USE OF COMPOUNDS IN INHIBITING OR KILLING MITES AND TREATING XEROPHTHALMIA

Abstract

Provided is a method for killing mites and treating xerophthalmia by compounds and salts, stereoisomers and solvates thereof.

Claims

1-113. (canceled)

114. A method of inhibiting and/or killing Demodex on a subject and/or to prevent and/or treat a disease of the subject caused by Demodex infection, comprising: administering a first compound, or a salt, ester, stereoisomer or solvate thereof, to the subject, wherein the first compound is a cytochrome P450 inhibitor selected from a group consisting of a compound of formula (I-A), ##STR00035## wherein, one or more Rj.sub.1, one or more Rj.sub.2, and one or more Rj.sub.3 are provided in the formula (I-A); each Rj.sub.1, each Rj.sub.2, and each Rj.sub.3 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; and ring A is a heterocyclic group; a compound of formula (I-B), ##STR00036## wherein, Rk.sub.1, Rk.sub.2, Rk.sub.3, Rk.sub.4, Rk.sub.5, and Rk.sub.6 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; or, Rk.sub.1 and Rk.sub.2 form an aryl or heterocyclic group together with carbon atoms to which they are attached; or, two of Rk.sub.3, Rk.sub.4, Rk.sub.5, and Rk.sub.6 form an aryl or heterocyclic group together with carbon atoms to which they are attached; represents a single bond or a double bond; Rk.sub.7 is selected from H, O, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; Rk.sub.8, Rk.sub.9, Rk.sub.10, Rk.sub.11, Rk.sub.12, Rk.sub.13, Rk.sub.14, Rk.sub.15, Rk.sub.16, and Rk.sub.17 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; and m is selected from an integer from 1 to 5; a compound of formula (I-C), ##STR00037## wherein, Rq.sub.1, Rq.sub.2, each Rq.sub.3, and each Rq.sub.4 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; Rq.sub.5, Rq.sub.6, Rq.sub.7, Rq.sub.8, and Rq.sub.9 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), NHC(?O)(C.sub.6-18 aryl), NHC(?O)(C.sub.1-10 aralkyl), NHC(?O)(C.sub.1-10 arylalkoxy), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), NHC(?O)(C.sub.1-8 alkyl)NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; or, two of Rq.sub.1, Rq.sub.2, Rq.sub.3, Rq.sub.4, Rq.sub.5, Rq.sub.6, Rq.sub.7, Rq.sub.8, and Rq.sub.9 form an aryl, cycloalkyl, or heterocyclic group together with carbon atoms to which they are attached; and m is selected from an integer from 1 to 5; a compound of formula (I-D), ##STR00038## wherein, Rs.sub.1, Rs.sub.2, Rs.sub.3, Rs.sub.4, Rs.sub.5, Rs.sub.6, Rs.sub.7, Rs.sub.8, Rs.sub.9, and Rs.sub.10 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH.sub.2, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; a compound of formula (I-E), ##STR00039## wherein, one or more Rw.sub.1 are provided in the formula (I-E); each Rw.sub.1 is independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; Rw.sub.2, Rw.sub.3, Rw.sub.4, Rw.sub.5, Rw.sub.6, Rw.sub.7, Rw.sub.8, Rw.sub.9, Rw.sub.10, Rw.sub.11, and Rw.sub.12 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; or, Rw.sub.3 and Rw.sub.4, or Rw.sub.4 and Rw.sub.5 form an aryl, cycloalkyl or heterocyclic group together with carbon atoms to which they are attached; Xw, Yw, Zw.sub.1, Zw.sub.2, and Zw.sub.3 are independently selected from CRw.sub.13Rw.sub.14, O, S, or NRw.sub.13; m1 is selected from an integer from 1 to 5; and Rw.sub.13 and Rw.sub.14 are independently of each other selected from H, halogen, C.sub.1-8 alkyl, C.sub.3-11 cycloalkyl, aryl, or heteroaryl; and a compound of formula (I-F), ##STR00040## wherein, one or more Rt.sub.1 are provided in the formula (I-F); each Rt.sub.1 is independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; Rt.sub.2, Rt.sub.3, Rt.sub.4, Rt.sub.5, and Rt.sub.6 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2; Rt.sub.7 and Rt.sub.8 are independently selected from H, C.sub.1-8 alkyl, or C.sub.3-6 cycloalkyl; Yt is selected from CRt.sub.9Rt.sub.10, O, S, or NRt.sub.9; Zt is C.sub.1-8 alkylene; and Rt.sub.9 and Rt.sub.10 are independently of each other selected from H, halogen, C.sub.1-8 alkyl, C.sub.3-11 cycloalkyl, aryl, or heteroaryl.

