WO2017168454A2 - Novel compounds as btk inhibitors - Google Patents

Novel compounds as btk inhibitors Download PDF

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WO2017168454A2
WO2017168454A2 PCT/IN2017/050127 IN2017050127W WO2017168454A2 WO 2017168454 A2 WO2017168454 A2 WO 2017168454A2 IN 2017050127 W IN2017050127 W IN 2017050127W WO 2017168454 A2 WO2017168454 A2 WO 2017168454A2
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alkyl
hydrogen
group
cycloalkyl
nitrogen
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PCT/IN2017/050127
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French (fr)
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WO2017168454A3 (en
Inventor
Prabal Sengupta
V.S.N. Murty KADIYALA
Dipali Manubhai DESAI
Sabbirhusen Yusufbhai CHIMANWALA
Tushar Mukund JARAG
Gaurav Sanjivkumar Sheth
Trinadha Rao Chitturi
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Sun Pharma Advanced Research Company Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • Rg, R9, Rjo are independently selected from a group consisting of hydrogen, d-6 alkyl, d-6 cycloalkyl, d-6 haloalkyl, d-6 halocycloalkyl, d-6 hydroxylalkyl, C 3 _6 hydroxycycloalkyl, d-6 alkyl-0-C 3 _ 6 cycloalkyl, CN, C(0)NR 12 Ri 3 , (CH 2 ) n C(0)NR 12 Ri , d-6 cyanoalkyl, C(0)OH, C(0)Od_ 6 alkyl, (CH 2 ) n C(0)OH, (CH 2 ) n dO)Od-6 alkyl, (CH 2 ) n NR 12 R 13 , C 4 _7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R 14 );
  • R 12 and R 13 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci-3 alkyl;
  • R 14 is selected from hydrogen, d-6 alkyl, C 3 _6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl and C 3 _6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen;
  • R 2 is a group selected from
  • R 38 is selected from hydrogen, -Cj_6 alkyl, -C 2 _6 alkenyl, -C 3 _ 7 cycloalkyl;
  • J is absent or -C(O)-
  • G is an electron withdrawing group selected from -C(0)OR 4 o, -C(0)N(R 4 o)2, -CN, -NO 2 , - SO3H, -S02N(R 4 o)2, -SO2R40 wherein R 4 o at each occurrence is independently selected from hydrogen, -Ci -3 alkyl and -C 4 _6 cycloalkyl;
  • W is CH and group A is substituted on W.
  • D is phenyl unsubstituted or substituted with one or more groups selected from halogen or d- 6 alkyl;
  • the present invention provides a compound of Formula I, wherein L is nitrogen and R 3 and R4 taken together with the nitrogen and L to which they are attached respectively, forms a 5 or 6 membered heterocyclic ring.
  • the heterocyclic ring is selected from piperazinyl, imidazolidinyl or hexahydropyrimidinyl.
  • the heterocyclic ring is piperazinyl.
  • n is 1 and R 1 2 and R13 together with the nitrogen atom to which they are attached forms a 6 membered heterocyclic ring containing 1 additional nitrogen atom substituted with methyl; preferably the heterocyclic ring is piperazinyl;
  • Rj and R 2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with methyl.
  • the hydrazines prepared as per the process provided in Schemes 1 to 4 were treated with aromatic electrophiles to obtain N-aryl/ heteroarylhydrazines belonging to Formula I.
  • Some of the representative aromatic electrophilic compounds are provided in Figure-6.
  • the aromatic electrophilic compound may also require some functional modifications depending upon the type of the substitution on them and such modifications are under the purview of a person skilled in the art.

Abstract

The present invention relates to novel compounds of Formula I as Bruton tyrosine kinase inhibitors, process of preparation thereof, and to the use of the compounds in the preparation 5 of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of Bruton tyrosine kinase in humans.

Description

NOVEL COMPOUNDS AS BTK INHIBITORS
RELATED APPLICATIONS This application claims the benefit of Indian Patent Application no. IN 201621011745 filed on April 02, 2016 and IN 201621023892 filed on July 12, 2016; which is hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to novel compounds as Bruton tyrosine kinase (BTK) inhibitors, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders involving mediation of Bruton tyrosine kinase in humans.
BACKGROUND OF THE INVENTION
Involvement of BTK in signal transduction pathways regulating B-cell proliferation, differentiation and survival has been a ground breaking discovery and has led to developments of drugs for the treatment of B-cell malignancies. Improper /auto activated BTK signaling is considered to be the major cause in several hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) etc. (Li et al. Journal of Med. Chem., 2014, 57(12), 5112-5128; Seng-Lai Tan et al., Pharmacology and Therapeutics, 2013, 138, 294-309).
First in class BTK inhibitor, ibrutinib, which is disclosed in US patent number 7514444 is presently marketed for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia under the trade name Imbruvica®. The clinical and commercial success of ibrutinib has led to discovery of newer BTK inhibitors. WIPO publication number WO 2015002894A1, WO2014188173A1, WO2014188173A1, WO2014100748A1, WO2011031896A2, WO2013155347A1, WO2014130856A2, WO2015165279A1; US patent numbers 7169791, 6596746, 6002008, 8114874, 7728131 and US publication US20150005277, US20140079690 discloses various compounds as BTK inhibitors. Recently acalabrutinib (ACP-196), chemically known as 4-[8-amino-3-[(25)-l-(l-oxo-2- butyn-l-yl)-2-pyrrolidinyl]imidazo[l,5-a]pyrazin-l-yl]-N-2-pyridinylbenzamide, a selective BTK inhibitor has shown remarkable clinical results (J. C. Byrd et.al., NEJM, 2015, 1-10). Noteworthy is the selectivity of ACP-196 to BTK over interleukin-2-inducible T-cell kinase (ITK), the latter being mainly expressed in T-Cells but not in B-cells. Selective inhibitors are perceived to be more effective as combination therapies in CLL in rendering superior efficacy. WIPO publication number WO2013010868A1 and WO2015057992A1 discloses imidazopyrazinylbenzamide derivatives and analogs as BTK inhibitors.
The present inventors have found novel compounds that are potent BTK inhibitors and are selective over ITK.
SUMMARY OF THE INVENTION The present invention provides a compound of Formula I
Figure imgf000003_0001
Formula I
or its stereoisomers and acid addition salts thereof, wherein
A is a group selected from a group consisting of hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, N(Ci_6 hydroxyalkyl)2, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl, NHC(0)R26, NHNHC(0)R26, ONHC(0)R26, C(R27R28)NHC(0)R26, NHCSR26, NHNHCSR26, ONHCSR26, C(R27R28)NHCSR26, CONHNHC(0)R26, 4 to 9 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen wherein nitrogen is substituted with Re; and wherein the alkyl and the cycloalkyl group is unsubstituted or substituted with 5 or 6 membered heterocycle containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen;
R6 is selected from hydrogen, Ci_6 alkyl, C(0)Ci_6 hydroxyalkyl, C3_6 cycloalkyl, ΝΗ(¾_6 cycloalkenone), Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, C3_6 cycloalkyl-O- d_6 alkyl, C3-6 heterocycloalkyl-O-d-e alkyl, C(0)C3-6 cycloalkyl, CN, N=0, C(0)N(Ci-3 alkyl)2, C(0)NH(d_3 alkyl), C(0)0 d_6 alkyl and -C1-6 aminoalkyl;
R26 is Ci_6 alkyl, C3_6 cycloalkyl or is a group selected from moieties provided in Figure-A
Figure imgf000004_0001
Figure-A
wherein, R2 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, -C3_7 cycloalkyl, OH, -OCi_6 alkyl or -NR^R^, wherein R41 and R42 are independently selected from hydrogen or Ci_6 alkyl;
R30 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, -C3_7 cycloalkyl;
or R2 and R30 together forms 4 to 10 membered substituted or unsubstituted mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or
Figure imgf000004_0002
alkyl group; the substitution on carbocyclic or the heterocyclic ring can be selected from -Ci-3 alkyl, -d_3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl or -C(0)NH2;
J is absent or -C(O)-;
G is an electron withdrawing group selected from-C(0)OR4o, -C(0)N(R4o)2, -CN, -NO2, - SO3H, -S(¾N(R4o)2, -SO2R40 wherein R4o at each occurrence is independently selected from hydrogen, -Ci-3 alkyl and -C4_6 cycloalkyl;
T is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or -C(0)-Ci_4 alkyl group; p is an integer selected from 1 and 2;
' { ' is the point of attachment to the rest of molecule;
R31, R32, R33 are independently selected from a group consisting of hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, C3_6 halocycloalkyl, Ci_6 hydroxyalkyl, C3_6 hydroxycycloalkyl, Ci_6 alkyl-0-C3-6 cycloalkyl, CN, C(0)NR34R35, (CH2)rC(0)NR34R35, Ci-β cyanoalkyl, C(0)OH, C(0)OQ_6 alkyl, (CH2)rC(0)OH, (CH2)rC(0)OC1.6 alkyl, (CH2)rNR34R35, C4.7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R36); wherein r is an integer selected from 0 to 4; or R31 and R32 taken together forms a bond;
R34 and R3s are independently selected from hydrogen, Ci_6 alkyl or R34 and R3s together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring;
R36 is selected from hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl and C3_6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen;
R27 and R2g are selected from hydrogen, C1-4 alkyl or R27 and R2g together forms 3 to 6 membered substituted or unsubstituted carbocyclic ring;
B is a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from oxygen, sulfur, nitrogen or -N(R7)- wherein R7 is selected from hydrogen, Ci_6 alkyl or C3_6 cycloalkyl; B is unsubstituted or substituted with one or more groups selected from halogen, OH, NH2, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl or C4_6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur, nitrogen or N(Ci_4 alkyl);
D is 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen wherein when the heteroatom is nitrogen it is optionally substituted with - Ci_6 alkyl or -C3_6 cycloalkyl and wherein D is unsubstituted or substituted with one or more groups selected from halogen, OH, NH2, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl or C4_6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur, nitrogen or N(Ci-4 alkyl); Rj is selected from hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, d_ 6 alkyl-O-d-6 alkyl, C(0)CH=CH2, C(0)0 d-6 alkyl and C4_6 heterocycloalkyl, wherein the heteroatom is selected from oxygen, sulfur, nitrogen or N(Ci-4 alkyl); R2 is selected form a group consisting of hydrogen, d-6 alkyl, C(0)CH20C(0)Ci_3 alkyl, C(0)C(0)Od_6 alkyl, d-6 cycloalkyl, d-6 cycloalkenone and CN; or
Figure imgf000006_0001
Figure- 1
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, d-6 alkyl, d-6 cycloalkyl, d-6 haloalkyl, d-6 halocycloalkyl, d-6 hydroxylalkyl, C3_6 hydroxycycloalkyl, d-6 alkyl-0-C3_6 cycloalkyl, CN, C(0)NR12Ri3, (CH2)nC(0)NR12Ri , d-6 cyanoalkyl, C(0)OH, C(0)Od_6 alkyl, (CH2)nC(0)OH, (CH2)ndO)Od-6 alkyl, (CH2)nNR12R13, C4_7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R14);
wherein n is an integer selected from 1 to 6; or Rg and R taken together forms a bond; Ri2 and R13 are independently selected from hydrogen and d-6 alkyl;
or R12 and R13 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci-3 alkyl;
R14 is selected from hydrogen, d-6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl and C3_6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen;
Rn is selected from a group consisting of hydrogen, Ci_6 alkyl, Ci_6 haloalkyl, cycloalkyl, CN, S02C!_6 alkyl, S02C3-6 cycloalkyl, C(0)OH, C(0)Od_6 alkyl and C(0)NR15R16 wherein RJS and Rj6 are independently selected from Ci_6 alkyl or RJS and Rj6 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring;
X', Y' and Z' are independently selected from CH or N;
Hal is one or more halogen radical;
EWG is selected from a group consisting of C(0)OR17, C(0)N(R17)2, CN, N02, S03H, S02N(R17)2 and S02Rn wherein R17 is selected from hydrogen, Ci_3 alkyl and C4_6 cycloalkyl;
or
R2 is a group selected from
Figure imgf000007_0001
Figure-1 a
wherein, R37 is selected from hydrogen, -Ci_6 alkyl, -C2_6 alkenyl, -C3_7 cycloalkyl, OH, -OCi_6 alkyl or -NR43R44, wherein R43 and R44 are independently selected from hydrogen or Ci_6 alkyl;
R38 is selected from hydrogen, -Cj_6 alkyl, -C2_6 alkenyl, -C3_7 cycloalkyl;
or R37 and R38 together forms 4 to 10 membered substituted or unsubstituted mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or
Figure imgf000007_0002
alkyl group; the substitution on mono- or bi-carbocyclic or the heterocyclic ring is selected from - d_3 alkyl, -Q_3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl or -C(0)NH2; G' is an electron withdrawing group selected from -C(0)OR39, -C(0)N(R 9)2, -CN, -N02, - SO3H, -S02N(R39)2, -SO2R39 wherein R39 at each occurrence is independently selected from hydrogen, -C1-3 alkyl and -C4-6 cycloalkyl;
T' is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or -C(0)-Ci_4 alkyl group; p' is an integer selected from 1 and 2;
' { ' is the point of attachment of R2 with nitrogen atom;
Figure imgf000008_0001
Figure- 2
wherein, R18 and R19 at each occurrence are independently selected from hydrogen, Cj_6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, -C(0)H, C(0)OR, -C(0)N(R)2, -CH=CHC(0)OR, - CH=CHC(0)NRR' , wherein R and R' are independently selected from hydrogen and -Ci_6 alkyl or R and R' together with the nitrogen to which they are attached forms a 5 or 6 membered saturated or unsaturated ring; or Rjg and R19 together forms substituted or unsubstituted 4 to 10 membered mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur and when the heteroatom is nitrogen it is optionally further substituted with Ci_4 alkyl or C(0)Ci_4 alkyl group; the substitution on mono- or bi-cyclic carbocyclic ring or heterocyclic ring is selected from -d_3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl, -C(0)NH2, =0;
R20 and R21 at each occurrence are independently selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl or -C3_7 cycloalkyl or R20 and R21 together forms 4 to 10 membered unsubstituted or substituted mono or bicyclic carbocyclic ring or a 5 or 6 membered unsubstituted or substituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or -C(0)-Ci-4 alkyl group; the substitution on mono- or bicyclic carbocyclic ring or heterocyclic ring is selected from -C1-3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-Ci-3 alkyl, -C(0)NH2, =0.
