DESC:FIELD OF INVENTION
[001] The present invention relates to novel substituted quinoline triazole compounds and/ or pharmaceutically acceptable salts thereof, that are useful in treating tuberculosis and other mycobacterial infections. Particularly, the present invention relates to novel substituted quinoline triazole compounds for treating Mycobacterium tuberculosis (Mtb).
BACKGROUND OF THE INVENTION
[002] Tuberculosis (TB) is a highly contagious infection caused by Mycobacterium tuberculosis. The disease primarily affects lungs, apart from other vital organs, and if not treated, it becomes life-threatening. Tuberculosis is highly infectious and can spread quickly over masses in a short span of time. It is known to have taken a heavy toll on human life in 18th and 19th centuries. Although, TB can now be treated with antibiotics, treatment time and side effects are the main concerns in effective treatment of TB. One major drawback of using antibiotics is developing resistance to the anti-TB drugs. TB either in the latent form or in the active form may develop resistance to the antibiotics. Emergence of new virulent forms of TB resistant to some or all anti-TB drugs, have further aggravated the spread of this disease.
[003] Many compounds are known in the prior art having anti-TB activity, however, most of the drugs have serious side effects. In recent years, focus has been shifted on natural compounds showing anti-TB activity. Quinoline nucleus occurs in several natural compounds and synthetic derivatives displaying a broad range of biological activity including antituberculosis. Many quinoline derivatives isolated from natural products were reported to exhibit moderate antitubercular activity. The quinoline ring was shown to confer anti-TB activity and confirms that quinoline-based scaffolds are promising leads for new TB drug developments. Many quinolines recognized as antimalarial agents showed anti-TB activity. Bedaquiline, a clinically important anti-TB drug, is the inspiration and model for designing novel antitubercular structures. (https://www.researchgate.net/profile/Juan-Casal/publication/320215708).
[004] Many quinolone derivatives are known for the treatment of mycobacterial diseases, particularly those diseases caused by pathogenic mycobacteria. Some of the Quinoline-based derivatives including quinolones displayed excellent in vitro and in vivo activities against multi-drug resistant tuberculosis (MDR-TB). Recently, new antituberculosis drugs, bedaquiline and delamanid have been approved for the treatment of TB, however, these drugs may cause severe side effects. For instance, bedaquiline may cause liver dysfunction. Considering the abovementioned difficulties, there is an urgent need to develop novel quinolone-based derivatives having enhanced therapeutic efficacy and minimal side effects.
OBJECTIVES OF THE INVENTION
[005] The primary objective of the present invention is to provide novel substituted quinoline triazole compounds and/or pharmaceutically acceptable salts thereof.
[006] Another objective of the invention is to provide novel substituted quinoline triazole compounds and/or pharmaceutically acceptable salts thereof for treating Mycobacterium tuberculosis (Mtb).
[007] Yet another objective of the invention is to provide novel substituted quinoline triazole compounds and/or pharmaceutically acceptable salts thereof for treating H37Rv strain of Mycobacterium tuberculosis (Mtb).
[008] Yet another objective of the invention is to provide a process of preparation of novel substituted quinoline triazole compounds.
[009] Another objective of the present invention is to provide novel substituted quinoline triazole compounds having high therapeutic efficacy and exhibiting minimal side effects.
[0010] Still another objective of the invention is to provide pharmaceutical composition comprising novel substituted quinoline triazole compounds and/or pharmaceutically acceptable salts thereof for the treatment of Mtb.
[0011] Other objectives and advantages of the present invention will become apparent from the following description taken in connection with the accompanying drawings, wherein, by way of illustration and example, the aspects of the present invention are disclosed.
SUMMARY OF THE INVENTION
[0012] The present invention relates to novel substituted quinoline triazole compounds of formula (1) or pharmaceutically acceptable salts thereof, which are useful in treating tuberculosis and other mycobacterial infections.

Where in:
R1 is independently selected from the group consisting of Hydrogen, Methyl and CF3.
R2, R3 and R4 are independently selected from the group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3, C1-C12 alkyl optionally substituted with CH3, OH; C3-C12 cycloalkyl, C2-C12 heterocycloalkyl , C6-C18 aryl optionally substituted with alkyl, alkoxy, cyano, phenyl, phenoxy; C1-C18 heteroaryl such as 3-pyridine, 4-pyridine and pyrimidine, C1-C12 alkyloxy optionally substituted with alkyl, alkoxy, methoxy, C2–C10 heteroalkyloxy optionally substituted with ethane-1,2-diol, 2-(dimethylamino), ethan-1-ol, C6-C18 aryloxy, and C1-C18 heteroaryloxy.
R5 is independently selected from the group consisting of H, C1-C12 alkyl, C2–C10 heteroalkyl, C3-C12 cycloalkyl , C6-C18 aryl optionally substituted with primary, secondary or tertiary alkanes, halogens, alkoxy, phenoxy or benzyl groups; and C1-C18 heteroaryl and acyl groups. Particularly, the present invention relates to novel substituted quinoline triazole compounds for treating Mycobacterium tuberculosis (Mtb).
DETAILED DESCRIPTION OF THE INVENTION

[0013] The present invention will be better understood after reading the following detailed description of the presently preferred aspects thereof, in which the features, other aspects and advantages of the invention shall be more apparent from certain exemplary embodiments of the invention.
[0014] Accordingly, those of ordinary skill in the art will recognize that various changes and modifications of the embodiments described herein can be made without departing from the scope of invention. In addition, descriptions of well-known terms and functions are omitted for clarity and conciseness.
[0015] The terms and words used in the following description are not limited to the bibliographical meanings, but, are merely used to enable a clear and consistent understanding of the invention. Accordingly, it should be apparent to those skilled in the art that the following description of exemplary embodiments of the present invention are provided for illustrative purpose only and not for the purpose of limiting the invention.
[0016] It is to be understood that the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.
[0017] The term “quinoline triazole compounds” herein includes derivatives, pharmaceutically acceptable salts, all optically active forms including, enantiomers, diastereomers, racemic mixtures and their pharmaceutically acceptable salts.
[0018] It should be emphasized that the term “comprises/comprising” when used in this specification is taken to specify the presence of stated features, integers, steps, or components but does not preclude the presence or addition of one or more other features, integers, steps, components, or groups thereof.
[0019] Accordingly, the present invention relates to novel substituted quinoline triazole compounds of formula (1) that are useful in treating tuberculosis and other mycobacterial infections.

Where in:

R1 is independently selected from the group consisting of Hydrogen, Methyl and CF3;
R2, R3 and R4 are independently selected from the group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3, C1-C12 alkyl optionally substituted with CH3, OH; C3-C12 cycloalkyl, C2-C12 heterocycloalkyl C6-C18 aryl optionally substituted with alkyl, alkoxy, cyano, phenyl, phenoxy; C1-C18 heteroaryl such as 3-pyridine, 4-pyridine and pyrimidine, C1-C12 alkyloxy optionally substituted with alkyl, alkoxy such as methoxy, C2–C10 heteroalkyloxy optionally substituted with ethane-1,2-diol, 2-(dimethylamino)ethoxy, ethan-1-ol, C6-C18 aryloxy, and C1-C18 heteroaryloxy.
R5 is independently selected from the group consisting of H, C1-C12 alkyl, C2–C10 heteroalkyl C3-C12 cycloalkyl C6-C18 aryl optionally substituted with primary, secondary or tertiary alkanes, halogens, alkoxy, phenoxy or benzyl groups, and C1-C18 heteroaryl and acyl groups.
[0020] Particularly, the present invention relates to novel substituted quinoline triazole compounds for treating Mycobacterium tuberculosis (Mtb).
[0021] In an embodiment, the present invention relates to novel substituted quinoline triazole compounds of formula (1) that are useful in treating tuberculosis and other mycobacterial infections.

Wherein:

R1 is independently selected from the group consisting of Hydrogen, Methyl and CF3;
R2, R3 and R4 are independently selected from the group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3, CH3, 3-pyridyl, 4-pyridyl, morpholine, pyrimidine, 2-(dimethylamino)ethoxy, ethan-1-ol, ethane-1,2-diol, 3-cyano phenyl, 2-methyl pyridine and 2-methoxy pyridine;
R5 is independently selected from the group consisting of H, 4-isopropyl phenyl, cyclopentyl, n-butyl, n-pentyl, 2,3-dimethyl phenyl and 4-tert butyl phenyl, 4-phenoxy phenyl, 3-phenoxy phenyl, 2,4-diflouro phenyl, 4-methoxy benzyl groups.
[0022] In a specific embodiment of the present invention, the present invention relates to novel substituted quinoline triazole compounds that are useful in treating tuberculosis and other mycobacterial infections selected from the group of:
i. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl) methanone;
ii. (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
iii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl) methanone;
iv. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl) methanone;
v. (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methanone;
vi. (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone;
vii. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methanone;
viii. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone;
ix. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
x. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xiii. (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl) quinolin-4-yl) piperazin-1-yl)methanone;
xiv. (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xv. (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xvi. (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xvii. (1-(2,4-diflourophenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xviii. (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xix. (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xx. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-morpholinoquinolin-4-yl) piperazin-1-yl)methanone;
xxi. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-morpholino quinolin-4-yl) piperazin-1-yl) methanone;
xxii. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone;
xxiii. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone;
xxiv. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
xxv. (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone;
xxvi. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxvii. (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxviii. (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxix. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxx. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone;
xxxi. (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxxii. (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxxiii. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)methanone;
xxxiv. (4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
xxxv. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(trifluoromethyl) quinolin-4-yl)piperazin-1-yl)methanone;
xxxvi. (4-(6-fluoroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xxxvii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methylquinolin-4-yl)piperazin-1-yl)methanone;
xxxviii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)methanone;
xxxix. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(6-methoxyquinolin-4-yl)piperazin-1-yl)methanone;
xl. (4-(8-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xli. (4-(2,8-bis(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methoxy-2-methylquinolin-4-yl)piperazin-1-yl)methanone;
xliii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methylquinolin-4-yl)piperazin-1-yl)methanone;
xliv. (4-(8-fluoroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlv. (4-(8-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlvi. (4-(2,8-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlvii. (4-(6-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlviii. (4-(7-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlix. (4-(2,6-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
l. (4-(8-bromo-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
li. (4-(6,8-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lii. (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
liii. 3-(4-(4-(1-(4-phenoxyphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile;
liv. (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lv. 3-(4-(4-(1-(3-phenoxyphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile;
lvi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lvii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-methylpyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lviii. 3-(4-(4-(1-(4-isopropylphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile;
lix. (4-(7-(2-methylpyridin-4-yl)quinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lx. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-methoxypyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxiii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxiv. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxv. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxvi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-morpholinoquinolin-4-yl)piperazin-1-yl)methanone;
lxvii. (4-(7-methoxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxviii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone;
lxix. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone;
lxx. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone;
lxxi. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone;
lxxii. (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxxiii. (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxiv. (4-(8-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxv. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)methanone;
lxxvi. (4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxxvii. (4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxviii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)methanone;
lxxix. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)methanone;
lxxx. (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxxi. (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxxxii. (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropyl phenyl)-1H-1,2,3-triazol-4-yl) methanone;

[0023] The present invention also provides a method of preparation of the substituted quinoline triazole compounds of formula (1), said process comprising the following steps:
[0024] Step 1: Preparing Intermediate-1:

reacting a substituted chloroquinoline compound of Formula (A), a base and Boc-piperazine in a ratio of 1:2:1 to 1:3:1 in the presence of solvents and stirring the reaction mixture at a temperature in the range of 80 to 1200C for a time period in the range 8 to 24 hours.
[0025] The solvents are selected from Ethanol, Isopropyl alocohol and NMP and the like.
[0026] The substituents on chloroquinoline compound is selected from Hydrogen, Chlorine, 4-pyridine, 3-Pyridyne, morpholine, Methoxy, Hydroxy, Ethylene glycol, 2-(Dimethylamino) ethanol, Trifluoro methyl, Fluoro, Pyrimidine, 3-Cyano phenyl, 2-methyl pyridine, 2-Methoxy pyridine, or a combination thereof.
[0027] Step 2: Preparing Intermediate-2:

adding trifluoro acetic acid in a ratio of 1:5 to Intermediate-1 in the presence of an organic solvent dropwise with continued stirring for at least 3 hours at room temperature and evaporating the reaction mixture under reduced pressure to obtain Intermediate-2 (Int-2).
[0028] The organic solvents are selected from Dichloromethane (DCM) and the like.
[0029] Step 3: Preparing Intermediate-3:

Adding HCl dropwise to substituted aromatic amine in organic solvent at 00C, followed by addition of nitrite reagent in a ratio of 1:2 to 1: 3 and stirring at room temperature for a period in the range 3 to 8 hours. Taken forward without any purification to the next step.
The organic solvents are selected from Ethanol and the like.

