JANUS KINASE INHIBITORS FOR TREATMENT OF DRY EYE AND OTHER EYE RELATED DISEASES

US 20100113416A1
Filed: 10/01/2009
Published: 05/06/2010
Est. Priority Date: 10/02/2008
Status: Abandoned Application

First Claim

Patent Images

1. A method of treating a dry eye disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an agent selected from:

(a) compounds of Formula I;

wherein;

A¹and A²are independently selected from C and N;

T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;

wherein the 5-membered ring formed by A¹, A², U, T, and V is aromatic;

X is N or CR⁴;

Y is C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, (CR¹¹R¹²)_p—

(C_3-10cycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(arylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(C_1-10heterocycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(heteroarylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_pO(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)O(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)NR^c(CR¹¹R¹²)^q, (CR¹¹R¹²)_pNR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^cC(O)NR^d(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)(CR¹¹R¹²)_q, (C¹¹R¹²)_pS(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)₂(CR¹¹R¹²)_q, or (CR¹¹R¹²)_pS(O)₂NR^c(CR¹¹R¹²)_q, wherein said C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D¹-D²-D³-D⁴;

Z is H, halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, ═

C—

Rⁱ, ═

N—

Rⁱ, Cy¹, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═

NRⁱ)NR^cR^d, NR^cC(═

NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═

NOH)R^b, C(═

NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═

NRⁱ)NR^cR^d, NR^cC(═

NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═

NOH)R^b, C(═

NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;

wherein when Z is H, n is 1;

or the —

(Y)_n—

Z moiety is taken together with i) A²to which the moiety is attached, ii) R⁵or R⁶of either T or V, and iii) the C or N atom to which the R⁵or R⁶of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —

(W)_m-Q;

W is C_1-8alkylenyl, C_2-8alkenylenyl, C_2-8alkynylenyl, O, S, C(O), C(O)NR^c′, C(O)O, OC(O), OC(O)NR^c′, NR^c′, NR^6′C(O)NR^c′, S(O), S(O)NR^c′, S(O)₂, or S(O)₂NR^c′;

Q is H, halo, CN, NO₂, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy², CN, NO₂, OR^a′, SR^a′, C(O)R^b′, C(O)NR^c′R^d′, C(O)OR^a′, OC(O)R^b′, OC(O)NR^c′R^d′, NR^c′R^d′, NR^c′C(O)R^b′, NR^c′C(O)NR^c′R^d′, NR^c′C(O)OR^a′, S(O)R^b′, S(O)NR^c′R^d′, S(O)₂R^b′, NR^c′S(O)₂R^b′, and S(O)₂NR^c′R^d′;

Cy¹and Cy²are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^b″, NR^c″C(O)OR^a″, NR^c″S(O)R^b″, NR^c″S(O)₂R^b″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, and S(O)₂NR^c″R^d″;

R¹, R², R³, and R⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR^cC(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;

R⁵is H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;

R⁶is H, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;

R⁷is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;

R⁸is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;

R⁹and R¹⁰are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkylcarbonyl, arylcarbonyl, C_1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;

or R⁹and R¹⁰together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;

R¹¹and R¹²are independently selected from H and -E¹-E²-E³-E⁴;

D¹and E¹are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;

D²and E²are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, (C_1-6alkylene)_r-O—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-S—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-NR^e—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-CO—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-COO—

(C_1-6alkylene)_s, (C_1-6alkylene)_r—

CONR^e—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-SO—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-SO₂—

(C_1-6alkylene)_s, (C_1-6alkylene)_r-SONR^e—

(C_1-6alkylene)_s, and (C_1-6alkylene)_r-NR^eCONR^f—

(C_1-6alkylene)_s, wherein each of the C_1-6alkylene, C_2-6alkenylene, and C_2-6alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;

D³and E³are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;

D⁴and E⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═

NRⁱ)NR^cR^d, NR^cC(═

NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═

NOH)R^b, C(═

NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═

NRⁱ)NR^cR^d, NR^cC(═

NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═

NOH)R^b, C(═

NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;

R^ais H, Cy¹, —

(C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^bis H, Cy¹, —

(C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^a′and R^a″are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^b′ and R^b″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^cand R^dare independently selected from H, Cy¹, —

(C_1-6alkyl)-Cy¹, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —

(C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;

or R^cand R^dtogether with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —

(C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;

R^c′ and R^d′ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, c_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R^c′ and R^d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^c″and R^d″are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, C_1-6haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R^c″ and R^d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

Rⁱis H, CN, NO₂, or C_1-6alkyl;

R^eand R^fare independently selected from H and C_1-6alkyl;

Rⁱis H, CN, or NO₂;

m is 0 or 1;

n is 0 or 1;

p is 0, 1, 2, 3, 4, 5, or 6;

q is 0, 1, 2, 3, 4, 5 or 6;

r is 0 or 1; and

s is 0 or 1;

wherein when X is N, n is 1, and the moiety formed by A¹, A², U, T, V, and —

(Y)_n—

Z has the formula;

then Y is other than (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q;

(b) compounds of Formula II;

wherein;

