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Title:
QUINOLINE AND QUINAZOLINE COMPOUNDS
Document Type and Number:
WIPO Patent Application WO/2016/055982
Kind Code:
A1
Abstract:
In some embodiments, the invention relates to quinazoline and quinoline compounds of Formula I: (I) or a pharmaceutically acceptable salt thereof, or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, in some embodiments, the present invention relates to quinazoline and quinoline compounds, pharmaceutical compositions thereof, and the use of the compounds and pharmaceutical compositions in the treatment of Bruton's tyrosine kinase (BTK) mediated disorders.

Inventors:
BARF TJEERD (NL)
DE ZWART EDWIN (NL)
VERKAIK SASKIA (NL)
HOOGENBOOM NIELS (NL)
DEMONT DENNIS (NL)
Application Number:
PCT/IB2015/057746
Publication Date:
April 14, 2016
Filing Date:
October 09, 2015
Export Citation:
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Assignee:
ACERTA PHARMA BV (NL)
International Classes:
C07D401/12; A61K31/47; A61K31/517; A61P35/00; C07D401/14; C07D405/14; C07D413/12
Domestic Patent References:
WO2013010868A12013-01-24
WO2010006947A12010-01-21
WO2009088986A12009-07-16
WO2009088880A12009-07-16
WO2011008302A12011-01-20
Foreign References:
US5908826A1999-06-01
US6267958B12001-07-31
US7682609B22010-03-23
US7592004B22009-09-22
US8298530B22012-10-30
US20100158925A12010-06-24
US5023252A1991-06-11
US4992445A1991-02-12
US5001139A1991-03-19
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Claims:
CLAIMS

We claim:

1. A compound of Formula I

Formula I

or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N, with the proviso that if B is N, A is CH;

B is CH or N, with the proviso that if A is N, B is CH;

T is CH or N;

U is CH or N;

V is NR5, O, S, SO or S02;

W is CH, N, O or S;

Y is CH, N or bond;

Z is CH or N;

with the proviso that:

0 to 2 atoms of W, X, Y can simultaneously be a heteroatom;

- when one atom selected from W, X, Y is O or S, then another atom selected from W, X, Y can not be O or S;

- when Y is CH or N then X is C(Re) or N and W is CH or N;

Ri is H, (Ci-4)alkyl optionally substituted with R7 or C(0)R7, or (Ci-5)alkoxy optionally substituted with R7 or C(0)R7, or 0-(C2-6)heterocycloalkyl optionally substituted with hydroxyl or (Ci-4)alkyl;

R3 is H, (Ci-3)alkyl optionally substituted with R7, or (C3-7)cycloalkyl optionally substituted with R7;

R4 is H, RiiC(O), Ri2S(0), R13SO2, or (C1-6)alkyl optionally substituted with RM;

Ri and R3 together may form a (C2-6)heterocycloalkyl;

R5 is H or (Ci-3)alkyl;

R2 is H, halogen, cyano, (Ci-4)alkyl, (C2-4)alkenyl, (C2-4)alkynyl, (Ci-3)alkoxy, (C3-6) cycloalkyl; all alkyl groups of R2 are optionally substituted with one or more halogen; or R2 is (C6-io)aryl or (C2-6)heterocycloalkyl;

R6 is H or (Ci-3)alkyl; or

R2 and Re together may form a (C3-7)cycloalkenyl, or (C2-6)heterocycloalkenyl; each optionally substituted with (Ci-3)alkyl, or one or more halogen;

R7 is H, (Ci-3)alkoxy, or a (C2-6)heterocycloalkyl; (one or more) hydroxyl, [(Ci-4) alkyl]amino, di[(Ci-4)alkyl]amino, (C3-7)cycloalkoxy;

R11 is independently selected from the group consisting of (Ci-6)alkyl, (C2-6)alkenyl and (C2- 6)alkynyl wherein each alkyl, alkenyl or alkynyl is optionally substituted with one or more groups selected from hydroxyl, (Ci-4)alkyl, (C3-7)cycloalkyl, (Ci-3)alkoxy, (C3-7)cycloalkoxy, [(Ci-4) alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, di[(Ci-4) alkyl]amino optionally substituted with hydroxyl, halogen, or (C6-io)aryl or (C3-7)heterocycloalkyl, or

R11 is (Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano.

R12 and Ri3 are independently selected from the group consisting of (C2-6)alkenyl or (C2-6) alkynyl both optionally substituted with one or more groups selected from hydroxyl, (C1-4) alkyl, (C3-7)cycloalkyl, [(Ci-4)alkyl]amino, di[(Ci-4)alkyl]amino, (Ci.3)alkoxy, (C3-7) cycloalkoxy, (C6-io)aryl, or (C3-7)heterocycloalkyl; or

(Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano;

Ri4 is independently selected from the group consisting of halogen, cyano or (C2-6)alkenyl or (C2-6)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (Ci-4)alkyl, (C3-7)cycloalkyl, [(Ci-4)alkyl]amino, di[(Ci-4)alkyl]amino, (C3-7) cycloalkoxy, (C6-io)aryl, (Ci-5)heteroaryl or (C3-7)heterocycloalkyl.

2. The compound according to any of Claim 1 wherein Ri is selected from the group consisting of (Ci.y)alkoxy, optionally substituted with (Cs^heterocycloalkyl, (di)alkylamino, alkoxy, or hydroxyl.

3. The compound according to any of Claims 1 to 2 wherein the ring containing W, X, and Y is selected from the group consisting of pyridyl, pyrimidyl, pyridazyl, triazinyl, thiazolyl, oxazolyl, and isoxazolyl.

4. The compound according to any of Claims 1 to 3 wherein the ring containing W, X, and Y is selected from the group consisting of pyridyl, pyrimidyl, and thiazolyl.

5. The compound according to any of Claims 1 to 4 wherein R2 is selected from the group consisting of hydrogen, fluorine, chlorine, (Ci-3)alkyl, (Ci-3)alkenyl, (Ci-3)alkynyl and (Ci_ 2)alkoxy; the (Ci-3)alkyl group of which is optionally substituted with one or more halogen.

6. The compound according to any of Claims 1 to 5 wherein R2 is selected from the group consisting of hydrogen, fluorine, methyl, ethyl, propyl, methoxy and trifluoromethyl.

7. The compound according to any of Claims 1 to 6 wherein R2 is hydrogen or (Ci-3)alkyl; and R3 is hydrogen or (Ci-6)alkyl.

8. The compound according to any of Claims 1 to 7 wherein Ri is selected from the group consisting of (Ci-v)alkoxy, optionally substituted with (di)alkylamino, alkoxy, or hydroxyl and R11 is independently selected from the group consisting of (Ci-6)alkyl, (C2-6)alkenyl or (C2-6)alkynyl each optionally substituted with one or more groups selected from hydroxyl, (Ci-4)alkyl, (C3-7)cycloalkyl, [(Ci-4)alkyl]amino, di[(Ci-4)alkyl]amino, (Ci_3)alkoxy, (C3-7) cycloalkoxy, (C6-io)aryl or (3-7C)heterocycloalkyl; or Rn is (Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano.

9. The compound according to any of Claims 1 to 8 wherein R4 is RnC(O) and Rn is selected from the group consisting of (C2-6)alkenyl or (C2-6)alkynyl each optionally substituted with one or more groups selected from hydroxyl, (Ci-4)alkyl, (C3-7)cycloalkyl, di[(Ci_

4)alkyl]amino, (Ci_3)alkoxy, (C3-7)cycloalkoxy or (C3-7)heterocycloalkyl.

10. A compound according to Claim 1 selected from the group consisting of: 3- {[6-(acryloylamino)quinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)quinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

3- {[6-(but-2-ynoylamino)quinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

4- {[6-(butyno-2-ylamino)quinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

4- { [6-(acryloylamino)quinazolin-4-y 1] oxy } -N-(pyridin-2-yl)benzamide;

4- {[6-(butyno-2-ylamino)quinazolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)quinazolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2-yl)benzamide; 4- {[6-(butyno-2-ylamino)quinazolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2- yl)benzamide;

4- {[6-(but-2-ynoylamino)-7-methoxyquinazolin-4-yl]amino}-N-(4-(trifluoromethyl)pyridin- 2-yl)benzamide;

4- {[6-(acryloylamino)-7-methoxyquinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)-7-methoxyquinazolin-4-yl]amino}-N-(4-(trifluoromethyl)pyridin-2- yl)benzamide;

4- {[6-(but-2-ynoylamino)-7-methoxyquinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

4- {[6-((4-methoxybut-2-ynoyl)amino)quinazolin-4-yl]amino}-N-(pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)quinazolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide;

4-[(6-(4-methoxybut-2-ynoyl)(methyl)aminoquinolin-4-yl)oxy]-N-(4-methylpyridin-2- yl)benzamide;

4- {[6-(5-(morpholin-4-yl)penty-2-nylamino)-7-methoxyquinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-(4-ethynylpyridin-2-yl)benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-(4-fluoropyridin-2-yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-(4-fluoropyridin-2-yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-(4-ethynylpyridin-2-yl)benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-(4-propylpyridin-2-yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-(4-propylpyridin-2-yl)benzamide;

4-[(6-((2ii)-4-dimethylaminobut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-fluoropyridin-2- yl)benzamide;

4-[(6-aminoquinolin-4-yl)oxy]-N-(4-propylpyridin-2-yl)benzamide; 4-[(6-((2i?)-4-dimethylaminobut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-propylpyridin-2- yl)benzamide;

4-[(6-(propanoylamino)quinolin-4-yl)oxy]-N-(4-propylpyridin-2-yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-(4-methoxypyridin-2-yl)benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-(4-methoxypyridin-2-yl)benzamide;

4-[(6-((2i?)-4-dimethylaminobut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-methoxypyridin-2- yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(4-methoxypyridin-2- yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(4-propylpyridin-2- yl)benzamide;

4-[(6-((2£')-4-methoxybut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-methoxypyridin-2- yl)benzamide;

4-[(6-((2£')-4-methoxybut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-propylpyridin-2- yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(4-ethynylpyridin-2- yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(4-fluoropyridin-2- yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide;

4-[(6-((4-hydroxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(5-ethyl-1.3-thiazol-2- yl)benzamide;

4- [(6-((but-2-ynoylamino)quinolin-4-yl)oxy]-N-(5-ethyl-1.3-thiazol-2-yl)benzamide;

5- {[6-(4-methoxybut-2-ynoylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)pyridine-2- carboxamide;

6- {[6-(4-methoxybut-2-ynoylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)pyridine-3- carboxamide;

6- {[6-(4-methoxybut-2-ynoylamino)quinolin-4-yl]oxy}-N-(4-methylpyridin-2-yl)pyridine- 3-carboxamide; 6- {[6-(4-methoxybut-2-ynoylamino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)pyridine-3- carboxamide;

6- {[6-(4-methoxybut-2-ynoylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)pyridazine-3- carboxamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-(5-tert-butyl-l,2-oxazol-3-yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-(pyrimidin-2-yl)benzamide;

4-[(6-(4-methoxybut-2-ynoylamino)quinolin-4-yl)oxy]-N-(5-tert-butyl-l,2-oxazol-3- yl)benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-(5-tert-butyl-l,2-oxazol-3-yl)benzamide;

4-[(6-acryloylamino)quinolin-4-yl]oxy}-N-(4-cyanopyridin-2-yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(pyrimidin-2-yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl]oxy}-N-(4-cyanopyridin-2- yl)benzamide;

4- {[6-(acryloyl(2-{morpholin-4-yl}ethyl)amino)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-[4-methylpyrimidin-2-yl]benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl]oxy}-N-(4-cyanopyridin-2-yl)benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-[4-methylpyrimidin-2- yl]benzamide;

4-[(6-{[(2i^-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}-N-(4-cyanopyridin-2- yl)benzamide;

4-((6-(but-2-ynamido)-7-(2-morpholinoethoxy)quinolin-4-yl)oxy)-N-(pyridin-2- yl)benzamide;

4- {[6-(but-2-ynoylamino)quinolin-4-yl]amino}-N-(pyridine-2-yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]amino}-N-(4-methylpyridine-2-yl)benzamide;

4- {[6-(but-2-ynoylamino)quinolin-4-yl]amino}-N-(4-methylpyridine-2-yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]amino}-N-(4-ethylpyridine-2-yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]amino}-N-(pyridine-2-yl)benzamide;

4- {[6-(acryloylamino)-7-methoxyquinolin-4-yl]oxy}-N-(4-ethylpyridine-2-yl)benzamide;

4- {[6-(acryloylamino)-7-methoxyquinolin-4-yl]oxy}-N-(4-methoxypyridine-2- yl)benzamide; 4- {[6-(But-2-ynoylamino)-7-methoxyquinolin-4-yl]amino}-N-(pyridine-2-yl)benzamide;

4- {[6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl]amino}-N-(4-ethylpyridine-2- yl)benzamide;

4- {[6-((4-methoxybut-2-ynoyl)amino)-7-methoxyquinolin-4-yl]amino}-N-(4-ethylpyridine- 2-yl)benzamide;

4- {[6-(4-(morpholin-4-yl)butyno-2-ylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide;

4- {[6-(4-(morpholin-4-yl)butyno-2-ylamino)quinolin-4-yl]oxy}-N-(4-methylpyridin-2- yl)benzamide;

4- {[6-(5-(morpholin-4-yl)penty-2-nylamino)quinolin-4-yl]oxy}-N-(4-methylpyridin-2- yl)benzamide;

4- {[6-(5-(morpholin-4-yl)penty-2-nylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2-yl)benzamide;

4- {[6-(butyno-2-ylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide;

4- {[6-(butyno-2-ylamino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide;

4- {[6-(butyno-2-ylamino)quinolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2-yl)benzamide;

4-[(6-{[(2i^-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}-N-(4-ethylpyridin-2- yl)benzamide;

4-[(6-{[(2i^-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4- {[6-(acryloylamino)quinolin-4-yl]oxy}-N-(4-methylpyridin-2-yl)benzamide;

4- {[6-(but-2-ynoylamino)quinolin-4-yl]oxy}-N-(4-methylpyridin-2-yl)benzamide;

4-[(6-{[(2i^-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}-N-(4-methylpyridin-2- yl)benzamide;

4- {[6-(acryloylamino)-7-methoxyquinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide;

4-[(6-aminoquinolin-4-yl)oxy]-N-(4-ethylpyridin-2-yl)benzamide;

(i?)-4-((4-(4-((4-ethylpyridin-2-yl)carbamoyl)phenoxy)quinolin-6-yl)amino)-N,N,N- trimethy l-4-oxobut-2-en- 1 -aminium;

4- {[6-(acryloylamino)cinnolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide; 4-[(6-{[4-methoxy-but-2-ynoyl]amino}quinolin-4-yl]oxy}-N-(4-ethylpyridin-2- yl)benzamide;

4-[(6-{[(2i^-4-methoxy-but-2-ynoyl]amino}quinolin-4-yl]oxy}-N-(4-methylpyridin-2- yl)benzamide;

4- [(6-{[(2£)-4-methoxy-but-2-ynoyl]amino}cinnolin-4-yl]oxy}-N-(4-ethylpyridin-2- yl)benzamide;

5- {[6-(acryloylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)pyridine-2-carboxamide;

5- {[6-(but-2-ynoylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)pyridine-2-carboxamide; 5-[(6-{[(2i^-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}-N-(pyridin-2- yl)pyridine-2-carboxamide;

4- {[6-(but-2-ynoyl(2-{dimethylamino}ethyl)amino)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4-[(6-{[(i?/Z)-4-morpholinobut-2-enoyl]amino}quinolin-4-yl)oxy]-N-(pyridin-2- yl)benzamide;

4-[(6-{[(i?)-4-morpholinobut-2-enoyl]amino}quinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide; 4-[(6-{[(Z)-4-morpholinobut-2-enoyl]amino}quinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide; 4- {[6- {[(i?/Z)-4-[2-hydroxyethyl(methyl)amino]but-2-enoyl]amino} quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6- {[(i?)-4-[2-hydroxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6- {[(Z)-4-[2-hydroxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6- {[(i?/Z)-4-[2-methoxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-y

(pyridin-2-yl)benzamide;

4- {[6- {[(i?)-4-[2-methoxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6- {[(Z)-4-[2-methoxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6- {[(i?)-4-[2-methoxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N-(4- ethylpyridin-2-yl)benzamide; 4- {[6- {[(i?)-4-[2-methoxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N-(4- methylpyridin-2-yl)benzamide;

4- {[6- {[(i?)-4-[2-methoxyethyl(methyl)amino]but-2-enoyl]amino}quinolin-4-yl]oxy}-N-(4- methoxypyridin-2-yl)benzamide;

4-[[7-(2-{morpholin-4-yl}oethoxy)-6-(acryloylamino)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4- {[6-(4-(morpholin-4-yl)butyno-2-ylamino)-7-methoxyquinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4- {[6-(4-(morpholin-4-yl)penty-2-nylamino)-7-methoxyquinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4- {[6-(but-2-ynoyl(2-{morpholin-4-yl}ethyl)amino)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4- {[6-(but-2-ynoyl(3-{dimethylamino}propyl)amino)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

5- [(6-{[(2i^-4-dimethylaminobut-2-enoyl](3-{morpholin-4-yl}propyl)amino}quinolin-4- yl]oxy}-N-(pyridin-2-yl)pyridine-2-carboxamide;

4- {[6-(but-2-ynoyl(3-{morpholin-4-yl}propyl)amino)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4- {[6-(acryloyl(3-{morpholin-4-yl}propyl)amino)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-[4-methylpyrimidin-2-yl]benzamide;

4-[(6-(but-2-ynoylamino)quinolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyrimidin-2- yl]benzamide;

4-[(6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyrimidin-2- yl]benzamide;

4-[[7-(2-methoxyethoxy)-6-(but-2-ynoylamino)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[(6-(acryloylamino)quinolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzamide;

4- {[6-(but-2-ynoylamino)-7-{[(3i?)-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}-N-

(pyridin-2-yl)benzamide; 4- {[6-(but-2-ynoylamino)-7-(tetrahydropyran-4-yloxy)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4- {[6-(but-2-ynoylamino)-7-{[(3<S)-tetrahydrofuran-3-yl]oxy}quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6-(but-2-ynoylamino)-7-(oxetan-3-yloxy)quinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(3-morpholinopropoxy)quinolin-4-yl]oxy]-N-(2- pyridyl)benzamide;

4-[[6-(but-2-ynoylamino)-7-[2-(l-piperidyl)ethoxy]quinolin-4-yl]oxy]-N-(2- pyridyl)benzamide;

4-[[6-(acryloylamino)-7-[2-(l-piperidyl)ethoxy]quinolin-4-yl]oxy]-N-(2-pyridyl)benzamide; 4- {[6-[[(£')-4-[methyl(tetrahydropyran-4-yl)amino]but-2-enoyl]amino] quinolin-4-yl]oxy}- N-(pyridin-2-yl)benzamide;

4- { [6- [4-(4-ethylpiperazin- 1 -y l)but-2-ynoylamino] quinolin-4-yl] oxy } -N-pyridin-2- yl)benzamide;

4-[[7-(2-{morpholin-4-yl}ethoxy)-6-(but-2-ynoylamino)quinolin-4-yl]oxy]-N-(4- methylpyridin-2-yl)benzamide;

4-[(6-((5-hydroxypent-2-ynoyl)amino)quinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(2-{morpholin-4-yl}ethoxy)quinolin-4-yl]oxy]-N-(4- methoxypyridin-2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(3-{l-piperidyl}propoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolin-4-yl]oxy]-N- (pyridin-2-yl)benzamide;

4- [ [6-(but-2-ynoy lamino)-7- [2-( 1 -pyrrolidy l)ethoxy ] quinolin-4-yl] oxy] -N-(2- pyridyl)benzamide;

4-[[6-(acryloylamino)-7-[2-(l-pyrrolidyl)ethoxy]quinolin-4-yl]oxy]-N-(2- pyridyl)benzamide;

4-[(l-(but-2-ynoyl)-2,3-dihydro-lH-[l,4]oxazino[3,2-g]quinolin-9-yl)oxy]-N-(pyridin-2- yl)benzamide; 4- {[6-[[(i?)-4-(dimethylamino)but-2-enoyl]amino]-7-methoxyquinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6-[4-(4-ethylpiperazin-l -yl)but-2-ynoylamino]-7-methoxyquinolin-4-yl]oxy} -N- (pyridine-2-yl)benzamide;

4- {[6-(5-hydroxypent-2-ynoylamino)-7-methoxyquinolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-methoxyquinolin-4-yl]oxy]-N-(4-methoxypyridin-2- yl)benzamide;

4-[[6-(4-(morpholin-4-yl)butyno-2-ylamino)-7-methoxyquinolin-4-yl]oxy]-N-(4- methoxypyridin-2-yl)benzamide;

4- {[6-(5-morpholinopent-2-ynoylamino)-7-methoxyquinolin-4-yl]oxy}-N-(4- methoxypyridin-2-yl)benzamide;

4- {[6-(but-2-ynoylamino)-7-[(3i?)-l-methylpyrrolidin-3-yl]oxyquinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide;

4- {[6-(acryloylamino)-7-[(3i?)-l-methylpyrrolidin-3-yl]oxyquinolin-4-yl]oxy}-N-(pyridin- 2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(3-(dimethylamino)propoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[[6-(acryloylamino)-7-(3-(dimethylamino)propoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(2-(dimethylamino)ethoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[[6-(acryloylamino)-7-(2-(dimethylamino)ethoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[(l-(4-methoxybut-2-ynoyl)-2,3-dihydro-lH-[l,4]oxazino[3,2-g]quinolin-9-yl)oxy]-N- (pyridin-2-yl)benzamide;

4-[[6-(acryloylamino)-7-(2-(4-methylpiperazin-l-yl)ethoxy)quinolin-4-yl]oxy]-N-(pyridin- 2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(2-(4-methylpiperazin-l-yl)ethoxy)quinolin-4-yl]oxy]-N- (pyridin-2-yl)benzamide; 4-[[6-(acryloylamino)-7-(3-(4-methylpiperazin-l-yl)propoxy)quinolin-4-yl]oxy]-N-(pyridin- 2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(3-hydroxypropoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-{[(2<S -2,3-dihydroxypropyl]oxy}quinolin-4-yl]oxy]-N-(pyridin- 2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-{[(2i?)-2,3-dihydroxypropyl]oxy}quinolin-4-yl]oxy]-N- (pyridin-2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(2-hydroxyethoxy)quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4-[[6-(acryloylamino)-7-(3-hydroxypropoxy)quinolin-4-yl]oxy]-N-(pyridin-2-yl)benzamide;

4-[[6-(acryloylamino)-7-{[(2<S -2,3-dihydroxypropyl]oxy}quinolin-4-yl]oxy]-N-(pyridin-2- yl)benzamide;

4- [ [6-(acryloylamino)-7- { [(2i?)-2,3 -dihydroxypropy 1] oxy} quinolin-4-y 1] oxy] -N-(pyridin-2- yl)benzamide;

4-[[6-(acryloylamino)-7-(2-hydroxyethoxy)quinolin-4-yl]oxy]-N-(pyridin-2-yl)benzamide;

4-[[6-(but-2-ynoylamino)-7-[3-(l-pyrrolidyl)propoxy]quinolin-4-yl]oxy]-N-(2- pyridyl)benzamide;

4-[[6-(acryloylamino)-7-[3-(l-pyrrolidyl)propoxy]quinolin-4-yl]oxy]-N-(2- pyridyl)benzamide;

4-[[6-(but-2-ynoylamino)-7-(2-morpholino-2-oxo-ethoxy)-4-quinolyl]oxy]-N-(2- pyridyl)benzamide;

4-[[6-(but-2-ynoylamino)-7-[2-(3-oxomorpholin-4-yl)ethoxy]-4-quinolyl]oxy]-N-(2- pyridyl)benzamide; and

4- [ [6-(but-2-ynoy lamino)-7- [3 -(3 -oxomorpholin-4-yl)propoxy ] -4-quinoly 1] oxy ]-N-(2- pyridyl)benzamide.

11. A compound of Formula IV:

Formula IV

or a pharmaceutically acceptable salt thereof, wherein:

T is CH or N;

U is CH or N;

V is NR5, O, S, SO or S02;

W is CH, N, O or S;

X is C(Re), N, O or S;

Y is CH, N or bond;

Z is CH or N;

with the proviso that:

0 to 2 atoms of W, X, Y can simultaneously be a heteroatom;

- when one atom selected from W, X, Y is O or S, then another atom selected from W, X, Y can not be O or S;

- when Y is CH or N then X is C(Re) or N and W is CH or N;

Ri is H, (Ci-4)alkyl optionally substituted with R7 or C(0)R7, or (Ci-5)alkoxy optionally substituted with R7 or C(0)R7, or 0-(C2-6)heterocycloalkyl optionally substituted with hydroxyl or (Ci-4)alkyl

R3 is H, (Ci-3)alkyl optionally substituted with R7, or (C3-7)cycloalkyl optionally substituted with R7

R4 is RiiC(O);

Ri and R3 together may form a (C2-6)heterocycloalkyl

R5 is H or (Ci-3)alkyl;

R2 is H, halogen, cyano, (Ci-4)alkyl, (C2-4)alkenyl, (C2-4)alkynyl, (Ci-3)alkoxy, (C3-6) cycloalkyl; all alkyl groups of R2 are optionally substituted with one or more halogen; or R2 is (C6-io)aryl or (C2-6)heterocycloalkyl;

R6 is H or (Ci-3)alkyl; or

R2 and Re together may form a (C3-7)cycloalkenyl, or (C2-6)heterocycloalkenyl; each optionally substituted with (Ci-3)alkyl, or one or more halogen;

R7 is H, (Ci-3)alkoxy, or a (C2-6)heterocycloalkyl; (one or more) hydroxyl, [(C1-4) alkyl]amino, di[(Ci-4)alkyl]amino, (C3-7)cycloalkoxy;

R11 is independently selected from a (C2-6)alkenyl and (C2-6)alkynyl each alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (Ci-4)alkyl, (C3-7) cycloalkyl, (Ci-3)alkoxy, (C3-7)cycloalkoxy, (Ce-io)aryl, (C3-7)heterocycloalkyl, [(Ci-4) alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, or di[(Ci-4) alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy.