The substitution on phenyl ring selected from halogens, Isopropyl, 2,3 -Dimethyl, difluoro, phenoxy substituted phenyl, etc.
[0030] Step 4: Preparing Intermediate-4:

To the mixture of intermediate-3 and methyl propiolate in 1:1 solvent ratio, added copper reagent and sodium ascorbate in water, stirred at room temperature in the range of 4-12 hours. The mixture of solvent is selected from water and tertiary butanol.
[0031] Step 5: Preparing Intermediate-5:

The compound intermediate-4 and a base are reacted in a ratio of 1:2 to 1:4 in the presence of solvents and stirring the reaction mixture at room temperature for a time period in the range 3 to 12 hours.
[0032] The solvents are selected from Methanol, ethanol, THF and water and/or combinations thereof.
[0033] The base is selected from potassium hydroxide, sodium hydroxide and lithium hydroxide and/or combinations thereof.
[0034] Step 6: Preparing Example - I:

[0035] To the acid compound in DMF, added base, coupling reagents, and followed by amine compound, stirred at room temperature for 4 to 12 hours. The base selected from Di isopropyl ethyl amine and coupling reagents selected from EDCI and HoBt.
[0036] Step 7: Preparing Example - II:

The halogenated compound and aromatic boronic acid were reacted in organic solvent, in presence of palladium catalyst and a base under argan atmosphere, stirring the reaction mixture at a temperature in the range of 800C to1200C for a time in the range of 8 to 24 hours.
[0037] The organic solvents are selected from 1,4-dioxane, THF and Toluene.
[0038] The base is selected from potassium carbonate, Caesium carbonate and sodium ethoxide.
[0039] The palladium catalyst is Tetrakis(triphenylphosphine)palladium (0).
[0040] Step 8: Preparing Example - III:

[0041] The halogenated compound and amine compounds were reacted in organic solvent, in presence of palladium and phosphorus catalysts and a base under argan atmosphere, stirring the reaction mixture at a temperature in the range of 800C to1200C for a time period in the range 8 to 24 hours.
[0042] The organic solvents are selected from 1,4-dioxane, THF and Toluene or a combination thereof.
[0043] The base is selected from potassium carbonate, Caesium carbonate, sodium ethoxide and potassium tertiary butoxide.
[0044] The palladium catalyst is Tris(dibenzylideneacetone)dipalladium(0) and phosphorous ligand is Xantphos.
Reagents, solvents, Reactants, process parameters-broad range
[0045] The symbols, abbreviations, and conventions in the processes, schemes, and examples are consistent with those used in contemporary scientific literature. Specifically, but not meant as limiting, the following abbreviations may be used in the examples and throughout the specification.
g (grams) L (liters)
Hz (Hertz) mol (moles)
RT (room temperature)
min (minutes)
MeOH (methanol)
CHCl3 (chloroform)
DCM (dichloromethane)
DMSO (dimethyl sulfoxide)
EtOAc (ethyl acetate)
mg (milligrams)
ml (milliliters)
psi (pounds per square inch)
mM (millimolar)
MHz (megahertz) hr (hours)
TLC (thin layer chromatography)
EtOH (ethanol)
CDCl3 (deuterated chloroform)
HCI (hydrochloric acid) DMF (N, N-dimethylformamide)
EDCl ( 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide)
HOBt (Hydroxybenzotriazole )
THF (tetrahydro furan)
RM (Reaction Mixture)
NMP(N-methyl-2-pyrrolidone)
DIPEA (N,N-diisopropylethylamine)
TFA (Trifluoro acetic acid)
Pd(PPh3)4 ( Tetrakis(triphenylphosphine)palladium(0) )
Pd(dba)3 (Tris(dibenzylideneacetone)dipalladium(0))
[0046] Unless otherwise indicated, all temperatures are expressed in °C (degree centigrade).
[0047] All reactions conducted at room temperature unless otherwise mentioned. All the solvents and reagents used are commercially available and purchased from Sigma Aldrich, Avra, BLD pharma, Rankem and Chempure.
[0048] NMR spectra were recorded on a Bruker AV 400. Chemical shifts are expressed in parts per million (ppm, d units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiple), or br (broad).
[0049] Mass spectra were obtained on UPLC-MS/MS TQD system from waters incorporation, using Electrospray ionization (ESI) either in positive or negative mode.
[0050] The following exemplary embodiments are provided hereinbelow for better understanding of the present invention and should not be construed to be limiting scope of the present invention.
[0051] An exemplary embodiment of the present invention has been illustrated in scheme-1 as shown below:

[0052] Reagents and conditions: (a) Substituted Chloroquinoline, NMP, DIPEA, 120 °C, 12 h; (b) TFA, DCM, RT, 3 h; (c) Aromatic amine, Aq. Hcl, NaNO2, Ethanol, NaN3, 0 °C – RT, 3h; (d) Methyl propiolate, CuSO4, Sodium ascorbate, tBuOH, H2O, RT, 4h; (e) LiOH, Methanol, THF, H2O, 8 h (f) DIPEA, EDCl, HoBt, DMF, RT, 12 h; (g) Aromatic boronic acid, Pd(PPh3)4, 1,4-Dioxane, H2O, K2CO3, 100°C, 12 h; (h) Amine, Potassium tert-butoxide, Pd(dba)3, xantphos, Toluene, 100°C 12 h.
Preparation of compounds of the present invention
Step 1: Preparation of Intermediate 1 (Int-1):
[0053] To the solution of 4-chloroquinoline in NMP, were added N,N-Diisopropylethylamine (DIPEA) (2.5 eq), Boc-piperazine (1 eq) and reaction mixture stirred at 1200C for overnight. After completion of the reaction, the reaction mixture was poured into ice cold water and extracted with Ethyl acetate. The combined organic layer was back washed with water, brine, dried over sodium sulfate and evaporated on rotavapor under reduced pressure to obtain the crude material. The crude was purified by silica column chromatography using ethyl acetate in hexane as eluent.
Step 2: Preparation of Intermediate 2 (Int-2):
[0054] To a stirred solution of Int-1 in DCM, Trifluoro acetic acid (5.0 eq) was added dropwise and continued stirring for 3 hours at room temperature. The reaction mixture was evaporated on rotavapor under reduced pressure and obtained crude was taken for next step without further purification.
Step 2: Preparation of Intermediate 3 (Int-3):
[0055] To a stirred solution of Aromatic amine in ethanol, added hydrochloric acid (conc.34%) dropwise at 00C, reaction mixture allowed to stir for 10 minutes, added Sodium nitrite (2eq) portion wise over 10 minutes. The reaction mixture was stirred for 30 min, added sodium azide (1.5eq) portion wise and continued stirring for 3 hours at room temperature. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The combined organic layer was back washed with water, brine, dried over sodium sulphate and evaporated on rotavapor under reduced pressure to obtain the crude material. The crude material was taken for next step without further purification.
Step 3: Preparation of Intermediate 4 (Int-4):
[0056] To the solution of Int-3 & Methyl propiolate (1.0 eq) in 1:1 mixture of water and tertiary butanol, added Copper (II) sulphate pentahydrate and freshly prepared 1M solution of L-Sodium ascorbate in water, stirred for 4 hours. The reaction mixture was diluted with DCM, washed with 10% NH4OH solution, water, brine solution and dried over sodium sulphate and concentrated on rotavapor. The obtained crude was purified by silica column chromatography using ethyl acetate in hexane as eluent.
Step 4: Preparation of Intermediate 5 (Int-5):
[0057] To a stirred solution of Int-4 in THF and Methanol, added Lithium hydroxide monohydride (3.0 eq) in water and the reaction mixture was stirred for overnight at room temperature. The reaction mixture was concentrated, redissolved in water, acidified with 10% HCl solution at 00C and extracted with Ethyl acetate. The combined organic layer was back washed with water, brine, dried over sodium sulphate and concentrated to get the desired product.
Preparation of Example-I:
[0058] To the stirred solution of Int-5 in DMF, were added 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide (1.3 eq), Hydroxybenzotriazole (1.3 eq) and Di isopropyl ethyl amine (5.0 eq), stirred at room temperature until clear solution was obtained. Then int-2 (1eq) was added to the reaction mixture and stirred for overnight at room temperature. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layer was back washed with water, brine, dried over sodium sulphate on rotavapor. The obtained crude was purified by silica column chromatography using ethyl acetate in hexane as eluent.
Preparation of Example-II:
[0059] To a stirred solution of Example-I (X1 is Cl, Br) in 1,4 dioxane under argon atmosphere, were added Aromatic boronic acid (1.2 eq), tetrakis (0.1 eq) and K2CO3 (3.0 eq) in water, the reaction mixture stirred at 1000C for overnight. The reaction mixture was diluted with water and extracted with Ethyl acetate and the combined organic layer was dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography over neutral alumina using eluent as methanol in ethyl acetate in hexane.
Preparation of Example-III:
[0060] To a stirred solution of Example-I (X1 is Cl, Br) in Toluene under argon atmosphere, were added Amine (1.1 eq), potassium tert-butoxide (1.5 eq), xantphos (0.2 eq), Pd(dba)3 (0.1 eq) and the reaction mixture heated to 1000C, stirred for overnight. The reaction mixture was diluted with water and extracted with Ethyl acetate and the combined organic layer was dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography over neutral alumina using eluent as ethyl acetate in hexane.

[0061] Example 1: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl) (4-(quinolin-4-yl)piperazin-1-yl)methanone

Compound 1 was synthesized from 1-(4-isopropylphenyl)-1H-1,2,3-triazole-4-carboxylic acid and 4-(piperazin-1-yl) quinoline TFA salt by following the similar procedure described in synthetic scheme I.

[0062] Example 2: (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 2 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-(4-isopropylphenyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.24-1.26 (d,6H), 2.96-3.03 (m,1H),3.92-3.95(d,6H), 4.4(s,2H),7.18-7.19(d,1H),7.48-7.50(d,2H),7.69-7.72(dd,1H)7.88-7.9(d,2H),8.014-8.019(d,1H)8.26-8.28(d,1H),8.71-8.73(d,1H) LC/MS (ESI-MS) m/z 461.4(M+1)
[0063] Example 3: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone

Compound 3 was synthesized from 4-(piperazin-1-yl) quinoline TFA salt and 1-(2, 3-dimethylphenyl)-1H-1, 2, 3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.98(s,3H),2.37(s,3H),3.32(s,4H),3.99(s,2H),4.40(s,2H),7.05-7.06(d,1H),7.30-7.35(m,2H),7.43-7.45(q,1H),7.57-7.61(m,1H),7.71-7.75(m,1H),7.97-7.99(dd,1H),8.14-8.16(d,2H),8.72-8.73 (d,1H),8.91 (s,1H) LC/MS (ESI-MS) m/z 413.2(M+1)
[0064] Example 4: (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 4 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-(2,3-dimethylphenyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.98(s,3H),2.36(s,3H),3.30(s,3H),3.98(s,2H),4.39(s,2H),7.08-7.09(d,1H),7.30-7.35(m,2H),7.43-7.45(q,1H),7.58-7.61(dd,1H)8.01-8.02(dd,1H),8.15-8.17(d,1H),8.74-8.75(d,1H),8.92(s,1H) LC/MS (ESI-MS) m/z 447.8 (M+1)
[0065] Example 5: (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methanone

Compound 5 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-(4-(tert-butyl) phenyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3,300 MHz) d (ppm) 1.381(s,10H),3.553(s,4H),4.119(s,2H),4.699(s,2H), 6.855-6.901(d,1H),7.477-7.484(d,1H),7.564-7.593(d,2H),7.674-7.703(d,2H),8.007-8.081(t,2H), 8.549(s,1H),8.762-8.778(d,1H) LC/MS (ESI-MS) m/z 475.6 (M+1)
[0066] Example 6: (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 6 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-(3-phenoxyphenyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.

