# US 9,434,695 B2 · Nitrogenous heterocyclic derivatives and their application in drugs

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- Number: US 9,434,695 B2
- Document ID: US9434695B2
- Status: Granted
- Kind: B2
- Application number: 14/396,754
- Filed: 2013-07-18
- Published: 2015-03-26
- Granted: 2016-09-06
- Earliest claimed: 2012-07-18
- Assignees: Sunshine Lake Pharma Co., Ltd.
- Applicants: Sunshine Lake Pharma Co., Ltd.
- Inventors: Yingjun Zhang; Jiancun Zhang; Xiaojun Wang; Runfeng Lin; Shengtian Cao; Zhaohe Wang; Jing Li
- Web page: https://patentgrep.com/patent/US9434695B2

## CPC

- C07D 239/36: as doubly bound oxygen atom or as unsubstituted hydroxy radical
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/08: of the prostate
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 35/00: Antineoplastic agents
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 213/64: attached in position 2 or 6
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 498/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to the field of medicine, provided herein are novel nitrogenous heterocyclic compounds, their preparation methods and their uses as drugs, especially for treatment and prevention of tissue fibrosis. Also provided herein are pharmaceutically acceptable compositions comprising the nitrogenous heterocyclic compounds and the uses of the compositions in the treatment of human or animal tissue fibrosis, especially for human or animal renal interstitial fibrosis, glomerular sclerosis, liver fibrosis, pulmonary fibrosis, peritoneal fibrosis, myocardial fibrosis, dermatofibrosis, postsurgical adhesion, benign prostatic hyperplasia, skeletal muscle fibrosis, scleroderma, multiple sclerosis, pancreatic fibrosis, cirrhosis, myosarcoma, neurofibroma, pulmonary interstitial fibrosis, diabetic nephropathy, alzheimer disease or vascular fibrosis.