EWG' is a group selected from C(0)OR22, C(0)N(R22)2, CN, N02, S03H, S02N(R22)2 and S02R22 wherein R22 at each occurrence is independently selected from hydrogen, Ci_3 alkyl and C4_6 cycloalkyl; q is an integer and at each occurrence is independently selected from 1 and 2; ' { ' is the point of attachment of Rj and R2 with nitrogen atom; or, Rj and R2 together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci_3 alkyl;
W, X, Y and Z are independently selected from CH or N; wherein at least one of W, X, Y and Z is CH;
U is a bond or a group selected from a group consisting of oxygen, sulfur, NH, N(Ci-6 alkyl), CH2 and C(O);
V is selected from a group consisting of -C(0)NH-, -C(0)N(d_4 alkyl)-, -NHC(O)-, -N(d_4 alkyl)C(O)-, -C(0)CH2-, -CH2C(0)-, -NHCH2-, -N(Ci-4 alkyl)CH2-, -CH2NH-, -CH2N(d alkyl)-, -SCH2-, -CH2S-, -OCH2-, -CH20-, -S02NH-, -NHS02-, -S02N(d_4 alkyl)-, -N(Ci_4 alkyl)S02-, -CH=CH-, -C≡C-, -C(S)NH-, -C(S)N(d-6 alkyl)-, -NHC(S)-, -N(d-6 alkyl)C(S)- and -C(S)CH2-; R5 is either absent or selected from a group consisting of halogen, Ci_6 alkyl, Ci_6 haloalkyl, C3-6 cycloalkyl, CN, OR23, SR23, S02R23, C(0)OR23, C(0)NR24R25 wherein R23 at each occurrence is independently selected from hydrogen, Ci_4 alkyl, _6 cycloalkyl; R24 and R2s at each occurrence are independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, _7 cycloalkyl or R24 and R2s together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl optionally containing 1 or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or
Figure imgf000010_0001
alkyl group; L is either absent or selected from a group consisting of -CH-, oxygen, sulfur and nitrogen or a moiet selected from the groups provided in Figure-3
Figure imgf000010_0002
Figure-3
wherein ' } ' denotes the point of attachment to the ring and ')' denotes point of attachment of
R4; m is an integer selected from 0 to 3 provided that when L is oxygen, sulfur or nitrogen then m is selected from 2 or 3;
R3 is a group selected from a group consisting of hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, CJS halocycloalkyl, C2-6 hydroxyalkyl, CJS hydroxycycloalkyl and Cj_6 alkyl-O- C3-6 cycloalkyl;
R4 is a group selected from a group consisting of hydrogen, Ci_6 alkyl and C3-6 cycloalkyl and R4 is absent when L is oxygen or sulfur; or R3 and R4 taken together forms a 5 to 8 membered heterocyclic ring; or R3 and R4 taken together forms a group selected from moieties provided in the Figure-4
Figure imgf000010_0003
Figure-4 The compounds of the present invention were found to be potent BTK inhibitors with selectivity over ITK, and can be useful in treatment of the diseases mediated by BTK receptors. DEFINITION
"Salts" according to the invention include those formed with either organic and inorganic acids or bases. Pharmaceutically acceptable acid addition salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, acetic, trifluoroacetic, triphenylacetic, phenylacetic, succinic, oxalic, fumaric, maleic, glutamic, aspartic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic, naphthalenesulphonic or naphthalenedisulphonic, salicylic, glutaric, gluconic, mandelic, cinnamic, ascorbic, oleic, naphthoic, hydroxynaphthoic (for example 1- or 3-hydroxy-2- naphthoic), benzoic, 4-methoxybenzoic, 2- or 4-hydroxybenzoic, 4-chlorobenzoic, 4- phenylbenzoic acids and butane- 1,4-disulfonic acid. Pharmaceutically acceptable base salts include ammonium salts, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. The term "α/AjZ" refers to a saturated hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, either linear or branched and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, w-propyl, 1-methylethyl (isopropyl), «-butyl, «-pentyl and 1,1-dimethylethyl (i-butyl). The alkyl chain may have 1 to 13 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary, all alkyl groups described or claimed herein may be unsubstituted or substituted with groups selected from halogen, -Od-6 alkyl, -OC3-6 cycloalkyl, CN, -C(0)OH, -C(0)0-d_3 alkyl, -C(0)N(-d_3 alkyl), -N02, -S02d-3 alkyl, -S02N-d-3 alkyl, -C(0)-d-3 alkyl.
The numerical in term like "d^ alkyl", refers to the number of carbon atoms; 1 to 4 carbon atoms in the alkyl chain for e.g. in the term "d_4 alkyl".
The term "carbocyclic" refers to non-aromatic mono- or multi-cyclic ring system containing 3 to 10 carbon atoms. The carbocyclic ring may be saturated or unsaturated (i.e. containing one or more double bonds). Unless set forth or recited to the contrary, the carbocyclic ring may be unsubstituted or substituted with the groups selected from -Ci_3 alkyl, -Ci_3 haloalkyl, -CN, -C(0)OH, -C(0)0-C1-3 alkyl, -C(0)NH2, =0 (oxo), or amino. The non-limiting examples of carbocyclic ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.
The term "cycloalkyl" refers to a carbocyclic mono- or multi-cyclic saturated ring system containing 3 to 7 carbon atoms. The non-limiting examples of cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl and the like. Unless set forth or recited to the contrary, all cycloalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "cycloalkenone" refers to a 4 to 7 membered carbocyclic ring containing at least one carbon-carbon double bond and substituted with at least one =0 (oxo) group. The non- limiting examples of cycloalkenone include cyclobutenone, cyclopentenone, cyclohexenone, cycloheptenone or positional isomers thereof.
The term "halo", as used herein refers to halogen radical which includes chloro, fluoro, bromo and iodo. Similarly the term "haloalky refers to halo substituted alkyl. The term "hydroxyalkyl" refers to an alkyl chain substituted with one or more hydroxyl (- OH) groups. The hydroxyl group may be present at any of the chain carbon atoms including the terminal carbon atom.
The term "hydroxycycloalkyl" refers to a cycloalkyl group substituted with one or more hydroxyl (-OH) groups.
The term "aminoalkyl" refers an alkyl chain substituted with one or more amino (-N¾) groups. The amino group may be present at any of the chain carbon atoms including the terminal carbon atom.
The term "heterocyclic " or "heterocycle" refers to substituted or unsubstituted non-aromatic 4 to 10 membered ring radical containing one to four heteroatoms selected from nitrogen, oxygen and sulfur. The heterocyclic ring radical may be a mono-, bi- or tricyclic ring system, which may include fused, bridged or spiro ring systems. In addition, the nitrogen atom may be optionally quarternized; also, unless otherwise constrained by the definition, the heterocyclic ring may optionally contain one or more olefinic bond(s). Examples of such heterocyclic ring radicals include, but are not limited to azepinyl, azetidinyl, benzodioxolyl, benzodioxanyl, chromanyl, dioxolanyl, isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, oxadiazolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, octahydroindolyl, octahydroisoindolyl, perhydroazepinyl, piperazinyl, imidazolidinyl, hexahydropyrimidinyl, pyrrolidinyl, piperidinyl, phenothiazinyl, phenoxazinyl, quinuclidinyl, tetrahydroisquinolyl, tetrahydrofuryl, tetrahydropyranyl, thiazolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide and thiamorpholinyl sulfone. The heterocyclic ring radical may be attached to the main structure through any heteroatom or carbon atom that results in the formation of a stable structure. Unless set forth or recited to the contrary, all heterocyclic ring described or claimed herein may be substituted or unsubstituted.
The term "heterocycloalkyl" refers to a 3 to 9 membered cycloalkyl ring containing one or more heteroatoms. Unless specifically specified, the heteroatom is selected from nitrogen, oxygen and sulfur. The non-limiting examples of heterocycloalkyl group include piperazinyl, piperidinyl, morpholinyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, hexahydroazepinyl, imidazolidinyl, hexahydropyrimidinyl, thiazolidinyl, oxazolidinyl, isooxazolidinyl, thiomorpholinyl and quinclidinyl. Unless set forth or recited to the contrary, all heterocycloalkyl groups described or claimed herein may be substituted or unsubstituted.
The term "alkeny refers to a hydrocarbon chain containing at least one carbon-carbon double bond, and may have (E) or (Z) configuration. An alkenyl group may contain 2 to 8 carbon atoms unless specified otherwise. Non-limiting examples of alkenyl groups include 2- propenyl (allyl), 2-methyl-2-propenyl, and (Z)-2-butenyl. Unless set forth or recited to the contrary, all alkenyl groups described or claimed herein may be straight chain or branched, unsubstituted or substituted with groups selected from halogen, -OCi-6 alkyl, -OC3-6 cycloalkyl, CN, -C(0)OH, -C(0)0-Ci-3 alkyl, -C(0)N(-Ci-3 alkyl), -N02, -SC^C^ alkyl, - S02N-Ci-3 alkyl, -C(0)-Ci-3 alkyl.
The term " halocycloalkyl" refers to a cycloalkyl ring substituted with one or more halogen atoms. The term "cyanoalkyl" refers to an alkyl chain substituted with one or more cyano (-CN) groups. The cyano group may be present at any of the chain carbon atoms including the terminal carbon atom. The term "aryl or aromatic" refers to an aromatic ring containing 6 to 10 carbon atoms. The non-limiting examples of the aryl or aromatic group include phenyl, naphthyl, etc. Unless set forth or recited to the contrary, all aryl or aromatic groups described or claimed herein may be substituted or unsubstituted. The term "heteroaryl" refers to 5 to 10 membered aryl ring containing one or more heteroatoms selected from nitrogen, oxygen or sulfur. The non-limiting examples of the heteroaryl include oxazolyl, isoxazolyl, imidazolyl, furyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, quinolinyl, isoquinolinyl and quinazolinyl.
