Janus Kinase Inhibitors for the treatment of Dry Eye and other diseases related to the eyes. Ophthalmic Insert

摘要

Claim 1: a method for the treatment of Dry Eye disorders in a patient in need thereof, characterized in that it comprises administering to the patient a therapeutically effective amount of an agent selected from (a) compounds of formula (1), where A1 and A2 are selec Clients independently between C and N; T, u, and V are selected irrespective of o, S, N, CR5,And NR6; where the five Member Ring formed by A1, A2, and T, u, V is Aromatic; X is n or CR4; and is alquileno C1 C2 alquenileno - 8 - 8 - 8 alquinileno C2 (cr11r12) P - (cicloalquilen C3 - (10) - cr11r12) Q (cr11r12) P - (arilen) - (cr11r12) Q (cr11r12) - (heterocicloalquilen C1 - (10) - cr11r12) Q (P - (heteroa cr11r12) Rilen) - (cr11r12) Q (cr11r12) PO (cr11r12) (cr11r12 (Q, q) cr11r12 (PS), cr11r12 (PC) or (Q,) cr11r12)(cr11r12) PC (or NRC) (cr11r12) Q (cr11r12 (PC) or (q) or cr11r12 (OC), cr11r12) (o) (cr11r12) (cr11r12 POC (q) or (q) cr11r12 (NRC), cr11r12 (PNRC) cr11r12) Q (cr11r12) pnrcc (o) (cr11r12 (NRD) cr11r12 PS (q) or (q) cr11r12 (PS), cr11r12 (NRC) or (q) cr11r12 (PS), cr11r12) (OR) 2 (cr11r12) or (Q, cr11r12 (PS) or (q) 2nrc cr11r12), where said alkyd Full alquenileno C2 C1 - 8 - 8 - 8 alquinileno C2, cicloalquileno, arylene, heterocicloalquileno,Heteroarileno is replaced or, optionally with 1, 2, or 3 substituents selected independently between D1 D2 D3 D4; Z is H, alkyl, Halo, C1 C2 alquenilo - 8 - 8 - 8 haloalquilo alquinilo C2, C1 - 4, halosulfanilo, hidroxialquilo c1-4, cianoalquilo c1-4, - n = c = RI, RI, Cy1, CN, NO2, ora, Mrs. C (or RB), C (o) C (o) nrcrd, ora, OC (or RB), OC (OR) nrcrd, nrcrd, NRCC (or RB), (OR) nrcrd NRCC, NRCC (or Lady)C = (NRI) nrcrd, NRCC (= nrcrd NRI), S (or RB), S (or S) nrcrd 2rb, (OR), (OR) NRCS 2rb, C (= Noh) (RB, c = (C1 - (6) and (OR) RB, S 2nrcrd, where The alkyl alquenilo C2 C1 - 8 - 8 - 8, or alquinilo C2 is replaced with either 1, 2, 3, 4, 5, or 6 selected regardless of Halo substituents, c1-4 alkyl Alquenilo C2, C2 - 4 - 4, alquinilo, haloalquilo c1-4, halosulfanilo, hidroxialquilo c1-4,Cianoalquilo c1-4, CY1, CN, NO2, ora, MS, RB, C (o) C (o) C (o) nrcrd, ora, OC (or RB), OC (OR) nrcrd, nrcrd, NRCC (or RB), (OR) nrcrd NRCC, NRCC (ORA) c = (NRI) nrcrd, NRCC (= nrcrd NRI), S (or RB), S (or S) nrcrd 2rb, (OR), (OR) NRCS 2rb, C (= Noh) (RB, c = (C1 - RB (6)), and S (OR) 2nrcrd; where z is h, N is 1 - (or portion; N - Z) and A2 (i) taken together with the portion to which is United, (ii) R5 or R6 of both T and VAnd (iii) The c or n Atom to which the R5 or R6 of both T and V are United to form a ring, cycloalkyl, aryl, heteroaryl, or 4 to 20 members heterocicloalquilo Ring FUSED to the 5 Member formed by A1, A2, and T, u, V, where the aryl ring, cycloalkyl, heteroaryl or h Eterocicloalquilo 4 to 20 members are optionally replaced with 1, 2, 3, 45 substituents or independently selected from - (W) M - Q; W is alquilenilo C1 C2 alquenilenilo - 8 - 8 - 8 alquinilenilo C2, o, S, C (o) C (or NRC), C (o) or oC (OC), (or NRC) 'NRC NRC', 'C' (NRD), S (or S), (OR) NRC 's (OR) 2, and (OR) 2nrc' s; Q is H, alkyl, Halo, CN, NO2, C1 C2 alquenilo - 8 - 8 - 8 alquinilo C2 Haloalquilo C1, - 8, halosulfanilo, cycloalkyl, aryl, heteroaryl or heterocicloalquilo,Where the alkyl alquenilo C2 C1 - 8 - 8 - 8 haloalquilo alquinilo C2, C1 - 8, cycloalkyl, aryl, heteroaryl or heterocicloalquilo