12. The compound of any of Claims 1 to 11 for use in the treatment of Bruton's Tyrosine Kinase (BTK) mediated disorders.

13. Use of a compound of Formula I, Formula II, Formula III, or Formula IV or a

pharmaceutically acceptable salt thereof according to any of the Claims 1 to 11 for the manufacture of a medicament for the treatment of a Bruton's Tyrosine Kinase (BTK) mediated disorder.

14. The use of Claim 13, wherein the Bruton's Tyrosine Kinase (BTK) mediated disorder is selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head, neck, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, aquired immune deficiency syndrome (AIDS)-related lymphoma, Kaposi's sarcoma, viral-induced cancer, glioblastoma, esophogeal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's lymphoma, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, ulcerative colitis, atopic dermatitis, pouchitis,

spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spoldylitis, Crohn's Disease, lupus, and lupus nephritis.

15. A method of treating a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or an autoimmune disorder comprising the steps of administering a therapeutically effective amount of a compound of Formula I, Formula II, Formula III, or Formula TV or a pharmaceutically acceptable salt thereof.

16. The method of Claim 15, wherein the hyperproliferative disorder is selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head, neck, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, aquired immune deficiency syndrome (AIDS)-related lymphoma, Kaposi's sarcoma, viral- induced cancer, glioblastoma, esophogeal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, and stage IV melanoma.

17. The method of Claim 15, wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spoldylitis, Crohn's Disease, lupus, and lupus nephritis.

18. A method of treating a solid tumor cancer comprising the steps of administering a

therapeutically effective amount of a compound of Formula I, Formula II, Formula III, or Formula IV, or a pharmaceutically acceptable salt thereof, wherein the therapeutically effective amount is effective to inhibit signaling between the solid tumor cancer cells and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid- derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

19. The method of Claim 18, wherein the solid tumor cancer is selected from the group

consisting of pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer.

20. A pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, or Formula IV or a pharmaceutically acceptable salt thereof according to any of Claims 1 to 11 , and at least one pharmaceutically acceptable excipient.

21. The pharmaceutical composition of Claim 21 , for use in treating a hyperproliferative

disorder, an inflammatory disorder, an immune disorder, an autoimmune disorder, or a BTK-mediated disorder.

22. The pharmaceutical composition of Claim 21, wherein the hyperproliferative disorder is selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head, neck, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, aquired immune deficiency syndrome (AIDS)-related lymphoma, Kaposi's sarcoma, viral-induced cancer, glioblastoma, esophogeal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, primary central nervous system lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, and stage IV melanoma.

23. The pharmaceutical composition of Claim 21, wherein the inflammatory disorder, immune disorder, or autoimmune disorder is selected from the group consisting of tumor

angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, psoriasis, eczema, scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spoldy litis, Crohn's Disease, lupus, and lupus nephritis.

Description:
QUINOLINE AND QUINAZOLINE COMPOUNDS

CROSS-REFERENCE TO RELATED APPLICATIONS

[001] This application claims the benefit of U.S. Provisional Application No. 62/062,823 filed on October 10, 2014, which is incorporated by reference herein in its entirety.

FIELD OF THE INVENTION

[002] In some embodiments, the present invention relates to heterocyclic compounds, to pharmaceutical compositions comprising these compounds, and to their use in therapy. In some embodiments, the present invention relates to the use of quinazoline and quinoline compounds in the treatment of Bruton's tyrosine kinase (BTK) mediated disorders.

BACKGROUND OF THE INVENTION

[003] B lymphocyte activation is critical in the generation of adaptive immune responses. Derailed B lymphocyte activation is a hallmark of many autoimmune diseases and modulation of this immune response is therefore of therapeutic interest. Recently, the success of B cell therapies in autoimmune diseases has been established. Treatment of rheumatoid arthritis (RA) patients with rituximab (anti-CD20 therapy) is an accepted clinical therapy. More recent clinical trial studies show that treatment with rituximab also ameliorates disease symptoms in relapsing remitting multiple sclerosis (RRMS) and systemic lupus erythematosus (SLE) patients. This success supports the potential for future therapies in autoimmune diseases targeting B cell immunity.

[004] Bruton's tyrosine kinase (BTK) is a Tec family non-receptor protein kinase expressed in B cells and myeloid cells. The function of BTK in signaling pathways activated by the engagement of the B cell receptor (BCR) and FcsRl on mast cells is well established. In addition, a function for BTK as a downstream target in Toll like receptor signaling is suggested. BTK is composed of the pleckstrin homology (PH), Tec homology (TH), Src homology 3 (SH3), Src homology 2 (SH2), and tyrosine kinase or Src homology 1 (TK or SHI) domains. The function of BTK in signaling pathways activated by the engagement of the B cell receptor (BCR) in mature B cells and FCER1 on mast cells is well established. Functional mutations in BTK in humans result in a primary immunodeficiency disease (X-linked agammaglobuinaemia) characterized by a defect in B cell development with a block between pro- and pre-B cell stages. The result is an almost complete absence of B lymphocytes, causing a pronounced reduction of serum immunoglobulin of all classes. These findings support a key role for BTK in the regulation of the production of auto-antibodies in autoimmune diseases.

[005] BTK is expressed in numerous B cell lymphomas and leukemias. Other diseases with an important role for dysfunctional B cells are B cell malignancies, as described in Hendriks, et ah, Nat. Rev. Cancer, 2014, 14, 219-231. The reported role for BTK in the regulation of proliferation and apoptosis of B cells indicates the potential for BTK inhibitors in the treatment of B cell lymphomas. BTK inhibitors have thus been developed as potential therapies for many of these malignancies, as described in D'Cruz, et ah, OncoTargets and Therapy 2013, 6, 161- 176. With the regulatory role reported for BTK in FcsR- mediated mast cell activation, BTK inhibitors may also show potential in the treatment of allergic responses, as described in Gilfillan, et ah, Immunologic. Rev. 2009, 288, 149-169. Furthermore, BTK is also reported to be implicated in RANKL-induced osteoclast differentiation, as described in Shinohara, et ah, Cell 2008, 132, 794-806, and therefore may also be of interest for the treatment of bone resorption disorders. Other diseases with an important role for dysfunctional B cells are B cell

malignancies. Indeed anti-CD20 therapy is used effectively in the clinic for the treatment of follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia, as described in Lim, et ah , Haematologica, 2010, 95, 135-143. The reported role for BTK in the regulation of proliferation and apoptosis of B cells indicates there is potential for BTK inhibitors in the treatment of B cell lymphomas as well. Inhibition of BTK seems to be relevant in particular for B cell lymphomas due to chronic active BCR signaling, as described in Davis, et ah, Nature, 2010, 463, 88-94.

[006] In many solid tumors, the supportive microenvironment (which may make up the majority of the tumor mass) is a dynamic force that enables tumor survival. The tumor microenvironment is generally defined as a complex mixture of "cells, soluble factors, signaling molecules, extracellular matrices, and mechanical cues that promote neoplastic transformation, support tumor growth and invasion, protect the tumor from host immunity, forster therapeutic resistance, and provide niches for dominant metastases to thrive," as described in Swartz, et ah, Cancer Res., 2012, 72, 2473. Although tumors express antigens that should be recognized by T cells, tumor clearance by the immune system is rare because of immune suppression by the microenvironment. Addressing the tumor cells themselves with e.g. chemotherapy has also proven to be insufficient to overcome the protective effects of the microenvironment. New approaches are thus urgently needed for more effective treatment of solid tumors that take into account the role of the microenvironment.

[007] Some of the BTK inhibitors reported to date are not selective over Src-family kinases. With dramatic adverse effects reported for knockouts of Src-family kinases, especially for double and triple knockouts, this is seen as prohibitive for the development of BTK inhibitors that are not selective over the Src-family kinases. Both Lyn-deficient and Fyn-deficient mice exhibit autoimmunity mimicking the phenotype of human lupus nephritis. In addition, Fyn- deficient mice also show pronounced neurological defects. Lyn knockout mice also show an allergic-like phenotype, indicating Lyn as a broad negative regulator of the IgE-mediated allergic response by controlling mast cell responsiveness and allergy-associated traits, as described in Odom, et al, J. Exp. Med., 2004, 199, 1491-1502. Furthermore, aged Lyn knock-out mice develop severe splenomegaly (myeloid expansion) and disseminated monocyte/macrophage tumors, as described in Harder, et al, Immunity, 2001, 15, 603-615. These observations are in line with hyperresponsive B cells, mast cells and myeloid cells, and increased Ig levels observed in Lyn-deficient mice. Female Src knockout mice are infertile due to reduced follicle development and ovulation, as described in Roby, et al, Endocrine, 2005, 26, 169-176. The double knockouts Src-/-Fyn-/- and Src-/- Yes-/- show a severe phenotype with effects on movement and breathing. The triple knockouts Src-/-Fyn-/-Yes-/- die at day 9.5, as shown by Klinghoffer, et al, EMBO J, 1999, 18, 2459-2471. For the double knockout Src-/-Hck-/-, two thirds of the mice die at birth, with surviving mice developing osteopetrosis, extramedullary hematopoiseis, anemia, leukopenia, as shown by Lowell, et al, Blood, 1996, 87, 1780-1792. Hence, an inhibitor that inhibits multiple or all kinases of the Src-family kinases simultaneously may cause serious adverse effects.

SUMMARY OF THE INVENTION

[008] In an embodiment, the invention includes a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N, with the proviso that if B is N, A is CH;

B is CH or N, with the proviso that if A is N, B is CH;

T is CH or N;

U is CH or N;

V is NR 5 , O, S, SO or S0 2 ;

W is CH, N, O or S;

X is C(Re), N, O or S;

Y is CH, N or bond;

Z is CH or N;

with the proviso that:

0 to 2 atoms of W, X, Y can simultaneously be a heteroatom;

- when one atom selected from W, X, Y is O or S, then another atom selected from W, X, Y can not be O or S;

- when Y is CH or N then X is C(Re) or N and W is CH or N;

Ri is H, (Ci-4)alkyl optionally substituted with R 7 or C(0)R 7 , or (Ci-5)alkoxy optionally substituted with R 7 or C(0)R 7 , or 0-(C2-6)heterocycloalkyl optionally substituted with hydroxyl or (Ci -4 )alkyl

R3 is H, (Ci-3)alkyl optionally substituted with R 7 , or (C3 -7 )cycloalkyl optionally substituted with R 7

R4 is H, RiiC(O), Ri 2 S(0), R13SO2, or (C 1-6 )alkyl optionally substituted with R M ;

Ri and R3 together may form a (C 2- 6)heterocycloalkyl

R 5 is H or (Ci -3 )alkyl; R 2 is H, halogen, cyano, (Ci-4)alkyl, (C 2 - 4 )alkenyl, (C 2-4 )alkynyl, (Ci-3)alkoxy, (C 3 - 6)cycloalkyl; all alkyl groups of R 2 are optionally substituted with one or more halogen; or R 2 is (C 6 -io)aryl or (C 2 -6)heterocycloalkyl;

R6 is H or (Ci-3)alkyl; or

R 2 and Re together may form a (C 3 -7)cycloalkenyl, or (C 2 -6)heterocycloalkenyl; each optionally substituted with (Ci-3)alkyl, or one or more halogen;

R7 is H, (Ci-3)alkoxy, or a (C 2 -6)heterocycloalkyl; (one or more) hydroxyl, [(Ci_

4)alkyl]amino, di[(Ci -4 )alkyl]amino, (C 3 -7)cycloalkoxy;

R 11 is independently selected from the group consisting of (Ci-6)alkyl, (C 2 -6)alkenyl and (C 2 - 6 )alkynyl each alkyl, alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (Ci -4 )alkyl, (C 3 -7)cycloalkyl, (Ci-3)alkoxy, (C 3 -7)cycloalkoxy, [(Ci_ 4 )alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, di[(Ci_ 4 )alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, (C 6 -io)aryl or (C 3 -7)heterocycloalkyl, or

R 11 is (Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano.

R 12 and Ri 3 are independently selected from the group consisting of (C 2 -6)alkenyl or (C 2 -

6 ) alkynyl both optionally substituted with one or more groups selected from hydroxyl, (Ci_ 4 )alkyl, (C 3 .7)cycloalkyl, [(Ci -4 )alkyl]amino, di[(Ci -4 )alkyl]amino, (Ci.3)alkoxy, (C 3 .

7) cycloalkoxy, (C 6 -io)aryl, or (C 3 -7)heterocycloalkyl; or

(Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano;

Ri 4 is independently selected from the group consisting of halogen, cyano or (C 2 -6)alkenyl or (C 2 -6)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (Ci -4 )alkyl, (C 3 .7)cycloalkyl, [(Ci -4 )alkyl]amino, di[(Ci -4 )alkyl]amino, (C 3-7 ) cycloalkoxy, (C 6 -io)aryl, (Ci-5)heteroaryl or (C 3 -7)heterocycloalkyl. DETAILED DESCRIPTION OF THE INVENTION

[009] While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention.

[0010] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

[0011] The terms "co-administration," "co-administering," "administered in combination with," and "administering in combination with" as used herein, encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more agents are present.

[0012] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application {in vitro or in vivo), or the subject and disease condition being treated {e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells, {e.g., the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0013] A "therapeutic effect" as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0014] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, gly colic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In selected embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves

intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

[0015] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the described compositions.

[0016] "Prodrug" is intended to describe a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgaard, Design of Prodrugs, Elsevier, Amsterdam, 1985). The term "prodrug" is also intended to include any covalently bonded carriers, which release the active compound in vivo when administered to a subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the active parent compound. Prodrugs include, for example, compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetates, formates and benzoate derivatives of an alcohol, various ester derivatives of a carboxylic acid, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound.

[0017] The term "in vivo" refers to an event that takes place in a subject's body.

[0018] The term "in vitro" refers to an event that takes places outside of a subject's body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0019] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13 C- or 14 C-enriched carbons, are within the scope of this invention.

[0020] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary from, for example, between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that "consist of or "consist essentially of the described features.

[0021] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (Ci-io)alkyl or Cno alkyl). Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range - e.g., "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term "alkyl" where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1 -methylethyl (iso-propyl), n-butyl, n-pentyl, 1 , 1 -dimethylethyl (t-butyl) and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , - N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), - S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0022] "Alkylaryl" refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0023] "Alkylhetaryl" refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0024] "Alkylheterocycloalkyl" refers to an -(alkyl) heterocycyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.

[0025] An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

[0026] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C 2 -io)alkenyl or C 2 - 10 alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range - e.g., "2 to 10 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-l-enyl (i.e., allyl), but-l-enyl, pent-l-enyl and penta-l,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , - N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0027] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl radical where alkenyl and cyclo alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.

[0028] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C 2 -io)alkynyl or C 2 - 10 alkynyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range - e.g., "2 to 10 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,

tnfluoromethyl, tnfluoromethoxy, mtro, tnmethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a ,

-N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0029] "Alkynyl-cycloalkyl" refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.

[0030] "Carboxaldehyde" refers to a -(C=0)H radical.

[0031] "Carboxyl" refers to a -(C=0)OH radical.

[0032] "Cyano" refers to a -CN radical.

[0033] "Cycloalkyl" refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C3-io)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range - e.g., "3 to 10 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , - N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0034] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0035] "Cycloalkyl-heterocycloalkyl" refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and

heterocycloalkyl, respectively.

[0036] "Cycloalkyl-heteroaryl" refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0037] The term "alkoxy" refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. "Lower alkoxy" refers to alkoxy groups containing one to six carbons.

[0038] The term "substituted alkoxy" refers to alkoxy wherein the alkyl constituent is substituted (i.e., -0-(substituted alkyl)). Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , - C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , - N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a )2, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0039] The term "alkoxycarbonyl" refers to a group of the formula (alkoxy)(C=0)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (Ci-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.

[0040] The term "substituted alkoxycarbonyl" refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality. Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , - N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), - S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0041] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-,

(heteroalkyl)-C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , - N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), - S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0042] "Acyloxy" refers to a R(C=0)0- radical wherein "R" is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the "R" of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , - OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , - N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), - S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0043] "Amino" or "amine" refers to a -N(R a ) 2 radical group, where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a -N(R a ) 2 group has two R a substituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, -N(R a ) 2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,

trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a ,

-N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0044] The term "substituted amino" also refers to N-oxides of the groups -NHR d , and NR d R d each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0045] "Amide" or "amido" refers to a chemical moiety with formula -C(0)N(R) 2 or

-NHC(0)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. The R 2 of -N(R) 2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7- membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

[0046] "Aromatic" or "aryl" or "Ar" refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -Cio aromatic or C 6 -Cio aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 10" refers to each integer in the given range; e.g., "6 to 10 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, mtro, tnmethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 ,

-N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or

heteroarylalkyl.

[0047] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0048] "Ester" refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano,

trifluoromethyl, trifluoromethoxy, nitro, tnmethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a ,

-N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0049] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0050] "Halo", "halide", or, alternatively, "halogen" is intended to mean fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl" and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0051] "Heteroalkyl", "heteroalkenyl" and "heteroalkynyl" include optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given - e.g., C 1 -C 4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, tnmethylsilanyl, -OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , - OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 ,

N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2),

-S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0052] "Heteroalkylaryl" refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0053] "Heteroalkylheteroaryl" refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0054] "Heteroalkylheterocycloalkyl" refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and

heterocycloalkyl, respectively.

[0055] "Heteroalkylcycloalkyl" refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[0056] "Heteroaryl" or "heteroaromatic" or "HetAr" refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range - e.g., "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene. A N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The poly cyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, benzo[b][l,4]oxazinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[<fJpyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-<fjpyrimidinyl, 5,6-dihydrobenzo[ z]quinazolinyl, 5,6-dihydrobenzo[ z]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[<fjpyrimidinyl, 5,6,7,8,9,10- hexahydrocycloocta[<fJpyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta[<fjpyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6- naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,l 0,10a- octahydrobenzo[/z]quinazolinyl, 1 -phenyl- lH-pyrrolyl, phenazinyl, phenothiazinyl,

phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4- (fjpyrimidinyl, pyridinyl, pyrido[3,2-<fJpyrimidinyl, pyrido[3,4-<fJpyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- (fjpyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-<fjpyrimi dinyl, 5,6,7,8- tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-</Jpyrimidinyl, thieno[3,2-</Jpyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , -N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or PC>3(R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0057] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-0-) substituents, such as, for example, pyridinyl N-oxides.

[0058] "Heteroarylalkyl" refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.

[0059] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as "3 to 18" refers to each integer in the given range - e.g., "3 to 18 ring atoms" means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 3-oxopiperazinyl, 2-oxomorpholinyl, 3-oxomorpholinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 2-oxothiomorpholinyl, 3-oxothiomorpholinyl,l-oxo-thiomorpholinyl, and 1,1- dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a

heterocycloalkyl moiety is optionally substituted by one or more substituents which

independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, - OR a , -SR a , -OC(0)-R a , -N(R a ) 2 , -C(0)R a , -C(0)OR a , -OC(0)N(R a ) 2 , -C(0)N(R a ) 2 , - N(R a )C(0)OR a , -N(R a )C(0)R a , -N(R a )C(0)N(R a ) 2 , N(R a )C(NR a )N(R a ) 2 , -N(R a )S(0) t R a (where t is 1 or 2), -S(0) t OR a (where t is 1 or 2), -S(0) t N(R a ) 2 (where t is 1 or 2), or P0 3 (R a ) 2 , where each R a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0060] "Heterocycloalkyl" also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1 -3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.

[0061] "Nitro" refers to the -N0 2 radical.

[0062] "Oxa" refers to the -O- radical.

[0063] "Oxo" refers to the =0 radical.

[0064] "Isomers" are different compounds that have the same molecular formula.

"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn- Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S). Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (5 -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0065] "Enantiomeric purity" as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (<S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (^-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (^-isomer and 20% (i?)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle's reagents, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0066] In preferred embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et al, Enantiomers, Racemates and Resolutions, Wiley Interscience, New York, 1981 ; Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, NY, 1962; and Eliel and Wilen, Stereochemistry of Organic Compounds, Wiley, New York, 1994.

[0067] The terms "enantiomerically enriched" and "non-racemic," as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1 : 1 by weight). For example, an enantiomerically enriched preparation of the (5)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (5)-enantiomer relative to the (i?)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a "substantially enantiomerically enriched" or a "substantially non-racemic" preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight. The terms "enantiomerically pure" or "substantially enantiomerically pure" refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0068] "Moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0069] "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic

tautomerization" or "proton-shift tautomerization" involves the migration of a proton

accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g. in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4- hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.

[0070] A "leaving group or atom" is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site.

Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.

[0071] "Protecting group" is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York, 1999.

[0072] "Solvate" refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.

[0073] "Substituted" means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0074] "Sulfanyl" refers to groups that include -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted

heterocycloalkyl).

[0075] "Sulfinyl" refers to groups that include -S(0)-H, -S(0)-(optionally substituted alkyl), -S(0)-(optionally substituted amino), -S(0)-(optionally substituted aryl), -S(0)-(optionally substituted heteroaryl) and -S(0)-(optionally substituted heterocycloalkyl).

[0076] "Sulfonyl" refers to groups that include -S(0 2 )-H, -S(0 2 )-(optionally substituted alkyl), -S(0 2 )-(optionally substituted amino), -S(0 2 )-(optionally substituted aryl), -S(0 2 )-(optionally substituted heteroaryl), and -S(0 2 )-(optionally substituted heterocycloalkyl).

[0077] "Sulfonamidyl" or "sulfonamido" refers to a -S(=0)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=0) 2 -NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0078] "Sulfoxyl" refers to a -S(=0) 2 OH radical.

[0079] "Sulfonate" refers to a -S(=0)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and

heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0080] Compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

BTK Inhibitors

[0081] BTK inhibitors of the present invention may include BTK inhibitors that bind covalently to the target (in an irreversible manner), and BTK inhibitors that bind non-covalently to the target (in a reversible manner). In an embodiment, the BTK inhibitor is a compound of Formula I:

Formula I

or a pharmaceutically acceptable salt thereof, wherein:

A is CH or N, with the proviso that if B is N, A is CH;

B is CH or N, with the proviso that if A is N, B is CH;

T is CH or N;

U is CH or N;

V is NR 5 , O, S, SO or S0 2 ;

W is CH, N, O or S;

X is C(Re), N, O or S;

Y is CH, N or bond;

Z is CH or N;

with the proviso that:

0 to 2 atoms of W, X, Y can simultaneously be a heteroatom;

- when one atom selected from W, X, Y is O or S, then another atom selected from W, X, Y can not be O or S;

- when Y is CH or N then X is C(Re) or N and W is CH or N;

Ri is H, (Ci-4)alkyl optionally substituted with R 7 or C(0)R 7 , or (Ci-5)alkoxy optionally substituted with R 7 or C(0)R 7 , or 0-(C2-6)heterocycloalkyl optionally substituted with hydroxyl or (Ci -4 )alkyl

R3 is H, (Ci-3)alkyl optionally substituted with R 7 , or (C3 -7 )cycloalkyl optionally substituted with R 7

R4 is H, RiiC(O), Ri 2 S(0), R13SO2, or (C 1-6 )alkyl optionally substituted with R M ;

Ri and R3 together may form a (C 2- 6)heterocycloalkyl

R 5 is H or (Ci -3 )alkyl; R 2 is H, halogen, cyano, (Ci-4)alkyl, (C2- 4 )alkenyl, (C2 -4 )alkynyl, (Ci-3)alkoxy, (C 3 - 6)cycloalkyl; all alkyl groups of R2 are optionally substituted with one or more halogen; or R2 is (C 6 -io)aryl or (C2-6)heterocycloalkyl;

R6 is H or (Ci-3)alkyl; or

R2 and Re together may form a (C 3 -7)cycloalkenyl, or (C2-6)heterocycloalkenyl; each optionally substituted with (Ci-3)alkyl, or one or more halogen;

R7 is H, (Ci-3)alkoxy, or a (C2-6)heterocycloalkyl; (one or more) hydroxyl, [(Ci_

4)alkyl]amino, di[(Ci -4 )alkyl]amino, (C 3 -7)cycloalkoxy;

R11 is independently selected from the group consisting of (Ci-6)alkyl, (C2-6)alkenyl and (C2- 6 )alkynyl each alkyl, alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (Ci -4 )alkyl, (C 3 -7)cycloalkyl, (Ci-3)alkoxy, (C 3 -7)cycloalkoxy, [(Ci_ 4 )alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, di[(Ci_ 4 )alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, (C 6 -io)aryl or (C 3 -7)heterocycloalkyl, or

R11 is (Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano.

R12 and Ri3 are independently selected from the group consisting of (C2-6)alkenyl or (C2-

6 ) alkynyl both optionally substituted with one or more groups selected from hydroxyl, (Ci_ 4 )alkyl, (C 3 .7)cycloalkyl, [(Ci -4 )alkyl]amino, di[(Ci -4 )alkyl]amino, (Ci.3)alkoxy, (C 3 .

7) cycloalkoxy, (C 6 -io)aryl, or (C 3 -7)heterocycloalkyl; or

(Ci_5)heteroaryl optionally substituted with one or more groups selected from halogen or cyano;

Ri 4 is independently selected from the group consisting of halogen, cyano or (C2-6)alkenyl or (C2-6)alkynyl both optionally substituted with one or more groups selected from hydroxyl, (Ci -4 )alkyl, (C 3 .7)cycloalkyl, [(Ci -4 )alkyl]amino, di[(Ci -4 )alkyl]amino, (C 3 . 7)cycloalkoxy, (C 6 -io)aryl, (Ci_5)heteroaryl or (C 3 -7)heterocycloalkyl.

2] In an embodiment, the BTK inhibitor is a compound of Formula II:

Formula II

wherein all labels and groups are defined as above.

[0083] In an embodiment, the BTK inhibitor is a compound of Formula III:

Formula III

wherein all labels and groups are defined as above.