DETAILED DESCRIPTION OF THE INVENTION
In one aspect, the present I
Figure imgf000014_0001
Formula I
or its stereoisomers and acid addition salts thereof wherein,
A is a group selected from a group consisting of hydrogen, Ci_6 alkyl, C3-6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, N(Ci_6 hydroxyalkyl)2, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl, NHC(0)R26, NHNHC(0)R26, ONHC(0)R26, C(R27R28)NHC(0)R26, NHCSR26, NHNHCSR26, ONHCSR26, C(R27R28)NHCSR26, C(0)NHNHC(0)R26, 4 to 9 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen wherein nitrogen is substituted with R6 and wherein the alkyl and the cycloalkyl group is unsubstituted or substituted with 5 or 6 membered heterocycle containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen. R6 is selected from hydrogen, Q_6 alkyl, C(0)Q_6 hydroxyalkyl, C3-6 cycloalkyl, NH(C3_6 cycloalkenone), Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 alkyl-O-Ci-6 alkyl, C3-6 cycloalkyl-O- d_6 alkyl, C3-6 heterocycloalkyl-O-d-e alkyl, C(0)C3-6 cycloalkyl, CN, N=0, C(0)N(Ci-3 alkyl)2, C(0)NH(d_3 alkyl), C(0)0 d_6 alkyl and -d_6 aminoalkyl.
R26 is Ci_6 alkyl, C3_6 cycloalkyl or is a group selected from moieties provided in Figure-A
Figure imgf000015_0001
Figure-A wherein, R29 is selected from hydrogen, -d-6 alkyl, -C2-6 alkenyl, -C3-7 cycloalkyl, OH, -Od- 6 alkyl or -NR^R^, wherein R41 and R42 are independently selected from hydrogen or d_6 alkyl;
R30 is selected from hydrogen, -d-6 alkyl, -d-6 alkenyl, -C3_7 cycloalkyl;
or R2 and R30 together forms 4 to 10 membered substituted or unsubstituted mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or -CO-d_4 alkyl group. The substitution on carbocyclic or the heterocyclic ring can be selected from -d-3 alkyl, -d_3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl or -C(0)NH2;
J is absent or -C(O)-;
G is an electron withdrawing group selected from -C(0)OR4o, -C(0)N(R4o)2, -CN, -NO2, - SO3H, -S02N(R4o)2, -SO2R40 wherein R4o at each occurrence is independently selected from hydrogen, -Ci-3 alkyl and -C4_6 cycloalkyl;
T is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or -C(0)-Ci_4 alkyl group; p is an integer selected from 1 and 2; '{ ' is the point of attachment to the rest of molecule;
R31, R32, R33 are independently selected from a group consisting of hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, Ci_6 haloalkyl, C3_6 halocycloalkyl, Ci_6 hydroxylalkyl, C3_6 hydroxycycloalkyl, d_ 6 alkyl-0-C3-6 cycloalkyl, CN, C(0)NR34R35, (CH2)rC(0)NR34R35, d-6 cyanoalkyl, C(0)OH, C(0)Od_6 alkyl, (CH2)rC(0)OH, (CH2)rC(0)Od_6 alkyl, (CH2)rNR34R35, C4_7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R36); wherein r is an integer selected from 0 to 4; or R31 and R32 taken together forms a bond thus forming a triple bond;
R34 and R3s are independently selected from hydrogen, d-6 alkyl or R34 and R3s together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring; R36 is selected from hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, d-6 alkyl-0-Ci_6 alkyl, d-6 aminoalkyl and C3_6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen; R27 and R2g are selected from hydrogen, C1-4 alkyl or R27 and R2g together forms 3 to 6 membered substituted or unsubstituted carbocyclic ring;
In one embodiment, when A is a 4 to 9 membered heterocycloalkyl group then the heterocycloalkyl group can be unsubstituted or substituted with a group selected from d-6 alkyl, C(0)Ci-6 hydroxyalkyl, C3-6 cycloalkyl, NH(C3-6 cycloalkenone), Ci-6 haloalkyl, Ci-6 hydroxyalkyl, d-6 alkyl-0-Ci_6 alkyl, C3_6 cycloalkyl-0-Ci_6 alkyl, C3_6 heterocycloalkyl-O- C1-6 alkyl, C(0)C3-6 cycloalkyl, CN, N=0, C(0)N(Ci-3 alkyl)2, C(0)NH(Ci-3 alkyl), C(0)0 d-6 alkyl and -Ci_6 aminoalkyl. In another embodiment, A is selected from a group consisting of d-6 alkyl or 4 to 9 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from oxygen, sulfur or nitrogen wherein nitrogen is substituted with R6 and wherein R6 is selected from hydrogen, d-6 alkyl, C3_6 cycloalkyl, d-6 haloalkyl, d-6 hydroxyalkyl, d-6 alkyl-0-Ci_6 alkyl, -C3_6 cycloalkyl-0-Ci_6 alkyl and -Ci_6 aminoalkyl. In another embodiment, A is selected from a group consisting of Q_3 alkyl, N(Cj_3 hydroxyalkyl)2 or a 6 membered heterocycloalkyl selected from piperidinyl, morpholinyl or piperazinyl, wherein nitrogen of the heterocycloalkyl is substituted with R6; and wherein R6 is selected from a group consisting of hydrogen, Ci_4 alkyl, C(0)Ci_4 hydroxyalkyl, NH(C3_6 cycloalkenone), Ci_3 hydroxyalkyl, Ci_3 alkyl-0-Ci_3 alkyl, C(0)C3_6 cycloalkyl, heterocycloalkyl-O-Ci-3 alkyl, CN, N=0, C(0)N(Ci-3 alkyl)2, C(0)NH(d_3 alkyl) and C(0)Od_3 alkyl. In a preferred embodiment, A is selected from methyl, Z?i5,-(2-hydroxyethyl)amino, piperidinyl, morpholinyl or piperazinyl substituted with methyl, -C(0)cyclopropyl, 2- hydroxyethyl, -NH-cyclopentenone, -C(0)CH(OH)CH2(OH), CN, N=0, methoxyethyl, CONHCH3, CON(CH3)2, C(0)OC2H5 or tetrahydropyranoxyethyl. B is a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from oxygen, sulfur, nitrogen or -N(R7)- wherein R7 is selected from hydrogen, Ci_6 alkyl or cycloalkyl; B is unsubstituted or substituted with one or more groups selected from halogen, OH, NH2, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl or C4_6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur, nitrogen or N(Ci_4 alkyl). Preferably B is thiazolyl.
D is 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen wherein nitrogen is optionally substituted with -Ci_6 alkyl or -C3_6 cycloalkyl and wherein D is unsubstituted or substituted with one or more groups selected from halogen, OH, NH2, Ci-6 alkyl, C3-6 cycloalkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, Ci-6 alkyl-0-Ci_6 alkyl or C4_6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur, nitrogen or N(Ci-4 alkyl).
In one embodiment, D is phenyl unsubstituted or substituted with one or more groups selected from halogen, OH, NH2, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci-6 alkyl-O-Ci-6 alkyl or C4-6 heterocycloalkyl containing 1 or 2 heteroatoms selected form oxygen, sulfur, nitrogen or N(Ci_4 alkyl). In another preferred embodiment, D is phenyl substituted with one or more groups selected from halogen and Ci_3 alkyl. In yet another preferred embodiment, D is 2-chloro-6-methyl -phenyl. Rj is selected from hydrogen, d-6 alkyl, -6 cycloalkyl, d-6 haloalkyl, d-6 hydroxyalkyl, Q_ 6 alkyl-O-Ci-6 alkyl, C(0)CH=CH2, C(0)OCi-6 alkyl and d-6 heterocycloalkyl, wherein the hetero atom is selected from oxygen, sulfur, nitrogen or N(Ci_4 alkyl).
R2 is selected from a group consisting of hydrogen, d-6 alkyl, C(0)CH20C(0) d-3 alkyl, C(0)C(0)Od_6 alkyl, d-6 cycloalkyl, d-6 cycloalkenone and CN;
R2
Figure imgf000018_0001
Figure- 1
wherein Rg, R9, Rjo at each occurrence are independently selected from a group consisting of hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, Ci-6 haloalkyl, C3-6 halocycloalkyl, Ci-6 hydroxylalkyl, C3-6 hydroxycycloalkyl, d-6 alkyl-0-C3-6 cycloalkyl, CN, C(0)NR12Ri3, (CH2)nC(0)NR12Ri , d-e cyanoalkyl, C(0)OH, C(0)Od_6 alkyl, (CH2)nC(0)OH, (CH2)nC(0)Od_6 alkyl, (CH2)nNR12R13 and C4-7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R14) and n is an integer selected from 1 to 6. Rg and R taken together can also form a bond thus forming a triple bond.
R12 and R13 at are independently selected from hydrogen and d_6 alkyl; or R12 and R13 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen, wherein the heterocyclic ring is unsubstituted or substituted with d-3 alkyl.
Ri4 is selected from hydrogen, d-6 alkyl, C3-6 cycloalkyl, d-6 haloalkyl, d-6 hydroxyalkyl, d_6 aikyl-0-d_6 alkyl, d_6 aminoalkyl and C3_6 cycloaikyl-O-d-6 alkyl. The alkyl and the cycloalkyl groups can be optionally fruther substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen. Rn is selected from a group consisting of hydrogen, Cj_6 alkyl, Cj_6 haloalkyl, C3_6 cycloalkyl, CN, SO2C1-6 alkyl, SO2C3-6 cycloalkyl, C(0)OH, C(0)0 Ci-e alkyl and C(0)NR15Ri6. R15 and Rj6 are independently selected from Ci_6 alkyl or RJS and Rj6 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring.
X', Y' and Z' are independently selected from CH or N, thus forming an aryl or heteroaryl ring containing 1 to 3 nitrogen atoms. Hal is one or more halogen radical, preferably, chlorine or bromine.
EWG is selected from a group comprising of C(0)OR17, C(0)N(R17)2, CN, N02, S03H, S02N(R17)2 and SO2R17 wherein R17 at each occurrence is independently selected from hydrogen, Ci_3 alkyl and C4_6 cycloalkyl. R2 can also be a group selec la
Figure imgf000019_0001
Figure-1 a
wherein, R37 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, -C3_7 cycloalkyl, OH, -OCi_ 6 alkyl or -NR^R^, R43 and R44 are independently selected from hydrogen or Ci_6 alkyl; R38 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, -C3_7 cycloalkyl;
or R37 and R38 together forms 4 to 10 membered substituted or unsubstituted mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or -C(0)-Ci_4 alkyl group. The substitution on mono- or bi-carbocyclic or the heterocyclic ring can be selected from -d_3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl or -C(0)NH2.
G' is an electron withdrawing group selected from -C(0)OR39, -C(0)N(R39)2, -CN, -NO2, - SO3H, -S02N(R39)2, -SO2R39 wherein R39 at each occurrence is independently selected from hydrogen, -Ci-3 alkyl and -C4_6 cycloalkyl; T' is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Cj_4 alkyl or -C(0)-Q_4 alkyl group; p' is an integer selected from 1 and 2;
' { ' is the point of attachment of I¾ with nitrogen atom;
Figure imgf000020_0001
Figure- 2
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, Ci_6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, -C(0)H, C(0)OR, -C(0)N(R)2, -CH=CHC(0)OR, - CH=CHC(0)NRR' ; wherein R and R' are independently selected from hydrogen and -Ci_6 alkyl or R and R' together with the nitrogen to which they are attached forms a 5 or 6 membered saturated or unsaturated ring.
Rjg and Rjg may together form substituted or unsubstituted 4 to 10 membered mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur and when the heteroatom is nitrogen it is optionally further substituted with Ci_4 alkyl or C(0)Ci_4 alkyl group. The substitution on mono- or bicyclic carbocyclic ring or heterocyclic ring is selected from -d_3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl, -C(0)NH2, =0.