[0067] Example 7: (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl) methanone

Compound 7 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-(2,4-difluorophenyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.254-1.293(d,1H),1.420-1.473(t,2H),2.813-2.847(d,1H), 3.361(s,4H),4.118(s,2H),4.663(s,2H),6.886-6.903(d,1H),7.097-7.152(t,2H),7.478-7.507(d,1H), 2167.901-7,977(m,1H), 8.004-8.034(d,1H),8.084(s,1H),8.604-8.611(d,1H),8.764-8.781(d,1H) LC/MS (ESI-MS) m/z 455.3(M+1)
[0068] Example 8: (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 8 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-(4-phenoxyphenyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm) 0.826-0.878(t,1H),1.254-1.334(t,3H),1.421(s,1H), 3.353(s,4H),4.112(s,2H),4.689(s,2H),6.881-6.898(d,1H),7.072-7.099(d,2H),7.139-7.226(q,4H), 7.385-7.575(m,7H),7.643-7.717(m,4H),8.004-8.033(d,1H),8.079(s,1H),8.519(s,1H),8.761-8.777(d,1H) LC/MS (ESI-MS) m/z 511.3(M+1)
[0069] Example 9: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 9 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.24-1.26(d,6H),2.95-3.05(m,1H),3.33-3.34(d,4H), 4.02(s,2H), 4.40(s,2H),7.09-7.11(d,1H),7.48-7.50(d,2H),7.88-7.92(m,4H),8.00-8.02(dd,1H),8.26-8.28(d,1H),8.40-8.41(d,1H),8.71-8.72(dd,2H),8.78-8.79(d,1H),9.27(s,1H) LC/MS (ESI-MS) m/z 504.4(M+1)
[0070] Example 10: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 10 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.98(s,3H),2,37(s,3H),3.34(s,4H),4.02(s,2H),4.43(s,2H),7.10-7.11(d,1H),7.32(t,2H),7.43-7.45(q,1H)7.91-7.92(dd,2H),8.00-8.02(dd,1H),8.26-8.28(d,1H),8.40-8.41(d,1H),8.71-8.72(d,2H),8.79-8.80(d,1H),8.92(s,1H) LC/MS (ESI-MS) m/z 490.3 (M+1)

[0071] Example 11: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 11 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl) methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.24-1.26(d,7H),2.97-3.04(m,1H),3.35-3.37(t,4H), 4.02(s,2H), 4.40(s,2H),7.08-7.10(d,1H),7.49-7.51(d,2H),7.55-7.58(q,1H),7.88-7.90(d,2H),7.96-7.99(dd,1H),8.25-8.32(m,3H)8.65-8.66(d,1H),8.77-8.78(d,1H).9.08-9.09(d,1H),9.27(s,1H) LC/MS (ESI-MS) m/z 504.6 (M+1)
[0072] Example 12: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 12 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR(DMSO,400MHz)1.984(s,3H),2.366(s,3H),3.35(s,4H),4.013(s,2H),4.42(s,2H),7.708-7.09(d,1H),7.31-7.33(t,2H),7.43-7.45(q,1H),7.54-7.58(q,1H),7.95-7.98(dd,1H),8.24-8.32(m,3H),8.64-8.65(dd,1H),8.77-8.78(d,1H),8.92(s,1H),9.082-9.087(d,1H) LC/MS (ESI-MS) m/z 490.4 (M+1)
[0073] Example 13: (1-(4-(tert-butyl) phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl) quinolin-4-yl)piperazin-1-yl)methanone

Compound 13 was synthesized from (1-(4-(tert-butyl) phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3,300 MHz) d (ppm) 1.256(s,3H),1.384(s,9H),3.410(s,4H),4.153(s,2H), 4.735(s,2H),6.924-6.941(d,1H),7.472(s,1H),7.569-7.597(d,2H),7.681-7.710(d,2H),7.789- 7.814(d,1H),8.053-8.078(d,1H),8.189-8.216(d,1H),8.329(s,1H), 8.558(s,1H),8.817(s,1H), 9.033(s,1H) LC/MS (ESI-MS) m/z 518.4 (M+1)
[0074] Example 14: (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 14 was synthesized from (1-(4-(tert-butyl) phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.382(s,10H),3.401(s,4H),4.152(s,2H),4.732(s,2H), 7.567- 7.596 (d,2H),7.679-7.707(t,4H),7.813-7.838(d,1H),8.189-8.217(d,1H),8.388(d,1H),8.388(s,1H), 8.557(s,1H),8.743(s,2H),8.822-8.838(d,1H) LC/MS (ESI-MS) m/z 518.9(M+1)
[0075] Example 15: (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 15 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm) 0.857-0.880(d,1H),1.255-1.333(q,6H), 1.419(s,1H), 2.049(s,1H),3.407(s,4H),4.154(s,2H),4.727(s,2H),6.934-6.950(d,1H),7.077-7.103(d,2H),7.145- 7.174(d,2H),7.205-7.235(d,1H),7.388-7.440(t,2H),7.677-7.724(t,4H),7.814-7.839(d,1H),8.188- 8.216(d,1H),8.388(s,1H),8.528(s,1H),8.742-8.759(d,2H),8.824-8.840(d,1H) LC/MS (ESI-MS) m/z 554.7(M+1)
[0076] Example 16: (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 16 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm)1.254-1.334(t,2H),3.416(s,4H), 4.154(s,2H), 4.724(s,2H), 6.921-6.937(d,1H),7.077-7.103(d,2H),7.145-7.230(q,4H),7.388-7.475(q,3H),7.695-7.724 (d,2H),7.782-7.811(d,1H),8.049-8.075(d,1H),8.184-8.214(d,1H),8.326(s,1H),8.527(s,1H),8.662- 8.678(d,1H),9.035(s,1H) LC/MS (ESI-MS) m/z 554.1(M+1)

[0077] Example 17: (1-(2, 4-diflourophenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 17 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme I.

[0078] Example: 18 (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 18 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm) 3.385-3.396(d,4H),4.142(s,2H),4.697(s,2H),6.926-6.942(d,1H),7.089-7.133(t,3H),7.188-7.237(t,1H),7.390-7.538(m,6H),7.674-7.693(d,2H),7.806-7.836(d,1H),8.179-8.208(d,1H),8.386(s,1H),8.534(s,1H),8.739-8.757(d,2H),8.819-8.835(d,1H), LC/MS (ESI-MS) m/z 554.8 (M+1)
[0079] Example 19: (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 19 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme I.
1HNMR (CDCl3, 300 MHz) d (ppm) 3.390-3.401(d,4H),4.140 (s,2H),4.693 (s,2H),6.693-6.930 (d,1H),7.089-7.188(t,3H),7.212-7.237(t,2H),7.405-7.435(t,3H),7.440-7.478(q,4H),7.77-7806(d,1H),8.0486-8.074(d,1H),8.175-8.204(d,1H),8.320(s,1H),8.533(s,1H),8.660-8.675(d,1H),8.809-8.826(d,1H),9.027(s,1H) LC/MS (ESI-MS) m/z 554.8 (M+1)
[0080] Example 20: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)methanone

Compound 20 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and morpholine by following the similar procedure described in synthetic scheme I.
1H NMR(DMSO,400MHz)1.24-1.26(d,6H),2.96-3.03(m,1H),3.23-3.29(m,10H),3.78-3.80(t,4H),3.96(s,1H),4.34(s,2H),6.81-6.82(d,1H),7.19-7.20(d,1H),7.39-7.42(dd,1H),7.48-7.50(dd,2H),7.87-7.89(dd,2H),7.94-7.97(d,1H),8.14(s,2H),8.55-8.57(d,1H) LC/MS (ESI-MS) m/z 512.4(M+1)
[0081] Example 21: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-morpholino quinolin-4-yl) piperazin-1-yl)methanone

Compound 21 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl) (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone and morpholine by following the similar procedure described in synthetic scheme I.
1HNMR ( DMSO,400 MHz) d (ppm) 1.97(s,3H),2.365(s,3H),3.271-3.295(t,9H),3.784-3.808(t,4H), 3.969(s,2H),4.370(s2H),6.819-6.831(d,1H),7.200-7.206(d,1H),7.298-7.347(m,2H), 7.396-7.450(m,2H),7.952-7.975(d,1H),8.562-8.574(d,1H),8.90(s,1H), LC/MS (ESI-MS) m/z 498.4(M+1)

SCHEME – II

[0082] Step 1: Preparation of Intermediate 6: Aliphatic alcohol (1eq) solution in DCM is stirred and to the stirred solution is added TEA (2-5 eq), followed by dropwise addition of methane sulfonyl chloride (1.2- 2 eq) at 0-5 0C, then continued stirring for 2-6 hours. The reaction mixture is poured in ice cold water and extracted with DCM. The combined organic layer is dried over sodium sulfate and concentrated to obtain a crude intermediate 6.
[0083] Step 2: Preparation of Intermediate 7: Intermediate obtained from step 1 is dissolved in DMF followed by sodium azide (2 – 4 eq) at 00C and stirred for at least 12 hours at room Temperature. The reaction mixture is then poured in ice cold water and extracted with Ethyl acetate. The combined organic layer is dried over sodium sulfate and concentrated to obtain crude compound. The crude compound is then purified by column chromatography over silica using ethyl acetate in hexane as eluent.
Exemplary embodiments:
Reagents and conditions:
[0084] Reagents and conditions: (i) Aliphatic alcohol, Methane sulfonyl chloride, TEA, DCM, 0-5oC, 2 h, (j) NaN3, DMF, RT,12h; Aliphatic azide intermediates were synthesized by the method described in scheme-II and prepared the corresponding final following compounds as per the scheme-I.
Preparation of int-6:
[0085] To a stirred solution of aliphatic alcohol in DCM, was added TEA (2.0 eq), followed by dropwise addition of methane sulfonyl chloride (1.3 eq), at 0 0C, then continued stirring for 2 hours. The reaction mixture was poured in ice cold water and extracted with DCM. The combined organic layer was dried over sodium sulfate and concentrated. The obtained crude was taken for next step without further purification.
Preparation of int-7:
[0086] To the obtained crude (Int-6) dissolved in DMF, was added sodium azide (2.0 eq) at 0 0C, then reaction mixture allowed to stir for 12 hours at Room Temperature. The reaction mixture was poured in ice cold water and extracted with Ethyl acetate. The combined organic layer was dried over sodium sulfate and concentrated, and the obtained crude was purified by column chromatography over silica using ethyl acetate in hexane as eluent.

[0087] Example 22: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone

Compound 22 was synthesized from 4-(piperazin-1-yl) quinoline TFA salt and 1-cyclopentyl-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz) 1.673-1.712(m,2H),1.80-1.84(m,2H),1.95-2.04(m,2H),2.16-2.22(m,2H),3.24-3.27(t,4H),3.94(s,2H),4.36(s,1H),4.99-5.06(m,1H)7.03-7.04(d,1H),7.56-7.60(m,1H),7.70-7.74(m,1H),7.95-7.98(dd,1H),8.11-8.13(d,1H),8.65(s,1H),8.70-8.71(d,1H) LC/MS (ESI-MS) m/z 377.6(M+1)
[0088] Example 23: (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 23 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-cyclopentyl-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)1.66-1.71(m,2H),1.80-1.84(q,2H),1.95-2.04(m,2H),2.16-2.22(m,2H),3.24-3.26(t,4H),3.93(s,2H),4.35(s,2H),7.05-7.06(d,1H),7.57-7.60(dd,1H),8.003-8.009(s,1H),8.13-8.15(d,1H),8.64 (s,1H),8.72-8.73(d,1H) LC/MS (ESI-MS) m/z 411.3(M+1)
[0089] Example 24: (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 24 was synthesized from 7-chloro-4-(piperazin-1-yl) quinoline TFA salt and 1-pentyl-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)0.84-0.87(t,3H),1.19-1.34(m,4H),1.81-1.89(m,2H),3.25-3.27(t,4H),3.93(s,2H),4.37-4.42(q,4H)7.05-7.07(d,1H),7.57-7.60(dd,1H),8.004-8.009 (d,1H),8.13-8.15(d,1H),8.62(s,1H),8.72-8.74(d,1H) LC/MS (ESI-MS) m/z 413.5(M+1)
[0090] Example 25: (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone

Compound 25 was synthesized from 4-(piperazin-1-yl)quinoline TFA salt and 1-pentyl-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)0.84-0.88(t,3H)1.20-1.25(m,6H),1.29-1.34(m,2H),1.82-1.89(m,2H)3.24-3.27(t,4H),3.95(s,2H),4.38-4.43(q,4H),8.62(s,1H),8.70-8.72(d,1H) LC/MS (ESI-MS) m/z 379.6(M+1)
[0091] Example 26: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 26 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)1.67-1.72(m,2H),1.81-1.85(m,2H),1.98-2.03(m,2H),2.17-2.23(m,2H),3.30-3.35(d,4H),3.37-3.41(t,1H),3.97(s,2H),4.39(s,2H),5.02-5.05(t,1H),7.08-7.09(d,1H),7.58-7.72(m,1H),7.89-7.91(dd,2H),7.99-8.01(dd,1H),8.24-8.26(d,1H),8.39-8.40(d,1H),8.64-8.65(d,1H),8.71-8.72(dd,2H),8.77-8.78(d,1H) LC/MS (ESI-MS) m/z 454.7 (M+1)
[0092] Example 27: (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 27 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanoneand pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)0.84-0.88 (t,3H),1.18-1.24(m,2H),1.26-1.35(m,2H),1.82-1.90(m,2H),3.29-3.31(t,4H),3.97(s,2H),4.40-4.43(t,4H),7.06-7.07(d,1H)7.54-7.58(m,1H),7.95-7.97(dd,1H),8.23-8.32(m,3H)8.63-8.65(q,2H),8.76-8.77(d,1H),9.08(d,1H) LC/MS (ESI-MS) m/z 456.8(M+1)
[0093] Example 28: (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 28 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)0.84-0.88 (t,3H),1.20-1.26(m,3H),1.29-1.35(q,2H),1.82-1.90(m,2H)3.29-3.30(d,4H),3.97(s,1H),4.40-4.43(t,4H),7.08-7.09 (d,1H),7.90-7.91(dd,2H),7.99-8.01(dd,1H),8.24-8.26(d,1H),8.40(dd,1H),8.63(s,1H),8.70-8.72(dd,2H),8.77-8.79(d,1H) LC/MS (ESI-MS) m/z 456.8(M+1)
[0094] Example 29: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 29 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme II.
LC/MS (ESI-MS) m/z 456.7 (M+1)

[0095] Example 30: (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 30 was synthesized from 7-chloro-4-(piperazin-1-yl)quinoline TFA salt and 1-(4-methoxybenzyl)-1H-1,2,3-triazole-4-carboxylic acid by following the similar procedure described in synthetic scheme II.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.254-1.286(d,1H),3.294(s,4H) ,3.821(s,3H), 4.046(s,2H), 4.633(s,2H),5.494(s,2H),6.853-6.932(q,3H),7.291(s,1H),7.459-7.488(d,1H), 7.979-8.067(t,3H), 8.744-8.760(d,1H) LC/MS (ESI-MS) m/z 463.2 (M+1)
[0096] Example 31: (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 31 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme II.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.255-1.285(d,2H),3.364(s,4H), 3.384(s,3H), 4.084(s,2H), 4.674(s,2H),5.500(s,2H),6.908-6.937(t,3H),7.297(s,1H),7.684(s,2H),7.796-7.823(d,1H), 8.016(s,1H),8.162-8.191(d,1H),8.388(s,1H),8.752(s,1H),8.803-8.820(d,1H) LC/MS (ESI-MS) m/z 506.8(M+1)
[0097] Example 32: (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 32 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme II.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.254-1.333(t,3H),3.349(s,4H),3.823(s,3H), 4.082(s,2H), 4.668(s,2H),5.500(s,2H),6.892-6.936(t,3H),7.297(s,1H),7.455-7.474(d,1H),7.764-7.793(d,1H), 8.015-8.067(t,2H),8.312(s,1H),8.675(s,1H),8.799-8.814(d,1H),9.029(s,1H) LC/MS (ESI-MS) m/z 506.4 (M+1)
[0098] Example 33: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)methanone

Compound 33 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone and morpholine by following the similar procedure described in synthetic scheme II.
1H NMR(DMSO,400MHz)1.62-1.85 (m,4H), 1.95-2.02 (m,2H),2.04-2.25(m,2H), 3.19-3.29(tt,8H),3.78-3.80(t,4H),3.92(s,2H),4.33(s,2H),5.00-5.007(m,1H),6.79-6.81(d,1H),7.19-7.20(d,1H),7.39-7.42(dd,1H),7.93-7.95(d,1H),8.55-8.56(d,1H),8.64(s,1H) LC/MS (ESI-MS) m/z 462.4(M+1)
[0099] Example 34: (4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 34 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone and morpholine by following the similar procedure described in synthetic scheme II.
1HNMR (DMSO, 400 MHz) d (ppm) 0.840-0.876(t,3H),1.179-1.337(m,5H),1.817-1.889(m,2H),3.243-3.293(q,8H), 3.779-3.802(t,4H),4.352(s,2H),4.389-4.424 (t,2H),6.801-6.814 (d,1H),7.186-7.192(d,1H),7.385-7.414(dd,1H),7.935-7.959(d,1H),8.147(d,2H),8.544-8.556(d,1H), 8.617(s,1H), LC/MS (ESI-MS) m/z 464.7 (M+1)

SCHEME – III:

[00100] Reagents and conditions: (k) DIPEA, EDCI, HoBt, DMF, RT, 12 h; (l) TFA, DCM, RT, 3 h; (m) Substituted Quinoline, NMP, DIPEA, 120 °C, 12 h; (g) Aromatic boronic acid, Pd(PPh3)4, 1,4-Dioxane, H2O, K2CO3, 100 °C, 12 h; (h) Amine, Potassium tert-butoxide, Pd(dba)3, xantphos, Toluene, 100 °C 12 h.
Exemplary embodiments:
Preparation of Int-8:
[00101] To the stirred solution of Int-5 in DMF, were added EDCI (1.3 eq), HOBT (1.3 eq) and DIPEA (5.0 eq), stirred at room temperature until clear solution was obtained. Then int-2 (1.0eq) was added to the reaction mixture and stirred for overnight at room temperature. The reaction mixture was poured into ice cold water and extracted with ethyl acetate. The combined organic layer was back washed with water, brine, dried over sodium sulphate and concentrated. The obtained crude was purified by column chromatography over silica using eluent as ethyl acetate in hexane.
Preparation of Int-9:
[00102] To a stirred solution of Int-8 in DCM, Trifluoro acetic acid (5.0 eq) was added dropwise and continued stirring for 3 hours at room temperature. The reaction mixture was evaporated on rotavapor under reduces pressure and obtained crude was taken for next step without further purification.

[00103] Example 35: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(trifluoromethyl) quinolin-4-yl)piperazin-1-yl)methanone

Compound 35 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-7-(trifluoromethyl)quinoline by following the similar procedure described in synthetic scheme III.
1HNMR ( CDCl3, 300 MHz) d (ppm) 1.29-1.31(d,6H),1.972-2.074(m,1H), 2.353-2.405(t,1H),2.848(s,1H),2.967-3.058(m,1H),3.347-3.40(m,5H),4.119-4.151(t,2H),4.708-4.736(t,2H),6.984-7.001(d,1H), 7.406-7.434(d,2H), 7.666-7.732(t,3H), 8.191-8.221(d,1H), 8.393(s,1H), 8.546(s,1H),8.85-8.87(1H) LC/MS (ESI-MS) m/z 495.67(M+1)
[00104] Example 36: (4-(6-fluoroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 36 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-6-fluoroquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.29-1.31(d,6H), 2.966-3.058(m,1H), 3.304-3.362(m,4H), 4.106-4.138(t,2H), 4.700(s,2H),6.925-6.941(d,1H),7.405-7.498(q,3H),7.668-7.694 (d,3H),8.072-8.121(q,1H),8.540(s,1H), 8.746-8.762(d,1H) LC/MS (ESI-MS) m/z 445.6 (M+1)
[00105] Example 37: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methylquinolin-4-yl)piperazin-1-yl)methanone

Compound 37 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-2-methylquinoline by following the similar procedure described in synthetic scheme III
1HNMR (CDCl3, 300 MHz) d (ppm) 1.295-1.31 (d,6H ), 2.69( s,3H), 2.95-3.055( q,1H),3.34(s,4H),4.11(s,2H),4.6(s,2H),6.78(s,1H),7.40-7.63(m,8H),7.66-7.77(m,6H),7.99-8.0(t,2H),8.53(s,1H); LC/MS (ESI-MS) m/z 441.79(M+1)

[00106] Example 38: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 38 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-8-(trifluoromethyl)quinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) .82-0.87 (s,2H),1.25(s,3H),1.29-1.31(d,7H),2.00-2.04 (d,1H),2.35-2.40(t,1H),2.84(s,1H),2.96-3.05(quint,1H),4.13(s,2H),4.71(s,2H)6.99-7.01(d,1H), 7.40-7.43(d,2H),7.57-7.62(t,1H),7.66-7.69(d,2H)8.06-8.08(d,1H),8.30-8.33(d,1H),8.54(s,1H), 8.92-8.94(d,1H) LC/MS (ESI-MS) m/z 495.3 (M+1)
[00107] Example 39: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(6-methoxyquinolin-4-yl)piperazin-1-yl)methanone

Compound 39 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-6-methoxyquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) 0.82-0.90(q,1H),1.25(s,2H),1.29-1.31(d,7H),2.96-3.05(quint,1H),3.33-3.34(d,4H),3.96(s,3H),4.13(s,2H),4.70(s,1H),6.89-6.90(d,1H),7.35-7.43(quint,5H),7.66-7.69(d,2H),7.99-8.02(d,1H),8.54(s,1H),8.65-8.66(d,1H) LC/MS (ESI-MS) m/z 457.3 (M+1)
[00108] Example 40: (4-(8-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 40 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl) (piperazin-1-yl) methanone TFA salt and 4,8 -Dichloroquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) 0.82-0.87(t,1H),(1.25-1.31 (t,8H ), 2.037( s,1H), 2.95-3.055 (q,1H),3.6(s,4H),4.11(s,2H),4.7(s,2H),6.96-6.98(s,1H),7.40-7.49(q,3H),7.66-7.69(d,2H),7.82-7.84(d,1H),8.02-8.04(d,1H),8.89-8.91(d,1H); LC/MS (ESI-MS) m/z 461.64(M+1)
[00109] Example 41: (4-(2,8-bis(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 41 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-2,8-bis(trifluoromethyl)quinoline by following the similar procedure described in synthetic scheme III.
1HNMR(CDCl3, 300 MHz) d (ppm) 1.29-1.31(d,6H), 2.84(s,1H), 2.96-3.05 (m,1H), 3.42(s,4H), 4.1(s,2H),4.74(s,2H),7.26-7.27(d,2H),7.66-7.71(t,3H),8.12-8.15(d,1H),8.30-8.33(d,1H),8.55(s,1H) ; LC/MS (ESI-MS) m/z 461.64(M+1)
[00110] Example 42: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methoxy-2-methylquinolin-4-yl)piperazin-1-yl)methanone

Compound 42 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-8-methoxy-2-methylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm)1.295-1.318(d,6H),2.70(s,3H),2.79 (s,3H),2.84(s,1H),2.96-3.05(m,1H),3.328(s,4H),4.07-4.107(d,6H),4.68(s,2H),6.757(s,1H),7.01-7.03(d,1H),7.37-7.42(t,3H), 7.58-7.61(d,1H)7,7.66-7.68(d,2H),8.538(s,1H); LC/MS (ESI-MS) m/z 455.88(M+1)
[00111] Example 43: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methylquinolin-4-yl)piperazin-1-yl)methanone