L^ais SO₂or CO;

R^1ais C_1-6alkyl, C_3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR^2aR^3a, or OR^4a, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4alkyl;

R^2aand R^3aare independently selected from H, C_1-4alkyl, and phenyl; and

R^4ais C_1-6alkyl, phenyl, or benzyl;

(c) compounds of Formula III;

wherein;

R^5aand R^6aare independently selected from H, F, CN, OH, C_1-4alkyl, benzyloxy, C_2-8dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4alkyl;

and pharmaceutically acceptable salts thereof;

provided that compound of Formula I is not selected from 4-[5-(2-isopropyl-5-methylcyclohexyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(4-tert-butylphenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-cyclopentylethyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(2,6-difluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(benzyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(3-fluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(phenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(4-methoxybenzyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(phenylthiomethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(3-methylbutyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-benzyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(2,2-dimethylpropyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-methyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(formyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(furan-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(1-methyl-1H-pyrrol-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-(sec-butyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;

4-[5-cyclopropyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine; and

pharmaceutically acceptable salts of any of the aforementioned.

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Abstract

Methods, kits, and compositions for treating dry eye disorders and other related eye diseases are provided, wherein the methods, kits, and compositions utilize a JAK inhibitor.

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56 Claims

1. A method of treating a dry eye disorder in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of an agent selected from:
- (a) compounds of Formula I;
  
  wherein;
  
  A¹and A²are independently selected from C and N;
  
  T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;
  
  wherein the 5-membered ring formed by A¹, A², U, T, and V is aromatic;
  
  X is N or CR⁴;
  
  Y is C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, (CR¹¹R¹²)_p—
  
  (C_3-10cycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(arylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(C_1-10heterocycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(heteroarylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_pO(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)O(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)NR^c(CR¹¹R¹²)^q, (CR¹¹R¹²)_pNR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^cC(O)NR^d(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)(CR¹¹R¹²)_q, (C¹¹R¹²)_pS(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)₂(CR¹¹R¹²)_q, or (CR¹¹R¹²)_pS(O)₂NR^c(CR¹¹R¹²)_q, wherein said C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D¹-D²-D³-D⁴;
  
  Z is H, halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, ═
  
  C—
  
  Rⁱ, ═
  
  N—
  
  Rⁱ, Cy¹, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  wherein when Z is H, n is 1;
  
  or the —
  
  (Y)_n—
  
  Z moiety is taken together with i) A²to which the moiety is attached, ii) R⁵or R⁶of either T or V, and iii) the C or N atom to which the R⁵or R⁶of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —
  
  (W)_m-Q;
  
  W is C_1-8alkylenyl, C_2-8alkenylenyl, C_2-8alkynylenyl, O, S, C(O), C(O)NR^c′, C(O)O, OC(O), OC(O)NR^c′, NR^c′, NR^6′C(O)NR^c′, S(O), S(O)NR^c′, S(O)₂, or S(O)₂NR^c′;
  
  Q is H, halo, CN, NO₂, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy², CN, NO₂, OR^a′, SR^a′, C(O)R^b′, C(O)NR^c′R^d′, C(O)OR^a′, OC(O)R^b′, OC(O)NR^c′R^d′, NR^c′R^d′, NR^c′C(O)R^b′, NR^c′C(O)NR^c′R^d′, NR^c′C(O)OR^a′, S(O)R^b′, S(O)NR^c′R^d′, S(O)₂R^b′, NR^c′S(O)₂R^b′, and S(O)₂NR^c′R^d′;
  
  Cy¹and Cy²are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^b″, NR^c″C(O)OR^a″, NR^c″S(O)R^b″, NR^c″S(O)₂R^b″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, and S(O)₂NR^c″R^d″;
  
  R¹, R², R³, and R⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR^cC(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;
  
  R⁵is H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁶is H, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁷is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁸is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁹and R¹⁰are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkylcarbonyl, arylcarbonyl, C_1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
  
  or R⁹and R¹⁰together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
  
  R¹¹and R¹²are independently selected from H and -E¹-E²-E³-E⁴;
  
  D¹and E¹are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D²and E²are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, (C_1-6alkylene)_r-O—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-S—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-NR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-CO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-COO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r—
  
  CONR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO₂—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SONR^e—
  
  (C_1-6alkylene)_s, and (C_1-6alkylene)_r-NR^eCONR^f—
  
  (C_1-6alkylene)_s, wherein each of the C_1-6alkylene, C_2-6alkenylene, and C_2-6alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D³and E³are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D⁴and E⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  R^ais H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^bis H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^a′and R^a″are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^b′ and R^b″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^cand R^dare independently selected from H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  or R^cand R^dtogether with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  R^c′ and R^d′ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, c_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c′ and R^d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^c″and R^d″are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, C_1-6haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c″ and R^d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  Rⁱis H, CN, NO₂, or C_1-6alkyl;
  
  R^eand R^fare independently selected from H and C_1-6alkyl;
  