[0084] In an embodiment, the BTK inhibitor is a compound of Formula IV:

Formula IV

or a pharmaceutically acceptable salt thereof, wherein:

T is CH or N;

U is CH or N;

V is NR 5 , O, S, SO or S0 2 ;

W is CH, N, O or S;

X is C(Re), N, O or S;

Y is CH, N or bond;

Z is CH or N;

with the proviso that:

0 to 2 atoms of W, X, Y can simultaneously be a heteroatom;

- when one atom selected from W, X, Y is O or S, then another atom selected from W, X, Y can not be O or S;

- when Y is CH or N then X is C(Re) or N and W is CH or N;

Ri is H, (Ci-4)alkyl optionally substituted with R 7 or C(0)R 7 , or (Ci-5)alkoxy optionally substituted with R 7 or C(0)R 7 , or 0-(C 2 -6)heterocycloalkyl optionally substituted with hydroxyl or (Ci- 4 )alkyl

R3 is H, (Ci-3)alkyl optionally substituted with R 7 , or (C 3-7 )cycloalkyl optionally substituted with R 7

R4 is RiiC(O);

Ri and R3 together may form a (C 2 -6)heterocycloalkyl

R 5 is H or (Ci -3 )alkyl;

R 2 is H, halogen, cyano, (Ci -4 )alkyl, (C 2-4 )alkenyl, (C 2-4 )alkynyl, (Ci-3)alkoxy, (C 3 - 6 )cycloalkyl; all alkyl groups of R 2 are optionally substituted with one or more halogen; or R 2 is (C 6 -io)aryl or (C2-6)heterocycloalkyl;

R6 is H or (Ci-3)alkyl; or

R 2 and Re together may form a (C 3 -7)cycloalkenyl, or (C 2- 6)heterocycloalkenyl; each optionally substituted with (Ci-3)alkyl, or one or more halogen;

R 7 is H, (Ci-3)alkoxy, or a (C 2- 6)heterocycloalkyl; (one or more) hydroxyl, [(Ci_

4)alkyl]amino, di[(Ci -4 )alkyl]amino, (C 3 -7)cycloalkoxy;

R11 is independently selected from a (C 2- 6)alkenyl and (C 2- 6)alkynyl each alkenyl or alkynyl optionally substituted with one or more groups selected from hydroxyl, (Ci -4 )alkyl, (C 3 - 7)cycloalkyl, (Ci-3)alkoxy, (C 3 -7)cycloalkoxy, (C 6 -io)aryl, (C 3 -7)heterocycloalkyl, [(Ci_ 4)alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy, or di[(Ci_ 4)alkyl]amino optionally substituted with hydroxyl, halogen, or (Ci-3)alkoxy.

Pharmaceutical Compositions

[0085] In selected embodiments, the invention provides pharmaceutical compositions for treating solid tumor cancers, lymphomas and leukemia.

[0086] The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a BTK inhibitor as the active ingredients, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. Where desired, the pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0087] The pharmaceutical compositions are administered as BTK inhibitor. Where desired, other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations for use in combination separately or at the same time.

[0088] In selected embodiments, the concentration of each of the BTK inhibitors provided in the pharmaceutical compositions of the invention is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v, relative to the total mass or volume of the pharmaceutical composition.

[0089] In selected embodiments, the concentration of each of the BTK inhibitors provided in the pharmaceutical compositions of the invention is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v, relative to the total mass or volume of the pharmaceutical composition.

[0090] In selected embodiments, the concentration of each of the BTK inhibitors of the invention is independently in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12% or approximately 1% to approximately 10% w/w, w/v or v/v, relative to the total mass or volume of the pharmaceutical composition.

[0091] In selected embodiments, the concentration of each of the BTK inhibitors of the invention is independently in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v or v/v, relative to the total mass or volume of the pharmaceutical composition.

[0092] In selected embodiments, the amount of each of the BTK inhibitors of the invention is independently equal to or less than 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g or 0.0001 g.

[0093] In selected embodiments, the amount of each of the BTK inhibitors of the invention is independently more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5, or 3 g.

[0094] Each of the BTK inhibitors according to the invention is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently range from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0095] Described below are non-limiting pharmaceutical compositions and methods for preparing the same. Pharmaceutical Compositions for Oral Administration

[0096] In selected embodiments, the invention provides a pharmaceutical composition for oral administration containing a BTK inhibitor of Formula I, and a pharmaceutical excipient suitable for oral administration.

[0097] In selected embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a BTK inhibitor of Formula I and (ii) a pharmaceutical excipient suitable for oral administration. In selected embodiments, the composition further contains (iii) an effective amount of a fourth compound.

[0098] In selected embodiments, the pharmaceutical composition may be a liquid

pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients.

Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0099] The invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time.

Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.

Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[00100] Each of the BTK inhibitors as active ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[00101] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre- gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[00102] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[00103] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[00104] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[00105] When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[00106] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[00107] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[00108] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non- ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[00109] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids,

oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[00110] Within the aforementioned group, ionic surfactants include, by way of example:

lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[00111] Ionic surfactants may be the ionized forms of lecithin, lysolecithin,

phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[00112] Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[00113] Other hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[00114] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides;

hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil- soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[00115] In an embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use - e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[00116] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol,

hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen- containing compounds such as 2-pyrrolidone, 2-piperidone, £-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.- caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[00117] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose,

hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[00118] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

[00119] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti- foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[00120] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium. [00121] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p- toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

[00122] In selected embodiments, the invention provides a pharmaceutical composition for injection containing the BTK inhibitors and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[00123] The forms in which the compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[00124] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and thimerosal.

[00125] Sterile injectable solutions are prepared by incorporating the BTK inhibitors in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by

incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are spray-drying, vacuum-drying and freeze-drying (lyophilization) techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Other lyophilized or spray-dried formulations known to those of skill in the art may also be employed with the present invention. Such formulations include those disclosed in U.S. Patent Nos. 5,908,826, 6,267,958, 7,682,609, 7,592,004, and 8,298,530, and U.S. Patent Application Publication No. 2010/0158925, the teachings of which are specifically incorporated by reference herein.

Pharmaceutical Compositions for Topical Delivery

[00126] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing the BTK inhibitors and a pharmaceutical excipient suitable for transdermal delivery.

[00127] Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[00128] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[00129] Another formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of BTK inhibitors in controlled amounts, either with or without another agent.

[00130] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252; 4,992,445 and 5,001,139, the disclosures of which are incorporated by reference herein. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Other Pharmaceutical Compositions

[00131] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal admfantiinistration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, et ah, Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds. , Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.

[00132] Administration of the BTK inhibitors or pharmaceutical compositions of these compounds can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical {e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The combination of compounds can also be administered

intraadiposally or intrathecally.

[00133] Parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[00134] The invention also provides kits. The kits include each the BTK inhibitors, either alone or in combination in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another agent. In selected embodiments, the BTK inhibitors and the agent are provided as separate compositions in separate containers within the kit. In selected embodiments, the BTK inhibitors and the agent are provided as a single composition within a container in the kit.

Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in selected embodiments, be marketed directly to the consumer.

Dosages and Dosing Regimens

[00135] The amounts of the BTK inhibitors administered will be dependent on the mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day.

[00136] In selected embodiments, the BTK inibitor is administered in a single dose. Typically, such administration will be by injection, for example by intravenous injection, in order to introduce the agents quickly. However, other routes may be used as appropriate. A single dose of the BTK inhibitor may also be used for treatment of an acute condition.

[00137] In selected embodiments, the BTK inhibitor is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In other embodiments, the BTK inhibitor is administered about once per day to about 6 times per day. In another embodiment the administration of the BTK inhibitor continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[00138] Administration of the agents of the invention may continue as long as necessary. In selected embodiments, the BTK inhibitor is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the BTK inhibitor is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In selected embodiments, the BTK inhibitor is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects.

[00139] An effective amount of the combination of the BTK inhibitor may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

Methods of Treatment

[00140] In some embodiments, the invention relates to a method of treating a hyperproliferative disorder, an inflammatory disorder, an immune disorder, or autoimmune disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a BTK inhibitor, or a pharmaceutically acceptable salt, ester, prodrug, cocrystal, solvate, or hydrate of the BTK inhibitor.

[00141] In some embodiments, the invention relates to a method of treating, with a BTK inhibitor, a hyperproliferative disorder in a mammal selected from the group consisting of bladder cancer, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, head, neck, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, aquired immune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophogeal tumors, hematological neoplasms, primary central nervous system lymphoma, non-small-cell lung cancer (NSCLC), chronic myelocytic leukemia, diffuse large B-cell lymphoma (DLBCL), esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus infection, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non- Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, or stage IV melanoma. In selected embodiments, the invention relates to a method of treating with a BTK inhibitor disorders such as hyperproliferative disorder, including but not limited to cancer such as acute myeloid leukemia, thymus, brain, lung, squamous cell, skin, eye, retinoblastoma, intraocular melanoma, oral cavity and oropharyngeal, bladder, gastric, stomach, pancreatic, bladder, breast, cervical, head, neck, renal, kidney, liver, ovarian, prostate, colorectal, esophageal, testicular, gynecological, thyroid, CNS, PNS, AIDS-related (e.g., lymphoma and Kaposi's sarcoma) or viral-induced cancer. In some embodiments, said pharmaceutical composition is for the treatment of a non-cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g., benign prostatic hypertrophy (BPH)).

[00142] In some embodiments, the invention relates to a method of treating an inflammatory, immune, or autoimmune disorder in a mammal with a BTK inhibitor. In selected embodiments, the invention also relates to a method of treating a disease with a BTK inhibitor, wherein the disease is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcets disease, polymyalgia rheumatica, giant- cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spoldylitis, Crohn's Disease, lupus, and lupus nephritis.

[00143] In some embodiments, the invention relates to a method of treating a solid tumor cancer with a composition including a BTK inhibitor, wherein the dose is effective to inhibit signaling between the solid tumor cells and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts. In selected embodiments, the invention relates to a method of treating pancreatic cancer, breast cancer, ovarian cancer, melanoma, lung cancer, head and neck cancer, and colorectal cancer using a BTK inhibitor, wherein the dose is effective to inhibit signaling between the solid tumor cells and at least one microenvironment selected from the group consisting of macrophages, monocytes, mast cells, helper T cells, cytotoxic T cells, regulatory T cells, natural killer cells, myeloid-derived suppressor cells, regulatory B cells, neutrophils, dendritic cells, and fibroblasts.

[00144] In some embodiments, the hyperproliferative disorder is a solid tumor cancer selected from the group consisting of bladder cancer, squamous cell carcinoma, head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thyoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity cancer, oropharyngeal cancer, gastric cancer, stomach cancer, cervical cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, prostate cancer, colorectal cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancers such as cervical carcinoma (human papillomavirus), B-cell lymphoproliferative disease, nasopharyngeal carcinoma (Epstein-Barr virus), Kaposi's sarcoma and primary effusion lymphomas (Kaposi's sarcoma herpesvirus), hepatocellular carcinoma (hepatitis B and hepatitis C viruses), and T-cell leukemias (Human T-cell leukemia virus- 1), glioblastoma, esophogeal tumors, head and neck tumor, metastatic colon cancer, head and neck squamous cell carcinoma, ovary tumor, pancreas tumor, renal cell carcinoma, hematological neoplasms, small-cell lung cancer, non-small-cell lung cancer, stage IV melanoma, and glioma.

[00145] In some embodiments, the hyperproliferative disorder is a B cell hematological malignancy selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic leukemia (SLL), non-Hodgkin's lymphoma (NHL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), Hodgkin's lymphoma, B cell acute lymphoblastic leukemia (B-ALL), Burkitt's lymphoma, Waldenstrom's

macroglobulinemia (WM), Burkitt's lymphoma, multiple myeloma, myelodysplatic syndromes, or myelofibrosis. In an embodiment, the invention relates to a method of treating a cancer in a mammal, wherein the cancer is chronic myelocytic leukemia, acute myeloid leukemia, DLBCL (including activated B-cell (ABC) and germinal center B-cell (GCB) subtypes), follicle center lymphoma, Hodgkin's disease, multiple myeloma, indolent non-Hodgkin's lymphoma, and mature B-cell ALL.

[00146] In some embodiments, the hyperproliferative disorder is a subtype of CLL. A number of subtypes of CLL have been characterized. CLL is often classified for immunoglobulin heavy- chain variable-region (IgVij) mutational status in leukemic cells. R. N. Damle, et al, Blood 1999, 94, 1840-47; T. J. Hamblin, et al, Blood 1999, 94, 1848-54. Patients with IgV H mutations generally survive longer than patients without IgV H mutations. ZAP70 expression (positive or negative) is also used to characterize CLL. L. Z. Rassenti, et al, N. Engl. J. Med. 2004, 351, 893-901. The methylation of ZAP-70 at CpG3 is also used to characterize CLL, for example by pyrosequencing. R. Claus, et al, J. Clin. Oncol. 2012, 30, 2483-91; J. A. Woyach, et al., Blood 2014, 123, 1810-17. CLL is also classfied by stage of disease under the Binet or Rai criteria. J. L. Binet, et al, Cancer 1977, 40, 855-64; K. R. Rai, T. Han, Hematol. Oncol. Clin. North Am. 1990, 4, 447-56. Other common mutations, such as l lq deletion, 13q deletion, and 17p deletion can be assessed using well-known techniques such as fluorescence in situ hybridization (FISH). In an embodiment, the invention relates to a method of treating a CLL in a human, wherein the CLL is selected from the group consisting of IgV H mutation negative CLL, ZAP-70 positive CLL, ZAP-70 methylated at CpG3 CLL, CD38 positive CLL, chronic lymphocytic leukemia characterized by a 17pl3.1 (17p) deletion, and CLL characterized by a 1 lq22.3 (l lq) deletion.

[00147] In some embodiments, the hyperproliferative disorder is a CLL wherein the CLL has undergone a Richter's transformation. Methods of assessing Richter's transformation, which is also known as Richter's syndrome, are described in P. Jain and S. O'Brien, Oncology, 2012, 26, 1146-52. Richter's transformation is a subtype of CLL that is observed in 5-10% of patients. It involves the development of aggressive lymphoma from CLL and has a generally poor prognosis.

[00148] In some embodiments, the hyperproliferative disorder is a CLL or SLL in a patient, wherein the patient is sensitive to lymphocytosis. In an embodiment, the invention relates to a method of treating CLL or SLL in a patient, wherein the patient exhibits lymphocytosis caused by a disorder selected from the group consisting of a viral infection, a bacterial infection, a protozoal infection, or a post-splenectomy state. In an embodiment, the viral infection in any of the foregoing embodiments is selected from the group consisting of infectious mononucleosis, hepatitis, and cytomegalovirus. In an embodiment, the bacterial infection in any of the foregoing embodiments is selected from the group consisting of pertussis, tuberculosis, and brucellosis.

[00149] In some embodiments, the hyperproliferative disorder is selected from the group consisting of myeloproliferative disorders (MPDs), myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), myelodysplastic syndrome, chronic myelogenous leukemia (BCR-ABL1 -positive), chronic neutrophilic leukemia, chronic eosinophilic leukemia, or mastocytosis.

[00150] In some embodiments, the inflammatory, immune, or autoimmune disorder is selected from the group consisting of tumor angiogenesis, chronic inflammatory disease, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma and melanoma, ulcerative colitis, atopic dermatitis, pouchitis, spondylarthritis, uveitis, Behcet's disease, polymyalgia rheumatica, giant-cell arteritis, sarcoidosis, Kawasaki disease, juvenile idiopathic arthritis, hidratenitis suppurativa, Sjogren's syndrome, psoriatic arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, lupus, and lupus nephritis.

[00151] In some embodiments, the inflammatory, immune, or autoimmune disorder is a disease related to vasculogenesis or angiogenesis in a mammal which can manifest as tumor

angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.

[00152] In some embodiments, the inflammatory, immune, or autoimmune disorder is the treatment, prevention, and/or management of asthma. As used herein, "asthma" encompasses airway constriction regardless of the cause, including reactive airway disease. Common triggers of asthma include, but are not limited to, exposure to an environmental stimulants (e.g., allergens), cold air, warm air, perfume, moist air, exercise or exertion, and emotional stress. Also provided herein is a method of treating, preventing and/or managing one or more symptoms associated with asthma. Examples of the symptoms include, but are not limited to, severe coughing, airway constriction, and mucus production.

[00153] Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing other indicated diseases or disorders described here can also be tested using various models known in the art. Efficacy in treating, preventing and/or managing asthma can be assessed using the ova induced asthma model described, for example, in Lee, et ah, J. Allergy Clin. Immunol. 2006, 118, 403-9. Efficacy in treating, preventing and/or managing arthritis {e.g., rheumatoid or psoriatic arthritis) can be assessed using the autoimmune animal models described in, for example, Williams, et al., Chem. Biol. 2010, 17, 123-34, WO 2009/088986, WO 2009/088880, and WO 2011/008302. Efficacy in treating, preventing and/or managing psoriasis can be assessed using transgenic or knockout mouse model with targeted mutations in epidermis, vasculature or immune cells, mouse model resulting from spontaneous mutations, and immuno-deficient mouse model with xenotransplantation of human skin or immune cells, all of which are described, for example, in Boehncke, et al, Clinics in

Dermatology, 2007, 25, 596-605. Efficacy in treating, preventing and/or managing fibrosis or fibrotic conditions can be assessed using the unilateral ureteral obstruction model of renal fibrosis, which is described, for example, in Chevalier, et al., Kidney International 2009, 75, 1145-1152; the bleomycin induced model of pulmonary fibrosis described in, for example, Moore, et al, Am. J. Physiol. Lung. Cell. Mol. Physiol. 2008, 294, L152-L160; a variety of liver/biliary fibrosis models described in, for example, Chuang, et al., Clin. Liver Dis. 2008, 12, 333-347 and Omenetti, et al., Laboratory Investigation, 2007, 87, 499-514 (biliary duct-ligated model); or any of a number of myelofibrosis mouse models such as described in Varicchio, et ah, Expert Rev. Hematol. 2009, 2, 315-334. Efficacy in treating, preventing and/or managing scleroderma can be assessed using a mouse model induced by repeated local injections of bleomycin described, for example, in Yamamoto, et ah, J. Invest. Dermatol. 1999, 112, 456-462. Efficacy in treating, preventing and/or managing dermatomyositis can be assessed using a myositis mouse model induced by immunization with rabbit myosin as described, for example, in Phyanagi, et al. , Arthritis & Rheumatism, 2009, 60(10), 3118-3127. Efficacy in treating, preventing and/or managing lupus can be assessed using various animal models described, for example, in Ghoreishi, et al., Lupus, 2009, 19, 1029-1035; Ohl, et ah, J. Biomed. & Biotechnol., Article ID 432595 (2011); Xia, et al, Rheumatology, 2011, 50, 2187-2196; Pau, et al., PLoS ONE, 2012, 7(5), e36761; Mustafa et al, Toxicology, 2011, 90, 156-168; Ichikawa et al., Arthritis & Rheumatism, 2012, 62(2), 493-503; Rankin, et al., J. Immunology, 2012, 188, 1656- 1667. Efficacy in treating, preventing and/or managing Sjogren's syndrome can be assessed using various mouse models described, for example, in Chiorini, et al., J. Autoimmunity, 2009, 33, 190-196.

[00154] Efficacy of the compounds and combinations of compounds described herein in treating, preventing and/or managing the indicated diseases or disorders can be tested using various models known in the art. For example, models for determining efficacy of treatments for pancreatic cancer are described in Herreros-Villanueva, et al., World J. Gastroenterol. 2012, 18, 1286-1294. Models for determining efficacy of treatments for breast cancer are described, e.g., in Fantozzi, Breast Cancer Res. 2006, 8, 212. Models for determining efficacy of treatments for ovarian cancer are described, e.g., in Mullany, et al., Endocrinology 2012, 153, 1585-92; and Fong, et al., J. Ovarian Res. 2009, 2, 12. Models for determining efficacy of treatments for melanoma are described, e.g., in Damsky, et al., Pigment Cell & Melanoma Res. 2010, 23, 853- 859. Models for determining efficacy of treatments for lung cancer are described, e.g., in Meuwissen, et al., Genes & Development, 2005, 19, 643-664. Models for determining efficacy of treatments for lung cancer are described, e.g., in Kim, Clin. Exp. Otorhinolaryngol. 2009, 2, 55-60; and Sano, Head Neck Oncol. 2009, 1, 32. Models for determining efficacy of treatments for colorectal cancer, including the CT26 model, are described in Castle, et al, BMC Genomics, 2013, 15, 190; Endo, et al., Cancer Gene Therapy, 2002, 9, 142-148; Roth et al., Adv. Immunol. 1994, 57, 281-351; Fearon, et al, Cancer Res. 1988, 48, 2975-2980.

[00155] Models for determining efficacy of treatments in hematological malignancies, including B cell cancers, may also be used. For example, efficacy in diffuse large B cell lymphoma (DLBCL) may be assessed using the PiBCLl murine model and BALB/c (haplotype H-2d) mice. Illidge, et al, Cancer Biother. & Radiopharm. 2000, 15, 571-80. Efficacy in non-Hodgkin' s lymphoma (NHL) may be assessed using the 38C13 murine model with C3H/HeN (haplotype 2- Hk) mice or alternatively the 38C13 Her2/neu model. Timmerman, et al., Blood 2001, 97, 1370- 77; Penichet, et al., Cancer Immunolog. Immunother. 2000, 49, Efficacy in CLL may be assessed using the BCL1 model using BALB/c (haplotype H-2d) mice. Dutt, et al. , Blood, 2011, 117, 3230-29.

EXAMPLES

[00156] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein. Reagents described in the examples are commercially available or may be prepared according to procedures described in the literature.

[00157] The following abbreviations are used:

HATU 0-(7- Azabenzotriazol- 1 -y 1)- 1 , 1 ,3 ,3 -tetramethy luroniumhexafluoro phosphate

DMF N,N-Dimethylformamide

DCM Dichloromethane

EtOAc Ethyl acetate

DIPEA N,N-Diisopropylethylamine

THF Tetrahydrofuran

EtOH Ethanol

EDCI 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide

DMAP Dimethylamino pyridine

HPLC High pressure liquid chromatography

LiHMDS Lithium hexamethyldisilazide

MeOH Methanol

n-BuLi ft-Butyllithium

NMR Nuclear magnetic resonance

LC-MS Liquid chromatography - mass spectrometry

SCX-2 Strong cation exchange-2

KOtBu Potassium tert. butoxide

T3P Propylphosphonic anhydride

RT Room temperature

Rt Retention time

NMP 1 -Methyl-2-pyrrolidinone TFA Trifluoroacetic acid

DMSO Dimethyl sulfoxide

DIAD Diisopropyl azodicarboxylate

THP Tetrahydropyran

TBDMS tert-butyldimethylsilyl

TEA Triethylamine

Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium(0)

TLC Thin layer chromatography

Example 1 - General Synthesis of Quinazoline and Quinoline Derivatives

[00158] The quinazoline and quinoline derivatives included in the present invention can be prepared by methods well known in the art of organic chemistry. See, for example, March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons, 2001. During synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This is achieved by means of conventional protecting groups, such as those described in T.W. Greene and P.G.M. Wutts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999. The protective groups are optionally removed at a convenient subsequent stage using methods well known in the art.

[00159] The products of the reactions are optionally isolated and purified, if desired, using conventional techniques, but not limited to, filtration, distillation, crystallization,

chromatography and the like. Such materials are optionally characterized using conventional means, including the measurement of physical constants and spectral data.

[00160] Quinazoline and quinoline derivatives of Formula I can be prepared by the general synthetic route shown in Scheme 1 - 10.

Scheme 1

Scheme 3

Scheme 5

Scheme 6

Scheme 7

Scheme 9

[00161] The present invention also includes within its scope all stereoisomeric forms of the quinazoline and quinoline derivatives according to the present invention resulting, for example, because of configurational or geometrical isomerism. Such stereoisomeric forms include enantiomers, diastereoisomers, cis and trans isomers, etc. For example where 4-(morpholin-4- yl)pent-2-ynoic acid acid is used as carboxylic acid, there exists a mixture of two enantiomers. In the case of the individual stereoisomers of compounds of Formula I or salts or solvates thereof, the present invention includes the aforementioned stereoisomers substantially free, i.e., associated with less than 5%, preferably less than 2% and in particular less than 1% of the other stereoisomer. Mixtures of stereoisomers in any proportion, for example a racemic mixture comprising substantially equal amounts of two enantiomers are also included within the scope of the present invention.

[00162] For chiral compounds, methods for asymmetric synthesis whereby the pure

stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, synthesis starting from chiral intermediates, enantioselective enzymatic conversions, separation of stereoisomers using chromatography on chiral media. Such methods are described in Collins, et ah, eds., Chirality in Industry, John Wiley & Sons, 1992. Likewise, methods for synthesis of geometrical isomers are also well known in the art.

[00163] The quinazoline and quinoline derivatives of the present invention, which can be in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may also be obtained by treating the free base of Formula I with an organic or inorganic acid such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, and ascorbic acid.

[00164] The quinazoline and quinoline derivatives of the present invention also exist as amorphous forms. Multiple crystalline forms, also known as polymorphic forms, are also possible. All the physical forms are included within the scope of the present invention.

[00165] Preparation of solvates is generally known. Thus, for example, Caira, et ah, J. Pharm. Sci., 2004, 93, 601-611 describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hydrates and the like are described by van Tonder, et al., AAPS PharmSciTech., 2004, 5(1), article 12; and Bingham, et al., Chem. Commun. 2001, 603-604. A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example IR spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).

[00166] The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ¾ ¾ 13 C, 14 C, 15 N, 17 0, 18 0, 18 F, 32 P, 35 S, and 36 C1, respectively.

[00167] Certain isotopically-labelled compounds of Formula I (e.g. those labeled with 3 H and 14 C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Isotopically labelled compounds of Formula I can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples described below, by substituting an appropriate isotopically labeled reagent for a non-isotoplically labeled reagent.

Example 2 - Analytical Methods

[00168] The following liquid chromatography (LC) and mass spectrometry (MS) methods may be used to characterize compounds included in the present invention.

Method A

LC-MS spectrometer (Agilent)

Detector: DAD (210, 254 and 280 nm)

Mass detector: API-ES (10-2000 amu, pos./neg. ion mode)

Eluents (mobile phase): A: 0.1% formic acid in MilliQ-water, B: acetonitrile

Column: Waters XTerra CI 8 MS, 50x4.6 mm ID, 2.5 μιη Flow rate: 0.5 mL/min

Gradient elution program:

Time (mm) A (%) B (%)

0.0 90 10

7.0 10 90

7.1 0 100

10.0 90 10

Method B

LC-MS spectrometer (Waters); Detector: DAD (214 nm)

Mass detector: API-ES (100-1000 amu, pos./neg. ion mode)

Eluents (mobile phase): A: 0.1% trifluoroacetic acid (TFA) in water; B: acetonitrile

LC-MS flow method: Gradient

Column: Acquity HSS-T3 (2.1 x 100 mm x 1.8 μιη)

Flow rate: 0.3 mL/min

Gradient elution program:

Time (min) A (%) B (%)

0.0 90.0 10.0

1.0 90.0 10.0

2.0 85.0 15.0

4.5 45.0 55.0

6.0 10.0 90.0

8.0 10.0 90.0

9.0 90.0 10.0

10.0 90.0 10.0

Method C

HPLC: Gilson analytical HPLC system

Column: Phenomenex Luna CI 8(2) (100 x 2.00 mm, 5 μπι)

Detector: UV/Vis (210/240 nm)

Flow rate: 1 mL/min Eluents (mobile phase): A: acetonitrile, B: acetronitrile / MilliQ-waterwater = 1/9 (v/v), C: 0,1% TFA in MilliQ-water.