## Claims

### Claim 1

A compound of Formula (I):
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, wherein:
V1 is CR1, V2 is N, V3 is CR3, and V4 is CR4;
X is a bond, NR5, or C1-10alkylene;
Y is O or S;
A is
wherein each n is independently 0, 1, 2 or 3;
each R8a is independently H, hydroxy, amino, F, Cl, Br, I, R7aR7N—, cyano, nitro, mercapto, C1-4 alkyl, C1-4haloalkyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl, or C1-9 heteroaryl;
B is —NR7R7a, C4-12 carbocyclyl, C4-12 cycloalkyl, heterocyclyl, aryl, heteroaryl, fused bicyclyl, fused heterobicyclyl, spiro bicyclyl, or spiro heterobicyclyl; wherein each of the C4-12 carbocyclyl, C4-12 cycloalkyl, heterocyclyl, aryl, heteroaryl, fused bicyclyl, fused heterobicyclyl, spiro bicyclyl, and spiro heterobicyclyl is unsubstituted or substituted with at least one substituent wherein the substituent is haloalkyl, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, C1-10 alkoxy, C1-10 alkylamino, C1-10 alkylthio, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, mercapto, nitro, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S(═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxyC1-6 alkoxy; wherein each of the —NR7R7a is unsubstituted or substituted with at least one substituent wherein the substituent is haloalkyl, hydroxy, amino, F, Cl, Br, I, cyano, C1-10 alkoxy, C1-10 alkylamino, C1-10 alkylthio, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, mercapto, nitro, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S(═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxyC1-6 alkoxy;
R1 is H, F, Cl, Br, I, cyano, aliphatic, haloalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, cycloalkyloxy, arylalkoxy, arylalkylamino, heteroarylalkoxy, heteroarylalkylamino, heterocyclylalkylamino, cycloalkylamino, heterocyclylalkoxy, carbocyclylalkoxy, carbocyclylalkylamino, aryloxy, heteroaryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, azidoalkoxy, heterocyclyl, cycloalkyl, aryl, heteroaryl, heterocyclyl aliphatic, cycloalkyl aliphatic, aryl aliphatic, heteroaryl aliphatic, aryl-(CH2)p-G-(CH2)m—, heteroaryl-(CH2)p-G-(CH2)m—, heterocyclyl-(CH2)p-G-(CH2)m—, or cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)N(R7)—, —OC(═O)N(R7)—, —OC(═O)—, —N(R7)C(═O)N(R7)—, —(R7)N—S(═O)t—, —OS(═O)t—, or —OS(═O)tN(R7)—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the aryl-(CH2)p-G-(CH2)m—, heteroaryl-(CH2)p-G-(CH2)m—, heterocyclyl-(CH2)p-G-(CH2)m—, and cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more haloalkyl, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, C1-10 alkoxy, C1-10 alkylamino, C1-10 alkylthio, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, mercapto, nitro, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S(═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxyC1-6 alkoxy;
R3 is H, F, Cl, I, cyano, aliphatic, C2-10haloalkyl, aryl-C2-10 alkoxy, heretoaryl-C3-10 alkoxy, cycloalkyl-C2-10 alkoxy, C1-4 heteroaryl, substituted aryl, heterocyclyl, cycloalkyl, heterocyclyl aliphatic, cycloalkyl aliphatic, C1-4 heteroaryl aliphatic, heterocyclylalkyl, alkoxy, hydroxyalkoxy, aminoalkoxy, haloalkoxy, alkylaminohaloalkoxy, alkylaminoalkoxy, alkoxyalkoxy, aryl-C2-10alkoxy, heterocyclylalkoxy, carbocyclylalkoxy, aryloxyalkoxy, arylaminoalkoxy, aryloxy, heteroaryloxyalkoxy, heterocyclyloxyalkoxy, carbocyclyloxyalkoxy, heterocyclyloxy, cycloalkyloxy, azidoalkoxy, aryl-(CH2)p-G-(CH2)m—, heteroaryl-(CH2)p-G-(CH2)m—, heterocyclyl-(CH2)p-G-(CH2)m—, or cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)N(R7)—, —OC(═O)N(R7)—, —OC(═O)—, —N(R7)C(═O)N(R7)—, —(R7)N—S(═O)t—, —OS(═O)t—, or —OS(═O)tN(R7)—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the aryl-(CH2)p-G-(CH2)m—, heteroaryl-(CH2)p-G-(CH2)m—, heterocyclyl-(CH2)p-G-(CH2)m—, and cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one haloalkyl, oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, C1-10 alkoxy, C1-10 alkylamino, C1-10 alkylthio, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, mercapto, nitro, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S(═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxyC1-6 alkoxy;
R4 is H;
each R5 is independently H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl;
each R7 is independently H, aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; and
each R7a is independently aliphatic, haloaliphatic, hydroxyaliphatic, aminoaliphatic, alkoxyaliphatic, alkylaminoaliphatic, alkylthioaliphatic, arylaliphatic, heteroarylaliphatic, heterocyclylaliphatic, cycloalkylaliphatic, aryloxyaliphatic, heterocyclyloxyaliphatic, cycloalkyloxyaliphatic, arylaminoaliphatic, heterocyclylaminoaliphatic, cycloalkylaminoaliphatic, aryl, heteroaryl, heterocyclyl or carbocyclyl; with the proviso that where R7 and R7a are bonded to the same nitrogen atom, R7 and R7a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring or a substituted or unsubstituted spiro bicyclic or fused bicyclic ring.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein B is —NR7R7a, C4-12 carbocyclyl, C4-12 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C5-12 fused bicyclyl, C5-12 fused heterobicyclyl, C5-12 spiro bicyclyl, or C5-12 spiro heterobicyclyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein:
R1 is H, F, Cl, Br, I, cyano, C1-6 aliphatic, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C1-6 alkylamino-C1-6-haloalkoxy, C1-6 alkylamino-C1-6-alkoxy, C1-6 alkoxy-C1-6-alkoxy, C3-10 cycloalkyloxy, C6-10 aryl-C1-6-alkoxy, C6-10 aryl-C1-6-alkylamino, C1-9 heteroaryl-C1-6-alkoxy, C1-9 heteroaryl-C1-6-alkylamino, C2-10 heterocyclyl-C1-6-alkoxy, C2-10 heterocyclyl-C1-6-alkylamino, C3-10 cycloalkylamino, C3-10 carbocyclyl-C1-6-alkoxy, C3-10 carbocyclyl-C1-6-alkylamino, C6-10 aryloxy-C1-6-alkoxy, C6-10 aryloxy, C1-9 heteroaryloxy, C1-9heteroaryloxy-C1-6-alkoxy, C2-10 heterocyclyloxy-C1-6-alkoxy, C3-10 carbocyclyloxy-C1-6-alkoxy, C2-10 heterocyclyloxy, C1-6 azidoalkoxy, C2-10 heterocyclyl, C3-10 cycloalkyl, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, I, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy or cyano;
R3 is H, F, Cl, I, cyano, C1-6 aliphatic, C2-10 haloalkyl, C6-10 aryl-C2-10-alkoxy, C1-9 heteroaryl-C3-6-alkoxy, C3-10 cycloalkyl-C2-10-alkoxy, C2-10 heterocyclyl, C3-10 cycloalkyl, C1-4 heteroaryl, substituted C6-10 aryl, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C1-4 heteroaryl-C1-6-aliphatic, C1-9 heteroaryloxy-C1-6-alkoxy, C2-10 hetrerocyclyl-C1-6-alkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C1-6 alkylamino-C1-6-haloalkoxy, C1-6 alkylamino-C1-6-alkoxy, C1-6 alkoxy-C1-6-alkoxy, C6-10 aryl-C2-10-alkoxy, C2-10 heterocyclyl-C1-6-alkoxy, C3-10 carbocyclyl-C1-6-alkoxy, C6-10 aryloxy-C1-6-alkoxy, C6-10 arylamino-C1-6-alkoxy, C6-10aryloxy, C2-10 heterocyclyloxy-C1-6-alkoxy, C3-10 carbocyclyloxy-C1-6-alkoxy, C2-10 heterocyclyloxy, C3-10 cycloalkyloxy, C1-6 azidoalkoxy, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one F, Cl, Br, I, C1-6 alkyl, C2-6 alkynyl, methoxy, ethoxy, propoxy, butoxy or cyano;