  Rⁱis H, CN, or NO₂;
  
  m is 0 or 1;
  
  n is 0 or 1;
  
  p is 0, 1, 2, 3, 4, 5, or 6;
  
  q is 0, 1, 2, 3, 4, 5 or 6;
  
  r is 0 or 1; and
  
  s is 0 or 1;
  
  wherein when X is N, n is 1, and the moiety formed by A¹, A², U, T, V, and —
  
  (Y)_n—
  
  Z has the formula;
  
  then Y is other than (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q;
  
  (b) compounds of Formula II;
  
  wherein;
  
  L^ais SO₂or CO;
  
  R^1ais C_1-6alkyl, C_3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR^2aR^3a, or OR^4a, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4alkyl;
  
  R^2aand R^3aare independently selected from H, C_1-4alkyl, and phenyl; and
  
  R^4ais C_1-6alkyl, phenyl, or benzyl;
  
  (c) compounds of Formula III;
  
  wherein;
  
  R^5aand R^6aare independently selected from H, F, CN, OH, C_1-4alkyl, benzyloxy, C_2-8dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4alkyl;
  
  and pharmaceutically acceptable salts thereof;
  
  provided that compound of Formula I is not selected from 4-[5-(2-isopropyl-5-methylcyclohexyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(4-tert-butylphenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-cyclopentylethyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(2,6-difluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(benzyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(3-fluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(phenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(4-methoxybenzyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(phenylthiomethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(3-methylbutyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-benzyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(2,2-dimethylpropyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-methyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(formyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(furan-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(1-methyl-1H-pyrrol-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(sec-butyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-cyclopropyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine; and
  
  pharmaceutically acceptable salts of any of the aforementioned.
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49)
- - 2. A method according to claim 1, wherein said dry eye disorder is aqueous tear-deficient dry eye.
  - 3. A method according to claim 1, wherein said dry eye disorder is evaporative dry eye.
  - 4. A method according to claim 1, wherein said dry eye disorder is Sjogren syndrome dry eye.
  - 5. A method according to claim 1, wherein said dry eye disorder is non-Sjogren syndrome dry eye.
  - 6. A method according to claim 1, wherein said treating comprises ameliorating a symptom selected from eye discomfort, visual disturbance, tear film instability, tear hyperosmolarity, and inflammation of the ocular surface.
  - 7. A method according to claim 1, wherein said treating comprises administering a pharmaceutical composition to said patient, said composition comprising said agent and a pharmaceutically acceptable carrier.
  - 8. A method according to claim 7, wherein said pharmaceutical composition is an oral dosage form.
  - 9. A method according to claim 1, wherein said treating comprises administering an ophthalmic composition to said patient, said composition comprising said agent and an ophthalmically acceptable carrier.
  - 10. A method according to claim 9, wherein said ophthalmic composition is a topical composition.
  - 11. A method according to claim 9, wherein said topical composition is an aqueous formulation, an aqueous suspension, an ointment or a gel.
  - 12. A method according to claim 9, wherein said ophthalmic composition is an ophthalmic insert.
  - 13. A method according to claim 12, wherein said ophthalmic insert comprises microspheres.
  - 14. A method according to claim 13, wherein said microspheres are injected to the posterior segment of the eye, in the chroidal space, in the sclera, intravitreally or sub-retinally.
  - 15. A method according to claim 12, wherein said ophthalmic insert comprises collagen, gelatin, or a polymer, wherein said polymer is selected from polycaprolactone (PCL), an ethylene/vinyl acetate copolymer (EVA), polyalkyl cyanoacralate, polyurethane, a nylon, poly(dl-lactide-co-glycolide) (PLGA), or a copolymer of any of the aforementioned.
  - 16. A method according to claim 12, wherein said ophthalmic insert is implanted under the upper eyelid, in the posterior segment of the eye, in the chroidal space, in the sclera, intravitreally or sub-retinally.
  - 17. A method according to claim 1, further comprising administering at least one additional therapeutic agent.
  - 18. A method according to claim 17, wherein said additional therapeutic agent is fluocinolone acetonide, rimexolone, cyclosporine, riaminolone, dexamethasone, fluocinolone, cortisone, prednisolone, flumetholone, civamide, testosterone, ecabet sodium, 15-(s)-hydroxyeicosatetraenoic acid, 2S,3S,4R,5R)-3,4-dihydroxy-5-[6-[(3-iodophenyl)methylamino]purin-9-yl]-N-methyl-oxolane-2-carboxamide, gefarnate, cevilemine, doxycline, minocycline, oxytetracycline, voclosporin, rivoglitazone, lacritin rebamipide, pilocarpine, tacrolimus, pimecrolimus, loteprednol etabonate, rituximab, diquafosol tetrasodium, dehydroepiandrosterone, anakinra, efalizumab, mycophenolate sodium, etanercept, hydroxychloroquine, or thalidomide.
  - 19. A method according to claim 18, wherein said additional therapeutic agent is sodium hyaluronate, hyaluronic acid, polyvinylalcohol, hydroxypropyl methylcellulose, glycerin, polyethylene glycol, or carboxymethyl cellulose.
  - 20. A method according to claim 1, wherein said agent is selected from compounds of Formula I:
21. A method according to claim 20, wherein n is 1 and Y is C_1-8alkylene optionally substituted with 1, 2, or 3 substituents independently selected from D⁴.
22. A method according to claim 20, wherein n is 1 and Y is C_1-8alkylene optionally substituted with 1, 2, or 3 halo, OH, CN, amino, C_1-4alkylamino, or C_2-8dialkylamino.
23. A method according to claim 20, wherein n is 1 and Y is C_1-8alkylene optionally substituted with cyano.
24. A method according to claim 20, wherein Z is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, each optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
- NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, and S(O)₂NR^cR^d.
25. A method according to claim 20, wherein Z is cyclopentyl, which is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
- NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, and S(O)₂NR^cR^d.
26. A method according to claim 20, wherein Z is cyclopentyl.
27. A method according to claim 20, wherein X is N.
28. A method according to claim 20, wherein A¹is C.
29. A method according to claim 20, wherein A²is N.
30. A method according to claim 20, wherein T is N.
31. A method according to claim 20, wherein U and V are independently CR⁵.
32. A method according to claim 20, wherein R¹, R², R³, and R⁴are each H.
33. A method according to claim 20, wherein the 5-membered ring formed by A¹, A², U, T, and V is selected from:
34. A method according to claim 20, wherein said agent is selected from compounds having Formula II:
- and pharmaceutically acceptable salts thereof.
35. A method according to claim 20, wherein the moiety formed by T, U, V, A¹, and A²is not the following moiety:
36. A method according to claim 20, wherein said agent is selected from 3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and pharmaceutically acceptable salts thereof.
37. A method according to claim 20, wherein said agent is selected from (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile and pharmaceutically acceptable salts thereof.
38. A method according to claim 1, wherein said agent is selected from compounds of Formula II:
- and pharmaceutically acceptable salts thereof.
39. A method according to claim 38, wherein L^ais SO₂.
40. A method according to claim 38, wherein R^1ais C_1-4alkyl.
41. A method according to claim 38, wherein R^1ais ethyl.
42. A method according to claim 38, wherein said agent is selected from {1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile and pharmaceutically acceptable salts thereof.
43. A method according to claim 38, wherein said agent is {1-(Ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile phosphoric acid salt.
44. A method according to claim 1, wherein said agent is selected from compounds of Formula III:
- and pharmaceutically acceptable salts thereof.
45. A method according to claim 44, wherein one of R^5aand R^6ais H and the other is selected from H, F, CN, OH, C_1-4alkyl, benzyloxy, C_2-8dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4alkyl.
46. A method according to claim 44, wherein R^5aand R^6aare independently selected from H and CN.
47. A method according to claim 44, wherein said agent is selected from 3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile and pharmaceutically acceptable salts thereof.
48. A method according to claim 44, wherein said agent is selected from cis-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile and pharmaceutically acceptable salts thereof.
49. A method according to claim 44, wherein said agent is selected from trans-3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutanecarbonitrile and pharmaceutically acceptable salts thereof.