R20 and R21 at each occurrence are independently selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl or -C3_7 cycloalkyl. R20 and R21 may together form a 4 to 10 membered unsubstituted or substituted mono or bicyclic carbocyclic ring or a 5 or 6 membered unsubstituted or substituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with C1-4 alkyl or C(0)Cj alkyl group; the substitution on mono- or bicyclic carbocyclic ring or heterocyclic ring is selected from -C1-3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-Ci-3 alkyl, -C(0)NH2, =0. EWG' is a group selected from C(0)OR22, C(0)N(R22)2, CN, N02, S03H, S02N(R22)2 and S02R22 wherein R22 at each occurrence is independently selected from hydrogen, C1-3 alkyl and C4_6 cycloalkyl; q is an integer and at each occurrence is independently selected from 1 and 2.
' { ' in Figure-2 is the point of attachment of Rj and R2 with nitrogen atom; A person skilled in the art would understand that when Rj and R2 together forms a group selected from the groups provided in Figure-2, Rj and R2 would together with nitrogen atom to which they are attached actually forms imino or heterocylyl group containing nitrogen
Figure imgf000021_0001
W, X, Y and Z are independently selected from CH or N; wherein at least one of W, X, Y and Z is CH, thus forming an aryl or a heteroaryl ring containing 1 to 3 nitrogen atoms.
In a preferred embodiment, W is CH and X, Y & Z all is N thus forming a triazine ring. In another preferred embodiment, W is CH, X is N, Y is CH and Z is N thus forming a pyrimidine ring. In another preferred embodiment, W is CH, X is N, Y is N and Z is CH thus forming a pyrimidine ring. In yet another preferred embodiment, W is CH, X is CH, Y is N and Z is N thus forming a pyrimidine ring.
In a preferred embodiment, W is CH and group A is substituted on W.
U is a bond or a group selected from a group consisting of oxygen, sulfur, NH, N(Ci-6 alkyl), CH2 and -C(O)-. In a preferred embodiment, U is NH.
V is selected from a group consisting of -C(0)NH-, -C(0)N(Ci_4 alkyl)-, -NHC(O)-, -N(d_4 alkyl)C(O)-, -C(0)CH2-, -CH2C(0)-, -NHCH2-, -N(Ci-4 alkyl)CH2-, -CH2NH-, -CH2N(d alkyl)-, -SCH2-, -CH2S-, -OCH2-, -CH20-, -S02NH-, -NHS02-, -S02N(d_4 alkyl)-, -N(Ci_4 alkyl)S02-, -CH=CH-, -C≡C-, -C(S)NH-, -C(S)N(d_6 alkyl)-, -NHC(S)-, -N(d_6 alkyl)C(S)- and -C(S)CH2-. In a preferred embodiment, V is -C(0)NH-.
R5 is either absent or selected from a group consisting of halogen, Ci_6 alkyl, Ci_6 haloalkyl, C3-6 cycloalkyl, CN, OR23, SR23, S02R23, C(0)OR23, C(0)NR24R25 wherein R23 at each occurrence is independently selected from hydrogen, Ci_4 alkyl, C3_6 cycloalkyl; R24 and R2s at each occurrence are independently selected from hydrogen, Ci_6 alkyl, C2_6 alkenyl, C3_7 cycloalkyl or R24 and R2s together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl optionally containing 1 or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or
Figure imgf000022_0001
alkyl group. In a preferred embodiment, R5 is absent.
L is either absent or selected from a group consisting of -CH-, oxygen, sulfur and nitrogen or a moiet selected from the groups provided in Figure-3
Figure imgf000022_0002
Figure-3
wherein ' } ' in Figure-3 denotes the point of attachment to the ring (the central ring in Formula I) and ')' denotes point of attachment of R4. Thus, '[' in the Figure-3 represents the point of attachment of chain connected to the hydrazine moiety. m is an integer selected from 0 to 3 provided that when L is oxygen, sulfur or nitrogen then m is selected from 2 or 3. A person skilled in the art will recognize that the compounds having m as 0 or 1 and L as oxygen, sulfur or nitrogen may result into unstable compounds which are excluded from the scope of the present claims. R3 is a group selected from a group consisting of hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, C3_6 halocycloalkyl, C2_6 hydroxyalkyl, C3_6 hydroxycycloalkyl and Ci_6 alkyl-O- C3_6 cycloalkyl. R4 is a group selected from a group consisting of hydrogen, d-6 alkyl and -6 cycloalkyl and a person skilled in the art will recognize that when L is oxygen or sulfur, the valency does not permit any substitution and thus R4 is absent when L is oxygen or sulfur. R3 and R4 taken together, along with the atoms (nitrogen and L, respectively) to which they are attached and the linker chain between L and the hydrazine group can also form a 5 to 8 membered heterocyclic ring; or R3 and R4 taken together forms a group selected from moieties provided in the Figure-4
Figure imgf000023_0001
Figure-4
In a preferred embodiment, the present invention provides a compound of Formula I or its stereoisomers and acid addition salts thereof, wherein
A is a group selected from a group consisting of Ci_3 alkyl, N(Ci_3 hydroxyalkyf or a 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen and nitrogen, wherein nitrogen is substituted with R6 and wherein R6 is selected from hydrogen, Ci_4 alkyl, C(0)Ci_6 hydroxyalkyl, NH(C3_6 cycloalkenone), Ci_3 hydroxyalkyl, Ci_3 alkyl-O- d_3 alkyl, C3-6 heterocycloalkyl-O-d-3 alkyl, C(0)C3-6 cycloalkyl, CN, N=0, C(0)N(Ci-3 alkyl)2, C(0)NH(d_3 alkyl) and C(0)OCi-3 alkyl;
B is thiazolyl;
D is phenyl unsubstituted or substituted with one or more groups selected from halogen or d- 6 alkyl;
Ri is selected from hydrogen, d-6 alkyl, C(0)CH=CH2 or C(0)OCi-4 alkyl;
R2 is selected from a group consisting of hydrogen, C(0)CH20C(0)Ci-3 alkyl, C(0)C(0)Od_3 alkyl, C3-6 cycloalkenone and CN; or R2 is a moiety selected from the following groups
Figure imgf000024_0001
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, Ci_6 alkyl, C(0)OH, (CH2)nNR12R13,
wherein n is an integer selected from 1 to 3;
or Rg and R taken together forms a bond;
Rj2 and Rj3 are together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci-3 alkyl;
R11 is hydrogen;
X' , Y' and Z' are independently selected from CH or N;
Hal is one or more halogen radical; preferably chlorine or bromine.
or, Rj and R2 together forms a group selected from
Figure imgf000024_0002
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, Ci_3 alkyl, C2-3 alkenyl, C3_6 cycloalkyl, -C(0)H, C(0)OR, wherein R is hydrogen or -C1-3 alkyl;
R20 and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom; or, Rj and R2 together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or C1-3 alkyl;
W is CH, and X, Y and Z are independently selected from CH or N; U is NH;
V is -C(0)NH-;
R5 is absent; L is either absent or nitrogen;
m is an integer selected from 2 or 3;
R3 is hydrogen;
R4 is a group selected from a group consisting of hydrogen, Ci_6 alkyl and cycloalkyl and R4 is absent when L is oxygen or sulfur; or R3 and R4 taken together forms a 5 or 6 membered heterocyclic ring.
In another embodiment, the present invention provides a compound of Formula I, wherein L is nitrogen and R3 and R4 taken together with the nitrogen and L to which they are attached respectively, forms a 5 or 6 membered heterocyclic ring. In another embodiment, the heterocyclic ring is selected from piperazinyl, imidazolidinyl or hexahydropyrimidinyl. In a preferred embodiment, the heterocyclic ring is piperazinyl. In another embodiment, the present invention provides a compound of Formula I, wherein Ri is selected from a group consisting of hydrogen, Ci_6 alkyl, C(0)CH=CH2 or
Figure imgf000025_0001
alkyl;
R2 is selected form a group consisting of hydrogen, cycloalkenone, C(0)CH20C(0)Ci_3
Figure imgf000025_0002
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, Ci_3 alkyl, C(0)OH, (CH2)nNR12R13,
wherein n is an integer selected from 1 to 3;
or Rg and R taken together forms a bond;
R12 and Rj3 are together with the nitrogen atom to which they are attached forms a 6 membered heterocyclic ring optionally containing 1 additional heteroatom selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci_3 alkyl;
R11 is hydrogen;
X', Y' and Z' are independently selected from CH or N;
Hal is one or more halogen radical; or, Rj and R2 together forms a group selected from
Figure imgf000026_0001
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, Ci_3 alkyl, C2-3 alkenyl, cycloalkyl, -C(0)H, C(0)OR, wherein R is hydrogen or -Ci_3 alkyl;
R20 and R2i at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom;
or, Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci-3 alkyl.
In a preferred embodiment, Rj is hydrogen, methyl or C(0)OC2H5 and R2 is selected from hydrogen, cyclopentenone, C(0)CH2OC(0)CH3, C(0)C(0)OC2H5, CN,
Figure imgf000026_0002
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, methyl, C(0)OH, (CH2)„N i2Ri3,
wherein n is 1 and R12 and R13 together with the nitrogen atom to which they are attached forms a 6 membered heterocyclic ring containing 1 additional nitrogen atom substituted with methyl; preferably the heterocyclic ring is piperazinyl;
or Rg and R taken together forms a bond;
R11 is hydrogen;
X', Y' and Z' are independently selected from CH or N;
Hal is a halogen radical, preferably chlorine or bromine;
or, Rj and R2 together forms a group selected from
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, methyl, ethylene, cyclopropyl, -C(0)H, C(0)OR, wherein R is hydrogen or methyl;
R20 and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom.
or, Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with methyl.
In another embodiment, the present invention provides a compound of Formula I, wherein L is absent, m is 0, R3 is hydrogen, Ri is selected from a group consisting of hydrogen, Ci-6 alkyl, C(0)CH=CH2 or C(0)OCi_4 alkyl and R2 is selected form a group consisting of hydrogen, C(0)CH2OC(0)C!_3 alkyl, C(0)C(0)OCi-3 alkyl;
or R2 is a moiety selected from the following groups:
Figure imgf000027_0001
wherein Rs, R9, Rio are independently selected from a group consisting of hydrogen, Ci-6 alkyl, C(0)OH,
Figure imgf000027_0002
wherein n is an integer selected from 1 to 3;
or Rg and R taken together forms a bond;
Rj2 and Rj3 are together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci-3 alkyl;
X', Y' and Z' are independently selected from CH or N;
Hal is one or more halogen radical;
or, Rj and R2 together forms a group
Figure imgf000027_0003
R20 and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom; or Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci-3 alkyl. In another preferred embodiment, the present invention provides a compound of Formula I, wherein L is absent, m is 0, R3 is hydrogen, Rj is selected from a group consisting of hydrogen, methyl, C(0)CH=CH2, C(0)0¾u, C(0)OC2H5 and R2 is selected from a group consisting of hydrogen, C(0)CH2OC(0)CH3, C(0)C(0)OC2H5, C(0)CH=CH2, or group
Figure imgf000028_0001
wherein Hal is halogen radical, preferably chlorine or bromine;
or Rj and R2 together form a group
Figure imgf000028_0002
wherein ' { ' is the point of attachment of Ri and R2 with nitrogen atom;
or Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with methyl.
The compounds of the present invention can be used as selective agents as inhibitors of BTK either alone or in combination with other related kinases inhibitors, or any other appropriate drugs. Thus the compound of present invention finds use in treating cancer, particularly in haematological malignancies such as chronic lymphocytic leukaemia (CLL), mantle cell lymphoma (MCL), follicular lymphoma (FL) or even disorder such as diffused large B-cell lymphoma (DLBCL) etc., in which the activated B-cell need to be controlled or the proliferation needs to be down regulated. In an embodiment, the compounds of Formula I (wherein L is nitrogen, m is 2 and R3 and R4 taken together with the nitrogen and L to which they are attached, respectively, forms piperazinyl ring) can be prepared by any of the following methods as described in Scheme 1.