115. The method of claim 114, wherein the ring A is selected from a group consisting of ##STR00041## wherein, X.sub.1, X.sub.2, X.sub.3, X.sub.4, and X.sub.5 are independently selected from CRj.sub.4, or N; and Rj.sub.4 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; and ##STR00042## wherein, Y.sub.1, Y.sub.2, Y.sub.3, and Y.sub.4 are independently selected from CRj.sub.5 or N; Y.sub.5 is selected from O, S, NRj.sub.5, or CRj.sub.5Rj.sub.6; and Rj.sub.5 and Rj.sub.6 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2.

116. The method of claim 114, wherein the ring A is selected from ##STR00043## and/or Rj.sub.1, Rj.sub.2, and Rj.sub.3 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2.

117. The method of claim 114, wherein Rk.sub.1, Rk.sub.2, Rk.sub.3, Rk.sub.4, and Rk.sub.6 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; Rk.sub.5 and Rk.sub.7 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; Rk.sub.8, Rk.sub.9, Rk.sub.10, Rk.sub.11, Rk.sub.12, Rk.sub.14, Rk.sub.15, Rk.sub.16, and Rk.sub.17 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; and/or Rk.sub.13 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, or C.sub.2-8 alkenyl.

118. The method of claim 114, wherein Rq.sub.1 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; Rq.sub.7 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, NHC(?O)(C.sub.1-8 alkyl), NHC(?O)(C.sub.6-18 aryl), NHC(?O)(C.sub.1-10 aralkyl), NHC(?O)(C.sub.1-10 arylalkoxy), OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; and/or Rq.sub.2, each Rq.sub.3, each Rq.sub.4, Rq.sub.5, Rq.sub.6, Rq.sub.8, and Rq.sub.9 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2.

119. The method of claim 114, wherein the compound of formula (I-D) is a compound of formula (II-D), ##STR00044## wherein, Rs.sub.11, Rs.sub.12, Rs.sub.13, Rs.sub.14, and Rs.sub.15 are independently selected from H, halogen, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), S(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, C.sub.3-11 cycloalkyl, aryl, heteroaryl, C.sub.3-11 heterocycloalkyl, O(C.sub.1-8 cycloalkyl), S(C.sub.1-8 cycloalkyl), NH(C.sub.1-8 cycloalkyl), N(C.sub.1-8 cycloalkyl)(C.sub.1-8 alkyl), OH, NH.sub.2, SH, SO.sub.2(C.sub.1-8 alkyl), C.sub.2-8 alkenyl, C.sub.2-8 alkynyl, CH?CH.sub.2, CH?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?CH.sub.2, C(C.sub.1-8 alkyl)?CH(C.sub.1-8 alkyl), C(C.sub.1-8 alkyl)?C(C.sub.1-8 alkyl).sub.2, OC(?O)(C.sub.1-8 alkyl), C(?O)(C.sub.1-8 alkyl), (C.sub.1-8 alkyl)CO.sub.2H, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C(?O)NH(C.sub.1-8 alkyl), C(?O)N(C.sub.1-8 alkyl).sub.2, N(C.sub.1-8 alkyl)C(?O)NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)C(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH(C.sub.1-8 alkyl), NHC(?O)N(C.sub.1-8 alkyl).sub.2, NHC(?O)NH.sub.2, N(C.sub.1-8 alkyl)SO.sub.2NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl)SO.sub.2N(C.sub.1-8 alkyl).sub.2, NHSO.sub.2NH(C.sub.1-8 alkyl), or NHSO.sub.2N(C.sub.1-8 alkyl).sub.2.

120. The method of claim 119, wherein Rs.sub.1, Rs.sub.2, Rs.sub.3, Rs.sub.4, Rs.sub.6, Rs.sub.7, Rs.sub.8, Rs.sub.9, Rs.sub.13, Rs.sub.14, and Rs.sub.15 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl; Rs.sub.5 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl; and/or Rs.sub.11 and Rs.sub.12 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl.