50. An ophthalmic insert comprising a therapeutically effective amount of an agent selected from:
- (a) compounds of Formula I;
  
  wherein;
  
  A¹and A²are independently selected from C and N;
  
  T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;
  
  wherein the 5-membered ring formed by A¹, A², U, T, and V is aromatic;
  
  X is N or CR⁴;
  
  Y is C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, (CR¹¹R¹²)_p—
  
  (C_3-10cycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(arylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(C_1-10heterocycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(heteroarylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_pO(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)O(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^cC(O)NR^d(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)₂(CR¹¹R¹²)_q, or (CR¹¹R¹²)_pS(O)₂NR^c(CR¹¹R¹²)_q, wherein said C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D¹-D²-D³-D⁴;
  
  Z is H, halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, ═
  
  C—
  
  Rⁱ, ═
  
  N—
  
  Rⁱ, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  wherein when Z is H, n is 1;
  
  or the —
  
  (Y)_n—
  
  Z moiety is taken together with i) A²to which the moiety is attached, ii) R⁵or R⁶of either T or V, and iii) the C or N atom to which the R⁵or R⁶of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —
  
  (W)_m-Q;
  
  W is C_1-8alkylenyl, C_2-8alkenylenyl, C_2-8alkynylenyl, O, S, C(O), C(O)NR^c′, C(O)O, OC(O), OC(O)NR^c′, NR^c′, NR^c′C(O)NR^d′, S(O), S(O)NR^c′, S(O)₂, or S(O)₂NR^c′;
  
  Q is H, halo, CN, NO₂, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy², CN, NO₂, OR^a′, C(O)R^b′, C(O)NR^c′R^d′, C(O)OR^a′, OC(O)R^b′, OC(O)NR^c′R^d′, NR^c′R^d′, NR^c′C(O)R^b′, NR^c′C(O)NR^c′
  
  R^d′, NR^c′C(O)OR^a′, S(O)R^b′, S(O)NR^c′R^d′, S(O)₂R^b′, NR^c′S(O)₂R^b′, and S(O)₂NR^c′R^d′;
  