Compound 43 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-8-methyl quinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.29-1.31(d,6H),2.96-3.05(m,1H), 3.343(s,4H), 4.109 (s,2H),4.686 (s,2H),6.91-692(d,1H),7.40-7.46 (q,4H), 7.54-7.56 (d,2H),7.84-7.87(d,1H), 8.54 (s,1H),8-2-8.8 (d,1H); LC/MS (ESI-MS) m/z 441.74(M+1)
[00112] Example 44: (4-(8-fluoroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 44 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-8-fluoro quinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.29-1.31(d,6H), 2.8(S,3H), 2.96-3.05(m,1H), 3.343(s,4H), 4.109 (s,2H),4.686 (s,2H),6.91-692(d,1H),7.40-7.46 (t,3H), 7.54-7.56 (d,2H),7.94-7.97(d,12H), 8.54 (s,1H),8-2-8.8 (d,1H); LC/MS (ESI-MS) m/z 445.66(M+1)
[00113] Example 45: (4-(8-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 45 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-8-fluoro-2-methylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm) 1.29-1.31(d,6H), 2.8(S,3H), 2.96-3.05(m,1H), 3.343(s,4H), 4.109 (s,2H),4.686 (s,2H),6.840 (s,1H),7.330-7.431 (q,4H), 7.605-7.691 (d,2H),7.78-7.81(d,1H), 8.54 (s,1H); LC/MS (ESI-MS) m/z 459.88(M+1)
[00114] Example 46: (4-(2,8-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 46 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-2,8-dimethylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm)1.295-1.318(d,6H),2.70(s,3H),2.79 (s,3H),2.84(s,1H),2.96-3.05(m,1H),3.328(s,4H),4.107(s,2H),4.68(s,2H),6.757(s,1H),7.33-7.42(q,3H),7.49-7.51(d,2H), 7.66-7.690(d,2H)7,7.88-7.90(d,1H),8.538(s,1H); LC/MS (ESI-MS) m/z 455.88(M+1)
[00115] Example 47: (4-(6-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 47 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-6-fluoro-2-methylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm)1.295-1.318(d,6H),2.68(s,3H),2.966(m,1H),3.328(s,4H), 4.107(s,2H),4.68(s,2H),6.757(s,1H),7.285(s,1H),7.404-7.431(d,2H),7.608-7.690(t,1H)7,7.99-8.049(t,1H),8.538(s,1H); LC/MS (ESI-MS) m/z 459.88(M+1)
[00116] Example 48: (4-(7-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 48 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-7-fluoro-2-methylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3, 300 MHz) d (ppm)1.295-1.318(d,6H),2.68(s,3H),2.966(m,1H),3.328(s,4H), 4.107(s,2H),4.68(s,2H),6.757(s,1H),7.285(s,1H),7.404-7.431(d,2H),7.608-7.690(t,1H)7,7.99-8.049(t,1H),8.538(s,1H); LC/MS (ESI-MS) m/z 459.9(M+1)
[00117] Example 49: (4-(2,6-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 49 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-2,6-dimethylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 1.296-1.316 (d,6H), 2.55 (s,3H),2.96(m,1H),3.332(s,4H),4.12 (s,2H), 4.68 (s,2H),6.76 (s,1H),7.404-7.431(d,2H),7.475-7.503 (d,2H), 7.66-7.69 ( d,2H),7.77 (s,1H), 7.88-7.91 (d,1H), 8.538(s,1H) LC/MS (ESI-MS) m/z 455.89 (M+1)
[00118] Example 50: (4-(8-bromo-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 50 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 8-bromo-4-chloro-2-methylquinoline by following the similar procedure described in synthetic scheme III
1HNMR (CDCl3, 300 MHz) d (ppm)1.295-1.318(d,6H),2.76(s,3H),2.84(s,1H),2.96-3.05(q,1H), 4.107(s,2H),4.68(s,2H),6.843(s,1H),7.291-7.244((t,1H),7.404-7.431(d,2H),7.66-7.690(d,2H)7,7.99-8.049(t,2H),8.536(s,1H); LC/MS (ESI-MS) m/z 519.52(M+1)
[00119] Example 51: (4-(6,8-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 51 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone TFA salt and 4-chloro-6,8-dimethylquinoline by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm)1.295-1.318(d,6H),2.352-2.407(t,1H), 2.533(s,3H), 2.76(s,3H), 2.84(s,1H),2.96-3.05(q,1H),3.330(s,4H), 4.122(s,2H),4.68(s,2H), 6.879-6.895(d,1H), 7.401-7.424((d,3H),7.663-7.708(t,3H),8.535(s,1H),8.741-8.757(d,1H); LC/MS (ESI-MS) m/z 455.87(M+1)
[00120] Example 52: (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 52 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyrimidin-5-yl boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm)0.857-0.880(d,1H), 1.255-1.333(t,5H), 3.408(s,4H), 4.152 (s,2H),4.736(s,2H),6.953-6.969(d,1H),7.076-7.232(m,6H),7.388-7.488(q,4H),7.553-7.643 (q,2H),7.694-7.786(t,4H),7.942-8.006(t,1H),8.155-8.259(q,1H),8.343(s,1H),8.512-8.529(d,1H). 8.790-8.854(q,1H),9.13(s,1H),9.287(s,1H) LC/MS (ESI-MS) m/z 555.7(M+1)
[00121] Example 53: 3-(4-(4-(1-(4-phenoxyphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile

Compound 53 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and (3-cyanophenyl)boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.82-0.89(q,1H),1.25(s,4H),1.28-1.33(d,2H),1.41(s,1H)1.99-2.05(t,1H)2.35-2.40(t,1H),2.84-2.91(t,1H),3.40(s,4H),4.14(s,2H),4.72(s,2H),6.92-6.94(d,1H),7.07-7.23(sxt,6H),7.38-7.44(t,2H),7.60-7.76(sxt,5H)7.98-8.03(t,2H),8.17-8.20(d,1H),8.29(s,1H),8.52(s,1H),8.81-8.83(d,1H) LC/MS (ESI-MS) m/z 578.8(M+1)
[00122] Example 54: (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 54 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyrimidin-5-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.830-0.880(t,2H),1.25(s,5H),1.28-1.33(d,2H),1.41(s,1H), 2.05(s,1H),3.39(s,4H),3.65(s,1H),4.12(s,2H),4.69(s,2H),6.96(s,1H),7.08-7.13(t,3H)7.187-7.24(t,1H),7.38-7.41(d,3H),7.44-7.50(t,4H),7.55-7.57(d,1H),7.70-7.74(d,2H),7.94-8.00(t,1H), 8.15-8.25(q,1H)8.34(q,1H),8.51-8.53(d,1H),8.78-8.84(q,1H),9.13(s,1H),9.28(s,1H) LC/MS (ESI-MS) m/z 555.8(M+1)
[00123] Example 55: 3-(4-(4-(1-(3-phenoxyphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile

Compound 55 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and (3-cyanophenyl)boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.82-0.89(q,2H),1.25(s,5H),1.28-1.33(t,3H),1.42(s,1H),2.00-2.05(t,1H),2.35-2.40(t,1H),2.84-2.91(t,1H),3.38(s,4H),4.14(s,2H),4.69(s,2H),6.91-6.93(d,1H), 7.08-7.13(t,3H),7.18-7.23(t,1H),7.39-7.41(d,3H),7.44-7.53(q,3H),7.60-7.65(t,1H), 7.697.76(t,2H),7.98-8.07(q,2H),8.16-8.19(d,1H),8.29(s,1H),8.533(s,1H),8.75-8.77(s,1H),8.81-8.83(s,1H) LC/MS (ESI-MS) m/z 578.7 (M+1)
[00124] Example 56: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 56 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyrimidin-5-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.82-0.87(t,3H),1.03(s,1H),1.25-1.31(t,10H),1.41(s,1H),2.96- 3.05(m,1H),3.40(s,4H),3.64(s,1H),4.15(s,2H),4.73(s,2H),6.95-6.97(d,1H),7.40-7.43(d,2H),7.48-7.50(d,1H),7.55-7.57(d,1H),7.66-7.69(d,3H),7.73-7.78(m,2H),7.94-8.00(t,1H),8.15-8.26(q,1H),8.34(s,1H),8.53-8.55(d,1H),8.79-8.85(q,1H),9.13(s,1H),9.28(s,1H) LC/MS (ESI-MS) m/z 505.6 s(M+1)
[00125] Example 57: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-methylpyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 57 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and (2-methylpyridin-4-yl)boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.82-0.88(t,3H),1.037(s,1H),1.25-1.32(t,17H), 1.42(s,2H), 1.94(s,1H),2.035(s,2H),2.12(s,1H),2.16-2.20(d,1H),2.68(s,3H),2.96-3.05(m,1H),3.41(s,4H), 4.15(s,2H),4.73(s,2H),6.63-6.65(d,1H),6.93-6.94(d,1H),7.04-7.08(d,1H),7.29(s,1H),7.40-7.43(d,2H),7.48-7.50(d,2H),7.55(s,1H),7.64-7.69(t,3H),7.79-7.82(d,1H),8.17-8.20(d,1H), 8.38(s,1H),8.55(s,1H),8.62-8.64(d,1H),8.22-8.83(d,1H) LC/MS (ESI-MS) m/z 518.2 (M+1)
[00126] Example 58: 3-(4-(4-(1-(4-isopropylphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile

Compound 58 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and (3-cyanophenyl)boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.82-0.87(t,6H),1.25-1.32(t,20H),1.40-1.42(d,1H),2.03(s,1H), 2.96-3.06(m,1H),3.40(s,4H),4.15(s,2H),4.73(s,2H),6.92-9.94(d,1H),7.40-7.43(d,2H),7.60-7.77(m,6H),7.98-8.03(t,2H),8.17-8.20(d,1H),8.29(s,1H),8.55(s,1H),8.81-8.83(d,1H)LC/MS (ESI-MS) m/z 528.4 (M+1)
[00127] Example 59: (4-(7-(2-methylpyridin-4-yl)quinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 59 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and (2-methylpyridin-4-yl)boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.82-0.88(t,2H),1.03(s,1H),1.25-1.29 (d,7H),1.42(s,2H), 1.94(s,1H),2.03(s,1H),2.16-2.20(s,1H),2.67(s,3H),3.38-3.39(d,4H), 4.13(d,2H),4.69(s,2H),6.92-6.93(d,1H),7.09-7.13(t,3H),7.18-7.23(t,1H),7.39-7.41(d,3H),7.44-7.51(t,3H),7.54(s,1H),7.79-7.82(d,1H),8.16-8.19(d,1H),8.36(s,1H),8.53(s,1H),8.61-8.63(d,1H),8.81-8.83(d,1H)LC/MS (ESI-MS) m/z 568.4 (M+1)s
[00128] Example 60: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 60 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.829-0.877(t,3H),1.255 (s,2H)1.296-1.320 (d,6H),2.037(s,1H),2.990-3.059 (t,1H),3.384 (s,4H),4.147(s,2H),4.726 (s,2H),6.953-6.968 (d,1H),7.407-7.434 (d,2H),7.630-7.734(m,6H), 8.186-8.213(d,2H),8.549 (s,1H),8.714 (s,1H), 8.797-9.813 (d,1H); LC/MS (ESI-MS) m/z 504.85 (M+1)
[00129] Example 61: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 61 was synthesized from (4-(8-chloroquinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 1.255(s,2H)1.296-1.320 (d,6H),2.037(s,1H),2.990-3.059 (t,1H),3.384 (s,4H),4.147(s,2H),4.726 (s,2H),6.953-6.968 (d,1H),7.407-7.434 (d,2H),7.630-7.734(m,6H), 8.186-8.213(d,2H),8.549 (s,1H),8.714 (s,1H), 8.797-9.813 (d,1H); LC/MS (ESI-MS) m/z 504.99 (M+1)
[00130] Example 62: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-methoxypyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 62 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone and (2-methoxypyridin-4-yl)boronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm) 0.829-0.877(t,3H),1.255 (s,2H)1.296-1.320 (d,6H),2.037(s,1H),2.990-3.059 (t,1H),3.384 (s,4H),4.022 (s,3H) , 4.143(s,2H),4.726 (s,2H),6.953-6.968 (d,1H),7.407-7.434 (d,2H),7.630-7.734(m,6H), 8.186-8.213(d,2H),8.549 (s,1H),8.714 (s,1H), 8.797-9.813 (d,1H); LC/MS (ESI-MS) m/z 535.01 (M+1)
[00131] Example 63: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 63 was synthesized from (4-(8-chloro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-4-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm)1.295-1.318(d,6H), 2.63(s,3H), 2.96-3.05(m,1H), 4.122(s,2H),4.73(s,2H), 6.85(s,1H), 7.435-7.435((d,2H),7.66-7.75(q,3H), 7.871(s,2H), 8.155-8.182 (d,1H)8.546(s,1H),8.706(s,2H); LC/MS (ESI-MS) m/z 518.96 (M+1)
[00132] Example 64: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 64 was synthesized from (4-(8-chloro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyridin-3-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm)1.184-1.187 (q,1H), 1.295-1.318(d,6H), 2.63(s,3H), 2.96-3.05(m,1H),3.352(s,4H),3.445-3.515(q,1H),4.137(s,2H),4.71(s,2H),6.85(s,1H),7.534-7.585(t,1H), 7.669-7.734 (t,3H), 8.100-8.126(t,1H), 8.542(s,1H), 8.608-8.620(d,1H), 8.984 ( s,1H) ; LC/MS (ESI-MS) m/z 518.91 (M+1)
[00133] Example 65: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone

Compound 65 was synthesized from (4-(8-chloro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and pyrimidin-5-ylboronic acid by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm)1.295-1.318(d,6H), 2.63(s,3H), 2.96-3.05(m,1H), 3.360(s,4H), 4.137(s,2H),4.71(s,2H), 6.85(s,1H), 7.564-7.615(d,1H),7.669-7.734 (q,3H), 8.141-8.169(d,1H), 8.546(s,1H), 9.159( s,2H), 9.220 ( s,1H) ; LC/MS (ESI-MS) m/z 519.99 (M+1)
[00134] Example 66: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-morpholinoquinolin-4-yl)piperazin-1-yl)methanone

Compound 66 was synthesized from (4-(8-chloro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and morpholine by following the similar procedure described in synthetic scheme III.
1HNMR (CDCl3,300MHz) d (ppm)1.295-1.318(d,6H)2.81(s,3H), 2.96-3.05(m,1H), 3.420(s,4H), 4.051-4.064(d,6H),4.65(s,2H), 6.77(s,1H), 7.092-7.097(d,1H),7.356-7.430 (q,3H), 7.66-7.701(t,3H), 8.530(s,1H) ; LC/MS (ESI-MS) m/z 526.72 (M+1)

SCHEME – IV:

[00135] Reagents and Conditions: (n) Chloro compound, NaOMe, CuI, Methanol, DMF, 110 0C, 12 h (o) BBr3, DCM, 0 °C – RT, 6 h; (p) Bromo compound, K2CO3, DMF, 60 °C, 2h
[00136] General Procedure :
Step-1: Preparation of Example-IV:
The starting material substituted triazole halogen compound in DMF was treated with 30% sodium methoxide (5 - 10 eq) in methanol and CuI (0.1- 0.2 eq), stirred for 12 - 24 hours at 1000C - 130 0C. The reaction mixture was poured into ice cold water and extracted with Ethyl acetate and purified by silica column chromatography using ethyl acetate in hexane as eluent.