Gradient elution program:

Time (min) A (%) B (%) C(%)

0.00 0 97 3

11.90 97 0 3

14.40 97 0 3

15.40 0 97 3

Method D

HPLC: Waters analytical HPLC system; Column: SunFire-C18 (46 x 50 mm, 5

Detector: UV/Vis (210/240 nm), Flow: 1 mL/min.

Eluents (mobile phase): A: 5 mM ammonium acetate in water, B: Acetronitrile

Gradient elution program:

Time (mm) A (%) B (%)

0.0 90 10

1.5 90 10

6.0 10 90

8.0 10 90

8.5 90 10

10.0 90 10

Method E

HPLC: Waters analytical HPLC system; Column: X-Bridge Shield-RP-18 (46 x 250 mm, 5 μιη),

Detector: UV/Vis (210/240 nm), Flow: 1 mL/min.

Eluents: A: 5 mM ammonium acetate in water, B: Acetronitrile.

Gradient elution program:

Time (mm) A (%) B (%)

0.0 80 20

1.5 80 20

14.0 40 60 15.0 10 90

18.0 10 90

18.5 80 20

20.0 80 20

Example 3 - Preparation of 4-hydroxy-N-(pyridine-2-yl)benzamide (I-l)

[00169] To a stirred solution of 4-hydroxybenzoic acid methyl ester (7.35 g, 48.3 mmol, 1.0 eq.), 2-aminopyridine (6.0 g, 48.3 mmol, 1.0 eq.) in THF (60 mL) was added Me 3 Al (2.0 M in toluene, 60.4 mL, 121 mmol, 2.35 eq.) at 0 °C. The reaction mixture was heated at 80 °C for 4 h. After completion of reaction (monitored by TLC), the reaction mixture was poured into vigorously stirred satd. aq. NH 4 C1 solution. After stirring for 15 min, the mixture was extracted with 10% MeOH in DCM, dried over Na 2 S0 4 and evaporated. The crude product was recrystalized from hot ethyl acetate to obtain pure 4-hydroxy-N-(pyridine-2-yl)benzamide (I-l) (9.2 g, 89%) as a brown solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): 5(ppm) = 8.36 (dd, 1H, J = 1.0, 4.8 Hz), 8.16 (d, 1H, J = 8.4 Hz), 7.93 (d, 2H, J = 8.7 Hz), 7.80 (t, 1H, J = 5.7 Hz), 7.12 (dd, 1H, J = 1.0, 5.7 Hz), 6.83 (d, 2H, J = 8.7 Hz)

[00170] The following compounds were prepared using a method analogous to that used for the preparation ofI-l: 4-Hydroxy-N-(4-methoxypyridin-2-yl)benzamide (1-2); 4-Hydroxy-N-(4- methylpyridin-2-yl)benzamide (1-3).

Example 4 - Preparation of 4-hydroxy-N-(4-ethylpyridin-2-yl)benzamide (1-4)

[00171] Preparation of 4-benzyloxybenzoyl chloride. Oxalyl chloride (6.5 ml, 75.6 mmol, 1.5 eq.) was added to a suspension of 4-benzyloxybenzoic acid (1 1.5 g, 50.4 mmol) followed by the addition of DMF (0.3 mL, cat.). Gas formation was observed and the mixture was stirred for 2 hours at room temperature during which it became homogeneous. The volatile compounds were removed under reduced pressure (45 °C) and the residue was stripped with toluene, affording a light pink solid (13.4 g, quant.).

[00172] Preparation of 4-(benzyloxy)-N-(4-ethylpyridin-2-yl)benzamide. 4-Benzyloxybenzoyl chloride (3.24 g, 13 mmol, 1 eq.) was added portion wise over a suspension of 2-amino-4- ethylaniline (2.4 g, 19.5 mmol, 1.5 eq.) in 25 ml of pyridine and the resulting mixture was stirred for 18 hours at RT. Water was added to promote the precipitation of a white solid which was filtered and washed with water. The title compound was obtained as a white solid which was used without any further purification for next step (3.7 g, 86%).

[00173] Preparation of 4-hydroxy-N-(4-ethylpyridin-2-yl)benzamide. Pd/C (370 mg, 10% wt) was added to a solution of 4-(Benzyloxy)-N-(4-ethylpyridin-2-yl)benzamide (3.7 g, 11.1 mmol, 1 eq.) and ammonium formate (10.5 g, 167 mmol, 15 eq.) in EtOH/H^O (1 : 1, 60 mL) and the resulting heterogeneous mixture was stirred for 2 hours at 90 °C (ext.). The mixture was filtered over Celite and the residue was washed with EtOH and EtOAc. The filtrate was evaporated under reduced (50 °C) pressure and the crude compound was washed with water to remove residual NH 4 HCO 2 . Recrystallization from methanol provided the target compound as a white solid (2.0g, 74%). LC-MS (Method A) Rt: 5.00 mm; m/z 243.1 (M+H) + .

[00174] The following compounds were prepared using a method analogous to that used for the preparation of 1-4: 4-Hydroxy-N-(4-phenylpyridin-2-yl)benzamide (1-5).

Example 5 - Preparation of 4-hydroxy-N-(4-propylpyridin-2-yl)benzamide (1-6)

[00175] This compound was prepared essentially as described for the preparation of compound I-l. The starting material 4-propylpyridin-2-amine was prepared via a Chichibabin amination of 4-propylpyridine with sodium amide.

[00176] Preparation of 4-propylpyridin-2-amine. NaNH 2 (3.2 g, 82.5 mmol, 1.0 eq.) was pulverized to a fine powder and added to a solution of 4-propyl-pyridine (6) (10.0 g, 82.5 mmol) in /7-cymene (100 mL). The suspension was heated to 150 - 160 °C under N 2 . After ca. 30 minutes the mixture started to become darker until a fully black mixture was obtained.

Additional NaNH 2 was added in 1 hour intervals (3 χ 3.2 g, 3.0 eq.). After 6 hours, 1H NMR showed 15% starting material remaining but work-up was started regardless. The mixture was cooled to ca. 30 °C and poured slowly under stirring into ice- water (1 L). The aqueous phase was acidified with HC1 (6 N, pH < 5), washed with CH 2 C1 2 (2x 250 mL) and alkalized with NaOH (33%, pH > 8). The white suspension was extracted with CH 2 C1 2 (3x 250 mL), the combined organic layers were dried over Na 2 S0 4 and concentration in vacuo (45 °C) provided the crude product as a black oil (ca. 7 g). This was purified by filtration over silica (500 mL) (eluent: CH 2 Cl 2 /MeOH + NH 4 (7 N). 98:2 (2 L)→ 97:3 (2 L).) The purest fractions were combined and concentrated (vac, 45 °C) to provide the target compound as a brown oil (4.2 g, -10% starting material). Additional material (1.4 g) was isolated from mix-fractions (total yield 50%).

Example 6 - Preparation of 4-hvdroxy-N-(4-ethvnylpyridin-2-vDbenzamide (1-7)

[00177] Preparation of 4-((trimethylsilyl)ethyn-2-yl)pyridin-2-amine. A solution of 2-amino-4- bromopyridine (380 mg, 2.2 mmol), Pd(Pl¾) 4 (213 mg, 0.18 mmol) and triethyl amine (1.85 ml, 13 mol, 6 eq.) in THF (4 mL) was degassed with N 2 and stirred under N 2 for 40 minutes. Cul (100 mg; 0.53 mmol, 0.3 eq.) and (trimethylsilyl)acetylene (373 ul, 2.6 mmol, 1.2 eq.) were added and the mixture was stirred overnight at RT. The reaction mixture was diluted with ethyl acetate, washed with water, sat NH 4 Cl(aq) and brine, dried over Na 2 S0 4 and concentrated. The residue was purified by Si0 2 -chromatography (0 to 30% acetone in toluene) to afford the title compound (350 mg, 84%).

[00178] Preparation of 4-[(4-((trimethylsilyl)ethyn-2-yl)pyridin-2-yl)carbamoyl]phe nyl acetate. A solution of 4-acetoxybenzoyl chloride (1.3 g, 6.67 mmol 1.0 eq.) in dichloromethane (8 rriL) was added slowly to a solution of 4-((trimethylsilyl)ethyn-2-yl)pyridin-2-amine (1.27 g, 6.67 mmol) in pyridine (10 mL) and the brown solution was stirred overnight at RT. The reaction mixture was poured into water and extracted two times with dichloromethane. The combined organic extracts were washed with brine, dried over Na 2 S0 4 and concentrated in vacuo. The brown oil was taken up in toluene and concentrated in vacuo. The residue was purified by Si0 2 - chromatography (0 to 40% ethyl acetate in heptane) to give the title compound (1.32 g, 56%) as a yellow solid.

[00179] Preparation of 4-hydroxy-N-(4-ethynylpyridin-2-yl)benzamide. A suspension of 4-[(4- ((trimethylsilyl)ethyn-2-yl)pyridin-2-yl)carbamoyl]phenyl acetate (425 mg, 1.2 mmol) and K 2 CO 3 (217 mg, 1.6 mmol, 1.3 eq.) in methanol (15 mL) was stirred for 1 hour at RT. HC1 (6N in water, 540 iL, 3.2 mmol, 2.7 eq.) was added, silica was added and the mixture was concentrated. The solids were loaded on a Si0 2 -column and purified by Si0 2 -chromatography (0 to 100% ethyl acetate in heptane) to give the title compound (218 mg, 76%) as a light yellow solid. 1H NMR (400 MHz, CDC1 3 , 300K): δ (ppm) = 10.65 (1H, s), 10.20 (1H, br.s), 8.39 (1H, dd, Jl = 5.0 Hz, J2 = 0.8 Hz), 8.24 (1H, m), 7.93 (2H, d, J = 8.8 Hz), 7.20 (1H, dd, Jl = 5.0 Hz, J2 = 1.4 Hz), 6.82 (2H, d, J = 8.8 Hz), 4.61 (1H, s).

Example 7 - Preparation of 4-hvdroxy-N-(4-fluoropyridin-2-yl)benzamide (1-8)

1-8

[00180] Preparation of 4-[(4-fluoropyridin-2-yl)carbamoyl]phenyl acetate. A solution of 4- acetoxybenzoyl chloride (1.77 g, 8.92 mmol 1.0 eq.) in dichloromethane (8 mL) was added slowly to a solution of 2-amino-4-fluoropyridine (1.0 g, 8.92 mmol) in pyridine (10 mL) and the brown solution was stirred overnight at RT. The reaction mixture was concentrated to a small volume (to remove DCM), poured into water. The solids were filtered off, washed with water and taken up in toluene and concentrated in vacuo to yield the title compound (2.38 g, 97%) as an off white solid. LC-MS (Method A) Rt: 6.83 mm; m/z 275.1 (M+H) + .

[00181] Preparation of N-(4-fluoropyridin-2-yl)-4-hydroxybenzamide. A suspension of 4-[(4- fluoropyridin-2-yl)carbamoyl]phenyl acetate (2.38 g, 8.68 mmol) and K 2 CO 3 (1.56 g, 11.3 mmol, 1.3 eq.) in methanol (35 rriL) was stirred for 1 hour at RT. HC1 (6 N in water, 3.76 ml, 22.6 mmol, 2.7 eq.) was added (pH=~7), silica was added and the mixture was concentrated. The solids were loaded on a SiC -column and purified by Si0 2 -chromatography (0 to 100% ethyl acetate in heptane) to give the title compound (2.38 g, 97%) as a white solid. LC-MS (Method A): Rt: 5.98 mm; m/z 233.1 (M+H) + .

[00182] The following compounds were prepared using a method analogous to that used for the preparation of 1-8: 4-Hydroxy-N-(4-trifluoromethylpyridin-2-yl)benzamide (1-9).

Example 8 - Preparation of 4- 6-aminoquinazolin-4-yl)oxyl-N-(pyridin-2-yl)benzamide (1-10)

[00183] Preparation of 4-[(6-nitroquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide. A

suspension of 4-chloro-6-nitroquinazoline (85 mg, 0.41 mmol), 4-hydroxy-N-(pyridin-2- yl)benzamide (95 mg, 0.44 mmol, 1.1 eq.) and potassium carbonate (61 mg, 0.44 mmol, 1.1 eq.) in acetonitrile (5 mL) was heated in the microwave for 30 minutes at 130 °C. The newly formed solids were filtered off and washed with acetonitrile. The residue was washed through the filter with dichloromethane and concentrated in vacuo to give 130 mg of 4-[(6-nitroquinazolin-4- yl)oxy]-N-(pyndin-2-yl)benzamide (82%) as a white solid. 1H NMR (400 MHz, CDC1 3 , 300K): δ (ppm) = 7.11 (1H, ddd, Jl = 7.3 Hz, J2 = 5.0 Hz, J3 = 1.0 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.80 (1H, m), 8.11 (2H, d, J = 8.8 Hz), 8.20 (1H, d, J = 9.2 Hz), 8.33 (1H, m), 8.40 (1H, dt, Jl = 8.4 Hz, J2 = 0.9 Hz), 8.64 (1H, s), 8.72 (1H, dd, Jl = 9.2 Hz, J2 = 2.3 Hz), 8.93 (1H, s), 9.33 (1H, dd, Jl = 2.8 Hz, J2 = 0.5 Hz). [00184] Preparation of 4-[(6-aminoquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide. Raney Nickel (suspension in ethanol, 50 mg) was added to a suspension of 4-[(6-aminoquinazolin-4- yl)oxy]-N-(pyridin-2-yl)benzamide (53 mg, 0.14 mmol) and ammonium formate (100 mg, 1.5 mmol, 11 eq.) in ethyl acetate/ethanol (2: 1, 10 mL) and the mixture was stirred for 3 hours at 30 °C. The reaction mixture was filtered over decalite, washed with ethyl acetate and ethanol and the filtrate was concentrated in vacuo. The residue was purified by SiCVchromatography (0 to 40% acetone in toluene) to give 16 mg of 4-[(6-aminoquinazolin-4-yl)oxy]-N-(pyridin-2- yl)benzamide (32%) as a yellow solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 5.99 (2H, s), 7.19 (1H, ddd, Jl = 7.3 Hz, J2 = 4.9 Hz, J3 = 0.9 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.39 (1H, dd, Jl = 9.0 Hz, J2 = 2.6 Hz), 7.45 (2H, d, J = 8.8 Hz), 7.71 (1H, d, J = 9.0 Hz), 7.86 (1H, ddd, Jl = 9.3 Hz, J2 = 7.4 Hz, J3 = 1.9 Hz), 8.15 (2H, d, J = 8.8 Hz), 8.22 (1H, dt, Jl = 8.3 Hz, J2 = 0.9 Hz), 8.38 (1H, s), 8.41 (1H, ddd, Jl = 4.8 Hz, J2 = 1.9 Hz, J3 = 0.9 Hz), 10.88 (1H, s).

Example 9 - Preparation of 4-{[6-(acryloylamino)quinazolin-4-ylloxy}-N-(pyridin-2- vDbenzamide (E-l)

[00185] Acryoyl chloride (50% in dichloromethane, 26 μΐ ^ , 0.16 mmol, 0.8 eq.) was added to a solution of 4-[(6-aminoquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (1-10, 79 mg, 0.20 mmol) and diisopropylethyl amine (83 ul, 0.50 mmol, 2.5 eq.) in dichloromethane NMP (6: 1, 7 mL) and the solution was stirred for 1 hour. The reaction mixture was concentrated, water was added and the mixture was centrifuged. The supernatant was removed and the solids were washed with water, taken up in dichloromethane/methanol (1 : 1), dried over Na 2 S0 4 and concentrated in vacuo. The residue was purified by Si0 2 -chromatography (0 to 8% methanol in dichloromethane) to give 36 mg of 4- {[6-(acryloylamino)quinazolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide (55%). LC-MS (Method A) Rt: 5.99 mm; m/z 412.1 (M+H) + . 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 5.86 (1H, dd, Jl = 10.0 Hz, J2 = 1.9 Hz), 6.35 (1H, dd, Jl = 16.9 Hz, J2 = 1.9 Hz), 6.52 (1H, dd, Jl = 16.9 Hz, J2 = 10.0 Hz), 7.19 (1H, ddd, Jl = 7.3 Hz, J2 = 4.8 Hz, J3 = 0.9 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.87 (1H, m), 8.02 (1H, d, J = 9.0 Hz), 8.15 (1H, dd, Jl = 9.2 Hz, J2 = 2.4 Hz), 8.17 (2H, d, J = 8.8 Hz), 8.22 (1H, d, J = 8.3 Hz), 8.41 (1H, m), 8.67 (1H, s), 8.93 (1H, d, J = 2.3 Hz), 10.73 (1H, s), 10.91 (1H, s).

Example 10 - Preparation of 4- 6-(but-2-vnoylamino)quinazolin-4-ylloxy}-N-(pyridin-2- vDbenzamide (E-2)

[00186] Diisopropylethyl amine (70 μΐ, 0.42 mmol, 3.5 eq.) was added to a solution of 4-[(6- aminoquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (1-10, 116 mg, 0.32 mmol), 2-butynoic acid (10 mg, 0.12 mmol, 1.0 eq.) and HATU (54 mg, 0.14 mmol, 1.2 eq.) in

dichloromethane/NMP (3: 1, 6 rriL) and the solution was stirred 3 hours at RT. The reaction mixture was concentrated, water was added and the suspension was centrifuged. The supernatant was removed and the solid washed with water. The residue was taken up in ethanol, and concentrated. The residue was purified by the following preparative HPLC method: LUNA CI 8 column, 150 x 21.20 mm, 5 μηι particle size, mobile phase 0 to 100% acetonitrile in water + TFA, to give 26 mg of 4-{[6-(but-2-ynoylamino)quinazolin-4-yl]oxy}-N-(pyridin-2- yl)benzamide trifluoroacetate (45%) as a white solid. Other salts or the free base of E-2 may be prepared by standard methods. LC-MS (Method A) Rt: 6.30 min; m/z 424.1 (M+H) + . 1H NMR

(400 MHz, DMSO-D 6 , 300K): δ (ppm) = 2.10 (3H, s), 7.20 (1H, ddd, Jl = 7.3 Hz, J2 = 4.8 Hz, J3 = 0.9 Hz), 7.50 (2H, d, J = 8.8 Hz), 7.87 (1H, m), 8.00 (1H, d, J = 9.2 Hz), 8.07 (1H, dd, Jl = 9.1 Hz, J2 = 2.3 Hz), 8.17 (2H, d, J = 8.8 Hz), 8.22 (1H, dt, Jl = 8.4 Hz, J2 = 0.9 Hz), 8.41 (1H, d, J = 4.7 Hz), 8.67 (1H, s), 8.83 (1H, d, J = 2.3 Hz), 10.92 (1H, s), 11.20 (1H, s). Example 11 - Preparation of 4-[(6-aminoquinazolin-4-yl)oxyl-N-[4-(trifluoromethyl)pyridi n-2- vHbenzamide (1-11)

[00187] Preparation of 4-[(6-nitroquinazolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyridi n-2- yl]benzamide. Cesium carbonate (480 mg, 2.8 mmol, 2 eq.) was added to a solution of 1-9 (400 mg, 1.4 mmol) in dry THF (5 mL) and the mixture was stirred for one hour at RT. 4-chloro-6- nitroquinazoline (295 mg, 1.4 mmol, 1 eq.) was added and the mixture was stirred at 50 °C for 6 hours. The reaction mixture was poured into water and extracted two times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na 2 S0 4 and concentrated in vacuo. The residue was purified by Si0 2 -chromatography (0 to 100% ethyl acetate in heptane) to give 132 mg 4-[(6-nitroquinazolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyridi n-2-yl]benzamide (21%) as a yellow solid.

[00188] Preparation of 4-[(6-aminoquinazolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyridi n-2- yl]benzamide. Raney Nickel (suspension in ethanol, ca.100 mg) was added to a solution of 4- [(6-nitroquinazolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyridin- 2-yl]benzamide (26 mg, 0.06 mmol) in ethyl acetate/ethanol (2: 1, 20 mL) and the mixture was stirred for 2 hours under an atmosphere of hydrogen. The reaction mixture was filtered, concentrated and taken up in ethyl acetate/THF (3: 1). Extracted with 2 N NaOH, water and brine. The organic extract was dried over Na 2 S0 4 and concentrated. The residue was purified by Si0 2 -chromatography (0 to 40% acetone in toluene) to give 5 mg 4-[(6-aminoquinazolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyridi n-2- yl]benzamide (20%) as a yellow solid. LC-MS (Method A) Rt: 7.38 min; m/z 426.0 (M+H) + . Example 12 - Preparation of 4-{[6-(acryloylamino)quinazolin-4-ylloxy}-N-[4- (trifluoromethyl)pyridin-2-yllbenzamide (E-3)

[00189] This compound was prepared, in an analogous manner as described for compound E-l from compound I-ll and acryloyl chloride to afford the title compound (37 mg, 86%). LC-MS (Method A) Rt: 7.86 mm; m/z 480.0 (M+H)+. 1H NMR (400 MHz, CDC1 3 , 300 K): δ (ppm) =5.89 (1H, dd, Jl = 10.2 Hz, J2 = 1.1 Hz), 6.35 (1H, dd, Jl = 16.8 Hz, J2 = 10.2 Hz), 6.55 (1H, dd, Jl = 16.8 Hz, J2 = 1.1 Hz), 7.32 (1H, d, J = 5.1 Hz), 7.45 (2H, d, J = 8.9 Hz), 7.67 (1H, s), 7.96 (1H, dd, Jl = 9.1 Hz, J2 = 2.4 Hz), 8.02 (1H, d, J = 9.0 Hz), 8.07 (2H, d, J = 8.9 Hz), 8.49 (1H, d, J = 5.1 Hz), 8.71 (1H, s), 8.73 (1H, s), 8.75 (1H, s), 8.86 (1H, d, J = 2.1 Hz).

Example 13 - Preparation of 4-{[6-(butvno-2-ylamino)quinazolin-4-ylloxy}-N-(4- trifluoromethylpyridin-2-yl)benzamide (E-4)

[00190] This compound was prepared, in an analogous manner as described for compound E-2 from compound I-ll and 2-butynoic acid, to afford the title compound (10 mg, 21%) as a white solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 2.10 (3H, s), 7.52 (2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 5.3 Hz), 8.00 (1H, d, J = 9.1 Hz), 8.07 (1H, dd, Jl = 9.0 Hz, J2 = 2.4 Hz), 8.19 (2H, d, J = 8.8 Hz), 8.57 (1H, s), 8.67 (1H, s), 8.69 (1H, d, J = 5.4 Hz), 8.83 (1H, d, J = 2.3 Hz). Example 14 - Preparation of 4-[(6-aminoquinazolin-4-yl)aminol-N-(pyridin-2-yl)benzamide (I-

12}

[00191] Preparation of N'-(2-cyano-4-nitrophenyl)-N,N-dimethylimidoformamide. A mixture of 5-nitroantranilonitrile (5.0 g, 36.5 mmoles) and dimethylformamide dimethyl acetal (20 mL) was refluxed for 2 h. The resulting mixture was cooled and filtered. The solid was washed with several portions of diethyl ether and dried in vacuo to yield 6.45 g of N-(2-cyano-4-nitrophenyl)- N,N-dimethylimidoformamide (81%) as a yellow solid.

[00192] Preparation of 4-[(6-nitroquinazolin-4-yl)amino]-N-(pyridin-2-yl)benzamide. iV-(2- cyano-4-nitrophenyl)-N,N-dimethylimidoformamide (1.37 g,6.3 mmol, 1.0 eq.) was added to a suspension of 4-amino-N-(2-pyridinyl)benzamide (1.34 g, 6.3 mmol) in acetic acid (25 mL) and the mixture was refluxed for 3 hours. After cooling the reaction to RT a precipitate formed which was filtered off and washed with diethyl ether to yield 692 mg of 4-[(6-nitroquinazolin-4- yl)amino]-N-(pyridin-2-yl)benzamide (25%) as a yellow solid.

[00193] Preparation of 4-[(6-aminoquinazolin-4-yl)amino]-N-(pyridin-2-yl)benzamide. Iron powder (450 mg, 8.1 mmol, 7 eq.) was added to a fine suspension of 4-[(6-nitroquinazolin-4- yl)amino]-N-(pyridin-2-yl)benzamide (520 mg, 1.14 mmol) and acetic acid (335 μL·, 5.7 mmol, 5 eq.) in THF (25 mL) and the mixture was refluxed for 2 hours. The reaction mixture was diluted with ethyl acetate, poured into ammonia (-10% in water, 250 mL) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over Na 2 S0 4 and concentrated in vacuo. The residue was purified by Si0 2 -chromatography (0 to 80% acetone in toluene) to give 270 mg of 4-[(6-aminoquinazolin-4-yl)amino]-N-(pyridin-2-yl)benzamide

(67%). Example 15 - Preparation of 4-{[6-(acryloylamino)quinazolin-4-yllamino}-N-(pyridin-2- vDbenzamide (E-5)

[00194] This compound was prepared, in an analogous manner as described for compound E-l from compound 1-12 and acryloyl chloride to afford the title compound (15 mg, 18%). 1H NMR

(400 MHz, DMSO-D 6 , 300K): δ (ppm) = 5.86 (1H, dd, Jl = 10.2 Hz, J2 = 1.9 Hz), 6.36 (1H, dd, Jl = 16.9 Hz, J2 = 1.9 Hz), 6.54 (1H, dd, Jl = 16.9 Hz, J2 = 10.2 Hz), 7.17 (1H, ddd, Jl = 7.3 Hz, J2 = 4.8 Hz, J3 = 0.9 Hz), 7.85 (2H, m), 7.95 (1H, dd, Jl = 9.0 Hz, J2 = 2.1 Hz), 8.04 (2H, m), 8.10 (2H, m), 8.22 (1H, dt, Jl = 8.3 Hz, J2 = 0.9 Hz), 8.40 (1H, ddd, Jl = 4.8 Hz, J2 = 2.0 Hz, J3 = 0.8 Hz), 8.64 (1H, s), 8.87 (1H, d, J = 1.9 Hz), 10.09 (1H, s), 10.55 (1H, s), 10.68 (1H, s).