121. The method of claim 114, wherein Rw.sub.1 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; Rw.sub.2, Rw.sub.3, Rw.sub.4, Rw.sub.5, Rw.sub.6, Rw.sub.7, Rw.sub.8, Rw.sub.9, Rw.sub.10, Rw.sub.11, and Rw.sub.12 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; Xw is NRw.sub.13, wherein Rw.sub.13 in said NRw.sub.13 is selected from H, C.sub.1-8 alkyl, or C.sub.3-11 cycloalkyl; Yw is O; Zw.sub.1 and/or Zw.sub.3 is O; Zw.sub.2 is CRw.sub.13Rw.sub.14, wherein, Rw.sub.13 and Rw.sub.14 in said CRw.sub.13Rw.sub.14 are independently selected from H, halogen, C.sub.1-8 alkyl, C.sub.3-11 cycloalkyl, aryl, or heteroaryl; and/or the compound of formula (I-E) is a compound of formula (II-E), ##STR00045##

122. The method of claim 114, wherein each Rt.sub.1, Rt.sub.2, Rt.sub.3, Rt.sub.4, Rt.sub.5, and Rt.sub.6 is independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; Rt.sub.7 and Rt.sub.8 are independently selected from H or C.sub.1-3 alkyl; Yt is selected from CH.sub.2, O, S, or NH; and/or Zt is C.sub.1-6 alkylene.

123. The method of claim 114, wherein the first compound is selected from a group consisting of a compound of formula (III-A), a compound of formula (II-B), a compound of (IT-C), a compound of formula (III-D), a compound of formula (III-E), and a compound of formula (II-F), ##STR00046## wherein, Rj.sub.4 is selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, or NO.sub.2; and Rs.sub.11 and Rs.sub.12 are independently selected from H, F, Cl, Br, I, C.sub.1-8 alkyl, O(C.sub.1-8 alkyl), NH(C.sub.1-8 alkyl), N(C.sub.1-8 alkyl).sub.2, OH, NH.sub.2, SH, CO.sub.2H, CN, CF.sub.3, CHF.sub.2, CH.sub.2F, NO.sub.2, C.sub.2-8 alkenyl, or C.sub.2-8 alkynyl.

124. The method of claim 123, wherein the first compound is selected from a group consisting of a compound of formula (IV-A), a compound of formula (II-B), a compound of (ITT-C), a compound of formula (ITT-D), a compound of formula (IV-E), and a compound of formula (III-F), ##STR00047##

125. The method of claim 114, wherein the first compound is selected from a group consisting of a compound of formula (V-A), a compound of formula (III-B), a compound of (IV-C), a compound of formula (IV-D), a compound of formula (V-E), and a compound of formula (IV-F), ##STR00048##

126. The method of claim 114, wherein the first compound is selected from a group consisting of a compound of formula (V-A), a compound of formula (IV-B), a compound of (V-C), a compound of formula (V-D), a compound of formula (VI-E), and a compound of formula (IV-F), ##STR00049##

127. The method of claim 114, wherein said administering is topical administering.

128. The method of claim 114, wherein said administering is ocular or dermal administering.

129. The method of claim 114, wherein said administering is administering an ophthalmic preparation or a topical dermatological preparation comprising the first compound to the subject, wherein the ophthalmic preparation is selected from a group consisting of eye drops, eye ointments, ophthalmic gels, ophthalmic emulsions, ophthalmic suspensions, ophthalmic films, ophthalmic solutions, and intraocular injections; or the topical dermatological preparation is selected from a group consisting of aerosols, powders, lotions, tinctures, liniments, films, ointments, gels, pastes, and emulsions.

130. The method of claim 114, wherein the disease is selected from a group consisting of an eye disease, a skin disease, and an allergic disease.

131. The method of claim 130, wherein the eye disease is selected from a group consisting of blepharitis, palpebral limbic keratoconjunctivitis, meibomian gland dysfunction, eyelash loss, abnormal eyelash arrangement, conjunctivitis, palpebral conjunctivitis, pterygium, keratitis, eyelid basal cell carcinoma, dry eye, and chalazion; the skin disease is selected from a group consisting of seborrheic dermatitis, acne, rosacea, pityriasis folliculitis, perioral dermatitis, Demodex diseases, sarcoptic mange, and basal cell carcinoma; or the allergic disease is selected from a group consisting of allergic asthma, allergic rhinitis, allergic dermatitis, and allergic conjunctivitis.