The triazole substitutents are selected from Hydrogen, 4- isopropyl phenyl, cyclopentyl, n-pentyl, 2,3-Dimethyl phenyl, 4-tertiarybutyl phenyl, 3-Phenoxy phenyl, 4-phenoxy phenyl, 2,4-Difluorophenyl and 4-Phenoxy phenyl methyl.
Step-2: Preparation of Example-V:
To the methoxy compound in anhydrous DCM, was added BBr3 (1.0 M in DCM, 3.0 eq - 5.0 eq) at 0 oC and stirred for 6 12 hours at room temperature. Then Reaction mixture was concentrated under reduced pressure. The obtained crude was purified by silica column chromatography.
Step-3 : Preparation of Example-VI:
[00137] The hydroxy compound taken in DMF, to this added K2CO3 (3.0 - 5.0 eq), Bromo compound (1.0 – 1.5 eq) and the reaction mixture was heated to 60 oC – 80 0C for 2 – 6 hours and reaction mixture was poured into ice cold water, extracted with Ethyl acetate and purified by silica column chromatography using ethyl acetate in hexane as eluent.
Exemplary Embodiments
Preparation of Example-IV:
[00138] The stirred solution of Example-I in DMF was treated with 30% sodium methoxide (5 eq) in methanol and CuI (0.1 eq), stirred for 12 hours at 110 0C. The reaction mixture was poured into ice cold water and extracted with Ethyl acetate. The combined organic layer was back washed with water, brine, dried over Sodium sulphate and evaporated on rotavapor under reduced pressure. The obtained crude was purified by silica column chromatography using ethyl acetate in hexane as eluent.
Preparation of Example-V:
[00139] To the stirred solution of Example-I in anhydrous DCM, was added BBr3 (1.0 M in DCM, 3.0 eq) at 0oC and stirred for 6 hours at room temperature. Then Reaction mixture was concentrated under reduced pressure. The obtained crude was purified by silica column chromatography.
Preparation of Example-VI:
[00140] To a stirred solution of Example-IV in DMF, were added K2CO3 (3.0 eq), Bromo compound (1.0 eq) and the Reaction mixture was heated to 60oC. The reaction was continued at 60oC for 2 hours and reaction mixture was poured into ice cold water, extracted with Ethyl acetate. The combined organic layer was dried over sodium sulfate, evaporated under reduced pressure to get the desired crude material and the obtained crude was purified by silica column chromatography using ethyl acetate in hexane as eluent.

[00141] Example 67: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone

Compound 67 was synthesized (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone and Sodium methoxide by following the similar procedure described in synthetic scheme IV.
1HNMR ( DMSO,400 MHz) d (ppm) 1.665-1.778(m,2H),1.805-1.875(m,2H),1.956-2.042(m,2H),2.165-2.247(m,2H),3.205-3.229(t,4H),3.905-3.952(d,5H),4.336(s,2H), 4.996-5.065(m,1H) 6.891-6.903(d,1H),7.189-7.218(dd,1H),7.337-7.343(d,1H),8.002-8.026 (d,1H),8.621-8.638(d,2H), LC/MS (ESI-MS) m/z 407.8 (M+1)
[00142] Example: 68 (4-(7-methoxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 68 was synthesized (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone and Sodium methoxide by following the similar procedure described in synthetic scheme IV.
1HNMR ( DMSO,400 MHz) d (ppm) 0.842-0.878(t,3H),1.181-1.287(m,2H),1.305-1.343(m,2H),1.819-1.892(m,2H),3.212-3.236(t,4H), 3.906-3.952(d,5H),4.354-4.426(q,4H), 6.893-6.905(d,1H),7.188-7.218(dd,1H),7.337-7.344(d,1H), 8.004-8.027(d,1H),8.614-8.634(t,2H) LC/MS (ESI-MS) m/z 409.6(M+1)
[00143] Example 69: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone

Compound 69 was synthesized from (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone and sodium methoxide by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.978(s,3H),2.364(s,3H),3.274(s,4H),3.911(s,1H), 3.970(s,2H), 4.374(s2H),6.915-6.928(d,1H),7.199-7.228(dd,1H),7.298-7.352(m,3H), 7.427-7.449(q,1H), 8.025-8.048(d,1H),8.633-8.646(d,1H),8.907(s,1H), LC/MS (ESI-MS) m/z 443.5 (M+1)
[00144] Example 70: (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone

Compound 70 was synthesized from (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and Sodium methoxide by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.243-1.260(d,6H),2.967-3.034(m,1H),3.243-3.266(t,4H),3.909(s,3H),3.974(s,1H),4.349(s,2H),6.908-6.920(d,1H),7.199-7.228(dd,1H),7.344-7.350(d,1H),7.482-7.503(d,2H),7.875-7.897(d,2H),8.020-8.043(d,1H),8.631-8.644(d,1H), LC/MS (ESI-MS) m/z 457.2(M+1)
[00145] Example 71: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone

Compound 71 was synthesized (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone and Boron tribromide by following the similar procedure described in synthetic scheme IV
1HNMR (DMSO,400 MHz) d (ppm) 1.673-1.729(m,2H),1.777-1.861(m,2H),1.955-2.041(m,2H),2.163-2.243(m,2H),3.225(s,4H),3.917(s,2H),4.327(s,1H), 4.996-5.065(m,1H) 6.813-6.826(d,1H),7.101-7.123(dd,1H),7.187-7.193(d,1H),7.951-7.974 (d,1H),8.545-8.558(d,1H), 8.642(s,1H) LC/MS (ESI-MS) m/z 393.7 (M+1)

[00146] Example 72: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone

Compound 72 was synthesized (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone and Boron tribromide by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.234-1.257(t,3H),1.297(s,2H),1.334(s,1H),1.978(s,3H), 2.364(s,3H),3.247(s,4H),3.969(s,2H), 4.364(s,2H),6.829-6.842(d,1H),7.107-7.138(dd,1H), 7.195-7.202(d,1H),7.966-7.989(d,1H), 8.559-8.571(d,1H),8.907(s,1H),10.061(s,1H) LC/MS (ESI-MS) m/z 429.6(M+1)
[00147] Example 73: (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 73 was synthesized (4-(7-methoxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone and Boron tribromide by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 0.84-0.88(t,3H),1.18-1.33(m,6H),1.39-1.41(t,1H),1.82-1.89(m,2H),3.19-3.21(t,5H), 3.92(s,2H),4.34-4.42(q,4H),7.95-7.97(d,1H),8.55-8.56(d,1H), 8.62(s,1H), LC/MS (ESI-MS) m/z 395.7 (M+1)

[00148] Example 74: (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 74 was synthesized (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone and Boron tribromide by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.242-1.260(d,6H),2.965-3.034(m,1H),3.222-3.245(t,4H),3.966(s,2H),4.338(s,2H),6.822-6.834(d,1H),7.107-7.136(dd,1H),7.194-7.200(d,1H),7.481-7.503(d,2H),7.875-7.897(d,2H),7.962-7.985(d,1H),8.556-8.568(d,1H), 9.251(s,1H),10.061(s,1H) LC/MS (ESI-MS) m/z 443.4(M+1)

[00149] Example 75: (4-(8-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 75 was synthesized from (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methoxy-2-methylquinolin-4-yl)piperazin-1-yl)methanone and Boron tribromide by following the similar procedure described in synthetic scheme IV.
1HNMR (CDCl3, 300 MHz) d (ppm) 2.31(s,3H), 2.65(s,1H), 3.00(s,2H),3.64 (s,1H), 3.80 (s,2H),3.89(s,2H),4.144(s,3H),4.79(s,2H),6.76-6.80(d,2H), 6.97-7.00(d,2H), 7.088(t,3H),7.415-7.43(d,2H),7.49-7.52(d,3H),7.61-7.68(t,2H),7.768-7.799(d,1H),7.89(s,2H),8.038-8.063(d,1H),8.575(s,1H) LC/MS (ESI-MS) m/z 457.97(M+1)
[00150] Example 76: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)methanone

Compound 76 was synthesized (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone and Ethylene carbonate solution by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.66-1.86(m,4H),1.95-2.04(m,2H),2.16-2.25(m,2H),3.77-3.81(q,2H),3.93(s,2H)s,4.13-4.15(t,2H),4.34(s,2H),4.93-4.95(t,1H),5.00-5.07(m,1H),6.90-d,66.91(d,1H),7.20-7.23(dd,1H),7.32-7.22(d,1H),8.01-8.04(d,1H),8.61-8.64(t,2H) LC/MS (ESI-MS) m/z 437.4 (M+1)
[00151] Example 77: (4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 77 was synthesized (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone and Ethylene carbonate solution by following the similar procedure described in synthetic scheme IV.
1HNMR ( DMSO,400 MHz) d (ppm) 0.84-0.88(t,3H),1.19-1.27(m,4H),1.29-1.34(q,2H),1.82-1.89(m,2H),3.22-3.24(t,4H),3.77-3.81(q,2H),3.93(s,2H),4.13-4.15(t,2H),4.36(s,2H),4.39-4.43(t,2H),4.92-4.95(t,1H),6.89-6.90(d,1H),7.20-7.23(dd,1H),7.33-7.33(dd,1H),8.01-8.03(d,1H), 8.61-8.63(t,2H), LC/MS (ESI-MS) m/z 439.4(M+1)
[00152] Example 78: (4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 78 was synthesized (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and Ethylene carbonate solution by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.24-1.26(d,6H),2.96-3.03(m,1H),3.16-3.17(d,1H),3.24-3.27(t,4H),3.77-3.81(q,2H),3.98(s,2H),4.13-4.15(t,2H),4.35(s,2H),4.92-4.95(t,1H),6.90-6.92(d,1H),7.21-7.24(dd,1H),7.33-7.34(d,1H),7.48-7.50(d,2H),7.88(dd,2H),8.02-8.04(d,1H),8.62-8.64(d,1H), LC/MS (ESI-MS) m/z 487.6(M+1)

[00153] Example 79: (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)methanone

Compound 79 was synthesized (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone and Ethylene carbonate solution by following the similar procedure described in synthetic scheme IV.
1HNMR (DMSO,400 MHz) d (ppm) 1.98(s,3H),2.37(s,3H),3.29(s,4H),3.76-3.81(q,2H),3.78-3.81(q,2H),3.97(t,2H),4.37(s2H),4.91-4.94(t,1H),6.91-6.92(d,1H),7.21-7.24(q,1H),7.31-7.35(m,3H),7.43-7.45(q,1H),8.03-8.05(d,1H),8.63-8.64(d,1H),8.90(s,1H), LC/MS (ESI-MS) m/z 473.8 (M+1)

[00154] Example 80: (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)methanone