Figure imgf000029_0001
Formula I
(Wherein L is nitrogen, m is 2 and R3 and R4 together with the nitrogen and L to which they are attached respectively, forms piperazinyl ring)
Scheme 1 The groups A, B, D, U, V, Ri, R2, R5, W, X, Y, Z in the Scheme 1 are as defined earlier in the specification for the compound of Formula I; LG represents a leaving group such as halogen or an alkanesulfonate (mesylate, triflate, nonaflate and the like) or arylsulfonate (tosylate, brosylate and the like); PG represents an amino protecting group such as tert- butyloxycarbonyl (Boc), fluorenylmethyloxycarbonyl (Fmoc) or carboxybenzyl (Cbz).
As shown in Scheme 1, the compound of Formula (l.a) can be converted to the compound of Formula (l.b) by coupling reaction with compound of Formula (l.e) in presence of a suitable base. The compound of Formula (l.b) can be converted to the compound of Formula (l.d) by coupling it with protected or unprotected piperazine in presence of a suitable base. Alternatively, the compound of Formula (l.d) can also be prepared by coupling reaction of compound of Formula (l.a) with protected or unprotected piperazine in presence of a suitable base to obtain the compound of Formula (l.e) followed by further coupling reaction with the compound of Formula (l.e) in presence of a suitable base. A skilled artisan can select a suitable solvent and other reaction conditions such as temperature, base, time, etc., depending on the starting material. For e.g. the coupling reaction can be carried out in polar aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetone, N-methylpyrrolidine, acetonitrile, 1,4-dioxane, or non-polar solvent such as toluene, xylene, dichloromethane, tetrahydrofuran (THF) or polar solvent such as water or mixtures thereof. The compound of Formula (l.d) thus formed can be converted to compound of Formula I on subsequent reactions, for e.g. the compound of Formula (l.d) can be deprotected and converted into corresponding nitroso compound under the condition known to skilled artisan. The nitroso derivative thus formed can be reduced under mild condition to obtain the hydrazines of the interest.
In another embodiment, the directly attached hydrazino-aromats (Compound of Formula I, wherein L is absent and m is 0) can be prepared by any of the following methods as described
Figure imgf000030_0001
Formula I
(Wherein L is absent and m is 0)
Scheme 2
The groups A, B, D, U, V, Rj, I¾, R3, R5, W, X, Y, Z in the Scheme 2 are as defined earlier in the specification for the compound of Formula I; LG is a leaving group and PG is an amino protecting group as described earlier in the specification.
As shown in Scheme 2, the compound of Formula (l.a) can be converted to the compound of Formula (l.b) by the coupling reaction with compound of (l.e) in presence of a suitable base. The compound of Formula (l.b) can be converted to the compound of Formula (2.b) by coupling it with suitably substituted hydrazine in presence of a suitable base. Alternatively, the compound of Formula (2.b) can also be prepared by coupling the compound of Formula (l.a) with suitably substituted hydrazine in presence of a suitable base to obtain the compound of Formula (2.a) followed by further coupling reaction with the compound of Formula (l .e) in presence of a suitable base. A skilled artisan can select a suitable solvent and other reaction conditions such as temperature, base, time, etc., depending on the starting material. For e.g. these coupling reactions can be carried out in polar aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide, N,N-dimethylacetamide, acetone, N- methylpyrrolidine, acetonitrile, 1 ,4-dioxane, or non-polar solvent such as toluene, xylene, dichloromethane, tetrahydrofuran (THF) or polar solvent such as water or mixtures thereof. The compound of Formula (2.b) thus formed can be converted to compound of Formula I on subsequent reactions, for e.g. deprotection and/or treatment with other electrophiles. In yet another embodiment, the central aromatic ring can be substituted sequentially to obtain other functionalized compounds of interest as shown in Scheme 3.
Figure imgf000031_0001
Formula I
Scheme 3
The LGs can successively be replaced with chosen amines or other nucleophiles of interest which fall under the described definitions of the compound of Formula I. This may involve direct displacements or coupling reactions such as Buchwald using organometallic chemistry procedures familiar to those skilled in the art.
In another embodiment, some of the compounds of Formula I (wherein L is -CH-, nitrogen, oxygen or sulfur; m is 2 and R3 and R4 are hydrogen or Ci_6 alkyl) can be synthesized by the method as shown in Scheme 4 below:
Figure imgf000032_0001
Formula I
(Wherein L is -CH-, nitrogen, oxygen or sulfur; m is
2 and R3 and R4 are hydrogen or C, _6 alkyl)
Scheme 4
The groups A, B, D, U, V, R R2, R5, W, X, Y, Z in Scheme 4 are as defined earlier in the specification for the compound of Formula I; LG is a leaving group as defined earlier in the specification and 'PC is a hydroxyl protecting group such as methoxymethyl (MOM), tetrahydropyranyl (THP), 2-methoxyethoxymethy (MEM), benzyl, trityl, etc. When L is selected from oxygen or sulfur M represents metal ion such as Li/Na/K or MgX; when L is CH then M represents MgX; and when L is nitrogen then M represents hydrogen or an alkyl group.
Accordingly, the intermediate (l.b) can be treated with the compound of Formula (4. a) to form compound of Formula (4.b). The compound of Formula (4.b) on deprotection gives free hydroxyl derivative of compound of Formula (4.c). The free hydroxyl group of the compound of Formula (4.c) can be transformed to a better leaving group such as an alkylsulfonate leaving group as shown in compound of Formula (4.d). The compound of Formula (4.d) on displacement reaction with the compound of Formula (4.f) and on subsequent reactions can be converted into the compound of Formula I. Hydrazines prepared as per the above methods described in Schemes 1 to 4 (wherein Rj and R2 are hydrogen), can be treated with suitable electrophilic compounds to afford compounds of Formula I. Some of the representative electrophilic compounds are provided in Figure-5. The electrophilic compound may require some functional modifications depending upon the type of the substitution on them which are under the purview of a person skilled in the art.
Figure imgf000033_0001
Figure-5
Ar in Figure-5 is an aryl group and Het.Ar is a heteroaryl group; Ra and R at each occurrence are independently hydrogen, -Ci_6 alkyl and -Cj,.(, cycloalkyl; Q is heteroatom selected from oxygen, sulfur or nitrogen.
In another embodiment, the hydrazines prepared as per the process provided in Schemes 1 to 4 (wherein Ri and R2 are hydrogen) were treated with aromatic electrophiles to obtain N-aryl/ heteroarylhydrazines belonging to Formula I. Some of the representative aromatic electrophilic compounds are provided in Figure-6. The aromatic electrophilic compound may also require some functional modifications depending upon the type of the substitution on them and such modifications are under the purview of a person skilled in the art.
Figure imgf000034_0001
Figure-6
Rc in Figure-6 is -Ci-6 alkyl.
In yet another embodiment, the hydrazines prepared according to the methods described above (Scheme 1 to 4, wherein Rj and R2 are hydrogen) can be treated with substrates containing aldehydes and ketones having either saturated or unsaturated functionalities as condensing agents to obtain the hydrazone compounds belonging to Formula I. Representa
Figure imgf000034_0002
Figure-7
Rd in Figure-7 is -Ci_6 alkyl.
Few representative compounds of Formula I are presented in Table 1. In case of conflict between the chemical structure and the chemical name provided in the specification, the chemical structure is determinative of the identity of the compound. Table 1
Figure imgf000035_0001
1.13 2-[2-Methyl-6-(4-propynoylamino-piperazin-l-yl)- pyrimidin-4-yl-amino]-thiazole-5-carboxylic acid (2- chloro-6-methylphenyl)amide
1.14 2- [2-Methyl-6-(4-( 1 -oxo-but-2- ynyl-aminopiperazin- 1 - yl)-pyrimidin-4-yl-amino]thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide
1.15 2-{6[4-Cyclopropanecarbonylamino-piperazin-l-yl]-2- methyl-pyrimidin-4-ylamino}-thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide
1.16 2-(6 { 4- [Cyclopropyl-ethylidene-amino] piperazin- 1 - yl}-2-methyl-pyrimidin-4-yl-amino)-thiazole-5- carboxylic acid (2-chloro-6-methylphenyl)amide
1.17 2-[2-Methyl-6-(4-{6-[prop-2-en-yl-ene- aminopiperazin-l-yl)pyrimidin-4-yl-amino]thiazole-5- carboxylic acid (2-chloro-6-methylphenyl)amide
1.18 2- [6-(4- { [ 1 -Cyclopropyl— methyl- idene]amino}piperazin-l-yl)-2-methyl-pyrimidin-4- ylamino]thiazole-5-carboxylic acid (2-chloro-6- methylphenyl)amide
1.19 2-(4- { 6-[5-(2-Chloro-6-methylphenyl- carbamoyl)thiazol-2-yl-amino]-2-methyl-pyrimidin-4- yl}piperazin-l-ylimino)-propionic acid methyl ester
1.20 2-(4- { 6-[5-(2-Chloro-6-methylphenyl- carbamoyl)thiazol-2-yl-amino]-2-methyl-pyrimidin-4- yl Jpiperazin- l-ylimino)-propionic acid
1.21 2- [-6-(4-Ethenesulf onylaminopiperazin- 1 -yl)-2- 1 o CL methylpyrimidin-4-yl-amino]-thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide
1.22 2- [2-(Ν' ,Ν' -Diacroloylhydrazino)-6-(4- methylpiperazin- 1 -yl)pyrimidin-4-ylamino] thiazole-5 - carboxylic acid (2-chloro-6-methylphenyl)amide
1.23 2- { 2-Methyl-6-[4-(3-oxo-cyclopent- 1- enylamino)piperazin- 1 - yl] -pyrimidin-4- ylamino}thiazole-5-carboxylic acid (2-chloro-6- methylphenyl)amide
1.24 W-Acryloyl-W-[4-[5-(2-chloro-6-methyl- phenylcarbamoyl)-thiazol-2-ylamino]6-(4- methylpiperazin-l-yl)pyrimidin-2- yl]hydrazinecarboxylic acid rert-butyl ester
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Compound no. 1.11, 1.16, 1.17, 1.18, 1.19 and 1.20 are obtained as a mixture of (E) and (Z) isomers. Experimental:
The following specific and non-limiting examples are to be considered in all respect as illustrative and are not intended to limit the scope of the claimed invention.
Example 1 : 2-(2-Methyl-6-piperazin-l-yl-pyrimidin-4-yl-amino)thiazole-5-carboxylic acid (2- hloro-6-methylphenyl)amide (IB)
Figure imgf000039_0002
A mixture of compound 1A (5.08 mmol), piperazine (6.0 g), diisopropylethylamine (12.7 mmol) and N-methyl-2-pyrolidinone (10 mL) was stirred at 120 °C for 2.5 h. The mixture was cooled at room temperature and diluted slowly with water (150 mL) to precipitate the product. The solid was collected by filtration and rinsed with water to afford the title compound IB.
Example 2: 2-[2-Methyl-6(4-nitroso-piperazin-l-yl-pyrimidin-4-yl-amino]-thiazole-5- carboxylic acid (2-chloro-6-methylphenyl)amide (1C)
Figure imgf000040_0001
To a stirred solution of compound IB (4.51 mmol) in glacial acetic acid (10 mL) was added an aqueous solution of sodium nitrite (11.2 mmol) drop wise at 0-5 °C. The reaction was stirred for 2 h at 0-5 °C, then warmed up to room temperature and maintained for 1 h. The reaction mixture was diluted slowly with water and the solid separated was collected by filtration and rinsed with extra water to afford the compound 1C.
Example 3: 2-[6-(4-Aminopiperazin-l-yl)2-methyl-pyrimidin-4-yl-amino]thiazole-5-
Figure imgf000040_0002
To a stirred solution of compound 1C (4.23 mmol) in glacial acetic acid (10 mL) was added zinc powder (16.92 mmol) at 0-5 °C and the reaction was stirred for 2 h at 0-5 °C. The reaction contents were warmed up to room temperature and maintained for 1 h. The reaction mass was diluted slowly with 10 % sodium hydroxide solution (20 mL). The solid was filtered, extracted in dichlorome thane and the crude product was purified by flash chromatography on silica gel (elution with 10 % methanol in dichloromethane) to get target compound ID.