  Cy¹and Cy²are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^b″, NR^c″C(O)OR^a″, NR^c″S(O)R^b″, NR^c″S(O)₂R^b″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, and S(O)₂NR^c″R^d″;
  
  R¹, R², R³, and R⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR^cC(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;
  
  R⁵is H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁶is H, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR², S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁷is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁸is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁹and R¹⁰are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkylcarbonyl, arylcarbonyl, C_1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
  
  or R⁹and R¹⁰together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
  
  R¹¹and R¹²are independently selected from H and -E¹-E²-E²-E⁴;
  
  D¹and E¹are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alklamino, and C_2-8dialkylamino;
  
  D²and E²are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, (C_1-6alkylene)_r-O—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-S—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-NR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-CO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-COO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_s-CONR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO₂—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SONR^e—
  
  (C_1-6alkylene)_s, and (C_1-6alkylene)_r-NR^eCONR^f—
  
  (C_1-6alkylene)_s, wherein each of the C_1-6alkylene, C_2-6alkenylene, and C_2-6alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D³and E³are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D⁴and E⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  R^ais H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^bis H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-4alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^a′ and R^a″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^b′ and R^b″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^cand R^dare independently selected from H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl,and halosulfanyl;
  
  or R^cand R^dtogether with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  R^c′ and R^d′ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c′ and R^d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^c″ and R^d″ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_l-6alkyl, C_1-6haloalkyl, halosulfanyl, C_1-6haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c″ and R^d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  Rⁱis H, CN, NO₂, or C_1-6alkyl;
  
  R^eand R^fare independently selected from H and C_1-6alkyl;
  
  Rⁱis H, CN, or NO₂;
  
  m is 0 or 1;
  
  n is 0 or 1;
  
  p is 0, 1, 2, 3, 4, 5, or 6;
  
  q is 0, 1, 2, 3, 4, 5 or 6;
  
  r is 0 or 1; and
  
  s is 0 or 1;
  
  wherein when X is N, n is 1, and the moiety formed by A¹, A², U, T, V, and —
  
  (Y)_n—
  
  Z has the formula;
  
  then Y is other than (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q;
  
  (b) compounds of Formula II;
  
  wherein;
  
  L^ais SO₂or CO;
  
  R^1ais C_1-6alkyl, C_3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR^2aR^3a, or OR^4a, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4alkyl;
  
  R^2aand R^3aare independently selected from H, C_1-4alkyl, and phenyl; and
  
  R^4ais C_1-6alkyl, phenyl, or benzyl;
  
  (c) compounds of Formula III;
  
  wherein;
  
  R^5aand R^6aare independently selected from H, F, CN, OH, C_1-4alkyl, benzyloxy, C_2-8dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4alkyl;
  
  and pharmaceutically acceptable salts thereof;
  
  provided that compound of Formula I is not selected from 4-[5-(2-isopropyl-5-methylcyclohexyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(4-tert-butylphenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-cyclopentylethyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(2,6-difluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)-1,2-4-oxadiazol-3yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(benzyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(3-fluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(phenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(4-methoxybenzyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(phenylthiomethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(3-methylbutyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-benzyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(2,2-dimethylpropyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-methyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(formyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(furan-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(1-methyl-1H-pyrrol-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(sec-butyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-cyclopropyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine; and
  
  pharmaceutically acceptable salts of any of the aforementioned.

51. A kit for treatment of dry eye disorder, comprising an ophthalmic or pharmaceutical composition and instructions;
- wherein said composition comprises a therapeutically effective amount of an agent selected from;
  
  (a) compounds of Formula I;
  
  wherein;
  
  A¹and A²are independently selected from C and N;
  
  T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;
  
  wherein the 5-membered ring formed by A¹, A², U, T, and V is aromatic;
  
  X is N or CR⁴;
  
  Y is C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, (CR¹¹R¹²)_p—
  
  (C_3-10cycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(arylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p—
  
  (C_1-10heterocycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(heteroarylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_pO(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)O(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^cC(O)NR^d(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)^pS(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)₂(CR₁₁R¹²)_q, or (CR¹¹R¹²)_pS(O)₂NR^c(CR¹¹R¹²)_q, wherein said C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D¹-D²-D³-D⁴;
  
  Z is H, halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, ═
  
  C—
  
  Rⁱ, ═
  
  N—
  
  Rⁱ, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^aR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  wherein when Z is H, n is 1;
  
  or the —
  
  (Y)_n—
  
  Z moiety is taken together with i) A²to which the moiety is attached, ii) R⁵or R⁶of either T or V, and iii) the C or N atom to which the R⁵or R⁶of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —
  
  (W)_m-Q;
  
  W is C_1-8alkylenyl, C_2-8alkenylenyl, C_2-8alkynylenyl, O, S, C(O), C(O)NR^c′, C(O)O, OC(O), OC(O)NR^c′, NR^c′, NR^c′C(O)NR^d′, S(O), S(O)NR^c′, S(O)₂, or S(O)₂NR^c′;
  