132. The method of claim 114, wherein the disease is xerophthalmia.

133. The method of claim 132, wherein the xerophthalmia is with one or more symptoms selected from a group consisting of eye itching, foreign body sensation, burning sensation, photophobia, blurred vision, fluctuated vision, dry eyes, easy fatigue of eyes, thick secretions, sensitivity to topical stimuli, redness and swelling of eyes, congestion, keratinization, and broken corneal epithelium with filamentous adhesion.

Description

DETAILED DESCRIPTION

[0210] Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by the ordinarily skilled in the art to which the present invention belongs.

[0211] The term alkyl refers to a hydrocarbon chain radical which is straight or branched and containing no unsaturation bonds, and which is attached to the rest of the molecule by a single bond. C.sub.1-8 alkyl includes C.sub.1 alkyl (that is, methyl), C.sub.2 alkyl (that is, ethyl), C.sub.3 alkyl (for example, n-propyl, and isopropyl), C.sub.4 alkyl (for example, n-butyl, isobutyl, and t-butyl), C.sub.5 alkyl, C.sub.6 alkyl, C.sub.7 alkyl, and C.sub.8 alkyl.

[0212] The term alkenyl refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one unsaturated bond, and which is attached to the rest of the molecule by a single bond. C.sub.2-8 alkenyl includes C.sub.2 alkenyl (that is, ethenyl), C.sub.3 alkenyl (for example, 1-propenyl, 2-propenyl, and 1-methyl-ethenyl), C.sub.4 alkenyl (for example, 1-butenyl, 2-butenyl, and 3-butenyl), C.sub.5 alkenyl, C.sub.6 alkenyl, C.sub.7 alkenyl, and C.sub.8 alkenyl.

[0213] The term alkynyl refers to a straight or branched hydrocarbon chain radical containing at least two carbon atoms and at least one carbon-carbon triple bond, and which is attached to the rest of the molecule by a single bond. C.sub.2-8 alkynyl includes C.sub.2 alkynyl (that is, ethynyl), C.sub.3 alkynyl (for example, 1-propynyl and 2-propynyl), C.sub.4 alkynyl (for example, 1-butynyl, 2-butynyl, and 3-butynyl), C.sub.5 alkynyl, C.sub.6 alkynyl, C.sub.7 alkynyl, and C.sub.8 alkynyl.

[0214] The term cycloalkyl refers to an alicyclic hydrocarbon such as cyclopropyl, cyclohexyl, adamantyl, or the like.

[0215] The term aryl refers to a monocyclic or polycyclic radical, including polycyclic radicals containing a monoaryl group and/or a fused aryl group, such as phenyl, naphthyl, biphenyl, indenyl, phenanthrenyl, anthracenyl, or the like.

[0216] The term heterocyclic group includes heteroaromatic and heteroalicyclic groups containing 1 to 3 monocyclic and/or fused rings and 3 to about 18 ring atoms, and the heterocyclic groups of the present invention containing 1, 2, or 3 heteroatoms selected from N, O, or S atoms. Heteroaryl includes, but are not limited to, coumarin, including 8-coumarin, quinolinyl, including 8-quinolinyl, isoquinolinyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl and the like; heteroalicyclic groups include, for example, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, oxathianyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxiranyl, thietanyl, azepinyl, oxazepinyl, diazepinyl, triazepinyl, 1,2,3,6-tetrahydropyridyl, 2-pyrrolidinyl, 3-pyrrolidinyl, dihydroindole, 2H-pyranyl, 4H-pyranyl, dioxacyclohexyl, 1,3-dioxopentyl, pyrazolyl, dithiyl, dithiopentyl, dihydropyranyl, dihydrothiophene, pyrazolyl, imidazolyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indole, quinazinyl, or the like.

[0217] Such groups may be substituted at one or more available positions with one or more suitable groups.

[0218] The term halogen includes fluorine, chlorine, bromine, and iodine.

[0219] The term salt shall be understood to mean any form of a compound used in accordance with the present invention, where the compound is in ionic form or is charged and coupled to an ion (cation or anion) with an opposite charge or in solution. Also included in the definition are quaternary ammonium salts and complexes of the molecule with other molecules and ions, particularly complexes formed by ionic interactions. The definition includes physiologically acceptable salts; the term is to be understood as equivalent to pharmacologically acceptable salts or pharmaceutically acceptable salts.