Example 4 : 2- [6- (4- Acryloylaminopiperazin- 1 -yl)-2-methylpyrimidin-4-yl- amino]thiazole-5-carbo-xylic acid (2-chloro-6-methylphenyl)amide (1.1)
Figure imgf000040_0003
a stirred mixture of compound ID (0.38 mmol) and triethylamine (0.76 mmol) in DMF (5 mL) at 0-5 °C was added a solution of acryloyl chloride (0.49 mmol) in dichloromethane slowly and was stirred for 1 h. After completion the solvents were evaporated under reduced pressure at 50 °C and the crude product was purified by flash chromatography on silica gel (elution with 10 % methanol in dichloromethane) to get 1.1 as off white solid.
Under similar reaction conditions, compounds 1.13, 1.14, 1.15 and 1.21 presented in Table 1 were prepared by treating ID with the reagents propynoyl chloride, 2-butynoyl chloride, cyclopropanoyl chloride and vinyl sulphonyl chloride respectively in place of acryloyl chloride.
Example 5: 2-(4-{6-[5-(2-chloro-6-methylphenylcarbamoyl)thiazol-2-yl-amino]- 2methylpyrimidin-4-yl}-piperazin-l-ylmino)propionic acid (1.20)
Figure imgf000041_0001
A mixture of compound ID (0.21 mmol) and pyruvic acid (0.26 mrnol) in methanol (10 mL) was stirred at 50 °C for 15 h, cooled at room temperature and then evaporated under reduced pressure. The precipitated product was stirred in methanol and the solid was collected by filtration to get target compound 1.20 as pale yellow solid.
Other compounds of interest such as 1.11, 1.16 to 1.19, 1.29, 1.30 and 1.32 were prepared by similar procedures as described in examples 1 to 5 using appropriate starting material. Example 6: 2-(6-Hydrazino-2-methylpyrimidin-4-ylamino)thiazole-5-carboxylic acid (2- chloro-6-meth
Figure imgf000041_0002
To a stirred solution of compound 1A (2.53 mmol) and N,N-diisopropylethylamine (5.07 mmol) in N,N-dimethylacetamide (5 mL) was added hydrazine hydrate (17.7 mmol) at room temperature. The mixture was stirred at 90 °C for 2 h and cooled to room temperature. Later it was quenched in water (50 ml), filtered, washed with water and dried under reduced pressure. The crude product was leached with methanol, filtered and dried to provide compound 2B. Example 7: 2-[6-(2,5-Dioxo-2,5-dihydro-pyrrol-lyl-amino)-2-methylpyrimidin-4- ylamino]thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide (1.5)
Figure imgf000042_0001
2B 1.5
A mixture of compound 2B (1.28 mmol) and maleic anhydride (1.28 mmol) in acetic acid (10 mL) was stirred at 120 °C for 4.5 h. The reaction mass was cooled and then evaporated under reduced pressure at 50 °C. The residue was stirred in methanol and the solid was collected by filtration to get 1.5. Example 8: 2-{6-[N-(2-Chloro-5-fluoropyrimidin-4yl)hydrazino]-2-methylpyrimidin-4- l-amino)-thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide (1.12)
Figure imgf000042_0002
A mixture of compound 2B (0.53 mmol), 2,4-dichloro-5-fluoropyrimidine (0.59 mmol) and diisopropylethylamine (1.18 mmol) in DMF (3 mL) was stirred at 50 °C for 3 h. The mixture was cooled at room temperature and diluted slowly with water (20 mL) to precipitate the product. The precipitated product was stirred in ethyl acetate and the white solid was collected by filtration to get compound 1.12.
Other compounds of interest such as 1.3, 1.4, 1.9 and 1.10 were prepared similarly as per the procedures described in example 6 and 8 using appropriate starting materials.
Example 9: 2-(4,6-Dichloro-[l,3,5]-triazinamino)thiazole-5-carboxylic acid (2-chloro-6- methyl-phenyl)
Figure imgf000042_0003
To a suspension of cyanuric chloride (16.2 mmol) in acetone (30 mL) and ice at 0 °C was added a solution of 2-amino-thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide (14.60 mmol) in acetone (30 mL). At the end of the reaction, the pH of the solution was made alkaline with 5 % aqueous sodium bicarbonate (30 mL). The precipitate obtained was filtered, washed with water and dried under reduced pressure to give 3A. This was used in the next step without further purification.
Example 10: 2-(4-Chloro-6-{4-[2-(tetrahydropyran-2-yloxy)ethyl]piperazin-l-yl}[l,3,5]- triazine-2-y -amino)thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide (3B)
Figure imgf000043_0001
3A 3B
Compound 3A (6.99 mmol) was dissolved in a solution of tetrahydrofuran (50 mL), acetone (5 mL) and water (5 mL) at 0 °C. To this solution was added l-[2-(tetrahydropyran-2- yloxy)ethyl]piperazine (6.99 mmol), followed by 5 % aqueous sodium bicarbonate (13 mL). The progress of reaction was monitored by TLC and the solution was diluted with water and extracted into ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel (elution with 10 % methanol in dichloromethane) to provide 3B. Example 11: 2-(4-Hydrazino-6-{4-[2-(tetrahydropyran-2-yloxy)ethyl]piperazin-l-yl}- [l,3,5]-triazine-2-yl-amino)thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide
(3C)
Figure imgf000043_0002
To a solution of compound 3B (0.8 mmol) in DMF (5 mL) at room temperature was added hydrazine hydrate (1.2 mmol), followed by triethylamine (1.2 mmol). The mixture was stirred until the reaction was complete. The reaction mixture was concentrated and triturated with water, filtered, washed with water and dried to afford the intermediate 3C. Example 12: 2-(4-(N'-Acryloylhydrazino)-6-{4-[2-(tetrahydropyran-2-yloxy)ethyl]- piperazin-l-yl}-[l,3,5]-triazin-2-yl-amino)-thiazole-5-carboxylic acid (2-chloro-6-
Figure imgf000044_0001
The compound 1.6 was prepared by the same process as described for the compound 1.1 in example 4 wherein the compound 3C was used instead of the compound ID.
Other compounds of interest such as 1.7, 1.8, 1.25, 1.34 to 1.36, 1.39 to 1.41, 1.43 to 1.47 presented in Table 1 were prepared by similar sequence of reactions provided in examples 9 to 12 using appropriate starting material.
Example 13: 2-{4-(N'-Acrolylhydrazino)-6-[4-(2-hydroxyethyl)piperazin-l-yl]-[l,3,5]- tri
Figure imgf000044_0002
3C 3D
To solution of compound 3C in methanol (0.09 mmol) at room temperature was added concentrated HC1 (0.06 ml) and stirred at 60°C until the reaction was complete detected by TLC. Then, concentration and trituration of the residue with ethyl acetate produced a solid which was filtered, washed with diethyl ether and dried to obtained compound 3D as hydrochloride salt.
Example 14: 2-{4-[4-(2-Hydroxyethyl)piperazin-l-yl]-6-[N'-(l-oxo-but-2-ynyl)- hydrazino]-[l,3,5]-triazin-2-ylamino}-thiazole-5-carboxylic acid (2-chloro-6-methyl- phenyl)amide (1.26)
Figure imgf000045_0001
Starting from the compound of Formula 3D, the compound 1.26 was prepared by the same process as described for the compound 1.1 in example 4 wherein butynoic acid was used instead of acryloyl chloride.
Other compounds of interest such as 1.27, 1.28, and 1.33 were prepared by similar sequence of reactions as provided in examples 13 and 14 using appropriate starting material.
Example 15: 2-[4-Chloro-6-(4-methylpiperazin-l-yl)-[l,3,5]-triazine-2-ylamino]- thiazole-5-carbox lic acid (2-chloro-6-methylphenyl)amide (3E)
Figure imgf000045_0002
Compound 3A (3.84 mmol) was dissolved in THF (30 mL), acetone (3 mL), and water (3 mL) at 0 °C. To this solution was added 1-methylpiperazine (3.07 mmol), followed by 10 % aqueous sodium bicarbonate. The solution was diluted with water and ethyl acetate. The aqueous layer extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The crude residue purified by column chromatography to yield compound 3E as an off white solid.
Example 16: 2-[4-Hydrazino-6-(4-methylpiperazin-l-yl)-[l,3,5]-triazine-2-ylamino]- thiazole-5-carbox lic acid (2-chloro-6-methylphenyl)amide (3F)
Figure imgf000045_0003
To a solution of compound 3E (0.39 mmol) in DMF (5 mL) was added triethylamine (0.59 mmol) followed by hydrazine hydrate (0.59 mmol). The mixture was stirred, concentrated, filtered, washed with water, ethyl acetate and dried to provide compound 3F. Example 17: {N'-[4-[5-(2-Chloro-6-methylphenylcarbamoyl)-thiazol-2-ylamino]-6-(4-
Figure imgf000046_0001
The solution of compound 3F (0.12 mmol), triethylamine (0.19 mmol) in N,N- dimethylacetamide (2 mL) was cooled to 0 °C. To this ethyl chlorooxoacetate (0.14 mmol) added slowly and the mixture was stirred until the reaction was complete. Then, the residue was concentrated and triturated with water, filtered, washed with water and dried to compound 1.37.
Other compounds of interest such as 1.38, 1.42 were prepared by similar process as provided in example 17 using appropriate starting material.
Example 18: 2-(4,6-Dichloro-[l,3,5]-triazin-amino)-thiazole-5-carboxylic acid (2-chloro- 6-methylpheny
Figure imgf000046_0002
To a suspension of 2,4,6-trichloropyrimidine (16.2 mmol) in acetone (30 mL) and ice at 0 °C was added a solution of 2-amino-thiazole-5-carboxylic acid (2-chloro-6-methylphenyl)amide (14.60 mmol) in acetone (30 mL). At the end of the reaction, the pH of the solution was made alkaline with 5 % aqueous sodium bicarbonate (30 mL). The precipitate obtained was filtered, washed with water and dried under reduced pressure to give 4A. This was used in the next step without further purification.
Example 19: 2-(2-Chloro-6-{4-methyl]piperazin-l-yl}-pyrimidin-4-ylamino)-thiazole-5- carboxylic acid (2-chloro-6-methylphenyl)amide (4B)
Figure imgf000047_0001
Compound 4A (6.99 mmol) was dissolved in a solution of tetrahydrofuran (50 mL), acetone (5 mL) and water (5 mL) at 0 °C. To this solution was added 1-methylpiperazine (6.99 mmol), followed by 5% aqueous sodium bicarbonate (13 mL). The progress of reaction was monitored by TLC and the solution was diluted with water and extracted into ethyl acetate. The aqueous layer was further extracted with ethyl acetate and the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated. The crude residue was purified by flash chromatography on silica gel (elution with 10 % methanol in dichlorome thane) to provide 4B.
Example 20: 2-(2-Hydrazino-6-{4-methyl]piperazin-l-yl}-pyrimidin-4-ylamino)thiazole- 5-carboxylic acid (2-chloro-6-methylphenyl)amide (4C)
Figure imgf000047_0002
To a solution of compound 4B (0.8 mmol) in DMF (5 mL) at room temperature was added hydrazine hydrate (1.2 mmol), followed by triethylamine (1.2 mmol). The mixture was stirred until the reaction was complete. The reaction mixture was concentrated and triturated with water, filtered, washed with water and dried to afford the intermediate 4C.
Example 21: 2-[2-(iV',iV'-Diacroloylhydrazino)-6-(4-methyl-piperazin-l-yl)pyrimidin-4- ylamino]-thi zole-5-carboxylic acid (2-chloro-6-methylphenyl)amide (1.22)
Figure imgf000047_0003
1.22
The solution of compound 4C (0.58 mmol), triethylamine (0.73 mmol) in THF (5 ml) was cooled initially to -78 °C. To this solution, acryloyl chloride (0.33 mmol) in dichloromethane was added and the mixture was stirred until the reaction was complete. Then, the reaction was concentrated and the crude residue product purified to get compound 1.22.