R4 is H;
wherein each R5 is independently H, C1-6 aliphatic, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6 alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryloxy-C1-6-aliphatic, C2-10 heterocyclyloxy-C1-6-aliphatic, C3-10 cycloalkyloxy-C1-6-aliphatic, C6-10 arylamino-C1-6-aliphatic, C2-10 heterocyclylamino-C1-6-aliphatic, C3-10 cycloalkylamino-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
wherein each R7 is independently H, C1-6 aliphatic, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6 alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryloxy-C1-6-aliphatic, C2-10 heterocyclyloxy-C1-6-aliphatic, C3-10 cycloalkyloxy-C1-6-aliphatic, C6-10 arylamino-C1-6-aliphatic, C2-10 heterocyclylamino-C1-6-aliphatic, C3-10 cycloalkylamino-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl; and
each R7a is independently C1-6 aliphatic, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6 alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryloxy-C1-6-aliphatic, C2-10 heterocyclyloxy-C1-6-aliphatic, C3-10 cycloalkyloxy-C1-6-aliphatic, C6-10 arylamino-C1-6-aliphatic, C2-10 heterocyclylamino-C1-6-aliphatic, C3-10 cycloalkylamino-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl; with the proviso that where R7 and R7a are bonded to the same nitrogen atom, R7 and R7a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring, or a substituted or unsubstituted C5-12 spiro bicyclic or C5-12 fused bicyclic ring.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein
each R1 is H, F, Cl, Br, I, cyano, C1-6 aliphatic, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C1-6 alkylamino-C1-6-alkoxy, C1-6 alkoxy-C1-6-alkoxy, C3-10 cycloalkyloxy, C6-10 aryl-C1-6-alkoxy, C6-10 aryl-C1-6-alkylamino, C1-9 heteroaryl-C1-6-alkoxy, C1-9 heteroaryl-C1-6-alkylamino, C3-10 cycloalkylamino, C2-10 heterocyclyl-C1-6-alkoxy, C6-10aryloxy, C1-9 heteroaryloxy, C1-9 heteroaryloxy-C1-6-alkoxy, C2-10 heterocyclyl, C3-10cycloalkyl, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryl, C1-9heteroaryl, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the C6-10aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, I, C1-6 alkyl, C2-6 alkynyl, C1-6 alkoxy or cyano;
each R3 is H, F, Cl, I, cyano, C1-6 aliphatic, C2-6 haloalkyl, C6-10 aryl-C2-6-alkoxy, C1-9 heteroaryl-C3-6-alkoxy, C1-9 heteroaryloxy-C1-6-alkoxy, C3-10 cycloalkyl-C2-6-alkoxy, C2-10 heterocyclyl, C3-10 cycloalkyl, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C1-4 heteroaryl, substituted C6-10 aryl, C1-4 heteroaryl-C1-6-aliphatic, C2-10 hetrerocyclyl-C1-6-alkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6haloalkoxy, C1-6 alkylamino-C1-6-haloalkoxy, C1-6alkylamino-C1-6-alkoxy, C1-6 alkoxy-C1-6-alkoxy, C6-10 aryl-C2-10-alkoxy, C2-10 heterocyclyl-C1-6-alkoxy, C3-10 carbocyclyl-C1-6-alkoxy, C2-10 heterocyclyloxy, C3-10 cycloalkyloxy, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; and
each R4 is H.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein

### Claim 6 (depends on 1)

The compound according to claim 1 having Formula (IV):
wherein V1 is CR1, V2 is N, V3 is CR3, and V4 is CR4;
T2 is N or CR10;
X is a bond, NR5, or —(CH2)m—, wherein each m is independently 0, 1, 2 or 3;
B is —NR7R7a, C4-12 carbocyclyl, C4-12 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C5-12 fused bicyclyl, C5-12 fused heterobicyclyl, C5-12 spiro bicyclyl, or C5-12 spiro heterobicyclyl; wherein each of the C4-12 carbocyclyl, C4-12 cycloalkyl, C2-10 heterocyclyl, C6-10 aryl, C1-9 heteroaryl, C5-12 fused bicyclyl, C5-12 fused heterobicyclyl, C5-12 spiro bicyclyl and C5-12 spiro heterobicyclyl is optionally substituted by oxo (═O), hydroxy, amino, F, Cl, Br, I, cyano, C6-10 aryl, C1-9 heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-10 heterocyclyl, mercapto, nitro, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxy C1-6 alkoxy; wherein each of the —NR7R7a is optionally substituted by hydroxy, amino, F, Cl, Br, I, cyano, C6-10 aryl, C1-9 heteroaryl, C1-6 alkoxy, C1-6 alkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-10 heterocyclyl, mercapto, nitro, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxy C1-6 alkoxy;
R1 is H, F, Cl, Br, I, cyano, C1-6 aliphatic, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C1-6 alkylamino-C1-6-alkoxy, C1-6 alkoxy-C1-6-alkoxy, C3-10 cycloalkyloxy, C6-10 aryl-C1-6-alkoxy, C6-10 aryl-C1-6-alkylamino, C1-9 heteroaryl-C1-6-alkoxy, C1-9 heteroaryl-C1-6-alkylamino, C3-10 cycloalkylamino, C2-10 heterocyclyl-C1-6-alkoxy, C6-10 aryloxy, C1-9 heteroaryloxy, C1-9 heteroaryloxy-C1-6-alkoxy, C2-10 heterocyclyl, C3-10 cycloalkyl, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano;
R3 is H, F, Cl, I, cyano, C1-6 aliphatic, C2-6 haloalkyl, C6-10 aryl-C2-6-alkoxy, C1-9 heteroaryl-C3-6-alkoxy, C1-9 heteroaryloxy-C1-6-alkoxy, C3-10 cycloalkyl-C2-6-alkoxy, C2-10 heterocyclyl, C3-10 cycloalkyl, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C1-4 heteroaryl, substituted C6-10 aryl, C1-4 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-alkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C1-6 alkylamino-C1-6-haloalkoxy, C1-6 alkylamino-C1-6-alkoxy, C1-6 alkoxy-C1-6-alkoxy, C6-10 aryl-C2-10-alkoxy, C2-10 heterocyclyl-C1-6-alkoxy, C3-10 carbocyclyl-C1-6-alkoxy, C2-10 heterocyclyloxy, C3-10 cycloalkyloxy, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano;
R4 is H;
each R5 is independently H, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, C1-3 alkoxy-C1-3-alkyl, C1-3 alkylamino-C1-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C6-10 aryl-C1-3-alkyl, C1-9 heteroaryl-C1-3-alkyl, C2-10 heterocyclyl-C1-3-alkyl, C3-10 cycloalkyl-C1-3-alkyl, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
each R7 is independently H, C1-6 aliphatic, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
each R7a is independently C1-6 aliphatic, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10cycloalkyl-C1-6-aliphatic, C6-10aryl, C1-9 heteroaryl, C2-10heterocyclyl or C3-10carbocyclyl; with the proviso that where R7 and R7a are bonded to the same nitrogen atom, R7 and R7a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring;
each R8a is independently H, hydroxy, amino, F, Cl, Br, I, —N(CH3)2, cyano, nitro, mercapto, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl or C1-9 heteroaryl;
n is 0, 1, 2 or 3; and
each R10 is independently H or F.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein:
B is —N(CH3)2, —N(CH2CH3)2, —N(CH2CH2CH3)2, —N(CH2CH2CH2CH3)2,
R1 is H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, phenyl-(CH2)p-G-(CH2)m—, (fluoro-substituted phenyl)-(CH2)p-G-(CH2)m—, thiazolyl-(CH2)p-G-(CH2)m—, pyridyl-(CH2)p-G-(CH2)m—, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m—, naphthyl-(CH2)p-G-(CH2)m—, or morpholinyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the phenyl-(CH2)p-G-(CH2)m—, (fluoro-substituted phenyl)-(CH2)p-G-(CH2)m—, thiazolyl-(CH2)p-G-(CH2)m—, pyridyl-(CH2)p-G-(CH2)m—, phenylethyl, cyclohexyl-(CH2)p-G-(CH2)m—, naphthyl-(CH2)p-G-(CH2)m—, or andmorpholinyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano;
R3 is H, F, Cl, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, phenyl-(CH2)p-G-(CH2)m—, (fluoro-substituted phenyl)-(CH2)p-G-(CH2)m—, thiazolyl-(CH2)p-G-(CH2)m—, or morpholinyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, S(═O), S(═O)2, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)—, —NHC(═O)NH—, —HN—S(═O)t, —OS(═O)t, or —OS(═O)tNH—; each t is 1 or 2; each p and m is independently 0, 1, 2, 3 or 4; or wherein each of the phenyl-(CH2)p-G-(CH2)m—, (fluoro-substituted phenyl)-(CH2)p-G-(CH2)m—, thiazolyl-(CH2)p-G-(CH2)m—, or morpholinyl-(CH2)p-G-(CH2)m— is optionally substituted by one F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy or cyano;
R4 is H;
each R5 is independently H, C1-4 alkyl, phenyl, benzyl, pyridyl or morpholino methyl;
each R8a is independently H, hydroxy, amino, F, Cl, Br, I, —N(CH3)2, cyano, nitro, mercapto, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl or C1-9 heteroaryl;
n is 0, 1, 2, or 3; and
each R10 is independently H or F.