Compound 80 was synthesized (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone and 2-bromo-N,N-dimethylethan-1-amine by following the similar procedure described in synthetic scheme IV.
1HNMR ( DMSO,400 MHz) d (ppm) 1.67-1.74(m,2H),1.77-1.85(m,2H).1.95-1.99(m,2H),2.00-2.23(m,2H),2.86-2.887(d,6H),3.61-3.62(d,2H),3.91-3.97(d,6H),4.40(s,2H),4.55-4.58(t,2H),5.01-5.08(m,1H),7.09-7.11(d,1H),7.35-7.38(q,1H),7.51-7.52(d,1H),8.21-8.24(d,1H),8.62-8.64(d,1H),8.70(s,1H) LC/MS (ESI-MS) m/z 464.7 (M+1)
[00155] Example 81: (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 81 was synthesized (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone and 2-bromo-N,N-dimethylethan-1-amine by following the similar procedure described in synthetic scheme IV.
1HNMR ( DMSO,400 MHz) d (ppm) 1.98(s,3H),2.24(s,6H),2.36(s,3H),2.68-2.71(t,2H), 3.27(s,4H),3.97(s,2H),4.19-4.22(t,2H),4.37(s,2H),6.91-6.92(d,1H).7.19-7.22(q,1H),7.31-7.36(m,3H),7.43-7.45(q,1H),8.01-8.04(d,1H),8.63-8.64(d,1H),8.91(s,1H), ) LC/MS (ESI-MS) m/z 500.4(M+1)
[00156] Example 82: (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone

Compound 82 was synthesized (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone and 2-bromo-N,N-dimethylethan-1-amine by following the similar procedure described in synthetic scheme IV.
1HNMR ( DMSO,400 MHz) d (ppm): 2.86-2.87(d,6H),3.56-3.62(t,2H),3.91-3.98(d,6H),4.40-4.44(t,4H),4.56-4.59(t,2H),7,09-7.11(d,1H),7.36-7.39(q,1H),8.21-8.24(d,1H),8.61-8.63(d,1H), 8.67(s,1H),10.83(s,1H),14.82(s,1H) LC/MS (ESI-MS) m/z 467.8 (M+1)
[00157] Example 83: (4-(7-(2-(dimethylamino) ethoxy)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone

Compound 83 was synthesized (4-(7-hydroxyquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone and 2-bromo-N,N-dimethylethan-1-amine by following the similar procedure described in synthetic scheme IV.

Experimental data:

[00158] The novel substituted quinoline triazole compounds of the present invention were synthesized in an iterative manner to establish the structure activity relationship. It was found that the compounds of the present invention show high therapeutic efficacy. Total 83 compounds were prepared and Minimum inhibitory concentration (MIC), Mouse Liver Microsomal stability (MLM), PK in mice and efficacy of the compounds were determined.

[00159] Minimum inhibitory concentration (MIC) of the compounds was determined by the standard broth dilution method (CLSI-M24, Franzblau 1998, Kaur,2015). The closest prior art compound by structure is 4-(4-((2-(4-isopropylphenyl)-2H-tetrazol-5-yl)methyl)piperazin-1-yl)-7-(pyridin-3-yl)quinoline ( reported MIC – 1 µg/ml ) and used Rifampicin ( reported MIC – 0.0078 µg/ml) as control. The test compounds were dissolved in DMSO, serially double-diluted in a 10-concentration dose-response (10c-DR) ranging from 64 to 0.125 ug/mL 96-well plates. In Middlebrook 7H9 broth (with 10% ADC), Mtb culture was added as 200µL in test wells at a final inoculum of 3-7X105 CFU/mL. The QC included: media controls, DMSO control, Mtb growth controls, and the reference drug inhibitors (Rifampicin and Isoniazid). The assay plates were incubated at 37°C, resazurin dye was added on the 6th day. Results were noted on the 7th day as colourimetric readout. The blue wells indicated inhibition of growth, while the pink wells indicated uninhibited growth. MIC was the minimum concentration of molecules that completely inhibited the colourimetric growth of bacteria.

[00160] Table 1: MIC determination against Mycobacterium tuberculosis (Mtb) H37Rv strain:
S.No Example MIC
( ug/ml) S.No Example MIC
( ug/ml)
1 Example 1 1 42 Example 42 0.125
2 Example 2 2 43 Example 43 0.25
3 Example 3 8 44 Example 44 8
4 Example 4 > 64 45 Example 45 16
5 Example 5 1 46 Example 46 4
6 Example 6 Insoluble 47 Example 47 > 32
7 Example 7 > 32 48 Example 48 Insoluble
8 Example 8 2 49 Example 49 Insoluble
9 Example 9 2 50 Example 50 0.25
10 Example 10 > 128 51 Example 51 0.25
11 Example 11 1 52 Example 52 8
12 Example 12 > 128 53 Example 53 16
13 Example 13 1 54 Example 54 32
14 Example 14 1 55 Example 55 Insoluble
15 Example 15 1 56 Example 56 2
16 Example 16 2 57 Example 57 2
17 Example 17 4 58 Example 58 > 32
18 Example 18 4 59 Example 59 4
19 Example 19 4 60 Example 60 16
20 Example 20 2 61 Example 61 0.125
21 Example 21 > 32 62 Example 62 > 32
22 Example 22 8 63 Example 63 0.125
23 Example 23 16 64 Example 64 0.125
24 Example 24 8 65 Example 65 0.125
25 Example 25 1 66 Example 66 0.125
26 Example 26 8 67 Example 67 16
27 Example 27 1 68 Example 68 4
28 Example 28 2 69 Example 69 16
29 Example 29 16 70 Example 70 1
30 Example 30 16 71 Example 71 > 32
31 Example 31 4 72 Example 72 32
32 Example 32 8 73 Example 73 32
33 Example 33 32 74 Example 74 4
34 Example 34 16 75 Example 75 2
35 Example 35 4 76 Example 76 > 32
36 Example 36 2 77 Example 77 2
37 Example 37 0.25 78 Example 78 16
38 Example 38 0.25 79 Example 79 32
39 Example 39 1 80 Example 80 > 32
40 Example 40 Insoluble 81 Example 81 32
41 Example 41 32 82 Example 82 > 32
83 Example 83 8

[00161] A total of 83 molecules were synthesized, with the MIC determined against Mycobacterium tuberculosis (Mtb) H37Rv strain (Table-2), stability studies in Mouse Liver Microsomes (MLM), a PK profile generated in mice for selected lead compounds, and cytotoxicity was evaluated. The results are summarized in the following table 2.
MIC range (ug/ml) 0.125 0.25 1 2 4 8 16 32 > 32 Insoluble
Total 83 compounds 6 5 10 11 9 8 10 7 12 5

[00162] Out of the 83 compounds, twenty compounds were found to be MIC range 1 ug/ml and below and highly effective against Mtb. The metabolic stability of all 21 active compounds (MIC = 1 ug/ml) was assessed in mouse liver microsomes.
In-vitro ADME and Cytotoxicity
Mouse Liver Microsomal Stability:
[00163] Mouse microsomal stability of the compound was determined. A homogenate of MLM/HLM (Mouse/Human Liver Matrix)- 0.625 mg/ml was prepared. Compounds at a concentration of 10 µm were spiked into the homogenate to get the final concentration of 1µm and kept in water bath at 370 C for 5min. Sample was collected in triplicates at 0 min and the reaction was quenched using 250 ng/ml acetonitrile containing Internal standard. nicotinamide adenine dinucleotide phosphate (NADPH), 10 mM was added to the above remaining sample to get the final concentration of 1mM and kept in water bath at 370C for different time points (0, 30 and 60min for microsomal stability and 0, 5, 15, 30, 45 and 60min for microsomal intrinsic clearance). At each time point 30µL of reaction mix was aliquoted and quenched using 90µL of acetonitrile containing Internal standard. The samples were centrifuged for 10 minutes at 13000 RPM, supernatant was collected and submitted for analysis.
[00164] Result: 21 MIC active compounds were chosen and tested for metabolic stability in mouse liver microsomes. Results are summarized in Table-3 and the compounds had wide range of metabolic profile.
Table-3:
S. No Example % Of compound Remaining S. No Example % Of compound Remaining
30 min 60 min 30 min 60 min
1 Example 1 62 45 11 Example 38 23 11
2 Example 5 37 31 12 Example 39 9 4
3 Example 11 43 33 13 Example 42 90 83
4 Example 13 96 84 14 Example 43 34 22
5 Example 14 53 35 15 Example 50 30 15
6 Example 15 61 48 16 Example 51 24 14
7 Example 25 1 1 17 Example 61 56 27
8 Example 27 9 6 18 Example 63 27 23
9 Example 28 11 3 19 Example 64 67 30
10 Example 37 20 9 20 Example 65 12 10

[00165] The introduction of various groups to different positions on the quinoline ring generated a diverse metabolic profile that aided in the synthesis of stable compounds in mouse liver microsomes. These compounds were profiled further for PK studies.
In-vivo Pharmacokinetics:
PK Protocol:
[00166] Animals were procured from the CPCSEA approved supplier and quarantined for 7 days. The animals were fed and water ad libitum. After Veterinarian examination, healthy animals were used for study. On the day of dosing, the animals were weighed and dosed orally or parenterally with the test compound prepared in appropriate formulation either in single or multiple doses. After dosing, blood samples (50 ul) were collected by saphenous vein puncture at 8 time points depending on the pharmacokinetic characteristics of the compound. There are 1 to 3 animals per time point and 4 time points from each animal. The blood samples were centrifuged at 5000 rpm for 10 mins, plasma was harvested and stored at –80°C which was then handed over to the analytical department for analysis.
Bioanalytical PK:
[00167] Before receiving in-vivo samples i.e., matrices, a bioanalytical method was developed using LC-MS/MS. The method was specific to the matrices. The usual calibration range was set at 10 to 5000 ng/mL with two sets of QC samples (LQC, MQC and HQC). However, the same can be altered based on molecules’ response. Most of the methods are developed following protein precipitation extraction technique. Followed by method development, the in-vivo samples were analyzed to determine PK parameters such as Cmax, Tmax, t1/2, AUC etc., Based on obtained data, the test compounds were further optimized to achieve desired PK parameters.

[00168] Result: The PK was performed both oral and IV in mice and the results were summarized in Table 4 & Table-5 respectively. The compounds of the present invention, particularly, compounds of Example 61 and Example 42 have shown a decent PK profile and all the compounds were orally bioavailable.
Table-4: Route of administration – Oral:
Parameters &
Units Example 1 Example 25 Example 27 Example 5 Example 13 Example 14 Example 15 Example 61 Example 42 Example 43
Dosage mg/kg b.w 30 50 30 30 30 30 30 30 30 30
t1/2 (h) 0.99 2.2 1.57 1.97 2.55 0.93 0.58 0.78 1.21 9.26
Tmax (h) 0.5 0.5 1 0.5 1 0.5 0.5 0.5 1 0.5
Cmax (ng/mL) 510 862.5 12 260 214 1081 214 1460 1446 168
AUC 0-t (ng/mL*h) 476 1407 43.01 621 632 2141 281 1536 1941 387

Table-5: Route of administration – IV:
Parameters &
Units Example 15 Example 61 Example 42 Example 43
Dosage mg/kg b.w 10 2.5 10 10
t1/2 (h) 0.45 0.52 9.9 20.21
Tmax (h) 0.08 0.08 0.08 0.08
Cmax (ng/mL) 9921 2010 1051 169
AUC 0-t (ng/mL*h) 5447 969 2761 798

[00169] The compound concentrations in Lung tissue were measured as well for both Oral and Intravenous Route (IV) routes for selected compounds Example 61 and Example 42 (Table-6).
Table:6: Example 42 and Example 61 lung Concentration Data
Time Point Example 61 Oral Example 61 IV Example 42 Oral Example 42 IV
Dose mg/Kg body weight 30 2.5 30 10
@ 6 hr ng/gm Nil 10952 5 573,709
@ 24 hr ng/gm Nil 13046 Nil 446,148

.
[00170] In an embodiment, the present invention also provides pharmaceutical composition comprising compound(s) of the present invention. For oral administration, a composition comprising 0.3 to 2 % of a compound of formula 1, and 0.5 % to 3% of pharmaceutically acceptable excipients selected from the group consisting of:, 99.9 % w/v of hydroxypropyl methylcellulose (HPMC) and 0.1% to 1% of Tween 80 is used. For Intravenous (IV) administration, a composition comprising 0.6 to 4% of a compound of formula 1 and 1 to 10 % of pharmaceutically acceptable excipients selected from the group consisting of:, 5% Dimethyl acetamide (DMA), 10% solutol and 85% normal saline) comprising novel substituted quinoline triazole compounds of formula (1) that are useful in treating tuberculosis and other mycobacterial infections.

