thereof, wherein at least one applied:

(a) U is a bond;

(b) V is a bond;

7. The compound of claim 1 , or a salt or solvate thereof, wherein: n is 0; or n is 1 or 2 and each R 6 is independently C 1 -C 6 alkyl optionally substituted by R 10A .

8. The compound of claim 1 , or a salt or solvate thereof, wherein R 1 is phenyl optionally substituted by R 10A .

9. The compound of claim 1 , or a salt or solvate thereof, wherein at least one applies:

(a) R 2 is C 1 -C 6 alkyl;

(b) R 3 is C 1 -C 6 alkyl;

(d) W is a bond;

(e) W is C 1 -C 4 alkylene optionally substituted by one or both of R W1 and R W2 ;

each of R X1 and R X2 is independently hydrogen or C 1 -C 6 alkyl;

(g) each of R Y1 and R Y2 is independently hydrogen or C 1 -C 6 alkyl;

(h) R 8 is hydrogen or C 1 -C 6 alkyl;

(i) R 9 is hydrogen or C 1 -C 6 alkyl optionally substituted by R 10 ;

(j) R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 ;

(k) R Y1 , R Y2 , R 8 and R 9 are taken together with the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

(l) R X1 and R 8 are taken together to form a methylene (—CH 2 —);

(m) R Y1 and R 8 are taken together to form a propylene (—CH 2 CH 2 CH 2 —);

(n) R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 are taken together with the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

(o) R 7 and R 8 are taken together to form an ethylene optionally substituted by R 10 .

10. The compound of claim 1 , or a salt or solvate thereof, wherein the —N(R 7 )—W—X—Y—N(R 8 )R 9 moiety is selected from the group consisting of:

11. The compound of claim 1 , or a salt or solvate thereof, wherein the compound is at least one of:

(a) the compound of formula (IIa-1a-2):

(b) the compound of formula (IIa-1b-2):

(d) the compound of formula (IIa-1d-2):

(e) the compound of formula (IIa-1e-2):

(f) the compound of formula (IIa-1f-2):

(g) the compound of formula (VIII-a-2):

12. The compound of claim 11 , or a salt or solvate thereof, wherein at least one applies:

(a) V is a bond;

(b) V is C 1 -C 2 alkylene;

(d) k is 1 or 2;

(e) n is 1 and R 6 is C 1 -C 6 alkyl;

(f) n is 0;

(g) R 8 and R 9 are independently C 1 -C 6 alkyl optionally substituted by R 10 ;

(h) R 8 and R 9 are taken together with the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl;

(i) R 10 is C 6 -C 14 aryl.

13. A compound selected from the group consisting of

N-(3-(benzyl(methyl)amino)propyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

(4-benzylpiperazin-1-yl)(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(1-methylazetidin-3-yl)piperidine-4-carboxamide;

N-(1-benzylazetidin-3-yl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide;

N-(3-(1H-imidazol-4-yl)propyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(3-amino-2,2-dimethylpropyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(isopropylamino)ethyl)piperidine-4-carboxamide;

3-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)-N-(2-(dimethylamino)ethyl)propanamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-((1-methylazetidin-3-yl)methyl)piperidine-4-carboxamide,

N-(3-(azetidin-1-yl)propyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)cyclobutyl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-((1r,3r)-3-(dimethylamino)cyclobutyl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-((1s,3s)-3-(dimethylamino)cyclobutyl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)pyrrolidine-3-carboxamide,

(S)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)pyrrolidine-3-carboxamide,

(R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)pyrrolidine-3-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)azetidine-3-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(isopropylamino)ethyl)piperidine-3-carboxamide,

(R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(isopropylamino)ethyl)piperidine-3-carboxamide,

(5)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(isopropylamino)ethyl)piperidine-3-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(1-methylpyrrolidin-3-yl)piperidine-4-carboxamide,

(S)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(1-methylpyrrolidin-3-yl)piperidine-4-carboxamide,

(R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(1-methylpyrrolidin-3-yl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(1-methylpiperidin-4-yl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-2-methylpiperidine-4-carboxamide,

(2S,4S)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-2-methylpiperidine-4-carboxamide,

(2R,4R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-2-methylpiperidine-4-carboxamide,

(2R,4S)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-2-methylpiperidine-4-carboxamide,

(2S,4R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-2-methylpiperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-4-methylpiperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-3-methylpiperidine-4-carboxamide,

(3S,4S)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-3-methylpiperidine-4-carboxamide,

(3R,4R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-3-methylpiperidine-4-carboxamide,

(3R,4S)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-3-methylpiperidine-4-carboxamide,

(3S,4R)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)-3-methylpiperidine-4-carboxamide,

2-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)-N-(3-(dimethylamino)propyl)acetamide,

1-(3,4-dimethyl-2-(pyridin-3-yl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(thiophen-3-yl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(tetrahydro-2H-pyran-4-yl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

