Imidazo[2,1-f][1,2,4]triazin-4-amine as TLR8 agonists

A compound of formula (I),

• or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, wherein:
• X is N or CR7;
• wherein R7 is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;
• L1 is —(CRaRb)m—, —O—, —S—, —S(O)—, —SO2—, —C(O)—, —C(O)O—, —OC(O)—, —NRa—, —C(O)NRa—, —NRaC(O)—, —NRaC(O)O—, —NRaC(O)NRb—, —SO2NRa—, —NRaSO2—, —NRaS(O)2NRb—, —NRaS(O)NRb—, —C(O)NRaSO2—, —C(O)NRaSO—, or —C(═NRa)NRb—,
• wherein m is 0 to 8, and one or two CRaRb moieties in —(CRaRb)m— are not replaced or replaced by one or more moieties selected from O, S, SO, SO2, C(O) or NRa;
• Ra and Rb in each occurrence are independently hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, heteroaryl or —ORc;
• wherein Rc is hydrogen, alkyl, alkoxy-alkyl-, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl or heteroaryl;
• R1 is —OR1a, —SR1a, —NR1aR1b, —COR1a, —SO2R1a, —C(═O) OR1a, —C(═O)NR1aR1b, —C(═NR1a)NR1bR1c, —N(R1a)C(═O)R1b, —N(R1a) C(═O)OR1b, —N(R1a)C(O)NR1bR1c, —N(R1a)S(O)NR1bR1c, —N(R1a)S(O)2NR1bR1c, —NR1aSO2R1b, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each independently and optionally substituted with one or two or three substituents R1d,
• R1a, R1b and R1c are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or two or three substituents selected from:
• halogen, —C1-8 alkyl optionally substituted with R1e, cycloalkyl optionally substituted with R1e, heterocyclyl optionally substituted with R1e, aryl optionally substituted with R1e, heteroaryl optionally substituted with R1e, CH3—(OCH2CH2)n— where n is 3 to 10, or —OR1f,
• wherein R1e is halogen, nitro, cyano, hydroxyl, —NH2, alkylamino, dialkylamino, —C1-6 alkyl optionally substituted with halogen, carboxyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl;
• wherein R1f is alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, each being optionally substituted with —C1-4 alkyl or halogen;
• R1d in each occurrence is independently hydrogen, oxo, —CN, —NO2, hydroxyl, —NH2, alkylamino, dialkylamino, halogen, haloalkyl, alkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;
• R2 and R3 in each occurrence are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are optionally substituted with 1-3 substituents selected from:
• oxo, —CN, —NO2, —NH2, alkylamino, dialkylamino, halogen, hydroxyl, haloalkyl, alkyl, haloalkoxy, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;
• R4 is hydrogen, halogen, cyano, —NO2, —OR4a, —SR4a, —NR4aR4b, —COR4a, —SO2R4a, —C(═O)OR4a, —C(═O)NR4aR4b, —C(═NR4a)NR4bR4c, —N(R4a)C(═O)R4b, —N(R4a)C(═O)OR4b, —N(R4a)C(O)NR4bR4c, —N(R4a) S(O)NR4bR4c, —N(R4a)S(O)2NR4bR4c, —NR4aSO2R4b, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each independently and optionally substituted with one or two or three substituents R4d,
• R4a, R4b and R4c are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with halogen, hydroxyl, —NH2, alkylamino, dialkylamino or alkoxy;
• R4d in each occurrence is independently hydrogen, oxo, —CN, —NO2, halogen, hydroxyl, —NH2, alkylamino, dialkylamino, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with halogen, hydroxyl, —NH2, alkylamino, dialkylamino or alkoxy;
• ring A is azetidin-3-yl, azepan-4-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperazin-1-yl, 7-azaspiro[3.5]non-2-yl, 2-azaspiro[3.3]hept-6-yl, 7-azaspiro[3.5]non-2-yl, 2-azaspiro[3.5]non-7-yl, 3-azabicyclo[3.1.0]hex-6-yl, 2-azabicyclo[2.2.1]hept-5-yl, 8-azabicyclo[3.2.1]oct-3-yl, 2-azabicyclo[4.1.0]hept-5-yl, cyclobutyl, bicyclo[1.1.1]pent-1-yl, bicyclo[1.1.1]pent-1-yl, or 1,2,3,6-tetrahydropyridin-4-yl;
• R5 is halogen, oxo, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy or —C(═O)OR5a, wherein R5a is hydrogen, alkyl or haloalkyl;
• p is 0, 1, 2 or 3;
• L2 is a direct bond, —(CRfRg)t—, —O—, —S—, —S(O)—, —SO2—, —C(O)—, —C(O)O—, —OC(O)—, or —NRd— where Rd is —C1-6 alkyl, wherein t is 1 to 8, and one or two CRfRg moieties in —(CRfRg)t— are not replaced or are replaced by one or more moieties selected from O, S, SO, SO2, C(O) or NRf;
• Rf and Rg are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;
• R6 is hydrogen, —NR6aR6b, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each independently and optionally substituted with one or two or three substituents R6c;
• R6a and R6b are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with halogen, hydroxyl, —NH2, alkylamino, dialkylamino or alkoxy;
• R6c is independently hydrogen, halogen, cyano, —NO2, —OR6d, —SR6d, —NR6dR6e, —COR6d, —SO2R6d, —C(═O)OR6d, —C(═O)NR6dR6e, —C(═NR6d) NR6eR6f, —N(R6d)C(═O)R6e, —N(R6d)C(═O)OR6e, —N(R6d)C(O)NR6eR6f, —N(R6d)S(O)NR6eR6f, —N(R6d)S(O)2NR6eR6f, —NR6dSO2R6e, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each independently and optionally substituted with one or two or three substituents R6g;
• R6d, R6e and R6f are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or two or three substituents R6g;
• R6g in each occurrence is independently hydrogen, halogen, cyano, —NO2, —OR6h, —SR6h, —NR6hR6i, —COR6h, —SO2R6h, —C(═O)OR6h, —C(═O)NR6hR6i, —C(═NR6h)NR6iR6j, —N(R6h)C(═O)R6i, —N(R6h)C(═O)OR6i, —N(R6h)C(O)NR6iR6j, —N(R6h)S(O)NR6iR6j, —N(R6h)S(O)2NR6iR6h, —NR6hSO2R6i, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl;
• and
• R6h, R6i and R6j are independently hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, heterocyclyl, aryl or heteroaryl are each independently and optionally substituted with one or two or three substituents selected from:
• halogen, —C1-4 alkyl, —C1-4 alkoxy, hydroxyl, nitro, —NH2, alkylamino, dialkylamino or cyano.