optionally replaced with 1, 2, 3 or 4 substituents selected independently between c1-4 alkyl, Halo, alquenilo C2 - 4, alquinilo haloalquilo C1 C2 - 4 - 4, h Alosulfanilo, hidroxialquilo c1-4, cianoalquilo c1-4, Cy2, CN, NO2, or ',' c '(or RB),C (or c) NRC 'rd', or '(OR), OC (OC (or RB)', or 'rd') NRC NRC NRC 'rd', 'c' (or RB), NRC (NRC) 'c' rd ',' C (or NRC) ora 's (or RB), S (or NRC)' rd 's (or NRC) 2rb' (or 's' s) 2rb and (OR) 2nrc' rd '; CY1 and Cy2 are selected independently between aryl, heteroaryl, and heterocicloalquilo cycloalkyl, optionally substituted, each With 1, 2, 3, 4 or 5 substituents selected independently between c1-4 alkyl, haloAlquenilo alquinilo C2 C2 - 4 - 4, haloalquilo c1-4, halosulfanilo, hidroxialquilo c1-4, cianoalquilo c1-4, NO2 or CN, '', '', C '' (or RB), C (or NRC) 'rd', 'c' (OR) ora 'rb' (or OC), OC (or NRC) 'rd', NRC NRC 'rd' ',' 'c' '(or RB), NRC (NRC)' 'c' 'rd', 'c' (or NRC) Pray, '' s (or RB) ',' s' (or NRC) 'rd', 's' (OR) 2rb, NRC' s (OR) 2 Rb, and S (OR) 2nrc 'rd', R1, R2, R3 and R4 are selected independently from h, haloC1-4 alkyl, alquenilo alquinilo C2 C2 - 4 - 4, haloalquilo c1-4, halosulfanilo, cycloalkyl, aryl, heteroaryl, heterocicloalquilo, CN, NO2, or7, SR7, R8, C (o) C (o) C (o) nr9r10, or7, OC (OC (R8), nr9r10 nr9r10 or), (OR), nr9c R8, nr9c (or or7), S (R8), S (or S) nr9r10, (OR) 2r8, nr9s 2r8 (OR), and S (OR) is 2nr9r10; R5 h, h Hello, c1-4 alkyl, alquenilo alquinilo C2 C2 - 4 - 4, haloalquilo c1-4, halosulfanilo, CN, NO2, or7,SR7, R8, C (o) C (o) C (o) or7 nr9r10, R8, OC (OC), (OR) nr9r10, nr9r10, nr9c (or nr9c (R8), or or7), S (R8), S (or S) nr9r10 2r8 (,, OR) nr9s 2r8 (OR), or s (OR) 2nr9r10; R6 is H, alkyl alquenilo C1 - C2 - 4, 4, 4 alquinilo haloalquilo C1 - C2, 4, or7, R8, C (o) C (o) C (o) nr9r10, or7, R8, S (or S) nr9r10 (or), (OR) 2r8 s, or s (OR) is 2nr9r10; R7 H, alkyl haloalquilo C1 C1 - 6, - 6, - 6 alquinilo alquenilo C2, C2 - 6, cycloalkyl, aryl,Heteroaryl, heterocicloalquilo, arylalkyl or heterocicloalquilalquilo, heteroarilalquilo, cicloalquilalquilo; R8 is H, alkyl haloalquilo C1 C1 - 6, - 6, - 6 alquinilo alquenilo C2, C2 - 6, cycloalkyl, aryl, heteroaryl, heterocicloalquilo, arylalkyl or cicloalquilalquilo, heteroarilalquilo, Heterocyclic Icloalquilalquilo; R9 and R10 is independently selected from h, alkyl C1 - 10Haloalquilo C1 - C2 - alquenilo 6, 6, 6 alquinilo alquilcarbonilo C1 C2, C1 alquilsulfonilo arilcarbonilo, - 6, - 6, arilsulfonilo, cycloalkyl, aryl, heteroaryl, heterocicloalquilo, arylalkyl, heteroarilalquilo, cicloalquilalquilo and heterocicloalquilalquilo; R9 and R10 or together with the atom of the cua L are connected to form a Group heterocicloalquilo 4, 56 or 7 members; R11 and R12 are independently selected from H and - E1 - E2 E3 E4; D1 and E1 are absent or are selected independently, regardless of alquileno C1 - C2 - alquenileno 6, 6, 6 alquinileno C2, arylene, cicloalquileno, heteroarileno, and heterocicloalquileno, where C Each of alquileno C1 - C2 - alquenileno 6, 6, 6 alquinileno C2, arylene, cicloalquileno,Heteroarileno, and optionally heterocicloalquileno is replaced with 1, 2 or 3 substituents selected independently between Halo, CN, NO2, N3, SNA, Oh, alkyl - 6 haloalquilo C1, C1 - C2 alkoxyalkyl Esters 6, - 8, - 6 haloalcoxi alkoxy C1, C1 - 6, 6 - amino alquilamino C1, C2, and dialquilamino - 8; D2 and E2 Regardless are absent or are selected independently between alquileno C1 - 6Alquenileno