### Claim 8 (depends on 1)

The compound according to claim 1 having Formula (VI):
wherein E is N or CR10;
J is O, S, S(═O), S(═O)2, NR13 or CR14R14a;
k is 0, 1, 2, 3 or 4;
q is 0, 1 or 2;
R1 is H, F, Cl, Br, I, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C6-10 aryl-C1-6 alkyl, C6-10aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)— or —NHC(═O)NH—; each p and m is independently 0, 1, 2 or 3; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10heterocyclyl-(CH2)p-G-(CH2)m—, C6-10 aryl-C1-6 alkyl, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, or cyano;
R3 is H, F, Cl, I, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)— or —NHC(═O)NH—; each p and m is independently 0, 1, 2 or 3; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one F, Cl, Br, I, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, ethoxy, or cyano;
each R5 is independently H, R7R7aNC(═O)—, R7OC(═O)—, R7C(═O)—, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, C1-3 alkoxy-C1-3-alkyl, C1-3 alkylamino-C1-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C6-10 aryl-C1-3-alkyl, C1-9 heteroaryl-C1-3-alkyl, C2-10 heterocyclyl-C1-3-alkyl, C3-10 cycloalkyl-C1-3-alkyl, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
each R8a is independently H, hydroxy, amino, F, Cl, Br, I, —N(CH3)2, cyano, nitro, mercapto, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl or C1-9 heteroaryl;
n is 0, 1, 2 or 3;
R10 is independently H or F;
each R12 is oxo (═O), hydroxy, amino, halo, cyano, C1-10 alkoxy, C1-10 alkylamino, C1-10 alkylthio, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, mercapto, nitro, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl, C6-10 aryloxy, carboxy, hydroxy-substituted C1-6 alkoxy, hydroxy-substituted C1-6 alkyl-C(═O)—, C1-6 alkyl-C(═O)—, C1-6 alkyl-S(═O)—, C1-6 alkyl-S(═O)2—, hydroxy-substituted C1-6 alkyl-S(═O)—, hydroxy-substituted C1-6 alkyl-S(═O)2—, or carboxy C1-6alkoxy;
R13 is H, C1-4 alkyl, C2-4 alkynyl, C1-4 alkoxy, hydroxy-substituted C1-4 alkoxy, C1-4carboxyalkoxy, C1-4 alkylcarbonyl or hydroxy-substituted C1-4 alkylcarbony; and
each R14 and R14a is independently H, hydroxy, carboxy, C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein:
R1 is independently H, F, Cl, Br, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C6-8 aryl-(CH2)p-G-(CH2)m— or C4-6 heteroaryl-(CH2)p-G-(CH2)m—, wherein each G is NR5, O or S, each p and m is independently 0, 1, 2 or 3; or wherein each of the C6-8 aryl-(CH2)p-G-(CH2)m— and C4-6 heteroaryl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, methoxy, or cyano; and
R3 is independently H, F, Cl, I, cyano, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, C6-8 aryl-(CH2)p-G-(CH2)m— or C4-6 heteroaryl-(CH2)p-G-(CH2)m—, wherein each G is O or S, each p and m is independently 0, 1, 2 or 3; or wherein each of the C6-8 aryl-(CH2)p-G-(CH2)m— and C4-6 heteroaryl-(CH2)p-G-(CH2)m— is optionally substituted by one F, Cl, Br, methyl, ethyl, propyl, ethynyl, propynyl, butynyl, or cyano.