  Q is H, halo, CN, NO₂, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy², CN, NO₂, OR^a′, SR^a′, C(O)R^b′, C(O)NR^c′R^d′, C(O)OR^a′, OC(O)R^b′, OC(O)NR^c′R^d′, NR^c′R^d′, NR^c′C(O)R^b′, NR^c′C(O)NR^c′R^d′, NR^c′C(O)OR^a′, S(O)R^b′, S(O)NR^c′R^d′, S(O)₂R^b′, NR^c′S(O)₂R^b′, and S(O)₂NR^c′R^d′;
  
  Cy¹and Cy²are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^b″, NR^c″C(O)OR^a″, NR^c″S(O)R^b″, NR^c″S(O)₂R^b″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, and S(O)₂NR^c″R^d″;
  
  R¹, R², R³, and R⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR^cC(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;
  
  R⁵is H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁶is H, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁷is H, C_1-6alkyl, haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁸is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁹and R¹⁰are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkylcarbonyl, arylcarbonyl, C_1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
  
  or R⁹and R¹⁰together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
  
  R¹¹and R¹²are independently selected from H and -E¹-E²-E³-E⁴;
  
  D¹and E¹are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkylenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-4dialkylamino;
  
  D²and E²are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, (C_1-6alkylene)_r-O—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-S—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-NR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-CO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-COO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-CONR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO₂—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r—
  
  SONR^e—
  
  (C_1-6alkylene)_sand (C_1-6alkylene)_r—
  
  NR^eCONR^f—
  
  (C_1-6alkylene)_s, wherein each of the C_1-6alkylene, C_2-6alkenylene, and C_2-6alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D³and E³are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D⁴and E⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  R^ais H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^bis H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^a′ and R^a″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^b′ and R^b″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^cand R^dare independently selected from H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  or R^cand R^dtogether with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  R^c′ and R^d′ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c′ and R^d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^c″ and R^d″ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, C_1-6haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c″ and R^d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  Rⁱis H, CN, NO₂, or C_1-6alkyl;
  
  R^eand r^fare independently selected from H and C_1-6alkyl;
  
  Rⁱis H, CN, or NO₂;
  
  m is 0 or 1;
  
  n is 0 or 1;
  
  p is 0, 1, 2, 3, 4, 5, or 6;
  
  q is 0, 1, 2, 3, 4, 5 or 6;
  
  r is 0 or 1; and
  
  s is 0 or 1;
  
  wherein when X is N, n is 1, and the moiety formed by A¹, A², U, T, V, and —
  
  (Y)_n—
  
  Z has the formula;
  
  then Y is other than (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q;
  
  (b) compounds of Formula II;
  
  wherein;
  
  L^ais SO₂or CO;
  
  R^1ais C_1-6alkyl, C_3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR^2aR^3a, or OR^4a, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4alkyl;
  
  R^2aand R^3aare independently selected from H, C_1-4alkyl, and phenyl; and
  
  R^4ais C_1-6alkyl, phenyl, or benzyl;
  
  (c) compounds of Formula III;
  
  wherein;
  
  R^5aand R^6aare independently selected from H, F, CN, OH, C_1-4alkyl, benzyloxy, C_2-8dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4alkyl;
  
  and pharmaceutically acceptable salts thereof;
  
  provided that compound of Formula I is not selected from 4-[5-(2-isopropyl-5-methylcyclohexyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(4-tert-butylphenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-cyclopentylethyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(2,6-difluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(1-tert-butyl-3-methyl-1H-pyrazol-5-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(benzyloxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(3-fluorophenyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(phenoxymethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(4-methoxybenzyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(phenylthiomethyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(3-methylbutyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-benzyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(2,2-dimethylpropyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-methyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(formyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(furan-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(1-methyl-1H-pyrrol-2-yl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-(sec-butyl)-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine;
  
  4-[5-cyclopropyl-1,2-4-oxadiazol-3-yl]-1H-pyrrolo[2,3-b]pyridine; and
  
  pharmaceutically acceptable salts of any of the aforementioned;
  
  and wherein said instructions comprise a direction to administer said composition to a patient in need of treatment of said dry eye disorder.

52-53. -53. (canceled)

54. A method of treating conjunctivitis, uveitis, chorioditis, retinitis, cyclitis, sclieritis, episcleritis, or iritis;
- treating inflammation or pain related to corneal transplant, LASIK (laser assisted in situ keratomileusis), photorefractive keratectomy, or LASEK (laser assisted sub-epithelial keratomileusis);
  
  inhibiting loss of visual acuity related to corneal transplant, LASIK, photorefractive keratectomy, or LASEK;
  
  or inhibiting transplant rejection related to conical transplant in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of an agent;
  
  wherein said agent is selected from;
  
  (a) compounds of Formula I;
  
  wherein;
  
  A¹and A²are independently selected from C and N;
  
  T, U, and V are independently selected from O, S, N, CR⁵, and NR⁶;
  
  wherein the 5-membered ring formed by A¹, A², U, T, and V is aromatic;
  
  X is N or CR⁴;
  