1-((3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)methyl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(2-isopropyl-3,4-dimethyl-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(oxazol-4-yl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(4-(dimethylamino)butyl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(5-(dimethylamino)pentyl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(4-methyl-3-phenyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(3-methyl-4-phenyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

1-(4-chloro-3-methyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(3-methyl-2-(m-tolyl)-4-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(6-(dimethylamino)hexyl)piperidine-4-carboxamide,

(4-ethylpiperazin-1-yl)(1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

N-(3-(dimethylamino)propyl)-1-(4-iodo-3-methyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(3-methyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

(4-(diethylamino)piperidin-1-yl)(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone,

(S)-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone,

(R)-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-(dimethylamino)pyrrolidin-1-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-((dimethylamino)methyl)pyrrolidin-1-yl)methanone,

(R)-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-((dimethylamino)methyl)pyrrolidin-1-yl)methanone,

(S)-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-((dimethylamino)methyl)pyrrolidin-1-yl)methanone,

N-(2-(dimethylamino)ethyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

N-(2-(dimethylamino)ethyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide,

(S)—N-(2-(dimethylamino)ethyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide,

(R)—N-(2-(dimethylamino)ethyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-3-carboxamide,

1-(7-chloro-3-methyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-4-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide,

N-(3-(dimethylamino)propyl)-1-(4-methyl-2-(p-tolyl)-2H-indazol-7-yl)piperidine-4-carboxamide,

N-(2-(dimethylamino)ethyl)-3-(1-(4-methyl-2-(p-tolyl)-2H-indazol-7-yl)piperidin-4-yl)propanamide,

N-(3-(dimethylamino)propyl)-1-(4-methyl-2-(p-tolyl)-1H-pyrrolo[2,3-d]pyridazin-7-yl)piperidine-4-carboxamide,

N-(2-(dimethylamino)ethyl)-3-(1-(4-methyl-2-(p-tolyl)-1H-pyrrolo[2,3-d]pyridazin-7-yl)piperidin-4-yl)propanamide,

N-(3-(dimethylamino)propyl)-1-(1-methyl-2-(p-tolyl)-1H-benzo[d]imidazol-4-yl)piperidine-4-carboxamide,

N-(2-(dimethylamino)ethyl)-3-(1-(1-methyl-2-(p-tolyl)-1H-benzo[d]imidazol-4-yl)piperidin-4-yl)propanamide,

N-(3-(dimethylamino)propyl)-1-(2-(p-tolyl)-2H-pyrazolo[4,3-c]pyridin-7-yl)piperidine-4-carboxamide, and

N-(2-(dimethylamino)ethyl)-3-(1-(2-(p-tolyl)-2H-pyrazolo[4,3-c]pyridin-7-yl)piperidin-4-yl)propanamide,

or a salt or solvate thereof.

14. A compound selected from the group consisting of

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(2-(phenylamino)ethyl)piperidine-3-carboxamide;

(4-(diethylamino)piperidin-1-yl)(1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

(3-((dimethylamino)methyl)pyrrolidin-1-yl)(1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

N-(2-(dimethylamino)ethyl)-3-(1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)propanamide,

N-(1-methylazetidin-3-yl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(2-(dimethylamino)ethyl)-1-(4-methyl-2-(p-tolyl)-3-(trifluoromethyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

N-(2-morpholinoethyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

(4-(azetidin-1-yl)piperidin-1-yl)(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

3-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)-N-(1-methylazetidin-3-yl)propanamide,

(4-(benzyl(methyl)amino)piperidin-1-yl)(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

(3-((benzyl(methyl)amino)methyl)pyrrolidin-1-yl)(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(4-morpholinopiperidin-1-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(3-(morpholinomethyl)pyrrolidin-1-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(5-methylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(2,7-diazaspiro[3.5]nonan-7-yl)methanone,

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(2,6-diazaspiro[3.4]octan-6-yl)methanone, and

(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)(2-methyl-2,6-diazaspiro[3.4]octan-6-yl)methanone,

or a salt or solvate thereof.

15. A compound selected from the group consisting of:

1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)-N-(3-(dimethylamino)propyl)piperidine-4-carboxamide;

N-(3-(dimethylamino)propyl)-1-(2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

2-(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)-N-(3-(dimethylamino)propyl)acetamide,

N-(3-(benzyl(methyl)amino)propyl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide;

(4-benzylpiperazin-1-yl)(1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidin-4-yl)methanone, and

N-(1-benzylazetidin-3-yl)-1-(3,4-dimethyl-2-(p-tolyl)-2H-pyrazolo[3,4-d]pyridazin-7-yl)piperidine-4-carboxamide,

or a salt or solvate thereof.

16. A pharmaceutical composition comprising a compound of claim 1 , or a salt or solvate thereof, and a pharmaceutically acceptable excipient.

17. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I):

or a salt or solvate thereof, wherein:

A 1 is C or N;

A 2 is CR 2 , N or NR 2a ;

A 3 is CR 30 , N or NR 3a ;

A 4 is N or CR 4 ;

A 5 is N or CR 5 ;

provided that two, three or four of A 1 , A 2 , A 3 , A 4 and A 5 are N; wherein the dashed lines indicate partial or delocalized bonds in an aromatic ring;

i and j are independently 0, 1 or 2;

R 1 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 2 , R 3 , R 30 , R 4 and R 5 is independently hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 2a and R 3a is independently hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl or 3-12-membered heterocyclyl; wherein the C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 14 aryl, 5-10-membered heteroaryl and 3-12-membered heterocyclyl are independently optionally substituted by R 10A ;

each R 6 , where present, is independently C 1 -C 6 alkyl optionally substituted by R 10A ;

n is 0, 1, 2, 3 or 4;

U is a bond or methylene optionally substituted by R 10 ;

V is a bond or C 1 -C 2 alkylene optionally substituted by R 10 ;

W is a bond or C 1 -C 4 alkylene optionally substituted by one or both of R W1 and R W2 ;

X is —CR X1 R X2 —;

Y is —CR Y1 R Y2 —;

R 7 is hydrogen, C 1 -C 6 alkyl, or taken together with R 8 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R X1 or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 ;

R 8 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10 , C 6 -C 14 aryl, 5-10-membered heteroaryl, or taken together with R 7 to form an ethylene optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R X1 , R X2 or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R 10 , where present, to form a C 1 -C 6 alkylene, or taken together with R 9 and the nitrogen atom to which they are attached to form a 3-12-membered heterocyclyl optionally substituted by R 10 or a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y1 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y2 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R W1 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 or R Y1 to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R W2 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R W2 , where present, is C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R W1 , R X1 , R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R X1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R Y1 or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X2 , R Y1 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

R Y1 is hydrogen, C 1 -C 6 alkyl optionally substituted by R 10A , or taken together with R 7 , R 8 , R X1 or R W1 , where present, to form a C 1 -C 6 alkylene optionally substituted by R 10 , or taken together with R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 , or taken together with R W1 , R W2 , where present, R X1 , R X2 , R Y2 , R 8 , R 9 and the atoms to which they are attached to form a 5-10-membered heteroaryl optionally substituted by R 10 ;

each R 10 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, halogen, —CN, —OR 11 , —SR 11 , —NR 12 R 13 , —NO 2 , —C═NH(OR 11 ), —C(O)R 11 , —OC(O)R 11 , —C(O)OR 11 , —C(O)NR 12 R 13 , —NR 11 C(O)R 12 , —NR 11 C(O)OR 12 , —NR 11 C(O)NR 12 R 13 , —S(O)R 11 , —S(O) 2 R 11 , —NR 11 S(O)R 12 , —NR 11 S(O) 2 R 12 , —S(O)NR 12 R 13 , —S(O) 2 NR 12 R 13 , or —P(O)(OR 12 )(OR 13 ); wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, 3-12-membered heterocyclyl, 5-10-membered heteroaryl and C 6 -C 14 aryl of R 10 are independently optionally substituted by halogen, —CN, oxo, —OR 14 , —SR 14 , —NR 14 R 15 , —C(O)R 14 , —C(O)OR 14 , —S(O)R 14 , —S(O) 2 R 14 , —P(O)(OR 14 )(OR 15 ), 3-12-membered heterocyclyl, 5-10-membered heteroaryl, C 6 -C 14 aryl, C 3 -C 8 cycloalkyl, or C 1 -C 6 alkyl optionally substituted by oxo, —OH or halogen, or taken together with R 8 to form a C 1 -C 6 alkylene;

each R 10A is independently oxo or R 10 ;

R 11 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6-membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6-membered heterocyclyl of R 11 are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17 , —P(O)(OR 16 )(OR 17 ), or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

R 12 and R 13 are each independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl or 3-6 membered heterocyclyl, wherein the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 6 -C 14 aryl, 5-6-membered heteroaryl and 3-6 membered heterocyclyl of R 12 and R 13 are independently optionally substituted by halogen, oxo, —CN, —OR 16 , —NR 16 R 17 or C 1 -C 6 alkyl optionally substituted by halogen, —OH or oxo;

or R 12 and R 13 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo, —OR 16 , —NR 16 R 17 or C 1 -C 6 alkyl optionally substituted by halogen, oxo or —OH;

or R 14 and R 15 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by halogen or oxo; and

or R 16 and R 17 are taken together with the atom to which they attached to form a 3-6 membered heterocyclyl optionally substituted by halogen, oxo or C 1 -C 6 alkyl optionally substituted by oxo or halogen;

wherein the compound is not