Other compounds of interest such as 1.24, 1.31, 1.48, 1.49 were prepared by similar sequence of reactions as provided in examples 16 to 19 using appropriate starting material.
Example 22: Preparation of 2-{2-Methyl-6-[4-(3-oxo-cyclopent-l-enyl amino)-piperazin- l-yl]-pyrimidin-4-ylamino}-thiazole-5-caboxylic acid (2-chloro-6-methyl-phenyl)-amide (1 23)
Figure imgf000048_0001
The solution of compound (ID) (0.15 g) and 1,3-cyclopentadione (0.3 g) in 20 mL (1: 1) THF:Methanol was stirred at room temperature. To this solution (0.1 mL) acetic acid was added and stirred at room temperature for 12 h. Progress of reaction was monitored by TLC , and after the completion of the reaction, solution was concentrated and residue leached by methanol, filtered washed with diethyl ether and dried to obtain the title compound (1.23).
Table 2 provides NMR data of few synthesized compounds.
Table 2
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000050_0001
Biological Data:
Radioligand binding assay BTK inhibition:
BTK (h) and the test compound were incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 250 μΜ KVEKIGEGTYGVVYK (Cdc2 peptide), 10 mM MgAcetate and [γ-33Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction was initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction was stopped by the addition of 3% phosphoric acid solution. 10 μΕ of the reaction was then spotted onto a P30 filtermat® and washed three times for 5 minutes with 75 mM phosphoric acid and once with methanol prior to drying and scintillation counting. The compounds of Formula I showed more than 50 % inhibition of BTK at 100 nM. Table 3 provides percentage inhibition of BTK at 100 nM for few representative compounds in radioligand binding assay. Table 3
Figure imgf000051_0001
Radioligand binding assay ITK inhibition:
ITK (h) and the test compound were incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.33 mg/mL myelin basic protein, 10 mM MgAcetate and [γ-33Ρ-ΑΤΡ] (specific activity approx. 500 cpm/pmol, concentration as required). The reaction is initiated by the addition of the MgATP mix. After incubation for 40 minutes at room temperature, the reaction is stopped by the addition of 3 % phosphoric acid solution. 10 μL· of the reaction is then spotted onto a P30 filtermat and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol prior to drying and scintillation counting.
Table 4 provides percentage inhibition of ITK at 100 nM for few representative compounds in radioligand binding assay.
Table 4
Figure imgf000051_0002
The compounds of Formula I showed insignificant ITK inhibition at 100 nM, thus showing good selectivity for BTK over ITK.

Claims

Claims:
1 A compound of Formula I
Figure imgf000052_0001
Formula I
or its stereoisomers and acid addition salts thereof wherein,
A is a group selected from a group consisting of hydrogen, Ci_6 alkyl, C3-6 cycloalkyl, Ci-6 haloalkyl, Ci-6 hydroxyalkyl, N(Ci-6 hydroxyalkyl)2, Ci-6 alkyl-O-Ci-6 alkyl, Ci-6 aminoalkyl, NHC(0)R26, NHNHC(0)R26, ONHC(0)R26, C(R27 28)NHC(0)R26, NHCSR26, NHNHCSR26, ONHCSR26, C(R27R28)NHCSR26, CONHNHC(0)R26, 4 to 9 membered heterocycloalkyl containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen wherein nitrogen is substituted with Re; and wherein the alkyl and the cycloalkyl group is unsubstituted or substituted with 5 or 6 membered heterocycle containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen;
R6 is selected from hydrogen, Ci_6 alkyl, C(0)Ci_6 hydroxyalkyl, C3-6 cycloalkyl, NH(C3_ 6 cycloalkenone), Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, C3-6 cycloalkyl-O-Ci-6 alkyl, C3_6 heterocycloalkyl-0-Ci_6 alkyl , C(0)C3_6 cycloalkyl, CN, N=0, C(0)N(d_3 alkyl)2, C(0)NH(d_3 alkyl ), C(0)0 Ci-e alkyl and -d_6 aminoalkyl;
R26 is Ci_6 alkyl, -6 cycloalkyl or is a group selected from moieties provided in Figure- A
Figure imgf000052_0002
Figure-A
wherein, R29 is selected from hydrogen, -Ci-6 alkyl, -C2-6 alkenyl, -C3-7 cycloalkyl, OH, - OCi_6 alkyl or -NR4jR42, wherein R^ and R42 are independently selected from hydrogen or Ci-6 alkyl; R30 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, - _7 cycloalkyl;
or R2 and R30 together forms 4 to 10 membered substituted or unsubstituted mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or -C(0)-Ci_
4 alkyl group; the substitution on carbocyclic or the heterocyclic ring can be selected from -d_3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl or -C(0)NH2;
J is absent or -C(O)-;
G is an electron withdrawing group selected from -C(0)OR4o, -C(0)N(R4o)2, -CN, -NO2, -SO3H, -S02N(R4o)2, -SO2R40 wherein R40 at each occurrence is independently selected from hydrogen, -Ci_3 alkyl and -C4_6 cycloalkyl;
T is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or -C(0)-Ci_4 alkyl group; p is an integer selected from 1 and 2;
'{ ' is the point of attachment to the rest of molecule; R31, R32, R33 are independently selected from a group consisting of hydrogen, Ci_6 alkyl,
C3-6 cycloalkyl, Ci-6 haloalkyl, C3-6 halocycloalkyl, Ci-6 hydroxyalkyl, C3-6 hydroxycycloalkyl, d_6 alkyl-O-d-e cycloalkyl, CN, C(0)NR34R35, (CH2)rC(0)NR34R35, d_6 cyanoalkyl, C(0)OH, C(0)Od_6 alkyl, (CH2)rC(0)OH, (CH2)rC(0)Od_6 alkyl, (CH2)rNR34R35, _7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R36); wherein r is an integer selected from 0 to 4; or R31 and R32 taken together forms a bond;
R34 and R35 are independently selected from hydrogen, Ci_6 alkyl or R34 and R35 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring;
R36 is selected from hydrogen, Ci_6 alkyl, _6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl, Ci_6 aminoalkyl and C3_6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen; R27 and R28 are selected from hydrogen, C1-4 alkyl or R27 and R28 together forms 3 to 6 membered substituted or unsubstituted carbocyclic ring;
B is a 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from oxygen, sulfur, nitrogen or -N(R7)- wherein R7 is selected from hydrogen, Ci-6 alkyl or C3_6 cycloalkyl; B is unsubstituted or substituted with one or more groups selected from halogen, OH, NH2, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl or C4_6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur, nitrogen or N(Ci_4 alkyl); D is 5 or 6 membered aromatic ring containing 0 to 3 heteroatoms selected from oxygen, sulfur and nitrogen wherein when the heteroatom is nitrogen it is optionally substituted with -Ci-6 alkyl or -C3_6 cycloalkyl and wherein D is unsubstituted or substituted with one or more groups selected from halogen, OH, N¾, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, Ci_6 alkyl-0-Ci_6 alkyl or C4_6 heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur, nitrogen or N(Ci_4 alkyl);
Rj is selected from hydrogen, Ci_6 alkyl, C3_6 cycloalkyl, Ci_6 haloalkyl, Ci_6 hydroxyalkyl, d_6 alkyl-0-d_6 alkyl, C(0)CH=CH2, C(0)Od_6 alkyl and C4_6 heterocycloalkyl wherein the hetero atom is selected from oxygen, sulfur, nitrogen or N(Ci-4 alkyl);
R2 is selected from a group consisting of hydrogen, Ci-6 alkyl, C(0)CH20C(0)Ci-3 alkyl , C(0)C(0)OCi_6 alkyl, C3_6 cycloalkyl, C3_6 cycloalkenone and CN; or R2 is a moiety selected from the groups provided in Figure- 1
Figure imgf000055_0001
Figure- 1
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, d-6 alkyl, d-6 cycloalkyl, d-6 haloalkyl, d-6 halocycloalkyl, d-6 hydroxylalkyl, d-6 hydroxycycloalkyl, d-6 alkyl-0-C3-6 cycloalkyl, CN, C(0)NR12Ri3, (CH2)nC(0)NR12Ri3, d_6 cyanoalkyl, C(0)OH, C(0)Od_6 alkyl, (CH2)nC(0)OH, (CH2)ndO)Od-6 alkyl,
(CH2)nNR12Rj3, C4_7 heterocycloalkyl wherein the heteroatom is selected from oxygen, sulfur or N(R14); n is an integer selected from 1 to 6; or Rg and R taken together forms a bond;
R12 and Rj3 are independently selected from hydrogen and d-6 alkyl;
or R12 and Rj3 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci_3 alkyl;
R14 is selected from hydrogen, d-6 alkyl, d-6 cycloalkyl, d-6 haloalkyl, d-6 hydroxyalkyl, d-6 alkyl-O-d-6 alkyl, d-6 aminoalkyl and C3_6 cycloalkyl-0-Ci_6 alkyl; wherein the alkyl and the cycloalkyl groups are optionally substituted with 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, sulfur and nitrogen; R11 is selected from a group consisting of hydrogen, d-6 alkyl, Ci_6 haloalkyl, cycloalkyl, CN, S02d_6 alkyl, S02C3-6 cycloalkyl, C(0)OH, C(0)0 d_6 alkyl and C(0)NR15R16 wherein RJS and Rj6 are independently selected from d_6 alkyl or RJS and Ri6 together with the nitrogen atom to which they are attached forms a 4 to 7 membered heterocycloalkyl ring;
X' , Y' and Z' are independently selected from CH or N; Hal is a one or more halogen radical;
EWG is selected from a group consisting of C(0)OR17, C(0)N(R17)2, CN, N02, S03H, S02N(Ri7)2 and SO2R17 wherein Rn is selected from hydrogen, C1-3 alkyl and C4-6 cycloalkyl;
or
R2 is a group selected from moieties provided in Figure- la
Figure imgf000056_0001
Figure-1a
wherein, R37 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, -C^ cycloalkyl, OH, - OCi-6 alkyl or -NR43R44, wherein R43 and R44 are independently selected from hydrogen or Ci-6 alkyl;
R38 is selected from hydrogen, -Ci_6 alkyl, -C2-6 alkenyl, -C3_7 cycloalkyl;
or R37 and R38 together forms 4 to 10 membered substituted or unsubstituted mono- or bi- carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or
Figure imgf000056_0002
alkyl group; the substitution on the mono- or bi- carbocyclic or the heterocyclic ring is selected from -C1-3 alkyl, -d_3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl or - C(0)NH2;
G' is an electron withdrawing group selected from -COOR39, -C(0)N(R39)2, -CN, -NO2, -SO3H, -S02N(R3 )2, -SO2R39 wherein R39 at each occurrence is independently selected from hydrogen, -Ci-3 alkyl and -C4_6 cycloalkyl;
T' is a heteroatom selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -C1-4 alkyl or -C(0)-Ci_4 alkyl group; p' is an integer selected from 1 and 2;
' { ' is the point of attachment of I¾ with nitrogen atom;
Figure imgf000057_0001
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, d-6 alkyl, d-e alkenyl, C3-7 cycloalkyl, -C(0)H, C(0)OR, -C(0)N(R)2, -CH=CHC(0)OR, - CH=CHC(0)NRR', wherein R and R' are independently selected from hydrogen and - d-6 alkyl or R and R' together with the nitrogen to which they are attached forms a 5 or 6 membered saturated or unsaturated ring; or Rjg and Rjg together forms substituted or unsubstituted 4 to 10 membered mono or bicyclic carbocyclic ring or a 5 or 6 membered substituted or unsubstituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen and sulfur and when the heteroatom is nitrogen it is optionally further substituted with d-4 alkyl or
Figure imgf000057_0002