  Y is C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, (CR¹¹R¹²)_p—
  
  (C_3-10cycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(arylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(C_1-10to heterocycloalkylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_p-(heteroarylene)-(CR¹¹R¹²)_q, (CR¹¹R¹²)_pO(CR¹¹R¹²)_q, (CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pC(O)NR^c(CR^{1l R}¹²)_q, (CR¹¹R¹²)_pC(O)O(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pOC(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_pNR^cC(O)NR^d(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)(CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)NR^c(CR¹¹R¹²)_q, (CR¹¹R¹²)_q, (CR¹¹R¹²)_pS(O)₂(CR¹¹R¹²_q, or (CR¹¹R¹²)_pS(O)₂NR^c(CR¹¹R¹²)_q, wherein said C_1-8alkylene, C_2-8alkenylene, C_2-8alkynylene, cycloalkylene, arylene, heterocycloalkylene, or heteroarylene, is optionally substituted with 1, 2, or 3 substituents independently selected from -D¹-D²-D³-D⁴;
  
  Z is H, halo, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, ═
  
  C—
  
  Rⁱ, ═
  
  N—
  
  Rⁱ, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(_1-6alkyl)R^b, and SO(₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  wherein when Z is H, n is 1;
  
  or the —
  
  (Y)_n—
  
  Z moiety is taken together with i) A²to which the moiety is attached, ii) R⁵or R⁶of either T or V, and iii) the C or N atom to which the R⁵or R⁶of either T or V is attached to form a 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring fused to the 5-membered ring formed by A¹, A², U, T, and V, wherein said 4- to 20-membered aryl, cycloalkyl, heteroaryl, or heterocycloalkyl ring is optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from —
  
  (W)_m—
  
  Q;
  
  W is C_1-8alkylenyl, C_2-8alkenylenyl, C_2-8alkynylenyl, O, S, C(O), C(O)NR^c′, C(O)O, OC(O), OC(O)NR^c′, NR^c′, NR^c′C(O)NR^d′, S(O), S(O)NR^c′, S(O)₂, or S(O)₂NR^c′;
  
  Q is H, halo, CN, NO₂, C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C_1-8alkyl, C_2-8alkenyl, C_2-8alkynyl, C_1-8haloalkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy², CN, NO₂, OR^a′, SR^a′, C(O)R^b′, C(O)NR^c′R^d′, C(O)OR^a′, OC(O)R^b′, OC(O)NR^c′R^d′, NR^c′R^d′, NR^c′C(O)R^b′, NR^c′C(O)NR^c′R^d′, NR^c′C(O)OR^a′, S(O)R^b′, S(O)N^c′R^d′, S(O)₂R^b′, NR^c′S(O)₂R^b′, and S(O)₂NR^c′R^d′;
  
  Cy¹and Cy²are independently selected from aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^b″, NR^c″C(O)OR^a″, NR^c″S(O)R^b″, NR^c″S(O)₂R^b″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, and S(O)₂NR^c″R^d″;
  
  R¹, R², R³, and R⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR^cC(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, and S(O)₂NR⁹R¹⁰;
  
  R⁵is H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, CN, NO₂, OR⁷, SR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, OC(O)R⁸, OC(O)NR⁹R¹⁰, NR⁹R¹⁰, NR⁹C(O)R⁸, NR⁹C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, NR⁹S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁶is H, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, OR⁷, C(O)R⁸, C(O)NR⁹R¹⁰, C(O)OR⁷, S(O)R⁸, S(O)NR⁹R¹⁰, S(O)₂R⁸, or S(O)₂NR⁹R¹⁰;
  
  R⁷is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heter heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁸is H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl;
  
  R⁹and R¹⁰are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6alkylcarbonyl, arylcarbonyl, C_1-6alkylsulfonyl, arylsulfonyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl;
  
  or R⁹and R¹⁰together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
  
  R¹¹and R¹²are independently selected from H and -E¹-E²-E³-E⁴;
  
  D¹and E¹are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D²and E²are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, (C_1-6alkylene)_r-O—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-S—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-NR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-CO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-COO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r—
  
  CONR^e—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SO₂—
  
  (C_1-6alkylene)_s, (C_1-6alkylene)_r-SONR^e—
  
  (C_1-6alkylene)_s, and (C_1-6alkylene)_r-NR^eCONR^f—
  
  (C_1-6alkylene)_s, wherein each of the C_1-6alkylene, C_2-6alkenylene, and C_2-6alkynylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, and C_2-8dialkylamino;
  
  D³and E³are independently absent or independently selected from C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene, wherein each of the C_1-6alkylene, C_2-6alkenylene, C_2-6alkynylene, arylene, cycloalkylene, heteroarylene, and heterocycloalkylene is optionally substituted by 1, 2 or 3 substituents independently selected from halo, CN, NO₂, N₃, SCN, OH, C_1-6alkyl, C_1-6haloalkyl, C_2-8alkoxyalkyl, C_1-6alkoxy, C_1-6haloalkoxy, amino, C_1-6alkylamino, an C_2-4dialkylamino;
  