[0220] Specifically, the pharmaceutically acceptable salts include acid addition salts and base addition salts.

[0221] Acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphonic acids, and salts derived from organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids. Thus, these salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, iodate, formate, acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, tosylate, phenyl acetates, citrates, lactates, maleates, tartrates and methanesulfonates, or also salts of amino acids such as arginate, glutamate, glycinate, gluconate, galacturonate, or the like. Acid addition salts can be prepared by contacting the free base form with enough amount of the desired acid to produce the salt in the conventional manner. The free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.

[0222] Base addition salts are formed with metals or amines, such as hydroxides of alkali and alkaline earth metals, or with organic amines. Examples of metals used as cations include, but are not limited to, sodium, potassium, magnesium, and calcium. Examples of suitable amines include, but are not limited to, N,N-dibenzylethylene diamine, chloroprocaine, choline, diethanolamine, ethylenediamine (ethane-1,2-diamine), N-methylglucamine, and procaine. Base addition salts can be prepared by contacting the free acid form with amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner.

[0223] In one embodiment of the present invention, the pharmaceutically acceptable salt is a hydrochloride salt, such as paroxetine hydrochloride.

[0224] The term solvate is to be understood as meaning any form of the compound according to the present invention in which the compound is attached to another molecule via a non-covalent bond (usually a polar solvent) and includes in particular, hydrates and alcoholates, for example, methanolates. Preferred solvates are hydrates.

[0225] Any compound referred to herein is intended to represent such specific compound and certain variations or forms thereof. Specifically, the compounds referred to herein may have asymmetric centers and thus exist in different enantiomeric or diastereomeric forms. Thus, any given compound referred to herein represents any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomers or geometric isomers of double bonds may also be present, whereby in some cases the molecule may exist as an (E)-isomer or as a (7)-isomer (trans and cis isomers). If a molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds of the molecule. In addition, compounds referred to herein may exist as atropisomers. All stereoisomers of the compounds referred to herein, including enantiomers, diastereomers, geometric isomers and atropisomers, and mixtures thereof, are within the scope of the present invention.

[0226] Unless otherwise indicated, the compounds of the present invention also include isotopically-labeled forms, that is, compounds which differ only in the presence of one or more isotopically-enriched atoms. For example, compounds having the present structures except for the replacement of at least one hydrogen atom with deuterium or tritium, or the replacement of at least one carbon with a .sup.13C- or .sup.14C-enriched carbon, or the replacement of at least one nitrogen with a .sup.15N-enriched nitrogen are within the scope of the present invention.

[0227] The term xerophthalmia refers to a variety of factors caused by dry eyes as the main symptom of tear secretion disorders, often accompanied by itching, foreign body sensation, burning sensation in both eyes, photophobia, blurred vision, vision fluctuations, and other manifestations. Common symptoms include dry eyes, easy fatigue, eye itching, foreign body sensation, pain and burning sensation, thick secretions, fear of wind and light, and sensitivity to topical stimuli; sometimes the eyes are too dry and lack basic tears, instead of stimulating reflex tear secretion, resulting in frequent lacrimation; in the more serious cases, the eyes will be red and swollen, congestion, keratinization, corneal epithelium broken and filiform substance adhesion, and the long-term damage can cause corneal and conjunctival lesions and affect vision. The xerophthalmia of the present invention includes keratoconjunctivitis sicca (KCS) and further includes any one type of xerophthalmia of reduced tear secretion type and hyper-evaporative tear type.

[0228] The xerophthalmia with reduced tear secretion is classified into xerophthalmia with Sjogren's syndrome and xerophthalmia without Sjogren's syndrome. The xerophthalmia with a Sjogren's syndrome type, includes congenital anacryadenopathy, sarcoidosis, graft versus host (GVHD) disease resulting from bone marrow transplantation; accompanied by ocular pemphigus, Stevens-Johnson syndrome, trachoma, or the like; diabetes, laser (-assisted) in Situ Keratomileusis (LASIK), or the like are causes of decreased reflex secretion.