alkyl group; the substitution on mono- or bicyclic carbocyclic ring or heterocyclic ring is selected from -C1-3 alkyl, -C1-3 haloalkyl, -CN, -C(0)OH, -C(0)0-d_3 alkyl, -C(0)NH2, =0;
R20 and R21 at each occurrence are independently selected from hydrogen, -Ci_6 alkyl, - d-6 alkenyl or -C3_7 cycloalkyl or R20 and R21 together forms 4 to 10 membered unsubstituted or substituted mono or bicyclic carbocyclic ring or a 5 or 6 membered unsubstituted or substituted heterocyclic ring containing 1 or 2 heteroatoms selected from oxygen, nitrogen, or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or -CO-Ci_4 alkyl group; the substitution on mono- or bicyclic carbocyclic ring or heterocyclic ring is selected from -Ci_3 alkyl, -Ci_3 haloalkyl, -CN, -C(0)OH, -C(0)0-d-3 alkyl, -C(0)NH2, =0; EWG' is a group selected from C(0)OR22, C(0)N(R22)2, CN, N02, S03H, S02N(R22)2 and S02R22 wherein R22 at each occurrence is independently selected from hydrogen, Q_ 3 alkyl and C4-6 cycloalkyl; q is an integer and at each occurrence is independently selected from 1 and 2;
' { ' is the point of attachment of Rj and R2 with nitrogen atom; or, Ri and R2 together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci_3 alkyl;
W, X, Y and Z are independently selected from CH or N; wherein at least one of W, X,
Y and Z is CH;
U is a bond or a group selected from a group consisting of oxygen, sulfur, NH, N(Ci_6 alkyl), CH2 and C(O);
V is selected from a group consisting of -C(0)NH-, -C(0)N(Ci_4 alkyl)-, -NHC(O)-, - N(Ci-4 alkyl)C(O)-, -C(0)CH2-, -CH2C(0)-, -NHCH2-, -N(d_4 alkyl)CH2-, -CH2NH-, -
CH2N(Ci-4 alkyl)-, -SCH2-, -CH2S-, -OCH2-, -CH20-, -S02NH-, -NHS02-, -S02N(CM alkyl)-, -N(d_4 alkyl)S02-, -CH=CH-, -C≡C-, -C(S)NH-, -C(S)N(d_6 alkyl)-, -NHC(S)-, -N(d_6 alkyl)C(S)- and -C(S)CH2-; R5 is either absent or selected from a group consisting of halogen, d-6 alkyl, d-6 haloalkyl, C3-6 cycloalkyl, CN, OR23, SR23, S02R23, C(0)OR23, C(0)NR24R25 wherein R23 at each occurrence is independently selected from hydrogen, C1-4 alkyl, C3-6 cycloalkyl; R24 and R¾ at each occurrence are independently selected from hydrogen, Ci_ 6 alkyl, C2_6 alkenyl, _7 cycloalkyl or R24 and R¾ together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl optionally containing
1 or 2 additional heteroatoms selected from oxygen, nitrogen or sulfur and when the heteroatom is nitrogen it is optionally further substituted with -Ci_4 alkyl or
Figure imgf000058_0001
alkyl group; L is either absent or selected from a group consisting of -CH-, oxygen, sulfur and nitrogen or a moiet selected from the groups provided in Figure-3
Figure imgf000059_0001
Figure-3
wherein ' } ' denotes the point of attachment to the ring and ')' denotes point of attachment of R4; m is an integer selected from 0 to 3 provided that when L is oxygen, sulfur or nitrogen then m is selected from 2 or 3;
R3 is a group selected from a group consisting of hydrogen, Ci-6 alkyl, C3-6 cycloalkyl, Ci_6 haloalkyl, halocycloalkyl, C2-6 hydroxylalkyl, C3_6 hydroxycycloalkyl and Ci_6 alkyl-0-C3_6 cycloalkyl;
R4 is a group selected from a group consisting of hydrogen, Ci_6 alkyl and C3_6 cycloalkyl and R4 is absent when L is oxygen or sulfur; or R3 and R^ taken together forms a 5 to 8 membered heterocyclic ring; or R3 and R^ taken together forms a group selected from moieties provides in the Figure - 4
Figure imgf000059_0002
Figure-4
2. The compound of Formula I as in claim 1 , wherein
A is a group selected from a group consisting of Ci_3 alkyl, N(Ci_3 hydroxyalkyl)2 or a 5 or 6 membered heterocycloalkyl containing 1 or 2 heteroatoms selected from oxygen, and nitrogen, wherein nitrogen is substituted with R6 and wherein R6 is selected from hydrogen, C1-4 alkyl, C(0)Ci-6 hydroxyalkyl, NH(C3-6 cycloalkenone), C1-3 hydroxyalkyl, d_3 alkyl-O-Ci.3 alkyl, d-6 heterocycloalkyl-0-Ci-3 alkyl, C(0)C3-6 cycloalkyl, CN, N=0, C(0)N(d_3 alkyl)2, C(0)NH(d_3 alkyl) and C(0)Od_3 alkyl;
B is thiazolyl;
D is phenyl unsubstituted or substituted with one or more groups selected from halogen or d-6 alkyl;
Ri is selected from hydrogen, d-6 alkyl, C(0)CH=CH2 or C(0)OCi-4 alkyl;
R2 is selected from a group consisting of hydrogen, C(0)CH20C(0)Ci_3 alkyl, C(0)C(0)Od_3 alkyl, C3_6 cycloalkenone and CN; or R2 is a moiety selected from the following groups
Figure imgf000060_0001
wherein R8, R9, R10 are independently selected from a group consisting of hydrogen, d_6 alkyl, C(0)OH,
Figure imgf000060_0002
wherein n is an integer selected from 1 to 3; R12 and R13 are together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci-3 alkyl; or Rg and R9 taken together forms a bond; R11 is hydrogen;
X', Y' and Z' are independently selected from CH or N;
Hal is one or more halogen radical; or, Rj and R2 together forms a group selected from
Figure imgf000061_0001
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, Ci_3 alkyl, C2-3 alkenyl, cycloalkyl, -C(0)H, C(0)OR, wherein R is hydrogen or -Ci_3 alkyl;
R20 and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom; or, Rj and R2 together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci_3 alkyl;
W is CH and X, Y and Z are independently selected from CH or N;
U is NH; V is -C(0)NH-; R5 is absent;
L is either absent or nitrogen; m is an integer selected from 2 or 3;
R3 is hydrogen;
R4 is a group selected from a group consisting of hydrogen, Ci_6 alkyl and C3_6 cycloalkyl and R4 is absent when L is oxygen or sulfur; or R3 and R4 taken together forms a 5 or 6 membered heterocyclic ring .
3. The compound of Formula I as in claim 1 or 2, wherein A is selected from a group consisting of Ci-3 alkyl, N(Ci-3 hydroxyalkyl)2 or a 6 membered heterocycloalkyl selected from piperidinyl, mo holinyl or piperazinyl, wherein nitrogen of the heterocycloalkyl is substituted with R6; wherein I¾ is selected from a group consisting of hydrogen, C1-4 alkyl, C(0)Ci_4 hydroxyalkyl, NH(C3_6 cycloalkenone), Ci_3 hydroxyalkyl, Ci_3 alkyl-O- d_3 alkyl, C(0)C3-6 cycloalkyl, C3-6 heterocycloalkyl-0-Ci-3 alkyl, CN, N=0, C(0)N(Ci-3 alkyl)2, C(0)NH(d_3 alkyl) and C(0)Od_3 alkyl.
4. The compound of Formula I as in claim 3, wherein A is methyl, bis-(2- hydroxyethyl)amino, piperidinyl, morpholinyl or piperazinyl substituted with methyl, - C(0)cyclopropyl, 2-hydroxyethyl, -NH-cyclopentenone, -C(0)CH(OH)CH2(OH), CN, N=0, methoxyethyl, CONHCH3, CON(CH3)2, C(0)OC2H5 or tetrahydropyranoxyethyl.
5. The compound of Formula I as in claim 1 or 2, wherein L is nitrogen and R3 and R4 taken together with the nitrogen and L to which they are attached, forms a 5 or 6 membered heterocyclic ring selected from piperazinyl, imidazolidinyl or hexahydropyrimidinyl.
6. The compound of Formula I as in claim 1 or 2, wherein Rj is selected from a group
consisting of hydrogen, Ci-6 alkyl, C(0)CH=CH2 or C(0)OCi-4 alkyl;
R2 is selected from a group consisting of hydrogen, C3_6 cycloalkenone, C(0)CH2OC(0)d_3 alkyl, C(0)C(0)Od_3 alkyl, CN,
Figure imgf000062_0001
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, Ci_3 alkyl, C(0)OH, (CH2)nNR12R13,
wherein n is an integer selected from 1 to 3;
or Rg and R9 taken together forms a bond; Rj2 and Rj3 are together with the nitrogen atom to which they are attached forms a 6 membered heterocyclic ring optionally containing 1 additional heteroatom selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci- 3 alkyl;
Rii is hydrogen;
X', Y' and Z' are independently selected from CH or N;
Hal is one or more halogen radical;
or, Rj and R2 together forms a group selected from
Figure imgf000063_0001
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, Ci_3 alkyl, C2-3 alkenyl, CJS cycloalkyl, -C(0)H, C(0)OR, wherein R is hydrogen or -Q_3 alkyl;
R20 and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom; or, Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci_3 alkyl.
The compound of Formula I as in claim 6, wherein Rj is hydrogen, methyl or C(0)OC2Hs and R2 is selected from hydrogen, cyclopentenone, C(0)CH20C(0)CH3,
Figure imgf000063_0002
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, methyl, C(0)OH, (CH2)nNR12Ri3,
wherein n is 1 and Rj2 and Rj3 together with the nitrogen atom to which they are attached forms a 6 membered heterocyclic ring containing 1 additional nitrogen atom substituted with methyl; or Rg and R taken together forms a bond;
Rn is hydrogen;
X', Y' and Z' are independently selected from CH or
Hal is a halogen radical;
or, Rj and R2 together forms a group selected from
Figure imgf000064_0001
wherein, Rjg and Rjg at each occurrence are independently selected from hydrogen, methyl, ethylene, cyclopropyl, -C(0)H, C(0)OR, wherein R is hydrogen or methyl; R20 and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom.
or, Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with methyl. The compound of Formula I as in claim 1 or 2, wherein
L is absent, m is 0, R3 is hydrogen, Rj is selected from hydrogen, Ci_6 alkyl, C(0)CH=CH2 or
Figure imgf000064_0002
alkyl and R2 is selected from a group consisting of hydrogen, C(0)CH2OC(0)C!_3 alkyl, C(0)C(0)OCi-3 alkyl;
or R2 is a moiety selected from the following groups:
Figure imgf000064_0003
wherein Rg, R9, Rjo are independently selected from a group consisting of hydrogen, Ci_6 alkyl, C(0)OH,
Figure imgf000064_0004
wherein n is an integer selected from 1 to 3; or Rg and R9 taken together forms a bond; R12 and R13 are together with the nitrogen atom to which they are attached forms a 5 or 6 membered heterocyclic ring optionally containing 1 or 2 additional heteroatoms selected from oxygen and nitrogen; wherein the heterocyclic ring is unsubstituted or substituted with Ci_3 alkyl; Χ', Y' and Ζ' are independently selected from CH or N; Hal is one or more halogen radical;
o together forms a group
Figure imgf000065_0001
and R21 at each occurrence are hydrogen;
' { ' is the point of attachment of Rj and R2 with nitrogen atom;
or Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with hydrogen or Ci_3 alkyl.
The compound of Formula I as in claim 8, wherein Rj is hydrogen, methyl, C(0)CH=CH2, C(0)0'Bu, C(0)OC2H5 and R2 is hydrogen, C(0)CH2OC(0)CH3,
C(0)CHCOOH, C(0)C≡CCH3 or group
Figure imgf000065_0002
wherein Hal is halogen radical; or Rj and R2 together form a group
Figure imgf000065_0003
wherein '{ ' is the point of attachment of Rj and R2 with nitrogen atom;
or Rj and R2 together with the nitrogen atom to which they are attached forms 6 membered heterocycloalkyl containing 1 additional nitrogen atom which is substituted with methyl.
10. A compound according to claim 1 or 2 selected from the group consisting of
Figure imgf000066_0001
Figure imgf000067_0001
66
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