  D⁴and E⁴are independently selected from H, halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl)R^b, and S(O)₂NR^cR^d, wherein said C_1-8alkyl, C_2-8alkenyl, or C_2-8alkynyl, is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, halosulfanyl, C_1-4hydroxyalkyl, C_1-4cyanoalkyl, Cy¹, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^b, NR^cC(O)NR^cR^d, NR^cC(O)OR^a, C(═
  
  NRⁱ)NR^cR^d, NR^cC(═
  
  NRⁱ)NR^cR^d, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, NR^cS(O)₂R^b, C(═
  
  NOH)R^b, C(═
  
  NO(C_1-6alkyl))R^b, and S(O)₂NR^cR^d;
  
  R^ais H, Cy¹, —
  
  (C₁₆alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^bis H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^a′ and R^a″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^b′ and R^b″ are independently selected from H, C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-6alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^cand R^dare independently selected from H, Cy¹, —
  
  (C_1-6alkyl)-Cy¹, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, or C_2-6alkynyl, is optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  or R^cand R^dtogether with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from Cy¹, —
  
  (C_1-6alkyl)-Cy¹, OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, and halosulfanyl;
  
  R^c′ and R^d′ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c′ and R^d′ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  R^c″ and R^d″ are independently selected from H, C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and heterocycloalkylalkyl, wherein said C_1-10alkyl, C_1-6haloalkyl, C_2-6alkenyl, C_2-6alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, halosulfanyl, C_1-6haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  or R^c″ and R^d″ together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 substituents independently selected from OH, CN, amino, halo, C_1-6alkyl, C_1-6haloalkyl, C_1-6haloalkyl, halosulfanyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;
  
  Rⁱis H, CN, NO₂, or C_1-6alkyl;
  
  R^eand R^fare independently selected from H and C_1-6alkyl;
  
  Rⁱis H, CN, or NO₂;
  
  m is 0 or 1;
  
  n is 0 or 1;
  
  p is 0, 1, 2, 3, 4, 5, or 6;
  
  q is 0, 1, 2, 3, 4, 5 or 6;
  
  r is 0 or 1; and
  
  s is 0 or 1;
  
  wherein when X is N, n is 1, and the moiety formed by A¹, A², U, T, V, and —
  
  (Y)_n—
  
  Z has the formula;
  
  then Y is other than (CR¹¹R¹²)_pC(O)NR^c(CR¹¹R¹²)_q;
  
  (b) compounds of Formula II;
  
  wherein;
  
  L^ais SO₂or CO;
  
  R^1ais C_1-6alkyl, C_3-7cycloalkyl, phenyl, 5- or 6-membered heteroaryl, indolyl, NR^2aR^3a, or OR^4a, wherein said alkyl, cycloalkyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from F, CN, and C_1-4alkyl;
  
  R^2aand R^1aare independently selected from H, C_1-4alkyl, and phenyl; and
  
  R^4ais C_1-6alkyl, phenyl, or benzyl;
  
  (c) compounds of Formula III;
  
  wherein;
  
  R^5aand R^6aare independently selected from H, F, CN, OH, C_1-4alkyl, benzyloxy, C_2-8dialkylaminosulfonyl, and 5-membered heteroaryl, wherein said alkyl is optionally substituted by 1, 2, or 3 substituents selected from F, OH, CN, and C_1-4alkoxy, and wherein said 5-membered heteroaryl is optionally substituted with C_1-4alkyl;
  
  and pharmaceutically acceptable salts thereof.
- View Dependent Claims (55, 56)
- - 55. The method according to claim 54, wherein said agent is administered preoperatively to a patient about to undergo a procedure selected from corneal transplant, LASIK, photorefractive keratectomy, and LASEK.
  - 56. The method according to claim 54, wherein said agent is administered postoperatively to a patient who has undergone a procedure selected from corneal transplant, LASIK, photorefractive keratectomy, and LASEK.

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Current Assignee
Incyte Corporation
Original Assignee
Incyte Corporation
Inventors
Friedman, Paul A., Luchi, Monica E., Williams, William V., Fridman, Jordan S.

Application Number

US12/571,834
Publication Number

US 20100113416A1
Time in Patent Office

Days
Field of Search
US Class Current

514/210.210
CPC Class Codes

A61K 31/437   the heterocyclic ring syste...

A61K 31/519   ortho- or peri-condensed wi...

A61K 9/0048   Eye, e.g. artificial tears

A61P 27/00   Drugs for disorders of the ...

A61P 27/02   Ophthalmic agents

A61P 27/04   Artificial tears; Irrigatio...

A61P 29/00   Non-central analgesic, anti...

A61P 37/02   Immunomodulators

A61P 37/06   Immunosuppressants, e.g. dr...

A61P 43/00   Drugs for specific purposes...

JANUS KINASE INHIBITORS FOR TREATMENT OF DRY EYE AND OTHER EYE RELATED DISEASES

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235 Citations

56 Claims

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JANUS KINASE INHIBITORS FOR TREATMENT OF DRY EYE AND OTHER EYE RELATED DISEASES

First Claim

1 Assignment

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0 Petitions

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Accused Products

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Abstract

235 Citations

56 Claims

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