### Claim 10 (depends on 1)

The compound according to claim 1 having Formula (VII):
wherein R1 is H, F, Cl, Br, I, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)— or —NHC(═O)NH—; each p and m is independently 0, 1, 2 or 3; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one or more F, Cl, Br, I, methyl, ethyl, propyl, cyano, ethynyl, methoxy, ethoxy, or propynyl;
R3 is H, F, Cl, I, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, C1-6 aminoalkoxy, C1-6 haloalkoxy, C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, or C3-10 cycloalkyl-(CH2)p-G-(CH2)m—, wherein each G is O, S, NR5, C(═O), —C(═O)NH—, —OC(═O)NH—, —OC(═O)— or —NHC(═O)NH—; each p and m is independently 0, 1, 2 or 3; or wherein each of the C6-10 aryl-(CH2)p-G-(CH2)m—, C1-9 heteroaryl-(CH2)p-G-(CH2)m—, C2-10 heterocyclyl-(CH2)p-G-(CH2)m—, and C3-10 cycloalkyl-(CH2)p-G-(CH2)m— is optionally substituted by one F, Cl, Br, I, methyl, ethyl, propyl, cyano, ethynyl, methoxy, ethoxy, or propynyl;
each R5 is independently H, R7R7aNC(═O)—, R7OC(═O)—, R7C(═O)—, C1-3 alkyl, C1-3 haloalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, C1-3 alkoxy-C1-3-alkyl, C1-3 alkylamino-C1-3-alkyl, C1-3 alkylthio-C1-3-alkyl, C6-10 aryl-C1-3-alkyl, C1-9 heteroaryl-C1-3-alkyl, C2-10 heterocyclyl-C1-3-alkyl, C3-10 cycloalkyl-C1-3-alkyl, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
each R7 is independently H, C1-6 alkyl, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
each R7a is independently C1-6 alkyl, C1-6 haloaliphatic, C1-6 hydroxyaliphatic, C1-6 aminoaliphatic, C1-6 alkoxy-C1-6-aliphatic, C1-6alkylamino-C1-6-aliphatic, C1-6 alkylthio-C1-6-aliphatic, C6-10 aryl-C1-6-aliphatic, C1-9 heteroaryl-C1-6-aliphatic, C2-10 heterocyclyl-C1-6-aliphatic, C3-10 cycloalkyl-C1-6-aliphatic, C6-10 aryl, C1-9 heteroaryl, C2-10 heterocyclyl or C3-10 carbocyclyl;
with the proviso that where R7 and R7a are bonded to the same nitrogen atom, R7 and R7a, together with the nitrogen atom they are attached to, optionally form a substituted or unsubstituted 3-8 membered ring;
each R8a is independently H, hydroxy, amino, F, Cl, Br, I, —N(CH3)2, cyano, nitro, mercapto, C1-4 alkyl, trifluoromethyl, C1-4 alkoxy, C1-4 alkylamino, C1-4 alkylthio, C6-10 aryl or C1-9 heteroaryl; and
n is 0, 1, 2 or 3.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein each R7 is independently H, C1-6 alkyl, C1-4 alkoxy-C1-6-alkyl,
each R7a is independently C1-6 alkyl, C1-4 alkoxy-C1-6-alkyl,

### Claim 12 (depends on 1)

The compound according to claim 1 having one of the following structures:
or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1; and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

### Claim 14 (depends on 1)

A method of managing, treating or lessening the severity of tissue or organ fibrosis in a patient comprising administering to the patient with a therapeutically effective amount of the compound according to claim 1;
wherein the tissue or organ fibrosis disorder is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneum fibrosis, myocardial fibrosis, dermatofibrosis, skeletal muscle fibrosis, dermatosclerosis, pancreatic fibrosis, liver cirrhosis, neurofibroma, pulmonary interstitial fibrosis, or vascular fibrosis.

### Claim 15 (depends on 13)

A method of managing, treating or lessening the severity of tissue or organ fibrosis in a patient comprising administering to the patient with a therapeutically effective amount of the composition according to claim 13;
wherein the tissue or organ fibrosis disorder is renal interstitial fibrosis, glomerulosclerosis, liver fibrosis, pulmonary fibrosis, peritoneum fibrosis, myocardial fibrosis, dermatofibrosis, skeletal muscle fibrosis, dermatosclerosis, pancreatic fibrosis, liver cirrhosis, neurofibroma, pulmonary interstitial fibrosis, or vascular fibrosis.