Example 16 - Preparation of 4-{[6-(but-2-vnoylamino)quinazolin-4-yllamino}-N-(pyridin-2- vDbenzamide (E-6)

[00195] This compound was prepared, in an analogous manner as described for compound E-2 from compound 1-12 and 2-butynoic acid. Purification was effected by SiCVchromatography (0 to 10% methanol in dichloromethane) to afford the title compound (28 mg, 21%) as a slightly yellow solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 2.10 (3H, s), 7.17 (1H, ddd,Jl = 7.3 Hz, J2 = 4.8 Hz, J3 = 1.0 Hz), 7.83 (3H, m), 8.00 (2H, d, J = 8.8 Hz), 8.09 (2H, d, J = 8.8 Hz), 8.22 (1H, dt, Jl = 8.3 Hz, J2 = 0.8 Hz), 8.40 (1H, m), 8.63 (1H, s), 8.80 (1H, s), 10.07 (1H, s), 10.68 (1H, s), 10.99 (1H, s).

Example 17 - Preparation of 4-[(6-amino-7-methoxyquinazolin-4-vnoxyl-N-(pyridin-2- vDbenzamide (1-13)

[00196] Preparation of 4-[(7-methoxy-6-nitroquinazolin-4-yl)oxy]-N-(pyridin-2-yl)be nzamide. A solution of 4-chloro-7-methoxy-6-nitroquinazoline (201 mg, 0.84 mmol) in acetonitrile (15 mL) was added to a mixture of 4-hydroxy-N-(pyridin-2-yl)benzamide (215 mg, 1.01 mmol, 1.2 eq.) and K 2 CO 3 (174 mg, 1.26 mmol, 1.5 eq.) and the suspension was heated in the microwave for 1 hour at 150 °C. The reaction mixture was diluted with water, filtered and washed water. The solids were coevaporated twice with toluene to give 162 mg of 4-[(7-methoxy-6- nitroquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (46%) as an off white solid. LC-MS (Method A) Rt: 7.28 mm; m/z 418.1 (M+H) + .

[00197] Preparation of 4-[(6-amino-7-methoxyquinazolin-4-yl)oxy]-N-(pyridin-2-yl)be nzamide. A mixture of 4-[(7-methoxy-6-nitroquinazolin-4-yl)oxy]-N-(pyridin-2-yl)be nzamide (80 mg, 0.19 mmol) and Raney Ni (ca. 100 mg, suspension in EtOH) in ethyl acetate/EtOH (4: 1, 10 mL) was stirred under an atmosphere of hydrogen for 4 hours at RT. The reaction mixture was filtered over a 4 μηι HPLC filter, and the filtrate was concentrated. The residue was purified by Si02-chromatography (0 to 40% acetone in toluene) to give 35 mg of 4-[(6-amino-7- methoxyquinazolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (48%) as a yellow solid. LC-MS (Method A) Rt : 5.84 mm; m/z 388.2 (M+H) + . Example 18 - Preparation of 4- 6-(Acryloylamino)-7-methoxyquinazolin-4-yllamino}-N- (pyridin-2-yl)benzamide (E-7)

[00198] This compound was prepared, in an analogous manner as described for compound E-l from compound 1-13 and acryoyl chloride, to afford the title compound (11 mg, 22%) as a white solid. LC-MS (Method A) Rt: 6.42 mm; m/z 442.2 (M+H) + . 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 4.11 (3H, s), 5.82 (1H, dd, Jl = 10.1 Hz, J2 = 1.8 Hz), 6.33 (1H, dd, Jl = 16.9 Hz, J2 = 1.8 Hz), 6.87 (1H, dd, Jl = 16.9 Hz, J2 = 10.2 Hz), 7.21 (1H, ddd, Jl = 7.3 Hz, J2 = 4.9 Hz, J3 = 1.0 Hz), 7.49 (3H, m), 7.89 (1H, m), 8.17 (2H, d, J = 8.9 Hz), 8.21 (1H, dt, Jl = 8.4 Hz, J2 = 0.9 Hz), 8.42 (1H, m), 8.63 (1H, s), 9.21 (1H, s), 9.88 (1H, s) 10.96 (1H, s).

Example 19 - Preparation of 4-{[6-(But-2-vnoylamino)-7-methoxyquinazolin-4-yllamino}-N- (pyridin-2-yl)benzamide E-8)

[00199] This compound was prepared, in an analogous manner as described in compound E-6 from compound 1-13 and 2-butynoic acid to afford the title compound (2 mg, 5%) as an off white solid. LC-MS (Method A) Rt: 6.72 mm; m/z 454.2 (M+H) + . Example 20 - Preparation of 4-[(6-amino-7-methoxyquinazolin-4-yl)oxyl-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide (1-14)

[00200] This compound was essentially prepared in an analogous manner as described for compound 1-13, starting from compound 1-9 and 4-chloro-7-methoxy-6-nitroquinazoline to afford the title compound (15 mg, 82%). LC-MS (Method A) Rt: 7.48 mm; m/z 456.1 (M+H) + .

Example 21 - Preparation of 4- { [6-(acryloylamino) -7-methoxyquinazolin-4-yllamino}-N-(4- (trifluoromethyl)pyridin-2-yl)benzamide (E-9)

[00201] This compound was prepared, in an analogous manner as described for compound E-l, from compound 1-14 and acryoyl chloride, to afford the title compound (11 mg, 22%) as a white solid. LC-MS (Method A) Rt: 8.08 mm; m/z 510.1 (M+H) + . 1H NMR (400 MHz, CDC1 3 , 300K): δ (ppm) = 4.13 (3H, s), 5.87 (1H, dd, Jl = 10.1 Hz, J2 = 1.2 Hz), 6.37 (1H, dd, Jl = 16.8 Hz, J2 = 10.1 Hz), 6.53 (1H, dd, Jl = 16.8 Hz, J2 = 1.2 Hz), 7.31 (1H, m), 7.38 (1H, s), 7.44 (2H, d, J = 8.8 Hz), 8.07 (2H, d, J = 8.8 Hz), 8.20 (1H, s), 8.49 (1H, d, J = 5.1 Hz), 8.67 (1H, s), 8.72 (1H, s), 8.77 (1H, s), 9.43 (1H, s). Example 22 - Preparation of 4- {[6-( but-2-vnoylamino)-7-methoxyquinazolin-4-yllamino}-N- (4-(trifluoromethyl)pyridin- -yl)benzamide (E-10)

[00202] Oxalyl chloride (10 ul, 0.119 mmol) + 1 drop of DMF were added to a solution of 2- butynoic acid (10 mg, 0.119 mmol) in acetonitrile (800 ul). The reaction mixture was stirred at 50°C for 30 minutes and cooled to RT. A solution of compound 1-14 (15 mg, 0.033 mmol) in dichloromethane/NMP (5: 1 , 4 mL) was cooled in an ice bath and the acid chloride solution (0.1 19 mmol, 2 eq.) was added. After 5 hours the dichloromethane was removed in vacuo and the residue treated with water. The solids were collected, washed with water and coevaporated with dioxane. The residue was purified by preparative HPLC using the following method:

Column: LUNA CI 8, 150 x 21.20 mm 5 μηι particle size, mobile phase: 0 to 100% acetonitrile in water + TFA, to give the title compound (2 mg, 10%) as a white solid. LC-MS (Method A) Rt: 8.21 mm; m/z 261.6 ((M+H)/2) + .

Example 23 - Preparation of 4-[(7-hvdroxy-6-nitro-4-quinolyl)oxyl-N-(2-pyridyl) benzamide (I-

15}

[00203] Preparation of 3-isopropoxy-4-nitroaniline: Sodium metal (29.4 g, 1288 mmol, 5 eq.) was taken in IPA (1600 mL) and refluxed to 100 °C. When all the sodium metal was dissolved, the solution was cooled to room temperature and 3-fluoro-4-nitroaniline (40 g, 256 mmol, 1 eq.) was added. The reaction mixture was heated at 60 °C for 16h. Then the reaction mixture was evaporated and poured into ice-cold water. The solid obtained was filtered, washed with cold water and dried to obtain 3-isopropoxy-4-nitroaniline (47.5 g, 94 %) as brown solid. 1 H NMR (400 MHz, CDC1 3 , 300K): δ (ppm) = 7.75 (1H, d, J = 8.7 Hz), 6.46 (2H, s), 6.27 (1H, s), 6.16 (1H, d, J = 8.6 Hz), 4.57 (1H, s), 1.30 (6H, m)

[00204] Preparation of 5-(((3-isopropoxy-4-nitrophenyl)amino)methylene)2,2-dimethyl -l ,3- dioxane-4,6-dione: A solution of 2,2-dimethyl-l,3-dioxane-4,6-dione (Meldrum's acid, 52.33 g, 363 mmol, 1.5 eq.) in tri ethyl orthoformate (530 mL, 13 eq.) was heated at 105 °C for 2h. 3- Isopropoxy-4-nitroaniline (47.5 g, 242 mmol, 1 eq.) was added and the reaction mixture was stirred overnight at 105 °C. After completion, the reaction mixture was cooled to room temperature, diluted with hexane. The solid precipitated was filtered off, washed with hexanes and dried to get 5-(((3-isopropoxy-4-nitrophenyl)amino)methylene)2,2-dimethyl -l,3-dioxane- 4,6-dione (80 g, 95.2%) as brown solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 1 1.24 (1H, s), 8.69 (1H, s), 7.91 (1H, d, J = 8.8 Hz), 7.66 (1H, s), 7.26 (1H, d, J = 8.5 Hz), 4.91 (1H, m), 1.68 (6H, s), 1.32 (6H, m)

[00205] Preparation of 7-isopropoxy-6-nitroquinolin-4-ol: A suspension of 5-(((3-isopropoxy-4- nitrophenyl)amino)methylene)2,2-dimethyl-l ,3-dioxane-4,6-dione (40 g, 114 mmol, 1 eq.) in diphenyl ether (400 mL) was heated at 200 °C for lh. After completion, the reaction mixture was cooled to room temperature and diluted with hexane. The solids obtained were filtered off, washed with hexane and dried to give crude 7-isopropoxy-6-nitroquinolin-4-ol (27 g, 95%) as brown solid which was carried to next step without purification

[00206] Preparation of 4-chloro-7-isopropoxy-6-nitroquinoline: A solution of crude 7- isopropoxy-6-nitroquinolin-4-ol (27 g, 108.7 mmol, 1 eq.) in phosphorus oxy chloride (240 mL) and DMF (0.4 mL) was heated at 1 10 °C for 3h. After completion, the reaction mixture was concentrated, treated with aq. saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate and concentrated to get crude residue which was purified by silica gel column chromatography (70: 30 % ethyl acetate in hexane) to obtain 4-chloro-7-isopropoxy-6-nitroquinoline (11 g, 38%) as brown liquid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 8.91 (1H, d, J = 4.6 Hz), 8.66 (1H, s), 7.98 (1H, s), 7.75 (1H, d, J = 4.4 Hz), 5.06 (m, 1H), 1.35 (m, 6H).

[00207] Preparation of 4-((7-isopropoxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2-yl) benzamide: To a solution of 4-chloro-7-isopropoxy-6-nitroquinoline (10 g, 37 mmol, 1 eq.) and compound I- 1 (9.52 g, 44 mmol, 1.2 eq.) in DMF (100 mL) was added potassium tert-butoxide (9.1 g, 81 mmol, 2.2 eq.). The reaction mixture was heated at 120 °C for 30 minutes. After completion, the reaction mixture was poured into ice-water. The solids obtained were filtered off and dissolved in DCM. The DCM layer was washed with brine, dried over sodium sulfate and concentrated to obtain crude compound which was purified by flash column chromatography on silica gel (4% MeOH in DCM) to obtain 4-((7-isopropoxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2- yl)benzamide (13 g, 78%) as brown solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 10.89 (s, 1H), 8.80 (d, 1H, d, J = 5.1 Hz), 8.75 (1H, s), 8.40 (d,lH, J = 4.04 Hz), 8.20 (d, 3H, J = 8.4 Hz), 7.86 (m, 1H), 7.79 (s, 1H), 7.45 (d, 2H, J = 8.5 Hz), 7.18 (m,lH), 6.71 (d, 1H, J = 5.1 Hz), 5.06 (m, 1H), 1.36 (m, 6H)

[00208] 4-((7-hydroxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2-yl)ben zamide. To a solution of 4-((7-isopropoxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2-yl) benzamide (12 g, 26 mmol, 1 eq.) in DCM (300 mL) was added aluminium trichloride (18 g, 134 mmol, 5 eq.) at 0 °C. The reaction mixture was vigorously stirred for 2h to reach room temperature. After completion, the reaction mixture including solids was poured into 1 N NaOH and stirred for 10 minutes. The mixture was acidified with solid citric acid and extracted with ethyl acetate: THF (3: 1). The aqueous layer was basified to pH~8 with solid sodium bicarbonate and extracted with ethylacetate:THF (3: 1). The combined organic layer was dried over sodium sulfate and concentrated to get crude product that was purified by silica gel column chromatography (5% methanol in DCM) to obtain 4-((7-hydroxy-6-nitroquinolin-4-yl)oxy)-N-(pyridine-2- yl)benzamide (10 g, 92%) as brown solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 11.63 (bs,lH), 10.88 (s, 1H), 8.75 (m, 2H), 8.40 (d, 1H, J = 3.8 Hz), 8.20 (d, 3H, J = 8.7 Hz), 7.85 (m, 1H), 7.56 (s, 1H), 7.45 (d, 2H, J = 8.6 Hz), 7.17 (m, 1H), 6.63 (d, 1H, J = 5.2 Hz).

Example 24 - Preparation of 4-[[6-amino-7-(2-morpholinoethoxy)-4-quinolylloxyl-N-(2- pyridvDbenzamide (1-16)

[00209] Preparation of 4-[[7-(2-morpholinoethoxy)-6-nitro-4-quinolyl]oxy]-N-(2- pyridyl)benzamide. Potassium carbonate (777 mg, 5.7 mmol, 2.3 eq.), 4-(2-chloroethyl)- morpholine hydrochloride (508 mg, 2.73 mmol, 1.1 eq.) and sodium iodide (cat.) were added to a solution of compound 1-15 (1.0 g, 2.48 mmol) in DMF (70 rriL) and the dark red mixture was stirred overnight at 50 °C. The reaction mixture was acidified with citric acid to pH = 5, sat. sodium bicarbonate (aq) was added and the mixture was filtered. The residue was purified by SiCh-chromatography (0 to 15% methanol in ethyl acetate) to give 4-[[7-(2-morpholinoethoxy)- 6-nitro-4-quinolyl]oxy]-N-(2-pyridyl)benzamide. (905 mg, 71%) as a light brown solid. LC-MS (Method A) Rt: 4.19 mm; m/z 516.1 (M+H) + . 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 2.52 (4H, m), 2.79 (2H, t, J = 5.4 Hz), 3.58 (4H, t, J = 4.6 Hz), 4.45 (2H, t, J = 5.3 Hz), 6.73 (1H, d, J = 5.3 Hz), 7.19 (1H, ddd, Jl = 7.3 Hz, J2 = 4.8 Hz, J3 = 1.0 Hz), 7.47 (2H, d, J = 8.9 Hz), 7.82 (1H, s), 7.86 (1H, m), 8.21 (3H, m), 8.41 (1H, ddd, Jl = 4.8 Hz, J2 = 2.0 Hz, J3 = 0.9 Hz), 8.80 (1H, s), 8.83 (1H, d, 5.3 Hz), 10.90 (1H, s).

[00210] Preparation of 4-[[6-amino-7-(2-morpholinoethoxy)-4-quinolyl]oxy]-N-(2- pyridyl)benzamide. Pd/C (containing 50% water, 10%, ca. 50 mg) was added to a solution of 4- [[7-(2-morpholinoethoxy)-6-nitro-4-quinolyl]oxy]-N-(2-pyridy l)benzamide (130 mg, 0.25 mmol) in THF/ethanol (2: 1, 25 rriL) and the reaction mixture was stirred under an atmosphere of hydrogen for 2 hours at 50 °C. The reaction mixture was filtered over Decalite, washed with ethyl acetate, THF and ethanol and concentrated in vacuo to give 4-[[6-amino-7-(2- morpholinoethoxy)-4-quinolyl]oxy]-N-(2-pyridyl)benzamide (94 mg, 77%) as a yellow solid. LC-MS (Method A) Rt: 2.98 mm; m/z 486.2 (M+H) + .

Example 25 - Preparation of 4-[[7-(2- {morpholin-4-yl}oethoxy)-6-(but-2-vnoylamino)quinolin- 4-ylloxyl-N-(pyridin-2-yl)benzamide (E-ll)

[00211] EDCI.HC1 (70 mg, 0.37 mmol, 2.5 eq.) was added to a solution of compound E-9 (71 mg, 0.15 mmol), and 2-butynoic acid (24 mg, 0.29 mmol, 2.0 eq.) in pyridine (3 rriL) and the solution was stirred for 2 hours at RT. The reaction mixture was concentrated and coevaporated twice with toluene. The residue was purified by preparative HPLC using a LUNA (CI 8) 150 x 21.20 mm 5 μπι column and a mobile phase of 0 to 80% acetonitrile in water + TFA. The pure fractions were combined, diluted with THF and washed with sat. sodium bicarbonate/sat. brine. The aqueous phase was extracted once with THF. The combined organic extracts were washed with sat. brine, dried over Na 2 S0 4 and concentrated in vacuo. The residue was triturated with acetonitrile to yield the title compound (14.1 mg, 17%). LC-MS (Method A) Rt: 3.53 min; m/z 552.1 (M+H) + , HPLC (Method C) Rt: 4.73 mm. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 2.07 (3H, s), 2.53 (4H, m), 2.83 (2H, t, J = 5.9 Hz), 3.62 (4H, t, J = 4.6 Hz), 4.38 (2H, t, J = 5.9 Hz), 6.67 (1H, d, J = 5.1 Hz), 7.18 (1H, ddd, Jl = 7.4 Hz, J2 = 4.8 Hz, J3 = 1.0 Hz), 7.36 (2H, d, J = 8.9 Hz), 7.60 (1H, s), 7.85 (1H, m), 8.19 (3H, m), 8.40 (1H, ddd, Jl = 4.8 Hz, J2 = 1.9 Hz, J3 = 0.8 Hz), 8.63 (1H, d, J = 5.2 Hz), 8.71 (1H, s), 9.71 (1H, s), 10.82 (1H, s).

Example 26 - Preparation of 4-[[7-(2-{morpholin-4-yl}oethoxy)-6-(acryloylamino)quinolin- 4- yll oxyl -N-(pyridin-2-yl)benzamide (E- 12)

[00212] EDCI.HC1 (86.86mg, 0.45 mmol) was added to a solution of compound 1-16 (88 mg, 0.18 mmol) and acrylic acid (0.02 mL, 0.3600 mmol) in pyridine (3 rriL) and stirred for 2 hours at RT. The reaction mixture was concentrated, coevaporated twice with toluene and the residue was purified by preparative HPLC using a LUNA (CI 8) 150 x 21.20 mm 5 μπι column and a mobile phase of 0 to 50% acetonitrile in water + TFA. The fractions containing the desired product were taken up in THF and washed with sat. aqueous sodium bicarbonate/sat. brine. The organic extract was dried over Na 2 S0 4 and concentrated in vacuo. The residue was triturated with acetonitrile to yield the title compound (21.3 mg, 22%). LC-MS (Method A) Rt: 3.41 min; m/z 540.1 (M+H) + , HPLC (Method C) Rt: 4.49 mm.

Example 27 - Preparation of 4-[[6-amino-7-(2-methoxyethoxy)-4-quinolylloxyl-N-(2- pyridvDbenzamide (1-17)

[00213] Preparation of 3-(2-methoxyethoxy)-4-nitroaniline. Sodium hydride (60% disp.) (589.33 mg, 14.73 mmol) was added to a solution of 2-methoxyethanol (5 mL, 63.41 mmol) in THF (15 mL) and the mixture was stirred for 1 hour at RT. 3-fluoro-4-nitro-aniline (1 g, 6.41 mmol) was added and the mixture was stirred overnight at RT. The reaction mixture was poured into sat. brine and extracted two times with THF. The combined organic extracts were dried over Na 2 S0 4 and concentrated in vacuo to give 3-(2-methoxyethoxy)-4-nitroaniline (1.36g, 100%) as a brown oil. LC-MS (Method A) Rt: 3.82 mm; m/z 213.1 (M+H) + .

[00214] Preparation of 5-({[3-(2-methoxyethoxy)-4-nitrophenyl]amino}methylidene)-2, 2- dimethyl-l,3-dioxane-4,6-dione. A solution of 2,2-dimethy 1-1 ,3 -dioxane-4,6-di one (0.92 g, 6.41 mmol) in diethoxymethoxyethane (1.07 mL, 6.41 mmol) was stirred at 105°C for 2 hours. 3- (2-methoxyethoxy)-4-nitro-aniline (1.36 g, 6.41 mmol) was added and the mixture was stirred overnight at 105 °C. The reaction mixture was cooled to RT, heptane (50 mL) was added and the solids were filtered off, washed with heptane and dried under vacuum to give 5-({[3-(2- methoxyethoxy)-4-nitrophenyl]amino}methylidene)-2,2-dimethyl -l,3-dioxane-4,6-dione (2.05 g, 87%) as a brown solid. This material was directly used in the next step.

[00215] Preparation of 7-(2-methoxyethoxy)-6-nitroquinolin-4(lH)-one. A solution of 5-({[3- (2-methoxyethoxy)-4-nitrophenyl]amino}methylidene)-2,2-dimet hyl-l,3-dioxane-4,6-dione (2.05 g, 5.6 mmol) in diphenyl ether (25 mL) was stirred at 200°C for 1 hour. The reaction mixture was cooled to RT and heptane (25 mL) was added. The solids were filtered off, washed with heptane and dried to give 7-(2-methoxyethoxy)-6-nitroquinolin-4(lH)-one. (0.95 g, 64%) as a brown solid. LC-MS (Method A) Rt: 3.46 min; m/z 265.0 (M+H) + . The following analytical methods may be used to characterize compounds included in the present invention.

[00216] Preparation of 4-chloro-7-(2-methoxyethoxy)-6-nitroquinoline. DMF (0.1 mL, 1.3 mmol) was added to a solution of 7-(2-methoxyethoxy)-6-nitroquinolin-4(lH)-one (0.95 g, 3.6 mmol) in phosphorus oxychloride (5 mL, 53.48 mmol) and the mixture was stirred for 1 hour at 105°C. The reaction mixture was concentrated, taken up in sat. sodium bicarbonate and extracted twice with ethyl acetate. The combined organic extracts were washed with sat. brine, dried over sodium sulfate and concentrated. The residue was purified by Si02-chromatography (0 to 100% ethyl acetate in heptane) to give 4-chloro-7-(2-methoxyethoxy)-6-nitroquinoline (688 mg, 68%) as a yellow solid. LC-MS (Method A) Rt: 5.72 mm; m/z 283.1 (M+H) + , 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 3.48 (3H,s), 3.86 (2H, t, J = 4.6 Hz), 4.40 (2H, t, J = 4.6 Hz), 7.48 (1H, d, J = 4.8 Hz), 7.65 (1H, s), 8.65 (1H, s), 8.83 (1H, d, J = 4.8 Hz)

[00217] Preparation of 4-[(7-(2-methoxyethoxy)-6-nitroquinolin-4-yl)oxy]-N-(pyridin -2- yl)benzamide. Potassium tert.butoxide (229.44 mg, 2.04 mmol) was added to a suspension of 4- hydroxy-N-(2-pyridyl)benzamide (283.43 mg, 1.32 mmol) and 4-chloro-7-(2-methoxyethoxy)-6- nitro-quinoline (340 mg, 1.2 mmol) in THF (14 mL) and NMP (3 mL) and the mixture was heated in the microwave for 2 hours at 150 °C. The reaction mixture was poured into water and extracted once with ethyl acetate. The organic extract was washed twice with 0.1 N NaOH(aq) and once with sat. brine, dried over Na 2 S0 4 and concentrated in vacuo. The residue was purified by Si0 2 -chromatography (0 to 80% acetone in toluene) to give 4-[(7-(2-methoxyethoxy)-6- nitroquinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (303 mg, 55% yield) as a yellow solid. LC- MS (Method A) Rt: 5.34 mm; m/z 461.1 (M+H) + .

[00218] Preparation of 4-[[6-amino-7-(2-methoxyethoxy)-4-quinolyl]oxy]-N-(2- pyridyl)benzamide. Pd/C (contains 50% water, 10%, ca. 100 mg) was added to a solution of 4- [(7-(2-methoxyethoxy)-6-nitroquinolin-4-yl)oxy]-N-(pyridin-2 -yl)benzamide (300 mg, 0.65 mmol) in THF (25 mL) and ethanol (5 mL) and the mixture was stirred under an atmosphere of hydrogen for 3 hours at 50 °C. The reaction mixture was filtered, washed with THF and ethanol and the filtrate was concentrated to give 4-[[6-amino-7-(2-methoxyethoxy)-4-quinolyl]oxy]-N- (2-pyridyl)benzamide (365 mg, 130% yield) as a brown oil. LC-MS (Method A) Rt: 3.81 min; m/z 431.1 (M+H) + .

Example 28 - Preparation of 4-[[7-(2-methoxyethoxyV6-(but-2-vnoylamino')quinolin-4-yllox yl- N-(pyridin-2-yl)benzamide (E-13)

[00219] This compound was prepared, in an analogous manner as described for compound E- 11, from compound 1-17 and 2-butynoic acid to afford the title compound (17 mg, 19%) as an off white solid. LC-MS (Method A) Rt: 4.27 mm; m/z 497.1 (M+H) + , HPLC (Method C) Rt: 5.96 min.

Example 29 - Preparation of 4-{[6-(Amino ' )quinolin-4-ylloxyl-N-(pyridin-2-yl ' )benzamide (I-

[00220] Preparation of 4-{[6-nitro)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide. A suspension of compound 1-1 (108 mg, 0.50 mmol), 4-chloro-6-nitroquinoline (100 mg, 0.48 mmol) and potassium carbonate (83 mg; 0.60 mmol) in acetonitrile (1 mL) was stirred in the microwave at 150 °C for 8 hours. The brown solid was filtered off and washed with acetonitrile and water. The product was purified using silica gel chromatography (dichlomethane/methanol = 95/5 v/v%) to give 128 mg of 4-{[6-(nitro)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide (69.3%). LC-MS (Method A) Rt: 7.31 mm; m/z 387.1 (M+H) + .