[0229] In addition, the xerophthalmia with hyper-evaporative tear type may include a condition accompanied by a decrease in the oil layer due to meibomian gland insufficiency, blepharitis, or the like; accompanied by blink insufficiency or eyelid closure insufficiency due to eyeball protrusion, rabbit eye, or the like; with decreased tear stability due to contact lens wear; accompanied by decreased mucin secretion from embryonic cells; conditions accompanied by VDT operation, or the like.

[0230] The term prevention or treatment includes therapeutic or prophylactic treatments or measures, the goal being to prevent or slow down a targeted pathological condition or disorder. A subject is successfully prevented or treated if, following administration of a therapeutically effective amount of a CYP450 inhibitor, pharmaceutical composition, or drug of the present invention according to the methods of the present invention, the subject exhibits an observable and/or measurable reduction or disappearance of one or more signs and symptoms of a particular disease.

[0231] In the present invention, the term animal generally refers to vertebrates, particularly mammals, including humans. The term non-human animal refers to any vertebrate animal other than a human, particularly a mammal. In some embodiments of the present invention, the non human animal of the present invention is a domesticated animal, that is, an animal that has been raised and domesticated by humans and whose reproduction can be controlled artificially, for functions such as eating, labor, fur, pets, experimentation, for example, commercial animals, pet animals, laboratory animals, or the like. Economic animals include such as domestic animals, for example, pigs, cattle, sheep, horses, donkeys, foxes, raccoon dogs, mink, camels, or the like. Pet animals include such as dogs, cats, rabbits, mice (for example, guinea pigs, hamsters, gerbils, chinchillas, squirrels, or the like), or the like. Experimental animals include such as monkeys, dogs, rabbits, cats, and mice (for example, rats or murine), or the like.

[0232] The disclosures of the various publications, patents, and published patent specifications cited herein are hereby incorporated by reference in their entirety.

[0233] The technical solutions in the embodiments of the present invention are clearly and completely described below with reference to FIGS. 1 to 9, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present application, all other embodiments obtained by those skilled in the art without an inventive step shall fall within the protection scope of the present application.

Example 1: Acaricidal Experiment

1. Experimental Object

[0234] This study strictly followed the ethical principles of the Declaration of Helsinki, and Ethical Guidelines for Biomedical Research Involving Human Subjects. In this study, Demodex was collected from patients diagnosed with ocular Demodex infection. Those meeting the inclusion criteria would be enrolled after an informed conversation and signing an informed consent form.

2. Demodex Detection

[0235] Demodex detection was performed according to the conventional eyelash microscopic examination method. 3 eyelashes were extracted from each eyelid, and a total of 12 eyelashes were extracted. The extracted eyelashes were immediately placed on a glass slide, and one piece of each three eyelashes was placed under an ordinary light microscope for observation. Demodex at all stages were counted and classified according to morphology (specific criteria were: Demodex brevis at a head-to-body ratio of 1:1 and Demodex folliculorum at a head-to-body ratio of 1:3 to 1:4). Only adults that were fully exposed to the field of view were taken as subjects (larvae and eggs were not considered as subjects since they were more fragile in early life).

3. Demodex Culture In Vitro

[0236] Based on the above detection of Demodex, 50 ?l of different solutions were added to each slide, and the survival of the worms was observed every 1 hour. The death was judged by observing whether the worms were active (body, limbs, or the like) under a microscope. Two skilled Demodex-related experimenters observed and judged separately during the experiment. If the judgment results were different, the third skilled experimenter was asked to make an independent judgment. The culture in vitro was performed in a climate chamber at 20? C. and 96% humidity. Slides were transported in a humid chamber under observation and the solution was added appropriately to ensure high humidity before vacuoles appeared on solution evaporation.

4. Screening of Anti-Mite Compounds

[0237] (1) Compound solution preparation: The compound (the structure is shown in V-A, IV-B, V C, V-D, VI-E, and IV-F) or salt thereof was taken to prepare the solution with 0.9% NaCl solution, and the final concentrations were shown in Table 1; [0238] (2) 50 ?l of each concentration of the compound solution was added dropwise to the mites, and coverslips were covered; [0239] (3) 50 ?l of the solute of the compound, that is, 0.9% NaCl solution, was added dropwise to the control group, and the coverslips were covered; [0240] (4) The number of mites and dosing time were recorded and the mites were placed in a climate chamber for cultivation; [0241] (5) The activity of the mites was observed under a microscope regularly until the mites died; [0242] (6) The time of death of the mites was recorded; [0243] (7) The anti-mite activity of the compounds was statistically summarized.

