Amine derivative compounds for treating ophthalmic diseases and disorders

A compound having a structure of Formula (Ia):

• or a tautomer thereof, or as a pharmaceutically acceptable salt, or N-oxide thereof,
• wherein:
• R1 and R2 are each the same or different and independently hydrogen, halogen, C1-C5 alkyl, fluoroalkyl, —OR6, or —NR7R8;
• or R1 and R2 form an oxo;
• R3 and R4 are each the same or different and independently hydrogen or alkyl;
• R5 is C5-C15 alkyl, aralkyl, heterocyclylalkyl, heteroarylalkyl or carbocyclylalkyl;
• R6 is hydrogen or alkyl;
• R7 and R8 are each the same or different and independently hydrogen, alkyl, carbocyclyl, or —C(═O)R13;
• or
• R7 and R8, together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• R9 and R10 are each the same or different and independently hydrogen, halogen, alkyl, fluoroalkyl, —OR6, —NR7R8 or carbocyclyl;
• or R9 and R10 form an oxo;
• R11 and R12 are each the same or different and independently hydrogen or —C(═O)R13;
• and
• R13 is alkyl, alkenyl, aryl, carbocyclyl, heteroaryl or heterocyclyl.

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (A) or tautomer, stereoisomer, geometric isomer, or pharmaceutically aceptable salt, or N-oxide thereof:

• wherein,
• Z is —C(R9)(R10)—C(R1)(R2)—, or —C(R9)(R10)—C(R1)(R2)—C(R36)(R37)—;
• G is selected from —C(R41)2—C(R41)2—R40, —C(R42)2—S—R40, —C(R42)2—SO—R40, —C(R42)2—SO2—R40, —C(R42)2—O—R40, —C(R42)2—N(R42)—R40, —C(═O)—N(R42)—R40;
• R40 is selected from —C(R16)(R17)(R18), or aryl;
• each R41 is independently selected from hydrogen, hydroxy, OR6, alkyl, or two R41 groups together may form an oxo;
• each R42 is independently selected from hydrogen or alkyl;
• R1 and R2 are each independently selected from hydrogen, halogen, C1-C5 alkyl, fluoroalkyl, —OR6 or —NR7R8;
• or R1 and R2 together form an oxo;
• R36 and R37 are each independently selected from hydrogen, halogen, C1-C5 alkyl, fluoroalkyl, —OR6 or —NR7R8;
• or R36 and R37 together form an oxo;
• or optionally, R36 and R1 together form a direct bond to provide a double bond;
• or optionally, R36 and R1 together form a direct bond, and R37 and R2 together form a direct bond to provide a triple bond;
• R3 and R4 are each independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or C-attached heterocyclyl;
• or R3 and R4 together with the carbon atom to which they are attached, form a carbocyclyl or heterocyclyl;
• or R3 and R4 together form an imino;
• R7 and R8 are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R13, SO2R13, CO2R13 or SO2NR24R25;
• or R7 and R8 together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• R9 and R10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR19, —NR20R21 or carbocyclyl;
• or R9 and R10 form an oxo;
• or optionally, R9 and R1 together form a direct bond to provide a double bond;
• or optionally, R9 and R1 together form a direct bond, and R10 and R2 together form a direct bond to provide a triple bond;
• R11 and R12 are each independently selected from hydrogen, —C(═O)R23, —C(NH)NH2, or CO2R23;
• each R13, R22 and R23 is independently selected from —CH3, —CH2CH3, —CH2CH2CH3, —C(H)(CH3)CH3, —CH2CH2CH2CH3, C5-C8 alkyl, heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;
• R6, R19, and R34 are each independently hydrogen or alkyl;
• R20 and R21 are each independently selected from hydrogen, alkyl, carbocyclyl, heterocyclyl, —C(═O)R22, SO2R22, CO2R22 or SO2NR26R27;
• or R20 and R21 together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• and
• each R24, R25, R26, and R27, is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;
• R16 and R17 are each independently selected from hydrogen, alkyl, halo, aryl, heteroaryl, aralkyl, heteroaryalkyl or fluoroalkyl;
• or R16 and R17, together with the carbon to which they are attached form a carbocyclyl or heterocycle;
• R18 is selected from hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl;
• each R33 is independently selected from halogen, hydroxy, alkyl, or fluoroalkyl;
• and n is 0, 1, 2, 3, or 4;
• with the provision that G is not an unsubstituted normal alkyl and the provision that the compound of Formula A is not:

A compound of the following formula, or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt, or N-oxide thereof:

• wherein,
• R1 and R2 are each independently selected from hydrogen, halogen, C1-C5 alkyl, fluoroalkyl, —OR6 or —NR7R8;
• or R1 and R2 together form an oxo;
• R3 and R4 are each independently selected from hydrogen or alkyl;
• or R3 and R4 together form an imino;
• R7 and R8 are each independently selected from hydrogen, alkyl, carbocyclyl or —C(═O)R13;
• or R7 and R8, together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• R9 and R10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR19, —NR20R21 or carbocyclyl;
• or R9 and R10 together form an oxo;
• R11 and R12 are each independently selected from hydrogen, —C(═O)R23 or —CO2R23;
• each R13, R22 and R23 is independently selected from methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, C5-C8 alkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;
• R6, R19 and R34 are each independently hydrogen or alkyl;
• R20 and R21 are each independently selected from hydrogen, alkyl, carbocyclyl, —C(═O)R22;
• or R20 and R21, together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• and
• each R24, R25, R26, and R27 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;
• R16 and R17 are each independently selected from hydrogen, C1-C13 alkyl, halo or fluoroalkyl;
• or R16 and R17, together with the carbon to which they are attached form a carbocyclyl or heterocycle;
• each R33 is independently selected from halogen, OR34, hydroxy, alkyl, or fluoroalkyl;
• n is 0, 1, 2, 3, or 4;
• and
• R18 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl.

A compound of the following formula, or tautomer, stereoisomer, geometric isomer or a pharmaceutically acceptable salt, or N-oxide thereof:

• wherein,
• R1 and R2 are each independently selected from hydrogen, halogen, C1-C5 alkyl, fluoroalkyl, —OR6 or —NR7R8;
• or R1 and R2 together form an oxo;
• R3 and R4 are each independently selected from hydrogen or alkyl;
• or R3 and R4 together form an imino;
• R7 and R8 are each independently selected from hydrogen, alkyl, carbocyclyl or —C(═O)R13;
• or R7 and R8, together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• R9 and R10 are each independently selected from hydrogen, halogen, alkyl, fluoroalkyl, —OR19, —NR20R21 or carbocyclyl;
• or R9 and R10 together form an oxo;
• R11 and R12 are each independently selected from hydrogen, —C(═O)R23 or —CO2R23;
• each R13, R22 and R23 is independently selected from alkyl, heteroalkyl, alkenyl, aryl, aralkyl, carbocyclyl, heteroaryl or heterocyclyl;
• R6, R19 and R34 are each independently hydrogen or alkyl;
• R20 and R21 are each independently selected from hydrogen, alkyl, carbocyclyl, —C(═O)R22;
• or R20 and R21, together with the nitrogen atom to which they are attached, form an N-heterocyclyl;
• and
• each R24, R25, R26, and R27 is independently selected from hydrogen, alkyl, alkenyl, fluoroalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl;
• R16 and R17, together with the carbon to which they are attached form a carbocyclyl or heterocycle;
• R18 is selected from a hydrogen, alkyl, alkoxy, hydroxy, halo or fluoroalkyl;
• each R33 is independently selected from halogen, OR34, hydroxy, alkyl, or fluoroalkyl;
• and
• n is 0, 1, 2, 3, or 4.