[00221] Preparation of 4-{[6-(amino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide.To a solution of 4-{[6-(nitro)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide (70 mg, 0.18 mmol) in ethyl acetate (4 mL) and ethanol (4 mL) was added palladium on carbon (50% wet with water, catalytic). The resulting mixture was stirred under a hydrogen atmosphere at room temperature overnight. Palladium on carbon was removed by filtration over dicalite and the filtrate was concentrated under reduced pressure to give 53 mg of 4-{[6-(amino)quinolin-4-yl]oxy}-N- (pyridin-2-yl)benzamide as a brown solid (82%). LC-MS (Method A) Rt: 4.65 min; m/z 357.2 (M+H) + .

Example 30 - Preparation of 4- 6-(Acryloylamino)quinolin-4-ylloxy}-N-(pyridin-2- vDbenzamide (E-14)

[00222] To a solution of compound 1-18 (25 mg, 0.065 mmol) in tetrahydrofuran (2 mL) was added acryloyl chloride (5.9 μΐ ^ , 0.072 mmol) at -10°C. The resulting mixture was stirred at -10 °C for 10 minutes. Diisopropylethylamine (13.4 μΐ ^ , 0.081 mmol) was added to the resulting suspension. The resulting solution was stirred at -lOoC for 30 minutes and 3 hours at room temperature. The mixture was concentrated in vacuo. The product was purified using silica gel chromatography (dichloromethane/methanol = 9/1 v/v%) to give 11.4 mg 4-{[6- (acryloylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide. LC-MS (Method A) Rt: 5.12 min; m/z 411.2 (M+H) + .

Example 31 - Preparation of 4-{[6-(Butvno-2-ylamino)quinolin-4-ylloxy}-N-(pyridin-2- vDbenzamide (E-15)

[00223] To a solution of compound 1-18 (25 mg, 0.065 mmol), diisopropylethylamine (40 μΐ ^ , 0.197 mmol) and 2-butynoic acid (6.5 mg, 0.077 mmol) in dichloromethane (1 mL) was added HATU (32.3 mg, 0.085 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 6.5 mg of 4-{[6-(butyno-2- ylamino)quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide ditrifluoroacetate (14% yield). Other salts or the free base of E-15 may be prepared by standard methods. LC-MS (Method A) Rt: 5.30 mm; m/z 423.1 (M+H) + .

Example 32 - Preparation of 4-[(6- (2£ ' )-4-Dimethylaminobut-2-enoyllamino}quinolin-4- ylloxy} -N-(pyridin-2-yl)benzamide (E-16)

[00224] A suspension of compound 1-18 (20 mg, 0.056 mmol), 4-(dimethylamino)-2-butenoic acid hydrochloride (11.2 mg, 0.067 mmol) and EDCI (12.9 mg, 0.067 mmol) in THF (1 mL) was stirred at 0 °C, after which pyridine (11 μΐ ^ , 0.135 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 3 hrs and at room temperature overnight. The reaction mixture was diluted with a aqueous solution of NaHCC and extracted with ethyl acetate. The waterlay er was extracted with ethyl acetate twice. The combined organic layers were dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The product was purified using silica column chromatography with 10% methanol in dichloromethane as eluent, to give 16 mg of 4-[(6- {[(2£ ' )-4-dimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}- N-(pyridin-2-yl)benzamide. (61% yield). LC-MS (Method A) Rt : 4.06 mm; m/z 468.2 (M+H) + ; HPLC Rt: 3.73 mm. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 2.19 (6H, S), 3.08 (2H, d, J = 6.0 Hz), 6.33 (1H, d, J = 15.4 Hz), 6.79 (1H, m), 7.18 (1H, m), 6.93 (1H, m), 7.37 (2H, d, J = 8.9 Hz), 7.86 (1H, m), 7.96 (1H, dd, Jl = 9.1 Hz, J2 = 2.3), 8.03 (1H, d, J = 9.5), 8.20 (3H, m), 8.40 (1H, m), 8.66 (1H, d, J = 5.0), 8.79 (1H, d, J = 2.3 Hz), 10.50 (1H, s), 10.87 (1H, s).

Example 33 - Preparation of 4-[(6-((4-hvdroxybut-2-vnoyl)amino)quinolin-4-yl)oxyl-N- (pyridin-2-yl)benzamide (E-17)

[00225] Triethyl amine (77 ul, 0.55 mmol, 5 eq.) was added to a solution of compound 1-18 (40 mg, 0.11 mmol), T3P (50% in ethyl acetate, 66 ul, 0.22 mmol, 2.0 eq.) and 4-(tert-butyl- dimethyl-silanyloxy)-but-2-ynoic acid (47 mg, 0.22 mmol, 2.0 eq.) in THF/NMP (4: 1 , 3 mL) and the dark brown solution was stirred overnight at RT. The reaction mixture was concentrated to a small volume, sat. NH 4 Cl(aq) was added and extracted two times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na 2 S0 4 and concentrated in vacuo to give a brown oil.

[00226] Procedure for TBDMS deprotection: Cone. HCl (10 drops) was added to a solution of previously mentioned brown oil in THF (25 mL) and the suspension was stirred for one hour at RT. Sat. NaHCC (aq) was added and the mixture extracted two times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by preparative HPLC using a LUNA (CI 8) 150 x 21.20 mm 5 micron column and a mobile phase of 0 to 50% acetonitrile in water + TFA to give 4-[(6- {[(2£)- 4-Hydroxy-but-2-ynoyl]amino} quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide ditrifluoroacetate (10.3 mg, 14%) as a light yellow solid. Other salts or the free base of E-17 may be prepared by standard methods. LC-MS (Method A) Rt: 4.86 min; m/z 439.2 (M+H) + , HPLC (Method C) Rt: 5.22 mm.

Example 34 - Preparation of 4- {[6-(amino ' )quinolin-4-ylloxyl-N-(4-trifluoromethylpyridin-2- vDbenzamide (1-19)

[00227] Preparation of 4- {[6-(nitro)quinolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2- yl)benzamide. A suspension of compound 1-9 (106 mg; 0.38 mmol), 4-chloro-6-nitroquinoline (75 mg; 0.36 mmol) and potassium carbonate (63 mg; 0.45) in acetonitrile (1 mL) was stirred in the microwave at 150 °C for 8 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, a saturated solution of NaHCCh and brine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 2/3 v/v%) to give 71 mg 4- { [6-(nitro)quinolin-4- yl]oxy}-N-(5-trifluoromethylpyridin-2-yl)benzamide (43%). LC-MS (Method A) Rt: 8.71 min; m/z 455.1 (M+H) + .

[00228] Preparation of 4- {[6-(amino)quinolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2- yl)benzamide. To a solution of 4- {[6-(nitro)quinolin-4-yl]oxy}-N-(4-trifluoromethylpyridin-2- yl)benzamide (70 mg, 0.15 mmol) and ammonium formate (49 mg; 0.77 mmol) in ethyl acetate (4 rriL) and ethanol (4 mL) was added Raney Nickel (suspension in ethanol, 50 mg). The resulting mixture was stirred for 6 hours at 60 °C. The reaction mixture was filtered over dicalite and the filtrate was concentrated under reduced pressure to give 80 mg of 4- {[6-(amino)quinolin- 4-yl]oxy} -N-(4-trifluoromethylpyridin-2-yl)benzamide as a brown solid (quant.). LC-MS (Method A) Rt: 5.85 mm; m/z 425.1 (M+H) + .

Example 35 - Preparation of 4- {[6-(Acryloylamino)quinolin-4-ylloxy}-N-(4- trifluoromethylpyridin-2-yl)benzamide (E-18)

[00229] To a solution of compound 1-19 (20 mg, 0.052 mmol) in tetrahydrofuran (2 mL) was added acryloyl chloride (4.7 iL, 0.058 mmol) at -10 °C. The resulting mixture was stirred at -10 °C for 10 minutes. Diisopropylethylamine (11 iL, 0.065 mmol) was added to the resulting suspension. The resulting solution was stirred at -10 °C for 30 minutes and 3 hours at room temperature. After evaporation, the residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 5.6 mg of 4- {[6- (acryloylamino)quinolin-4-yl]oxy}-N-(4-trifluoromethylpyridi n-2-yl)benzamide

ditrifluoroacetate (15% yield). Other salts or the free base of E-18 may be prepared by standard methods. LC-MS (Method A) Rt: 6.45 mm; m/z 479.2 (M+H)+. 1H NMR (400 MHz, DMSO- D 6 , 300K): δ (ppm) = 5.84 (1H, dd, Jl = 10.1 Hz, J2 = 1.9 Hz), 6.34 (1H, dd, Jl = 16.9 Hz, J2 = 1.9 Hz), 6.52 (1H, dd, Jl = 16.9 Hz, J2 = 10.0 Hz), 6.91 (1H, d, J = 5.6 Hz), 7.47 (2H, d, J = 8.8 Hz), 7.55 (1H, d, J = 5.1 Hz), 8.10 (2H, m), 8.26 (2H, d, J = 8.8 Hz), 8.58 (1H, s), 8.70 (1H, d, J = 5.1 Hz), 8.77 (1H, d, J = 5.7 Hz), 8.89 (1H, d, J = 1.9 Hz), 10.68 (1H, s), 11.40 (1H, s).

Example 36 - Preparation of 4-{[6-(butvno-2-ylamino)quinolin-4-ylloxy}-N-(4- trifluoromethylpyridin-2-yl)benzamide (E-19)

[00230] To a solution of compound 1-19 (20 mg, 0.047 mmol), diisopropylethylamine (30 μΐ ^ , 0.165 mmol) and 2-butynoic acid (4.4 mg, 0.052 mmol) in dimethylformamide (1 mL) was added HATU (23.7 mg, 0.062 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and washed sequentially with water, a saturated solution of NaHC03 and brine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 1.5 mg of 4-{[6-(butyno-2-ylamino)quinolin-4- yl]oxy}-N-(4-trifluoromethylpyridin-2-yl)benzamide ditrifluoroacetate (4% yield). Other salts or the free base of E-19 may be prepared by standard methods. LC-MS (Method A) Rt: 6.63 min; m/z 491.1 (M+H) + . 1H NMR (400 MHz, MeOD, 300K): δ (ppm) = 2.07 (3H, s), 6.94 (1H, d, J = 5.8 Hz), 7.44 (1H, m), 7.48 (2H, d, J = 8.8 Hz), 8.05 (2H, m), 8.21 (2H, d, J = 8.8 Hz), 8.61 (2H, m), 8.72 (2H, d, J = 5.8 Hz), 8.90 (1H, s). Example 37 - Preparation of 4- 6-(Amino)quinolin-4-ylloxy}-N-(4-ethylpyridin-2- vDbenzamide (1-20)

[00231] Preparation of 4- {[6-(nitro)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzami de. A suspension of compound 1-4 (115 mg; 0.46 mmol), 4-chloro-6-nitroquinoline (80 mg; 0.38 mmol) and potassium carbonate (95 mg; 0.69) in acetonitrile (1 mL) was stirred in the microwave at 150 °C for 8 hours. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, a saturated solution of NaHCC and brine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated in vacuo. The product was purified using silica gel chromatography (heptane/ethyl acetate = 2/3 v/v%) to give 72 mg 4- { [6-(nitro)quinolin-4- yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide (45%). LC-MS (Method A) Rt : 7.50 min; m/z 415.2

(M+H) .

[00232] Preparation of 4-{[6-(amino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benza mide. To a solution of 4- {[6-(nitro)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzami de (70 mg, 0.17 mmol) in ethyl acetate (4 mL) and ethanol (2 mL) was added palladium on carbon (10%, 50% wet with water, catalytic). The resulting mixture was stirred for overnight under a hydrogen atmosphere. The reaction mixture was filtered over dicalite and the filtrate was concentrated under reduced pressure to give 56 mg of 4-{[6-(amino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2- yl)benzamide as a brown solid (86%). This material was directly used in Example 38. Example 38 - Preparation of 4- 6-(Acryloylamino)quinolin-4-ylloxy}-N-(4-ethylpyridin-2- vDbenzamide (E-20)

[00233] To a solution of compound 1-20 (19 mg, 0.049 mmol) in tetrahydrofuran (2 mL) was added acryloyl chloride (4.7 μΐ ^ , 0.058 mmol) at -10 °C. The resulting mixture was stirred at -10 °C for 10 minutes. Diisopropylethylamine (4.5 μΐ ^ , 0.055 mmol) was added to the resulting suspension. The resulting solution was stirred at -10 °C for 30 minutes and 3 hours at room temperature. After evaporation, the residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 5.4 mg of 4-{[6- (acryloylamino)quinolin-4-yl]oxy} -N-(4-ethylpyridin-2-yl)benzamide ditrifluoroacetate (16% yield). Other salts or the free base of E-20 may be prepared by standard methods. LC-MS

(Method A) Rt: 5.42 mm; m/z 439.2 (M+H)+. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 1,23 (3H, t, J = 7.6), 2.69 (2H, q, J = 7.7), 5.85 (1H, dd, Jl = 10.2 Hz, J2 = 1.8 Hz), 6.33 (1H, dd, Jl = 17.1 Hz, J2 = 1.9 Hz), 6.51 (1H, dd, Jl = 17.0 Hz, J2 = 10.1 Hz), 6.93 (1H, d, J = 5.8 Hz), 7.10 (1H, d, J = 5.4 Hz), 7.48 (2H, d, J = 8.8 Hz), 8.09 (1H, s), 8.14 (1H, m), 8.26 (2H, d, J = 8.8), 8.30 (1H, d, J = 5.1 Hz), 8.82 (1H, d, J = 5.8 Hz), 8.93 (1H, s), 10.74 (1H, s), 10.92 (1H, s).

Example 39 - Preparation of 4-{[6-(Butvno-2-ylamino)quinolin-4-ylloxy}-N-(4-ethylpyridin -2- vDbenzamide (E-21)

[00234] To a solution of compound 1-20 (19 mg, 0.049 mmol), diisopropylethylamine (30 μΐ, 0.17 mmol) and 2-butynoic acid (4.6 mg, 0.054 mmol) in dichloromethane (1 mL) was added HATU (24.8 mg, 0.065 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC. Fractions containing product were collected and lyophilized to afford 6.8 mg of 4-{[6-(butyno-2- ylamino)quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide ditrifluoroacetate (22% yield). Other salts or the free base of E-21 may be prepared by standard methods. LC-MS (Method A) Rt: 5.59 mm; m/z 451.2 (M+H) + . 1H NMR (400 MHz, DMSO-D6, 300K): δ (ppm) = 1,23 (3H, t, J = 7.5), 2.09 (3H, s), 2.69 (2H, q, J = 7.5), 6.88 (1H, d, J = 5.7 Hz), 7.09 (1H, d, J = 5.2 Hz), 7.46 (2H, d, J = 8.7 Hz), 8.00 (1H, m), 8.10 (1H, m), 8.22 (2H, d, J = 8.9), 8.30 (1H, d, J = 5.4 Hz), 8.78 (1H, d, J = 5.5 Hz), 8.81 (1H, s), 10.90 (1H, s), 11.16 (1H, s).

Example 40 - Preparation of 4-[(6-{[(2£ ' )-4-Dimethylaminobut-2-enoyllamino}quinolin-4- ylloxy} -N-(4-ethylpyridin-2- l)benzamide (E-22)

[00235] To a solution of 4-(dimethylamino)-2-butenoic acid hydrochloride (10.3 mg, 0.062 mmol) in acetonitrile (1 ml) and 1 drop DMF was added oxalylchloride (10 μΐ, 0.062 mmol). The reaction mixture was stirred at 60 °C for 30 minutes. To this solution was added dropwise a solution of compound 1-20 (20 mg, 0.052 mmol) in NMP (1 ml) at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCC . The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. Water was added to the residue, centrifuged and the supernatant was removed. This procedure was performed three times. The solid was taken up in dioxane and concentrated under reduced pressure. The residue was purified using preparative HPLC to give 2,5 mg of 4-[(6-{[(2£)-4-dimethylaminobut-2-enoyl]amino}quinolin- 4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide. LC-MS (Method A) Rt: 4.43 min; m/z 496.2 (M+H) + . 1H NMR (400 MHz, MeOD, 300K): δ (ppm) = 1,31 (3H, t, J = 7.5), 2.74 (2H, q, J = 7.7), 2.89 (6H, S) 3.95 (2H, d, J = 7.5 Hz), 6.60 (1H, d, J = 15.2 Hz), 6.74 (1H, m), 6.84 (1H, d, J = 5.2 Hz), 6.93 (1H, m), 7.07 (1H, d, J = 5.3 Hz), 7.40 (2H, d, J = 8.7), 7.97 (1H, d, J = 9.3), 8.04 (1H, d, J = 9.3), 8.12 (1H, s) 8.15 (2H, d, J = 8.9), 8.24 (1H, d, J = 5.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.89 (1H, s).

Example 41 - Preparation of 4-[(6- (2£ ' )-4-N,N,N-Trimethylaminobut-2-enoyllamino}quinolin- 4-ylloxy}-N-(5-ethyl ridin-2-yl)benzamide, iodide (E-23)

[00236] Methyl iodide (6 μΐ; 0.09 mmol) was added to a warm solution of compound E-22 (30 mg; 0.08 mmol) in THF (2 ml). The mixture was stored in the refrigerator for three days. Almost complete conversion to desired product. The reaction mixture was concentrated under reduced pressure and ethyl acetate was added. The suspension was centrifuged and the supernatant was taken off. The solid suspended in ethyl acetate and centrifuged again. The supernatant was taken off and the solid was dried under reduced pressure to give 20 mg of 4-[(6-{[(2E)-4-N,N,N- trimethylaminobut-2-enoyl]amino}quinolin-4-yl]oxy}-N-(5-ethy lpyridin-2-yl)benzamide, iodide. This ammonium iodide salt may be exchanged using standard methods with other suitable counterions, such as chloride and bromide. LC-MS (Method A) Rt: 4.71 min; m/z 511.2 (M+H) + ; HPLC (Method C) Rt: 4.35 mm; 1H NMR (400 MHz, MeOD, 300K): δ (ppm) = 1,31 (3H, t, J = 7.5), 2.74 (2H, q, J = 7.7), 2.89 (6H, S) 3.95 (2H, d, J = 7.5 Hz), 6.60 (1H, d, J = 15.2 Hz), 6.74 (1H, m), 6.84 (1H, d, J = 5.2 Hz), 6.93 (1H, m), 7.07 (1H, d, J = 5.3 Hz), 7.40 (2H, d, J = 8.7), 7.97 (1H, d, J = 9.3), 8.04 (1H, d, J = 9.3), 8.12 (1H, s) 8.15 (2H, d, J = 8.9), 8.24 (1H, d, J = 5.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.89 (1H, s).

Example 42 - Preparation of 4-[(6-{[(2£")-4-Methoxy-but-2-vnoyllamino|quinolin-4-ylloxy |-N- (4-ethylpyridin-2-yl)benzamide E-24)

[00237] To a suspension of compound 1-20 (50 mg, 0.13 mmol), 4-Methoxy-2-butynoic acid (29.7 mg, 0.26 mmol) and EDCI (49.9 mg, 0.26 mmol) in THF (2 ml) and NMP (1 ml) was added pyridine (21 μΐ, 0.26 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed sequentially with a aqueous solution of NaHCC and brine. The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The product was purified using silica column chromatography with gradient 0-30% acetone in toluene as eluent. The product was lyophilized from dioxane to give 23 mg of 4-[(6- {[(2£ ' )-4-methoxy-but-2-ynoyl]amino}quinolin-4-yl]oxy}-N-(4- ethylpyridin-2-yl)benzamide as a white solid. LC-MS (Method A) Rt : 5.67 mm; m/z 481.1 (M+H) ; HPLC (Method C) Rt : 6.74 mm; 1H NMR (400 MHz, MeOD, 300K): δ (ppm) = 1,31 (3H, t, J = 7.5), 2.74 (2H, q, J = 7.7), 2.89 (6H, S) 3.95 (2H, d, J = 7.5 Hz), 6.60 (1H, d, J = 15.2 Hz), 6.74 (1H, m), 6.84 (1H, d, J = 5.2 Hz), 6.93 (1H, m), 7.07 (1H, d, J = 5.3 Hz), 7.40 (2H, d, J = 8.7), 7.97 (1H, d, J = 9.3), 8.04 (1H, d, J = 9.3), 8.12 (1H, s) 8.15 (2H, d, J = 8.9), 8.24 (1H, d, J = 5.3 Hz), 8.64 (1H, d, J = 5.3 Hz), 8.89 (1H, s). Example 43 - Preparation of 4- 6-(Amino)quinolin-4-ylloxy}-N-(4-methylpyridin-2- vDbenzamide (1-21)

[00238] Preparation of 4- {[6-(nitro)quinolin-4-yl]oxy}-N-(4-methylpyridin-2-yl)benzam ide. A suspension of compound 1-3 (229 mg; 1.00 mmol), 4-chloro-6-nitroquinoline (200 mg; 0.96 mmol) and cesium carbonate (394 mg; 1.21) in DMF (2 mL) was stirred at 50 °C overnight. The reaction mixture was poured into 20 ml water and stirred for 1 hr. The solid was filtered off and dried under reduced pressure overnight to give 340 mg of 4-{[6-(nitro)quinolin-4-yl]oxy}-N-(4- methylpyridin-2-yl)benzamide (89%). LC-MS (Method A) Rt: 6.90 min; m/z 401.2 (M+H) + .

[00239] Preparation of 4- { [6-(Amino)quinolin-4-yl]oxy } -N-(4-methylpyridin-2-yl)benzamide. To a solution of 4-{[6-(nitro)quinolin-4-yl]oxy}-N-(4-methylpyridin-2-yl)benz amide (340 mg, 0.85 mmol) in tetrahydrofuran (20 ml) and acetic acid (49 μΐ; 0.85 mmol) was added iron (664 mg; 11.89 mmol). The resulting mixture was stirred under reflux for 4 hours, after which time more acetic acid (486 μΐ; 8.49 mmol) was added. The reaction mixture was stirred overnight at reflux. The reaction mixture was poured into 10% ammonia solution and extracted two times with ethyl acetate. The combined organic extracts were washed with brine, dried over Na 2 S0 4 and concentrated under reduced pressure. The product was purified using silica gel

chromatography (dichloromethane/methanol = 95/5 v/v %) to give 85 mg 4- { [6-(nitro)quinolin- 4-yl]oxy}-N-(4-methylpyridin-2-yl)benzamide as a yellow solid. LC-MS (Method A) Rt: 4.45 mm; m/z 371.2 (M+H) + . Example 44 - Preparation of 4- 6-(Acryloylamino)quinolin-4-ylloxy}-N-(4-methylpyridin-2- vDbenzamide (E-25)

[00240] A suspension of compound 1-21 (20 mg, 0.054 mmol), acrylic acid (7.4 μΐ, 0.081mmol) and EDCI (15.5 mg, 0.081 mmol) in THF (1 ml) and NMP (1 ml) was stirred at room

temperature, after which pyridine (13 μΐ, 0.162 mmol) was added. The reaction mixture was stirred at room temperature overnight. More EDCI (0.5 eq.) and acrylic acid (0.5 eq.) were added and the reaction mixture was stirred for 2 hrs. The reaction mixture was diluted with ethyl acetate and washed sequentially with water, a saturated aqueous solution of NaHC03 and brine. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The product was purified using silica gel chromatography with gradient 0-5% methanol in dichloromethane. The pure fractions were concentrated under reduced pressure and lyophilized from water and acetonitrile, to give 10 mg 4-{[6-(acryloylamino)quinolin-4-yl]oxy}-N-(4- methylpyndin-2-yl)benzamide (44%). LC-MS (Method A) Rt: 4.98 mm; m/z 425.2 (M+H) + ;

HPLC (Method C) Rt: 5.49 mm, 1H NMR (400 MHz, DMSO-D6, 300K): δ (ppm) = 1,23 (3H, t, J = 7.6), 2.69 (2H, q, J = 7.7), 5.85 (1H, dd, Jl = 10.2 Hz, J2 = 1.8 Hz), 6.33 (1H, dd, Jl = 17.1 Hz, J2 = 1.9 Hz), 6.51 (1H, dd, Jl = 17.0 Hz, J2 = 10.1 Hz), 6.93 (1H, d, J = 5.8 Hz), 7.10 (1H, d, J = 5.4 Hz), 7.48 (2H, d, J = 8.8 Hz), 8.09 (1H, s), 8.14 (1H, m), 8.26 (2H, d, J = 8.8), 8.30 (1H, d, J = 5.1 Hz), 8.82 (1H, d, J = 5.8 Hz), 8.93 (1H, s), 10.74 (1H, s), 10.92 (1H, s). Example 45 - Preparation of 4-{[6-(Butvno-2-ylamino)quinolin-4-ylloxy}-N-(4-methylpyridi n- 2-yl)benzamide (E-26)

[00241] This compound was prepared in an analogous manner as described for compound E-25 from compound 1-21 and butynoic acid, to afford the title compound (1.7 mg, 7%). LC-MS (Method A) Rt: 5.15 mm; m/z 437.2 (M+H) + . HPLC (Method C) Rt: 5.90 mm.

Example 46 - Preparation of 4-[(6-{[(2£ ' )-4-Dimethylaminobut-2-enoyllamino}quinolin-4- ylloxyl -N-(4-methylp ridin-2-vDbenzamide (E-27)

[00242] This compound was prepared, in an analogous manner as described for compound E-25 from compound 1-21 and 4-(dimethylamino)-2-butenoic acid hydrochloride, to afford the title compound (2.8 mg, 11%). LC-MS (Method A) Rt: 4.05 mm; m/z 482.2 (M+H) + . HPLC (Method C) Rt: 3.96 min.