##STR00034##

[0244] The results are shown in Table 1.

TABLE-US-00001 TABLE 1 Results of the acaricidal experiment Average survival Average survival time of mites in Compound Concentration time of mites the control group V-A 3 mg/mL ~23.63 h 61.01 ? 14.80 h 0.3 mg/mL ~33.01 h 61.01 ? 14.80 h Sulfate salt of 10 mg/mL 5 h >72 IV-B 5 mg/mL 5.35 ? 2.09 h 61.01 ? 14.80 h 1 mg/mL 8.33 ? 4.02 h 61.01 ? 14.80 h Hydrochloride 30 mg/mL 2.24 ? 1.32 h 61.01 ? 14.80 h salt of V-C 10 mg/mL 2.89 ? 1.08 h 61.01 ? 14.80 h 3 mg/mL 5.66 ? 0.91 h 61.01 ? 14.80 h 1 mg/mL 7.44 ? 6.07 h 61.01 ? 14.80 h Hydrochloride 10 mg/mL 2.50 ? 1.37 h ~37.27 ? 17.51 h salt of V-D 1 mg/mL 9.07 ? 6.72 h ~37.27 ? 17.51 h VI-E 1 mg/mL 2.44 ? 2.04 h 64.56 ? 21.78 h Citrate salt of 10 mg/mL 4.35 ? 2.05 h 45.92 ? 23.60 h IV-F 1 mg/mL ~7.09 ? 1.44 h 45.92 ? 23.60 h

Example 2: Clinical Study on Treatment of Dry Eye Caused by Mite Infection

(I) Inclusion and Exclusion Criteria

[0245] 1. Case inclusion criteria [0246] (1) Patients who meet the dry eye diagnostic criteria after inquiry of medical history; (2) 18 to 70 years old; [0247] (3) any gender; [0248] (4) Patients who can cooperate with the treatment;

[0249] 2. Case exclusion criteria [0250] (1) Slit lamp examination for patients with iridescent cyclitis; [0251] (2) Patients with high or low intraocular pressure [0252] (3) Patients with ulceration wound on eyelid skin and corneal epithelial infiltration lesion on corneal surface [0253] (4) Exclusion of systemic diseases such as Sjogren's syndrome in patients with impaired liver and kidney function; [0254] (5) Patients under 18 years old or over 70 years old; [0255] (6) Those whose mental state does not allow them to cooperate in the evaluation; (7) Pregnant and lactating women.

[0256] 3. Shedding and elimination criteria: [0257] (1) Patients who are unable or unwilling to continue treatment due to other diseases during treatment; [0258] (2) Patients who cannot cooperate or whose symptoms worsen during treatment and are unwilling to continue treatment; [0259] (3) Those who violate the study protocol and use other drugs that are not used in this study; [0260] (4) Those with incomplete final information to determine efficacy.

(II) Endpoint Indicators

[0261] Before treatment and weekly after treatment, the patient had ocular surface discomfort score, general ophthalmologic examination (visual acuity, intraocular pressure, and slit lamp examination), three tests for dry eye (conjunctival hyperemia score, BUT test, and Schirmer I test), ocular surface disease index (OSDI) score, dry eye analyzer, and ocular Demodex examination.

(III) Data Statistics

1. Sample Size Estimation

[0262] Considering that dry eye was a common ocular surface disease in the clinic, the positive rate of ocular Demodex reached 23.8% to 90.0%. Using the formula of sample size calculation for the validity test of quantitative data, it was concluded that there were 30 cases in the experimental group and 30 cases in the control group.

2. Statistics and Analysis of Study Data

[0263] SPSS20.0 software and Excel were used for statistical processing. Paired sample t-test was used for normal distribution data of count data, the ?2 test was used for measurement data, and the non-parametric test was used for non-normal distribution data. The results were expressed as mean?standard deviation (x+s), with P<0.05 as the difference.

[0264] The above is only a preferred example of the present invention and is not intended to limit the present invention, and any modifications, equivalent substitutions, or the like made within the spirit and principles of the present invention shall be included in the scope of protection of the present invention.

[0265] The foregoing examples and methods described in the present invention may vary based on the ability, experience, and preferences of the skilled in the art.

[0266] The mere listing of the steps of the method in a certain order in the present invention does not constitute any limitation on the order of the steps of the method.