[00171] In an embodiment, the present invention provides pharmaceutical compositions that include any administrable form including solid (tablets, pills, capsules, granules and the like) liquid (solutions, suspensions, emulsions and the like) for oral, topical or parenteral administration.
ADVANTAGES OF THE INVENTION
[00172] The quinoline triazole series compounds of the present invention are easily synthesizable and have adopted a convergent synthesis method. With the commercial availability of required starting materials, low-cost and moderate reaction conditions make this series is easily scalable and adoptable as well.

[00173] As per WHO classification, antibiotics are innovative if they meet one of the following criteria - no cross-resistance to existing antibiotics, new chemical class, new target and new mechanism of action. The compounds of the present invention meet all the required criterion.
[00174] While the present invention has been described with reference to one or more preferred aspects, which aspects have been set forth in considerable detail for the purposes of making a disclosure of the invention, such aspects are merely exemplary and are not intended to be limiting or represent an exhaustive enumeration of all aspects of the invention. The scope of the invention, therefore, is defined solely by the claims presented herein. Further, it will be apparent to those of skill in the art that numerous changes may be made in such details without departing from the principles of the invention.
,CLAIMS:WE CLAIM:

1. A substituted quinoline triazole compound of Formula (I)

or pharmaceutically acceptable salts thereof, for treating tuberculosis and other mycobacterial infections, wherein:
R1 is independently selected from the group consisting of Hydrogen, Methyl and CF3;
R2, R3 and R4 are independently selected from the group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3; C1-C12 alkyl optionally substituted with CH3, OH; C3-C12 cycloalkyl; C2-C12 heterocycloalkyl, C6-C18 aryl optionally substituted with alkyl, alkoxy, cyano, phenyl, phenoxy; C1-C18 heteroaryl such as 3-pyridine, 4-pyridine, pyrimidine, C1-C12 alkyloxy optionally substituted with alkyl, alkoxy, methoxy; C2–C10 heteroalkyloxy optionally substituted with ethane-1,2-diol, 2-(dimethylamino), ethan-1-ol, C6-C18 aryloxy, and C1-C18 heteroaryloxy.
R5 is independently selected from the group consisting of H, C1-C12 alkyl, C2–C10 heteroalkyl, C3-C12 cycloalkyl, C6-C18 aryl optionally substituted with primary, secondary or tertiary alkanes, halogens, alkoxy, phenoxy or benzyl groups, and C1-C18 heteroaryl and acyl groups.

2. The substituted quinoline triazole compound of Formula (I) as claimed in claim 1,

or pharmaceutically acceptable salts thereof, for treating tuberculosis and other mycobacterial infections,
wherein:
R1 is independently selected from the group consisting of Hydrogen, Methyl and CF3;
R2, R3 and R4 are independently selected from the group consisting of Hydrogen, Halogens, OH, OCH3, CF3, OCF3, CH3, 3-pyridyl, 4-pyridyl, morpholine, pyrimidine, 2-(dimethylamino)ethoxy, ethan-1-ol, ethane-1,2-diol, 3-cyano phenyl, 2-methyl pyridine and 2-methoxy pyridine.,
R5 is independently selected from the group consisting of H, 4-isopropyl phenyl, cyclopentyl, n-butyl, n-pentyl, 2,3-dimethyl phenyl and 4-tert butyl phenyl, 4-phenoxy phenyl, 3-phenoxy phenyl, 2,4-diflouro phenyl and 4-methoxy benzyl groups.

3. The quinoline triazole compound as claimed in claim 1, wherein the compound of formula (I) is selected from the group of:
i. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl) methanone;
ii. (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
iii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl) methanone;
iv. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl) methanone;
v. (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-chloroquinolin-4-yl)piperazin-1-yl)methanone;
vi. (4-(7-chloroquinolin-4-yl) piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone;
vii. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(2,4-difluorophenyl)-1H-1,2,3-triazol-4-yl)methanone;
viii. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone;
ix. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
x. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xiii. (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl) quinolin-4-yl) piperazin-1-yl)methanone;
xiv. (1-(4-(tert-butyl)phenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xv. (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xvi. (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xvii. (1-(2,4-diflourophenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xviii. (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xix. (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl) piperazin-1-yl)methanone;
xx. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-morpholinoquinolin-4-yl) piperazin-1-yl)methanone;
xxi. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-morpholino quinolin-4-yl) piperazin-1-yl) methanone;
xxii. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone;
xxiii. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-cyclopentyl-1H-1,2,3-triazol-4-yl)methanone;
xxiv. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
xxv. (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(quinolin-4-yl)piperazin-1-yl)methanone;
xxvi. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxvii. (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxviii. (1-pentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxix. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxx. (4-(7-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methanone;
xxxi. (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxxii. (1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
xxxiii. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)methanone;
xxxiv. (4-(7-morpholinoquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
4. The quinoline triazole compound as claimed in claim 1, wherein the compound of formula (I) is selected from the group of:
xxxv. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(trifluoromethyl) quinolin-4-yl)piperazin-1-yl)methanone;
xxxvi. (4-(6-fluoroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xxxvii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methylquinolin-4-yl)piperazin-1-yl)methanone;
xxxviii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)methanone;
xxxix. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(6-methoxyquinolin-4-yl)piperazin-1-yl)methanone;
xl. (4-(8-chloroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xli. (4-(2,8-bis(trifluoromethyl)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methoxy-2-methylquinolin-4-yl)piperazin-1-yl)methanone;
xliii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-methylquinolin-4-yl)piperazin-1-yl)methanone;
xliv. (4-(8-fluoroquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlv. (4-(8-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlvi. (4-(2,8-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlvii. (4-(6-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlviii. (4-(7-fluoro-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
xlix. (4-(2,6-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
l. (4-(8-bromo-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
li. (4-(6,8-dimethylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lii. (1-(4-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
liii. 3-(4-(4-(1-(4-phenoxyphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile;
liv. (1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lv. 3-(4-(4-(1-(3-phenoxyphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile;
lvi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lvii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-methylpyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lviii. 3-(4-(4-(1-(4-isopropylphenyl)-1H-1,2,3-triazole-4-carbonyl)piperazin-1-yl)quinolin-7-yl)benzonitrile;
lix. (4-(7-(2-methylpyridin-4-yl)quinolin-4-yl)piperazin-1-yl)(1-(3-phenoxyphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lx. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-methoxypyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxiii. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyridin-4-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxiv. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyridin-3-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxv. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(2-methyl-8-(pyrimidin-5-yl)quinolin-4-yl)piperazin-1-yl)methanone;
lxvi. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(8-morpholinoquinolin-4-yl)piperazin-1-yl)methanone;
5. The quinoline triazole compound as claimed in claim 1, wherein the compound of formula (I) is selected from the group of:
lxvii. (4-(7-methoxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxviii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone;
lxix. (1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-methoxyquinolin-4-yl)piperazin-1-yl)methanone;
lxx. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone;
lxxi. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)methanone;
lxxii. (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxxiii. (4-(7-hydroxyquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxiv. (4-(8-hydroxy-2-methylquinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxv. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)methanone;
lxxvi. (4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxxvii. (4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxviii. (1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)(4-(7-(2-hydroxyethoxy)quinolin-4-yl)piperazin-1-yl)methanone;
lxxix. (1-cyclopentyl-1H-1,2,3-triazol-4-yl)(4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)methanone;
lxxx. (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-(2,3-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methanone;
lxxxi. (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-pentyl-1H-1,2,3-triazol-4-yl)methanone;
lxxxii. (4-(7-(2-(dimethylamino)ethoxy)quinolin-4-yl)piperazin-1-yl)(1-(4-isopropyl phenyl)-1H-1,2,3-triazol-4-yl) methanone;
6. A method of preparation of quinoline triazole compound as claimed in claim 1, comprising:
(a) preparing an intermediate having formula X-N3 (Int-3) from the compounds selected from the group of X-NH2 and X-OH; wherein X is independently selected from the group including but not limited to halogens, Isopropyl, 2,3 -Dimethyl, difluoro, phenoxy substituted phenyl or the like.
(b) adding methyl propanoate (1.0 eq) in 1:1 mixture of water and tertiary alcohol ( 10 volumes ) and adding Copper (II) sulphate pentahydrate ( 0.1 – 0.2 eq ) and freshly prepared 1M solution of L-sodium ascorbate (0.5 – 1 eq ) in water, stirring the mixture for 3-4 hours, washing and drying followed by purification to obtain triazole carboxylate intermediate having formula Int-4

(c) treating compound of formula Int-4 in THF and Methanol by adding Lithium hydroxide monohydride (3 eq. in water) and stirring the mixture for at least 12 hours, extracting organic layer, to prepare an intermediate having formula Int-5

Int-5
(d) obtaining a substituted chloroquinoline compound of Formula (A),

(e) treating the intermediate-5 of step (c) or the substituted chloroquinoline compound of step (d) with a base and Boc-piperazine stirring the reaction mixture at a temperature in the range of 800C to 1200C for a time in the range 8 to 24 hours to obtain Boc-piperazine substituted Intermediate (Int-1 or Int-5);
(f) treating Boc-piperazine substituted Intermediate with Trifluoro acetic acid (5.0 eq) with continued stirring for 3 hours at room temperature to form Int-2 or Int-9;
(g) coupling chloroquinoline compound with triazole carboxylate intermediate in the presence of a base and at least one coupling agent to form compound as claimed in claim 1.
(h) optionally substituting halide group at R2, R3 or R4 with groups selected from hydroxy group , alkoxy group optionally substituted with -OH, dialkylamino groups.

7. The method of preparation of quinoline triazole compound as claimed in claim 6, comprising the steps of:
(a) reacting a substituted chloroquinoline compound of Formula (A), a base and Boc-piperazine in a ratio of 1:2:1 to 1:3:1 in presence of solvents; (A)
(b) stirring the reaction mixture at a temperature in the range of 80 to 1200C for a time period in the range 8 to 24 hours to obtain intermediate-1

(c) adding trifluoro acetic acid in a ratio of 1:5 to Intermediate-1 in the presence of an organic solvent dropwise with continued stirring for at least 3 hours at room temperature and evaporating the reaction mixture under reduced pressure to obtain Intermediate-2 (Int-2);

(d) adding HCl dropwise to substituted aromatic amine of formula B in organic solvent at 00C, followed by addition of nitrite reagent in a ratio of 1:2 to 1: 3 and stirring at room temperature for a period in the range 3 to 8 hours to form Intermediate-3;

(e) adding methyl propiolate in 1:1 solvent ratio to the mixture of intermediate-3, followed by adding copper reagent and sodium ascorbate in water, stirred at room temperature for a time period in the range of 4-12 hours to form Intermediate-4;
(f) reacting intermediate-4 obtained from step (e) with a base in a ratio of 1:2 to 1:4 in the presence of solvents and stirring the reaction mixture at room temperature for a time period in the range 3 to 12 hours to form Intermediate-5;
(g) coupling intermediate-2 with intermediate-5 in the presence of a base and at least one coupling agent to form compounds as claimed in claim 3; and

8. The method as claimed in claim 6, wherein the substituents of the substituted chloroquinoline compound is selected from the group consisting of Hydrogen, Chlorine, 4-pyridine, 3-Pyridyne, morpholine, Methoxy, Hydroxy, Ethylene glycol, 2-(Dimethylamino)ethanol, Trifluoro methyl, Fluoro, Pyrimidine, 3-Cyano phenyl, 2-methyl pyridine, 2-Methoxy pyridine, or a combination thereof.
9. The method as claimed in claim 5, wherein the solvent is selected from the group of solvents are selected from Ethanol, Isopropyl alocohol and NMP.
10. The method as claimed in claim 5, wherein the base is selected from potassium hydroxide, sodium hydroxide and lithium hydroxide and/or combinations thereof.
11. The method as claimed in claims 5-7, wherein the base is Di isopropyl ethyl amine.
12. The method as claimed in claims 5-7, coupling reagent is selected from EDCI, HoBt or a combination thereof.
13. An oral composition comprising:
• 0.3 to 2 % of a compound of formula 1 as claimed in claim 1; and
• 0.5% to 3% of pharmaceutically acceptable excipients selected from the group consisting of:, 99.9 % w/v of hydroxypropyl methylcellulose (HPMC) and 0.1 to 1 % of Tween 80;
14. An Intravenous (IV) composition comprising :
• 0.6 to 4 % of a compound of formula 1 as claimed in claim 1; and

• 1 to 10 % of pharmaceutically acceptable excipients selected from the group consisting of:, 5% Dimethyl acetamide (DMA), 10% solutol and 85% normal saline %.