Example 47 - Preparation of 4-[(6- (jyZ)-4-morpholinobut-2-enoyllamino}quinolin-4-yl)oxyl- N-(pyridin-2-yl)benzamide (E-28)

[00243] Preparation of 4-[(6-{[(iv / Z)-4-bromobut-2-enoyl]amino}-4-quinolyl)oxy]-N-(2- pyridyl)benzamide. To a solution of 4-bromocrotonic acid (500 mg, 3.03 mmol) in DCM (5 mL) was added oxalyl chloride (289 μΐ, 3.40 mmoL) and several drops of DMF. The reaction was stirred at room temperature for 1.5 hours. The solvent and excess reagent were removed under reduced pressure. The resulting residue was dissolved in 1 mL THF and added to a 0 °C mixture of compound 1-18 (540 mg, 1.51 mmol) in THF (4 ml). The reaction was stirred at 0 °C for 3 hours. Water was added to the reaction mixture and the product was extracted into DCM. The organic layer was dried over Na2S04, filtered and concentrated under reduced pressure. The residue was suspended in ethanol and ethyl acetate. The solid was filtered off, to give 117 mg of a mixture of desired chloride and bromide in 15% yield. The filtrate was concentrated under reduced pressure and the crude material was chromatographed on silica gel eluting with 0-10% MeOH/DCM, to give 4-[(6-{[(£ Z)-4-bromobut-2-enoyl]amino}-4-quinolyl)oxy]-N-(2- pyridyl)benzamide (314 mg, 40%; purity=83%.

[00244] Preparation of 4-[(6-{[(iv / Z)-4-morpholinobut-2-enoyl]amino}quinolin-4-yl)oxy]-N- (pyridin-2-yl)benzamide. Morpholine (20 mg, 0.23 mmol) was added to a solution of 4-[(6- {[(£ Z)-4-bromobut-2-enoyl]amino}-4-quinolyl)oxy]-N-(2-pyridyl)be nzamide (58 mg, 0.12 mmol) and TEA (0.048 mL, 0.35 mmol) in 1 mL DMF at 0 °C. The reaction was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC with 0-100% acetonitrile in water with TFA. The pure fractions were poured over a SCX2 column and washed from the column with 10% DIPEA in MeOH. The compound was lyophilized from water, to give 9.8 mg (17%) 4- [(6- {[(E/Z)-4- morpholinobut-2-enoyl]amino} quinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamidea light yellow solid. LC-MS (Method A) Rt: 3.00 mm; m/z 510.1 (M+H) ; HPLC (Method C) Rt: 4.12 mm.

Example 48 - Preparation of (£")-4-[2-methoxyethyl(methvnaminolbut-2-enoic acid (1-22)

1-22

[00245] Preparation of methyl (E)-4-[2-methoxyethyl(methyl)amino]but-2-enoate. To a solution of N-(2-methoxyethyl)methylamine (1.1 g; 12.3 mmol) in 25 mL of THF was added 4-trans- bromomethylcrotonate (1 g; 5.6 mmol), and the mixture was stirred at room temperature for overnight. The reaction mixture was diluted by ethyl acetate (25 mL). Then it was washed with brine six times, dried over Na 2 S0 4 , filtered and concentrated under reduced pressure to give methyl (£)-4-[2-methoxyethyl(methyl)amino]but-2-enoate (895 mg, 86%).

[00246] Preparation of (£)-4-[2-methoxyethyl(methyl)amino]but-2-enoic acid. To a solution of methyl (£)-4-[2-methoxyethyl(methyl)amino]but-2-enoate (895 mg, 4.8 mmol) in THF/H 2 0 (20 rriL/20 mL) was added LiOH.H 2 0 (420 mg, 10 mmol), and the mixture was stirred at 25°C for 12h. Then the pH value of the mixture was adjusted to about 7. The solvent was removed under reduced pressure to give (£)-4-[2-methoxyethyl(methyl)amino]but-2-enoic acid (1.8 g) as a crude product. The product was taken up in toluene and the salts were filtered off. The filtrate was concentrated under reduced pressure. The residue was taken up in 10 ml isopropanol and slowly 10 ml of diethylether was added. The solid was filtered off and washed with diethylether to give (£)-4-[2-methoxyethyl(methyl)amino]but-2-enoic acid (410 mg; 49%) as a white hygroscopic solid. The filtrate was concentrated under reduced pressure. The residue was taken up in 5 ml isopropanol and slowly 15 ml diethylether was added. The supernatant was taken off and the solid was dried under reduced pressure to give (£)-4-[2-methoxyethyl(methyl)amino]but- 2-enoic acid (466 mg, 56%) as a white hygroscopic solid (56%). LC-MS (Method A) Rt: 0.70 mm; m/z 174.1 (M+H) + . Example 49 - Preparation of 4- 6-{[(iT)-4-[2-methoxyethyl(methyl)aminolbut-2- enoyllamino} quinolin-4-yl oxy} -N-(4-ethylpyridin-2-yl)benzamide (E-29)

[00247] To a solution of compound 1-20 (50 mg; 0.13 mmol), compound 1-22 (45 mg; 0.26 mmol) and EDCI (50 mg; 0.26 mmol) in THF (2 ml) was added pyridine (21 μΕ; 0.26 mmol). The reaction mixture was stirred at room temperature for 1 hr. 1 ml DMF was added and 1-22 (45 mg; 0.26 mmol), EDCI (50 mg; 0.26 mmol) and pyridine (21 μΕ; 0.26 mmol) were added and the reaction mixture was stirred for 4 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC with gradient 0-100% acetonitrile in water with TFA. The pure fractions were extracted with THF and a saturated aqueous solution of NaHCC saturated with NaCl. The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure. The residue was taken up in water and lyophilized to give 21 mg of 4-{[6-{[(£ ' )-4-[2-methoxyethyl(methyl)amino]but-2- enoyl]amino}quinolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benzam ide as a brown solid (30%). LC- MS (Method A) Rt: 3.50 mm; m/z 540.2 (M+H) + ; HPLC (Method C) Rt: 5.00 mm.

Example 50 - Preparation of [(S^-tetrah drofuran-S-yll 4-methylbenzenesulfonate (1-23)

[00248] To a solution of (3<S -tetrahydrofuran-3-ol (193 μΕ, 2.8 mmol) in pyridine (5 mL) at 0 °C was added benzenesulfonyl chloride (601 mg, 3.4 mmol). The reaction mixture was stirred for 1 hr at 0 °C and overnight at room temperature. The reaction mixture was concentrated under reduced pressure and purified by silica column chromatography with a gradient of 0-30% ethyl acetate in heptane. The pure fractions were collected to give 275 mg [(35)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate as a colorless oil (40%). This material was directly used in the next step.

Example 51 - Preparation of 4-{[6-amino-7-{[(3i?)-tetrahvdrofuran-3-ylloxy}quinolin-4- ylloxy} -N-(pyridin-2-yl)benzamide 1-24)

[00249] Preparation of 4-{[6-nitro-7-{[(3i?)-tetrahydrofuran-3-yl]oxy}quinolin-4-yl ]oxy}-N- (pyridin-2-yl)benzamide. A suspension of compound 1-15 (100 mg, 0.25 mmol), potassium carbonate (86 mg, 0.62 mmol) and compound 1-23 (66 mg, 0.27 mmol) in DMF (1 mL) was stirred at 50 °C overnight. About 70% conversion to the desired product was observed. The reaction mixture was stirred for 8 hrs at 60 °C and was stored in the freezer over the weekend. The reaction mixture was stirred for 4 hrs at 60 °C. The reaction mixture was diluted with ethyl acetate and washed with a saturated solution of NaHCC and brine. The organic layer was dried over Na 2 S0 4 , concentrated under reduced pressure and purified by silica column

chromatography with a gradient of 0-5% methanol in dichloromethane to give 66 mg 4-{[6-nitro- 7- { [(3R)-tetrahydrofuran-3-yl]oxy } quinolin-4-yl]oxy} -N-(pyridin-2-yl)benzamide (56%). LC- MS (Method A) Rt: 5.31 mm; m/z 473.1 (M+H) + .

[00250] Preparation of 4- { [6-amino-7- { [(3i?)-tetrahydrofuran-3-yl]oxy} quinolin-4-yl]oxy} -N- (pyridin-2-yl)benzamide. To a solution of 4-{[6-nitro-7-{[(3i?)-tetrahydrofuran-3- yl]oxy}quinolin-4-yl]oxy}-N-(pyridin-2-yl)benzamide (66 mg, 0.14 mmol) in ethanol (5 mL) and THF (5 mL) was added Pd/C (25 mg) and the reaction mixture was stirred at 60 °C under a hydrogen atmosphere for 4 hrs. The reaction mixture was filtered over dicalite and the filtrate was concentrated under reduced pressure. The residue was purified by silica column chromatography with gradient 0 to 5% methanol in dichloromethane to give 4- {[6-amino-7- { [(3i?)-tetrahy drofuran-3 -y 1] oxy } quinolin-4-y 1] oxy} -N-(pyridin-2-yl)benzamide (40 mg, 0.0841 mmol, 60.2% yield) as a yellow oil. LC-MS (Method A) Rt: 3.77 mm; m/z 443.1 (M+H) + .

Example 52 - Preparation of 4- 6-(but-2-ynoylamino)-7- {[(3i?)-tetrahydrofuran-3- yll oxy } quinolin-4-yll oxy } -N- ridin-2-yl)benzamide (E-30)

[00251] This compound was prepared in an analogous manner as described for compound E-ll from compound 1-24 and 2-butynoic acid to afford the title compound (21 mg, 52%) as a beige solid. LC-MS (Method A) Rt: 4.33 mm; m/z 509.1 (M+H) + , HPLC (Method C) Rt : 6.43 mm.

Example 53 - Preparation of 4-[(6-(4-methoxybut-2-vnoyl)(methyl)aminoquinolin-4-yl)oxyl- N- (4-methylpyridin-2-yl)benzamide E-31)

[00252] Preparation of 4-[(6-(Methyl)aminoquinolin-4-yl)oxy]-N-(4-methylpyridin-2- yl)benzamide. A suspension of compound 1-21 (85 mg; 0.23 mmol) and paraformaldehyde (21 mg; 0.69 mmol) in MeOH (2 rriL) was heated to 70°C in a sealed tube for 2 hrs. The reaction mixture was cooled to room temperature and then filtered to remove excess paraformaldehyde. Sodium cyanoborohydride (14 mg; 0.23 mmol) was added and the mixture was stirred at room temperature for 17 hrs. The mixture was diluted with EtOAc and washed with brine. The organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC. Fractions containing product were concentrated to afford 20 mg of 4-[(6-(methyl)aminoquinolin-4-yl)oxy]- N-(4-methylpyridin-2-yl)benzamide (23% yield).

[00253] Preparation of 4-[(6-(4-methoxybut-2-ynoyl)(methyl)aminoquinolin-4-yl)oxy]- N-(4- methylpyridin-2-yl)benzamide ditrifluoroacetate. To a solution of 4-[(6-(methyl)aminoquinolin- 4-yl)oxy]-N-(4-methylpyridin-2-yl)benzamide (20 mg; 0.052 mmol) in THF (2 mL) was added 4-methoxybut-2-ynoic acid (12 mg; 0.104 mmol), pyridine (8.4 μΐ.; 0.104 mmol) and EDCI (20 mg; 0.104 mmol). The mixture was stirred at room temperature for 3 hours. 4-methoxybut-2- ynoic acid (12 mg; 0.104 mmol), pyridine (8.4 μΐ.; 0.104 mmol) and EDCI (20 mg; 0.104 mmol) were added together with 400 μΐ ^ of NMP. Stirring was continued for 17 hrs. 500 μL· of water was added. THF was removed in vacuo and the residue was purified by preparative HPLC. Fractions containing product were concentrated and lyophilized to afford 4.9 mg of 4-[(6-(4- methoxybut-2-ynoyl)(methyl)aminoquinolin-4-yl)oxy]-N-(4-meth ylpyridin-2-yl)benzamide trifluoroacetate 1 :2 (20% yield). Other salts or the free base of E-31 may be prepared by standard methods. LC-MS (Method A) Rt: 5.58 mm; m/z 481.1 (M+H) + . HPLC (Method C) Rt 6.56 mm.

Example 54 - Preparation of 4-mor holinopent-2-ynoic acid (1-25)

[00254] Preparation of 4-(l-methylprop-2-ynyl)morpholine. 3-bromobut-l -yne (1 g, 7,52 mmol), potassium carbonate (0.57 g; 4.14 mmol) and morpholine (0.65 mL; 7.52 mmol) were taken up in methanol (10 mL) and cooled in an ice bath. 3-bromobut-l-yne (1 g; 7.52 mmol) was added drop wise under stirring. The ice bath was removed after 30 minutes, and stirring continued overnight at room temperature to give an off-white suspension. The precipitated salts were removed by filtration. The filtrate was evaporated to dryness and then treated with DCM, which gave another suspension. Precipitates were removed by filtration, and the filtrate was evaporated to dryness again before being treated with diethyl ether. This gave yet another precipitate. After a final filtration/evaporation step, the product was obtained as a yellow oil (320 mg; 30% yield). [00255] Preparation of 4-morpholinopent-2-ynoic acid. 4-(l-methylprop-2-ynyl)morpholine (320 mg; 2.3 mmol) was dissolved in THF (10 rriL) under a nitrogen atmosphere and cooled to - 78 °C. n-Butyllithium in hexanes (1.44 mL; 2.3 mmol) was added dropwise under stirring. After 1 hour, crushed carbon dioxide (2023 mg; 45.98 mmol) was added in one portion, after which the mixture was allowed to come to room temperature. Water and EtOAc were added to the mixture, and the layers were separated. The aqueous layer was then evaporated to dryness. The crude product was dissolved in MeOH. Insoluble salts were separated by filtration, after which the solution was evaporated to dryness to give 4-morpholinopent-2-ynoic acid (405 mg; 2.21 mmol; 96% yield) as a yellow solid.

Example 55 - Preparation of 4-[(6-Aminoquinazolin-4-yl)oxyl-N-[4-(ethyl)pyridin-2- yllbenzamide (1-26)

[00256] Preparation of 4-[(6-Nitroquinazolin-4-yl)oxy]-N-[4-(ethyl)pyridin-2-yl]ben zamide. A solution of compound 1-4 (450 mg; 1.90 mmol), 4-chloro-6-nitroquinoline (410 mg; 2.00 mmol) and potassium carbonate (260 mg; 2.00 mmol) in acetonitrile (5 ml) was stirred for 45 minutes in the microwave at 135°C, followed at 150°C for 1 hr. The reaction was filtered and washed with acetonitrile and water, taken up in toluene and coevaporated twice, to give 88 mg 4-[(6- nitroquinazolin-4-yl)oxy]-N-[4-(ethyl)pyridin-2-yl]benzamide (11%).

[00257] 4-[(6-Aminoquinazolin-4-yl)oxy]-N-[4-(ethyl)pyridin-2-yl]ben zamide. Raney Nickel suspension (80 mg) was added to a solution of 4-[(6-nitroquinazolin-4-yl)oxy]-N-[4- (ethyl)pyridin-2-yl]benzamide (88 mg; 0.21 mmol) and ammonium formate (80 mg; 1.27 mmol) in ethyl acetate and ethanol. The reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was filtered over decalite, washed with ethyl acetate and ethanol 1/1 and concentrated in vacuo. The residue was purified by preparative HPLC with gradient 0-100% acetonitrile in water with TFA. The pure fractions were collected yielding in 3.6 mg 4-[(6-aminoquinazolin-4- yl)oxy]-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide (4%).

Example 56 - Preparation of 4- 6-(Acryloylamino)quinazolin-4-ylloxy}-N-[4-(ethyl)pyridin-2- yllbenzamide (E-32)

[00258] This compound was prepared, in an analogous manner as described for compound E-18 from compound 1-26 and acryoyl chloride, to afford the title compound (4.7 mg, 91%) as a TFA salt. Other salts or the free base of E-32 may be prepared by standard methods. LC-MS (Method A) Rt: 6.26 mm; m/z 440.5 (M+H) + HPLC (Method C) Rt 7.14 mm.

Example 57 - Preparation of 4-[(6-Nitroquinolin-4-yl)aminolbenzoic acid (1-27)

[00259] 4-Chloro-6-nitroquinoline (2.876 mmol, 600 mg) and 4-aminobenzoic acid (3.020 mmol, 414 mg) were suspended in ethanol (15 mL). After addition of approximately 25 drops of concentrated hydrochloric acid (37%, catalytic), the reaction was stirred for 3h at reflux. The reaction mixture was cooled to room temperature and the solids were filtered off. The solids were washed with ethanol and dried in vacuo, yielding 730 mg of 4-[(6-nitroquinolin-4- yl)amino]benzoic acid as a tanned solid (82%). LC-MS (Method A) Rt: 4.398 min; m/z 310.1

(M+H) .

Example 58 - Preparation of 4-[6-Aminoquinolin-4-yl)aminol-N-(pyridine-2-yl)benzamide (I- 28)

[00260] Preparation of 4-[6-nitroquinolin-4-yl)amino]-N-(pyridine-2-yl)benzamide. Compound 1-27 (0.266 mmol, 82 mg), 2-aminopyridine (0.292 mmol, 28 mg ), EDCI (0.399 mmol, 76 mg) and DMAP (0.032 mmol, 4 mg) were combined in a flask and dissolved in a mixture of DCM and NMP (2/1 v/v%) (2 mL) and was stirred overnight at room temperature. The reaction mixture was concentrated, water was added and the mixture was centrifuged. The supernatant was removed and the solids were washed with water, taken up in dioxane and concentrated in vacuo. The residue was purified by Si02-chromatography (0 to 8% methanol in DCM) to give 55 mg of 4-[6-nitroquinolin-4-yl)amino]-N-(pyridine-2-yl)benzamide (54%). LC-MS (Method A) Rt : 4.731 mm; m/z 386.1 (M+H) + .

[00261] Preparation of 4-[6-Aminoquinolin-4-yl)amino]-N-(pyridine-2-yl)benzamide. 4-[6- Nitroquinolin-4-yl)amino]-N-(pyridine-2-yl)benzamide (55 mg, 0.143 mmol) was dissolved in a mixture of ethyl acetate and ethanol (2/1 v/v%) (6 mL). The solution was purged with nitrogen gas followed by addition of a catalytic amount of Pd on carbon (10%, wet). Subsequently, the reaction mixture was purged again with nitrogen gas , followed stirring overnight at room temperature under an atmosphere of hydrogen gas. The reaction mixture was filtered over dicalite and concentrated in vacuo, yielding 52 mg of 4-[6-aminoquinolin-4-yl)amino]-N- (pyridine-2-yl)benzamide as a brown oil (100%). LC-MS (Method A) Rt: 4.425 min; m/z 356.2 (M+H) + . Example 59 - Preparation of 4- 6-(But-2-vnoylamino)quinolin-4-yllamino}-N-(pyridine-2- vDbenzamide (E-33)

[00262] Compound 1-28 (0.071 mmol, 25 mg), HATU (0.094 mmol, 36 mg) and 2-butenoic acid (0.079 mmol, 7 mg) were suspended in DCM 1.5 mL. DIPEA (0.250 mmol, 41 μΐ) was added. The reaction mixture was stirred overnight at room temperature. After concentrating the mixture in vacuo, the residu was purified by Strong Cation Exchange (SCX2) with a mixture of methanol/water (1/1 v/v %), followed by rinsing with 10v/v% DIPEA in methanol to obtain the crude product. The crude product was purified using semi-preperative HPLC. The product containing fractions were concentrated in vacuo, yielding 9 mg of 4-{[6-(but-2- ynoylamino)quinolin-4-yl]amino}-N-(pyridine-2-yl)benzamide (20 %) as a TFA salt. Other salts or the free base of E-33 may be prepared by standard methods. LC-MS (Method A) Rt: 4.978 mm; m/z 211.7 ((M+H)/2) + .

Example 60 - Preparation of 4-{[6-(Acryloylamino)quinolin-4-yllamino}-N-(pyridine-2- vDbenzamide (E-34)

[00263] Compound 1-28 (0.026 mmol, 9 mg), EDCI (0.052 mmol, 10 mg) and acrylic acid (0.052 mmol, 3,5 μΐ) were suspended in a mixture of THF and NMP (1/1 v/v%). Pyridine (0.104 mmol, 8 μΐ) was added. The reaction mixture was stirred overnight at room temperature. After concentrating, the mixture was quenched by a small amount of water and diluted with methanol. The solution was subjected to Strong Cation Exchange (SCX2) using a mixture of methanol/water (1/1 v/v%) as eluent, followed by rinsing with 10 v/v% DIPEA in methanol to obtain the crude product. The crude product was purified using semi-preperative HPLC. The product containing fractions were concentrated in vacuo, yielding 3 mg of 4-{[6- (acryloylamino)quinolin-4-yl]amino}-N-(pyridine-2-yl)benzami de (25%). LC-MS (Method A) Rt: 4.845 mm; m/z 410.2 (M+H) + , HPLC (A) Rt : 4.531.

Example 61 - Preparation of 4-[(6-Aminoquinolin-4-yl)aminol-N-(4-methylpyridin-2- vDbenzamide (1-29)

[00264] The title compound was synthesized using the method described for compound 1-28, yielding 52 mg of 4-[(6-aminoquinolin-4-yl)amino]-N-(4-methylpyridin-2-yl)benz amide in a quantative yield. LC-MS (Method A) Rt: 4.367 min; m/z 370.2 (M+H) + .

Example 62 - Preparation of 4- 6-(But-2-vnoylamino)quinolin-4-yllamino}-N-(4- methylpyridine-2-yl)benzamide E-35)

[00265] Compound 1-29 (0.052 mmol, 19 mg), HATU (0.069 mmol, 26 mg) and 2-butenoic acid (0.057 mmol, 5 mg) were suspended in DCM 1.5 mL. DIPEA (0.183 mmol, 30 μΐ) was added. The reaction mixture was stirred overnight at room temperature. After concentrating the mixture in vacuo, the residu was purified by Strong Cation Exchange (SCX2) with a mixture of methanol/water (1/1 v/v%), followed by rinsing with 10v/v% DIPEA in methanol to obtain the crude product. The crude product was purified using semi-preperative HPLC. The product containing fractions were concentrated in vacuo, yielding 7 mg of 4-{[6-(but-2- ynoylamino)quinolin-4-yl]amino}-N-(4-methylpyridine-2-yl)ben zamide ditrifluoroacetate (19%). Other salts or the free base of E-35 may be prepared by standard methods. LC-MS (Method A) Rt: 4.843 mm; m/z 436.2 (M+H) + , HPLC (Method C) Rt : 4.655.

Example 63 - Preparation of 4-{[6-(Acryloylamino)quinolin-4-yllamino}-N-(4-methylpyridin e- 2-yl)benzamide (E-36)

[00266] Compound 1-29 (0.048 mmol, 18 mg) was dissolved in 1 mL DCM. DIPEA was added and the mixture was cooled to 0°C. Acryloyl chloride was added and the reaction mixture was stirred for 4h at 0°C. After concentrating the mixture in vacuo, the residu was purified by Strong Cation Exchange (SCX2) with a mixture of methanol/water (1/1 v/v%), followed by rinsing with 10v/v% DIPEA in methanol to obtain the crude product. The crude product was purified using semi-preperative HPLC. The product containing fractions were concentrated in vacuo, yielding 9 mg of 4-{[6-(acryloylamino)quinolin-4-yl]amino}-N-(4-methylpyridin e-2-yl)benzamide ditrifluoroacetate (27%). Other salts or the free base of E-36 may be prepared by standard methods. LC-MS (Method A) Rt: 4.735 mm; m/z 424.2 (M+H) + , HPLC (Method C) Rt: 4.396.

Example 64 - Preparation of 4-[(6-Aminoquinolin-4-yl)aminol-N-(4-ethylpyridin-2- vDbenzamide (1-30)

[00267] The title compound was synthesized using the method described for Compound 1-29, yielding 69 mg of 4-[(6-aminoquinolin-4-yl)amino]-N-(4-ethylpyridin-2-yl)benza mide (86%). LC-MS (Method A) Rt: 5.029 mm; m/z 192.6 ((M+H)/2) + .

Example 65 - Preparation of 4- {[6-(Acryloylamino)quinolin-4-yllamino} -N-(4-ethylpyridine-2- vDbenzamide (E-37)

[00268] The title compound was synthesized using the method described for compound E-34, yielding 4 mg of 4- {[6-(Acryloylamino)quinolin-4-yl]amino} -N-(4-ethylpyridine-2- yl)benzamide (15%). LC-MS (Method A) Rt: 5.263 mm; m/z 438.2 (M+H) + , HPLC (Method C) Rt: 5.215. Example 66 - Preparation of 4-{[6-((4-methoxybut-2-vnoyl)amino)quinolin-4-yllamino}-N-(4 - ethylpyridine-2-yl)benzamide E-38)

[00269] The title compound was synthesized using the method described for compound E-34, yielding 3 mg of 4-{[6-((4-methoxybut-2-ynoyl)amino)quinolin-4-yl]amino}-N-(4 - ethylpyndine-2-yl)benzamide (7%). LC-MS (Method A) Rt : 5.797 mm; m/z 240.7 ((M+H)/2)+, HPLC (Method C) Rt : 5.579.

Example 67 - Preparation of 4-chloro-7-methoxy-6-nitroquinoline (1-31)

[00270] Preparation of 5-{(£ ' )-[(3-methoxy-4-nitrophenyl)imino]methyl}-2,2-dimethyl -l,3- dioxane-4,6-dione. 3-methoxy-4-nitroaniline (3,75 g, 18,7 mmol) and 5-(ethoxymethylidene)- 2,2-dimethyl-l,3-dioxane-4,6-dione (3,15 g, 18, 7mmol) were suspended in ethanol (100 mL) and stirred for lh at 85°C. The reaction mixture was cooled to room temperature. The solid was filtered off, washed with ethanol and dried in vacuo yielding the title compound in 97% yield. This material was directly used in the next step.

[00271] Preparation of 7-methoxy-6-nitroquinolin-4-ol. 5-{(£)-[(3-methoxy-4- nitrophenyl)imino]methyl}-2,2-dimethyl-l,3-dioxane-4,6-dione (5.82 g, 18,1 mmol) was suspended in diphenylether (50 mL). The reaction mixture was stirred for lh at 220°C. The mixture was coolee to room temperature and filtered. The residual solid was washed with DCM and THE. Subsequently, the product was washed from the filter using a gradient of 20 - 50% methanol in DCM. Concentration of the product fractions resulted in yielding the title compound as a light brown solid (68%). 1H NMR (400 MHz, DMSO-d 6 , 300K): δ = 3.99 (3H, s), 6.06 (1H, d, J = 7.6 Hz), 7.19 (1H, s), 7.95 (1H, d, J = 7.6 Hz), 8.53 (1H, s), 11.90 (1H, br s)

[00272] Preparation of 4-chloro-7-methoxy-6-nitroquinoline. 7-methoxy-6-nitroquinolin-4-ol (2.7 g, 12.3mmol) was suspended in thionyl chloride (50 mL). A small amount of DMF (0.5 rriL) was added and the mixture was stirred at reflux for 4h. The reaction mixture was concentrated in vacuo and coevaporated twice with toluene yielding a brown solid, which was dried on the oil pump. The crude product was trituated with diethylether and the isolated solid was dried in vacuo, resulting a yellowish/light brown solid in quantitative yield. LC-MS (Method B) Rt: 7.479 mm; m/z 239.1 (M+H)+.