C2 - 6, 6 - (rent alquinileno C2, C1 - (6) - R or - C1 - 6 Rent (rent) s, C1 - R - S - (6) Let C1 - 6) s, (C1 - 6 - Rent (rent) R NRE - C1 - 6) s r (rent C1 - 6) - CO - (C1 - 6 Rent (rent) s, C1 - 6) R - C (o) o - (C1 - Rent (rent C1 s, 6) - 6 - (R) - conre C1 - 6 Rent (rent) s, C1 - 6) R - os - (rent C1 - 6 S (R), rent (rent) - SO2 - C1 - 6 (S,) Let C1 - 6 - (R) - you get s, C1 - 6)(rent) - and R - (- nreconrf Rent C1 6) s, where each of alquileno - 6 alquenileno C1, C2 and C2 - 6, 6 - alquinileno optionally replaced with 1, 2 or 3 substituents selected independently between Halo, CN, NO2, N3, SNA, Oh, alkyl C1 - 6 haloalquilo C1, C2 alkoxyalkyl esters - 6, - 8, - alkoxy C1 6 Haloalcoxi C1 - 6, amino, alquilamino C1 - 6And dialquilamino C2 - 8; D3 and E3 are absent or are selected independently, regardless of alquileno C1 - C2 - alquenileno 6, 6, 6 alquinileno C2, arylene, cicloalquileno, heteroarileno, and heterocicloalquileno, where each of alquileno C1 - C2 - alquenileno 6, 6, 6 alquinileno C2, Cicloalquileno, arylene, heteroarileno, and optionally heterocicloalquileno is replaced with 12 or 3 substituents selected regardless of its Halo, CN, NO2, N3, SNA, Oh, alkyl haloalquilo C1 C1 - 6 - 6, 6 - alkoxy alkoxyalkyl Esters C1, C1 haloalcoxi - 6, 6 - amino alquilamino C1, C1, and C2 - 6, - 8 dialquilamino D4 and E4 are selected independently; between h, c1-4 alkyl, Halo, alquenil Alquinilo C2 or C2 - 4, - 3, - 4 halosulfanilo haloalquilo C1, C1, C1 cianoalquilo hidroxialquilo - 4 - 4Cy1, CN, NO2, ora, MS, RB, C (o) C (o) C (o) nrcrd, ora, OC (or RB), OC (OR) nrcrd, nrcrd, NRCC (or Rb (NRCC), or nrcrd (NRCC), C (= o) ora, NRI nrcrd, NRCC (NRI) = S (o)) nrcrd, RB, S (or S) nrcrd 2rb, (OR), (OR) NRCS 2rb, C (= Noh) (RB, c = (C1 - (6) and S (RB), or where the alkyl 2nrcrd); alquenilo C1 C1 - 8, - 8, - 6 or alquinilo C1, Optionally replaced with 1, 2, 3, 4, 5,Or 6 substituents selected independently between c1-4 alkyl, Halo, alquenilo alquinilo C2 C2 - 4 - 4, haloalquilo c1-4, halosulfanilo, hidroxialquilo c1-4, cianoalquilo c1-4, CY1, CN, NO2, ora, MS, RB, C (o) C (o) C (nrcrd, ora, OC (OR) or oC (RB), or nrcrd nrcrd, NRCC), Rb (OR), (OR) nrcrd NRCC, NRCC (or Lady) C = (NRI) nrcrd, NRCC (= nrcrd NRI), S (or RB), S (or S) nrcrd 2rb, (OR), (OR) NRCS 2rb, RB, C (= Noh)C = (C1 - 6 (RB)), and S (OR) 2nrcrd; RA - (CY1 is H, alkyl, C1 - 6) - alkyl - 6 CY1, C1, C2 alquenilo haloalquilo C1 - 6, - 6, - 6 alquinilo C2, where the alkyl haloalquilo C1 - 6 6 alquenilo C1, C2 or C2 - 6, 6 - alquinilo optionally replaced with 1, 2, or 3 substituents selected independently Between Oh, CN, amino alkyl, Halo, haloalquilo C1 C1 - 6 - 6, halosulfanilo, aryl, arylalkyl,Heteroaryl, heteroarilalquilo, cycloalkyl and heterocicloalquilo; Rb (CY1 is H, alkyl, - C1 - 6) - alkyl - 6 CY1, C1, C2 alquenilo haloalquilo C1 - 6, - 6, - 6 alquinilo C2, where the alkyl haloalquilo C1 C1 - 6, - 6, - 6 alquenilo C2 or C2 alquinilo 6 be replaced optionally with 1, 2, or 3 substituents are Selected independently between Oh, CN, amino alkyl, alkyl, Halo, Halo, C1 - 6Haloalquilo C1 - 6, halosulfanilo, aryl, heteroaryl, arylalkyl, heteroarilalquilo, cycloalkyl and heterocicloalquilo; ra and Ra 'are selected independently from h, alkyl haloalquilo C1 C1 - 6, - 6, - 6 alquinilo alquenilo C2, C2 - 6, cycloalkyl, aryl, heteroaryl, heterocicloalquilo, arilalq Uilo, heteroarilalquilo, cicloalquilalquilo and heterocicloalquilalquilo