Example 68 - Preparation of 4-[(6-amino-7-methoxyquinolin-4-yl)oxyl-N-(pyridin-2- vDbenzamide (1-33)

[00273] Preparation of 4-[(6-nitro-7-methoxyquinolin-4-yl)oxy]-N-(pyridin-2-yl)benz amide. A suspension of compound 1-32 (4.19 mmol, 1.00 g), compound 1-1 (4.61 mmol, 0.99 g) and potassium tert-butoxide (7.12 mmol, 0.80 g) in NMP (4mL) and THF (16 mL) was stirred at 150°C for 2 h in the microwave. The reaction mixture was diluted with EtOAc and washed with water, aqueous 1M NaOH, aqueous saturated sodiuym bicarbonate and brine, dried with sodium sultfate and concentrated in vacuo. The crude product was purified by silica gel chromatography using a gradient of 0-40% of acetone in toluene. Pure fractions were combined and evaporated to dryness, yielding 870 mg (50%) of the title compound as a light brown solid. LC-MS (Method B) Rt : 7.040 mm; m/z 417.1 (M+H) + .

[00274] Preparation of 4-[(6-amino-7-methoxyquinolin-4-yl)oxy]-N-(pyridin-2-yl)benz amide. A solution of 4-[(6-nitro-7-methoxyquinolin-4-yl)oxy]-N-(pyridin-2-yl)benz amide (2.09 mmol, 870 mg) in THF/EtOH (75mL, 2/1 v/v%) was purged with nitrogen. Pd/C (10%, wet, excess) was added and the mixture was purged with nitrogen again. The mixture was stirred overnight at r.t. with a hydrogen flow bubbling through the mixture. The Pd/C was removed by filtration over Dicalite and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography using a gradient of 0-10% of MeOH in DCM. The fractions were combined and concentrated in vacuo yielding 590 mg (73%) of the title compound as a light brown foam. LC- MS (Method B) Rt: 4.961 mm; m/z 387.1 (M+H) + .

Example 69 - Preparation of 4-{[6-(But-2-vnoylamino)-7-methoxyquinolin-4-yllamino}-N- (pyridine-2-yl)benzamide E-39)

[00275] A solution of compound 1-33 (0.194 mmol, 75 mg) and 2-butynoic acid (0.388 mmol, 32 mg) in pyridine (1.5 mL) was treated with EDCI (0.776 mmol, 149 mg). The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness to give a red/brown oil. The crude product was purified by preparative HPLC (Luna C-18) using a gradient of 0-50% of acetonitril in water + 0,1% TFA. The fractions containing the product were saturated with sodium bicarbonate and extracted with EtOAc. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness to give an off-white sticky solid, which was reworked into a fine powder by soni cation in diethylether followed by filtration, yielding 38 mg (43%) of the title compound as an off-white solid. LC-MS (Method A) Rt: 3.828 min; m/z 453.2 (M+H)+, HPLC (Method C) Rt: 5.908 mm, 1H NMR (400 MHz, DMSO-d6, 300K): δ (ppm) = 2.05 (3H, s), 4.03 (3H, s), 6.66 (1H, d, J = 5.1 Hz), 7.17 (1H, t, J = 4.8 Hz), 7.36 (2H, d, J = 8.8 Hz), 7.51 (1H, s), 7.85 (1H, t, J = 8 Hz), 8.18 (3H, m), 8.40 (1H, m), 8.63 (1H, d, J = 5.1 Hz), 8.74 (1H, s), 9.85 (1H, s), 10.8 (1H, s). Example 70 - Preparation of 4-{[6-((4-methoxybut-2-vnoyl)amino)-7-methoxyquinolin-4- yllamino} -N-(4-ethylpyridine-2- l)benzamide (E-40)

[00276] To a solution of compound 1-33 (0.115 mmol, 41 mg), 4-methoxy-2-butynoic acid (0.127 mmol, 10 μΐ) and triethylamine (0.577 mmol, 80 μΐ) in DCM (1 mL) was added 1- propanephosphonic acid cyclic anhydride (50 wt% in ethyl acetate) (0.137 mmol, 41 μΐ) at room temperature. The reaction mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture. Organic layer was separated and dried using a PE-filter. The organic was concentrated using a N2-flow. The crude product was purified using flash chromatography (0 - 6% methanol in DCM, 35 min), followed by purification semi-preperative HPLC (0 - 100% MeCN + TFA, 20min), yielding the title compound in a 4% yield (3 mg) as a TFA salt. Other salts or the free base of E-40 may be prepared by standard methods. LC-MS (Method A) Rt: 3.917 mm; m/z 484.2 (M+H) + , HPLC (Method C) Rt : 6.060 mm.

Example 71 - Preparation of 4-[(6-amino-7-methoxyquinolin-4-yl)oxyl-N-(4-ethylpyridin-2- vDbenzamide (1-34)

[00277] The title compound was synthesized using the method described for compound 1-33, yielding 190 mg of 4-[(6-amino-7-methoxyquinolin-4-yl)oxy]-N-(4-ethylpyridin-2- yl)benzamide (22% over 2 steps). LC-MS (Method A) Rt : 5.232 mm; m/z 415.2 (M+H) + .

Example 72 - Preparation of 4-[(6-amino-7-methoxyquinolin-4-vnoxyl-N-(4-methoxypyridin-2 - vDbenzamide (1-35)

[00278] The title compound was synthesized using the method described for compound 1-33, yielding 60 mg 4-[(6-amino-7-methoxyquinolin-4-yl)oxy]-N-(4-methoxypyridin- 2-yl)benzamide (13% over 2 steps). LC-MS (Method A) Rt : 4.611 mm; m/z 209.1 ((M+H)/2) + .

Example 73 - Preparation of BTK inhibitors

[00279] The following compounds were synthesized following the methods described for compounds E-1 to E-40. Salts can be converted to the corresponding free base or to other salts by standard reactions.

Example 74 - 4-((6-amino-7-(2-(piperidin-l -yl)ethoxy)quinolin-4-yl)oxy)-N-(pyridin-2- vDbenzamide (1-36)

[00280] Preparation of 4-((6-nitro-7-(2-(piperidin-l-yl)ethoxy)quinolin-4-yl)oxy)-N -(pyridine- 2-yl)benzamide. To a solution of compound 1-15 (1.0 g, 24 mmol, 1 eq.) in THF (12 mL) was added 2-(N-piperidyl)ethyl alcohol (390 mg, 37.3 mmol, 1 eq.) and triphenyl phosphine (1.3 g, 49 mmol, 2 eq.) at room temperature. DIAD (0.9 mL, 49 mmol, 2 eq.) was added at 0 °C and the reaction mixture was stirred at 0 °C for 2h. After completion, the reaction mixture was concentrated under reduced pressure, diluted with 10% methanol in DCM and washed with water. The organic layer was dried over sodium sulfate and concentrated to get crude residue that was purified by SiCVchromatography (8% methanol in DCM) to get 4-((6-nitro-7-(2- (piperidin-l-yl)ethoxy)quinolin-4-yl)oxy)-N-(pyridine-2-yl)b enzamide (1.1 g, 74.3%) as brown solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 10.89 (s, 1H), 8.82 (d, 1H, J = 5.2 Hz), 8.78 (s, 1H), 8.40 (d, 1H, J = 4.0 Hz), 8.20 (dd, 3H, J = 3.6, 8.6 Hz), 7.86 (m, 1H), 7.80 (s, 1H), 7.45 (d, 2H, J = 8.6 Hz), 7.27 (m, 3H), 6.72 (d, 1H, J = 5.2 Hz), 4.4 (m, 2H), 2.78 (d, 2H, J = 2.36 Hz), 2.33 (4H, m), 1.36 (m, 6H).

[00281] Preparation of 4-((6-amino-7-(2-(piperidin-l -yl)ethoxy)quinolin-4-yl)oxy)-N-(pyridin- 2-yl)benzamide. To a suspension of 4-((6-nitro-7-(2-(piperidin-l -yl)ethoxy)quinolin-4-yl)oxy)- N-(pyridine-2-yl)benzamide (1.1 g, 2 mmol, 1 eq.) in ethanol was added iron powder (2.4 g, 42.9 mmol, 20 eq.) and concentrated HCl (1.79 mL, 10 eq.). The reaction mixture was heated at 50 °C for 2h. After completion, the reaction was filtered through celite and washed with 10% methanol in DCM. The organic layer was basified with aqueous ammonia and dried over sodium sulfate and concentrated to get crude residue that was purified by SiC -chromatography (10% methanol in DCM) to get the title compound (370 mg, 26.4%) as brown solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 10.89 (s, 1H), 8.82 (d, 2H, J = 4.96 Hz), 8.18 (d, 1H, J = 8.52 Hz), 8.13 (d, 2H, J = 8.6 Hz), 7.83 (m, 1H), 7.32 (s, 1H), 7.18 (m, 3H), 7.09 (s, 1H), 6.72 (d, 1H, J = 3.3 Hz), 5.48 (m, 2H), 4.23 (m, 2H), 2.84 (m, 4H), 1.66 (m, 6H).

Example 75 - Preparation of 4-((6-(but-2-vnamido)-7-(2-(piperidin-l-yl)ethoxy)quinolin-4 - yl)oxy)-N-(pyridin-2-yl)benzamide (E-95)

[00282] To a solution of compound 1-36 (150 mg, 0.292 mmol, 1 eq.) in pyridine (6 mL) was added EDC.HC1 (139 mg, 0.731 mmol, 1.5 eq.) and 2-butynic acid (36 mg, 0.428 mmol, 2.5 eq.) at 0 °C. The reaction mixture was stirred at 0 °C for lh and then at room temperature for 2h. After completion, the reaction was poured in ice water and extracted with 10% methanol in DCM. The organic layer was dried over sodium sulfate and concentrated to get crude residue that was purified by SiCVchromatography (10% methanol in DCM) to get the title compound (24 mg, 15%) as off white solid. 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) 10.85 (s, 1H), 9.76 (s, 1H), 8.76 (s, 1H), 8.62 (d, 1H, J = 5.0 Hz), 8.19 (m, 3H), 7.85 (t, 1H, J = 8.0 Hz), 7.60 (s, 1H), 7.36 (d, 2H, J = 8.5 Hz), 7.18 (m, 1H), 6.66 (d, 1H, J = 5.0 Hz), 4.36 (t, 2H, J = 5.8 Hz), 2.76 (m, 2H), 2.49 (m, 4H), 2.06 (s, 3H), 1.54 (m, 4H), 1.35 (m, 2H

Example 76 - Preparation of 4-((6-amino-7-(2-(l -pyrrolidyl)ethoxy)quinolin-4-yl)oxy)-N- (pyridin-2-yf)benzamide (1-37)

[00283] Preparation of 4-((6-nitro-7-(2-bromoethoxy)quinolin-4-yl)oxy)-N-(pyridine- 2- yl)benzamide. To a solution of 1-15 (1.5g, 37.3 mmol, 1 eq.) in THF (20 rriL) was added 2- bromo ethanol (0.26 rriL, 37.3 mmol, 1 eq.) and triphenyl phosphine (1.95 g, 74.6 mmol, 2 eq.) at room temperature. DIAD (1.46 mL, 74.6 mmol, 2 eq.) was added at 0 °C and the reaction mixture was stirred at same temperature for 1 h and at room temperature for 16 h. After completion, the reaction mixture was concentrated under reduced pressure to get crude 4-((6- nitro-7-(2-bromoethoxy)quinolin-4-yl)oxy)-N-(pyridine-2-yl)b enzamide (6.0 g crude) as orange colour compound.

[00284] Preparation of 4-((6-nitro-7-(2-(l-pyrrolidyl)ethoxy)quinolin-4-yl)oxy)-N-( pyridin-2- yl)benzamide. To a solution of 4-((6-nitro-7-(2-bromoethoxy)quinolin-4-yl)oxy)-N-(pyridine- 2- yl)benzamide (6.0 g, 11.8 mmol, 1 eq.) in DMF (50 mL) was added potassium carbonate (4.89 g, 35.4 mmol, 3 eq.). Pyrrolidine (1.07 mL, 12.9 mmol, 1.1 eq.) was added and the reaction mixture was heated at 100 °C for 2 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude mass that was purified by column chromatography (silica: 100-200; elution: 5% methanol in DCM) to get pure 4-((6-nitro-7-(2-(l-pyrrolidyl)ethoxy)quinolin-4- yl)oxy)-N-(pyridin-2-yl)benzamide (1.4 g, 80%) yellow solid compound.

[00285] Preparation of 4-((6-amino-7-(2-(l-pyrrolidyl)ethoxy)quinolin-4-yl)oxy)-N-( pyridin-2- yl)benzamide. To a solution of 4-((6-nitro-7-(2-(l-pyrrolidyl)ethoxy)quinolin-4-yl)oxy)-N- (pyridin-2-yl)benzamide (1.4 g, 2.8 mmol, 1 eq.) in ethanol (10 mL) was added iron powder (3.08 g, 56.1 mmol, 20 eq.) and cone. HCl (2.5 mL, 28.0 mmol, 10 eq.) at room temperature. The reaction mixture was heated at 50 °C for 2 h. After completion, the reaction mixture was filtered through celite and washed with 10% methanol in DCM and ammonia solution. The layers were separated and the reaction mixture was concentrated to get crude compound that was purified by column chromatography (silica: 100-200; elution: 10% methanol in DCM) to get the desired 4- ((6-amino-7-(2-(l -pyrrolidyl)ethoxy)quinolin-4-yl)oxy)-N-(pyridin-2-yl)benzam ide (650 mg, 50%) as yellow solid compound.

Example 77 - Preparation of 4-[[6-(but-2-vnoylamino)-7-[2-(l-pyrrolidyl)ethoxylquinolin- 4- ylloxyl-N-(2-pyridyl)benzamide E-98)

[00286] To a solution of compound 1-37 (200 mg, 0.4 mmol, 1 eq.) in pyridine (5 mL) were added 2-butynoic acid (53 mg, 0.6 mmol, 1.5 eq.) and EDC.HC1 (202 mg, 1.06 mmol, 2.5 eq.) at 0 °C. The reaction mixture was stirred at room temperature for 2h. After completion, the reaction mixture diluted with ice water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude compound that was purified by column chromatography (silica: 230-400; elution: 10% methanol in DCM) to get the title compound (58 mg, 25.4%) as light yellow solid compound. LC-MS (Method B) Rt : 4.67 min; m/z 524.5 (M+H) + ; 1H NMR (400 MHz, DMSO-D 6 , 300K): δ (ppm) = 10.86 (1H, s), 9.97 (1H, s), 8.76 (1H, s), 8.63 (1H, d, J= 5.2 Hz), 8.40 (1H, d, J= 4.4 Hz), 8.20-8.17 (3H, m), 7.87-7.83 (1H, m), 7.60 (1H, s), 7.38 (2H, d, J= 8.8 Hz), 7.19-7.16 (1H, m), 6.66-6.65 (1H, m), 4.37-4.34 (2H, m), 2.90-2.87 (2H, m), 2.60 (4H, s), 2.06 (3H, s), 1.74 (4H, s) Example 78 - Preparation of BTK Inhibitors

[00287] The following compounds were synthesized following the methods described for Example E-95 and E-98.

Example 79 - Preparation of 4-((6-amino-7-(2-hvdroxyethoxy)quinolin-4-yl)oxy)-N-(pyridin -2- vDbenzamide (1-38)

[00288] Preparation of 4-((6-nitro-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)quinoli n-4- yl)oxy)-N-(pyridine-2-yl)benzamide. Compound 1-15 (1.6 g, 3.9 mmoles), 2-(tetrahydro-2H- pyran-2-yloxy)ethanol (0.672 g, 4.6 mmoles) and PPI13 (2.5 g, 9.7 mmoles) were taken in THF (20 mL), cooled to 0 °C, DIAD (1.5 mL, 7.8 mmoles) was added dropwise and reaction mixture was stirred at same temperature for 1 h. Reaction mixture was concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-2% MeOH in DCM to give 4-((6-nitro-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)quinoli n-4- yl)oxy)-N-(pyridine-2-yl)benzamide (1.8 g, 90%) as a brown sticky solid.

[00289] Preparation of 4-((6-amino-7-(2-hydroxyethoxy)quinolin-4-yl)oxy)-N-(pyridin e-2- yl)benzamide. 4-((6-nitro-7-(2-(tetrahydro-2H-pyran-2-yloxy)ethoxy)quinoli n-4-yl)oxy)-N- (pyridine-2-yl)benzamide (1.8 g, 3.3 moles) was taken in EtOH (20 mL), Fe-powder (3.6 g, 66.0 mmoles) and cone. HCl (3.0 mL, 33.0 mmoles) were added and reaction mixture was heated at 50°C for 1 h. Reaction mixture was diluted with ethyl acetate, basified with NH 4 OH solution and washed with water. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to give 4-((6-amino-7-(2-hydroxyethoxy)quinolin-4-yl)oxy)-N- (pyridin-2-yl)benzamide (1.2 g , 85.7%) as a light brown solid.

Example 80 - Preparation of 4-[[6-(but-2-vnoylamino)-7-(2-hvdroxyethoxy)quinolin-4-yllox yl- N-(pyridin-2-yl)benzamide E-110)

[00290] To a solution of compound 1-38 (0.200 g, 0.48 mmoles) in pyridine (4 mL), EDC.HC1 (0.230 g, 1.2 mmoles) and 2-butynoic acid (0.060g, 0.72 mmoles) were added at 0 °C and reaction mixture was stirred at RT for 2 h. Water was added and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was taken in THF:H 2 0 (1 : 1) (5 mL), LiOHH 2 0 (4 eq.) was added and reaction mixture was stirred at rt for lh. Water was added and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-3% MeOH in DCM to give the title compound (0.040 g , 18.1%) as off white solid. LC-MS (Method B) Rt: 5.20 mm; m/z 483.2 (M+H) + ; 1H NMR (400 MHz, DMSO-D 6 ): δ (ppm) = 10.85 (s, 1H), 9.94 (s, 1H), 8.94 (s, 1H), 8.60 (d, 1H, J = 5.12 Hz), 8.40 (d, 1H, J = 4.0 Hz), 8.20-8.17 (m, 3H), 7.87-7.83 (m, 1H), 7.49-7.47 (m, 1H), 7.37-7.35 (m, 2H), 7.19-7.16 (m, 1H), 6.64 (d, 1H, J = 5.0 Hz), 5.28-5.25 (t, 1H), 4.23-4.22 (m, 2H), 3.86-3.85 (t, 2H) and 2.50 (s, 3H). HPLC (Method D) Rt: 5.197 mm.

Example 81 - Preparation of BTK inhibitors

[00291] The following compounds were synthesized essentially following the methods described for compound E-110, using THP- or TBDMS -protected diols or dialkylacetal- protected triols.

Example 82 - Preparation of 4-{[(6-(2-{morpholin-4-yl}ethyl)amino)quinolin-4-ylloxy}-N- (pyridin-2-yl)benzamide 1-39)

[00292] Compound 1-18 (1.0 g, 2.8 mmoles) and morpholin-4-ylacetaldehyde HC1 salt (1.3 g, 8.4 mmoles) were taken in EtOH (15 mL) and reaction mixture was stirred for 30 min. After that, NaCNBH3 (0.879 g, 14.0 mmoles) was added and reaction mixture was stirred for overnight. Reaction mixture was concentrated, water was added and extracted with 10% MeOH in DCM. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to give 1-39 (0.700 g, 53.8%) as yellow solid.

Example 83 - Preparation of 4-{[6-(acryloyl(2-{morpholin-4-yl}ethyl)amino)quinolin-4-yll oxy- N-(pyridin-2-yl)benzamide E-117)

[00293] To a solution of 1-39 (0.200 g, 0.42 mmoles) in DCM (6 mL) at 0°C, NEt 3 (0.3 mL, 2.1 mmoles) and acryloyl chloride (0.13 mL, 1.68 mmoles) were added and reaction mixture was stirred at RT for 12 h. Water was added and extracted with DCM. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was taken in THF:H 2 0 (1 : 1) (5 mL), LiOH H 2 0 (4 eq.) was added and reaction mixture was stirred at rt for lh. Water was added and extracted with ethyl acetate. The organic part was dried over Na2S04, filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-4% MeOH in DCM to give the title compound (0.060 g, 27.2%) as light yellow solid. LC-MS (Method B) Rt : 4.90 mm; m/z 524.4 (M+H) + ; 1H NMR (400 MHz, DMSO-D6): δ (ppm) = 10.87 (s, 1H), 8.81-8.80 (m, 1H), 8.45-8.40 (m, 1H), 8.25-8.15 (m, 5H), 7.89-7.82 (m, 1H), 7.81-7.75 (m, 1H), 7.75-7.42 (m, 2H), 7.20-7.15 (m, 1H), 6.90-6.83 (m, 1H), 6.22-6.20 (m, 1H), 6.10-6.09 (m, 1H), 5.58-5.56 (m, 1H), 3.93-3.91 (m, 2H), 3.45-3.42 (m, 4H), 2.44-2.41 (m, 2H) and 2.30-2.29 (m, 4H). HPLC (Method D) Rt: 4.985 mm.

Example 84 - Preparation of 4-{[6-(but-2-vnoyl(2-{morpholin-4-yl}ethyl)amino)quinolin-4- ylloxyl -N-(pyridin-2-yf benzamide (E-l 18)

[00294] This compound was prepared in an analogous manner as described for compound E- 117 using compound 1-39 and 2-butynoic acid. LC-MS (Method B) Rt: 6.90 min; m/z 536.45 (M+H) + .

Example 85 - Preparation of 4-{[(6-(3-{dimethylamino}propyl)amino)quinolin-4-ylloxy}-N- (pyridin-2-yl)benzamide 1-40)

[00295] Preparation of 4-[(6-iodoquinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide. To a solution of compound 1-1 (3.2 g, 14.9 mmoles) in DMF (40 mL), Cs 2 C0 3 (9.7 g, 29.8 mmoles) and 4- chloro-6-iodo-quinoline (5.1 g, 17.8 mmoles) were added and reaction mixture was heated at 120 °C for 12 h. Water was added and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-80% ethyl acetate in hexane to give 4-[(6- iodoquinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (5.0 g, 74.6 mmoles) as brown solid.

[00296] Preparation of 4-{[(6-(3-{dimethylamino}propyl)amino)quinolin-4-yl]oxy}-N-( pyridin- 2-yl)benzamide. 4-[(6-Iodoquinolin-4-yl)oxy]-N-(pyridin-2-yl)benzamide (1.0 g, 2.1 mmoles), N,N-dimethylpropane-l,3-diamine (0.857 g, 8.4 mmoles) and CS2CO3 (1.3 g, 4.2 mmoles) were taken in toluene (12 mL) and reaction mixture was degassed under nitrogen for 10 min. Then, Pd 2 (dba)3 (0.096 g, 0.105 mmoles) and Xanthphos (0.121 g, 0.210 mmoles) were added and reaction mixture was heated at 150 °C for 1 h in microwave. The reaction mixture was cooled, water was added and extraction was performed with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude product which was further purified by column chromatography using silica gel (100-200 mesh) and 0-10% methanolic ammonia in DCM to give 1-40 (0.700 g, 74.4%) as brown solid.

Example 86 - Preparation of 4-{[6-(but-2-vnoyl(3- {dimethylamino}propyl)amino)quinolin-4- ylloxy} -N-(pyridin-2- l)benzamide (E-l 19)

[00297] To a solution of 1-40 (0.220 g, 0.49 mmoles) in THF (5 mL) at 0 °C, DIPEA (0.9 mL, 4.9 mmoles), 2-butynoic acid (0.201 g, 2.4 mmoles) and T3P (1.5 mL, 2.4 mmoles) were added and reaction mixture heated at 70 °C for 16 h. Reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was taken in THF:H 2 0 (1 : 1) (5 mL), LiOH H 2 0 (4 eq.) was added and reaction mixture was stirred at rt for 1 h. Water was added and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by prep to give the title compound (0.010 g, 4%) as white solid. LC-MS (Method B) Rt: 3.76 mm; m/z 508.2 (M+H) + ; 1H NMR (400 MHz, DMSO-D 6 ): δ (ppm) = 10.80 (s, 1H), 8.81-8.79 (m, 1H), 8.40 (d, 1H, J = 3.96 Hz), 8.21-8.19 (m, 4H), 8.10-8.07 (m, 1H), 7.88-7.82 (m, 2H), 7.43-7.41 (m, 2H), 7.19-7.16 (m, 1H), 6.87-6.82 (m, 1H), 3.84-3.81 (m, 2H), 2.20-2.19 (m, 2H), 2.11-2.02 (m, 9H) and 1.77-1.60 (m, 2H). HPLC (Method D) Rt: 8.791 mm.

Example 87 - Preparation of BTK Inhibitors

[00298] The following compounds were synthesized following methods analog

methods described for compounds E-117 and E-119.

yl]oxy}-/V-(pyridin-2-yl)benzamide

Example 88 - Preparation of 4-Hvdroxy-N-[4-(trifluoromethyl)pyrimidin-2-yllbenzamide (1-41)

[00299] Preparation of 4-methoxy-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzamide. To a stirred solution of 4-(trifluoromethyl)pyrimidin-2-amine (4.6 g, 28.2 mmol, 1 eq.) in pyridine (50 rriL) was added 4-methoxybenzoyl chloride (3.8 mL, 28.2 mmol, 1 eq.) at 0 °C. The reaction mixture was stirred at same temperature for 1 h and then at room temperature for 1 h. After completion, the reaction mixture was diluted with ethyl acetate and extracted with 1 N HCl by keeping pH acidic. The organic layer was dried over sodium sulfate and concentrated to get crude compound that was purified by column chromatography (neutral alumina; elution; 40-60% ethyl acetate in hexane) to get 4-methoxy-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzamide (1.5 g, 17.9 %) as white fluffy solid.

[00300] Preparation of 4-hydroxy-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzamide: To a solution of 4-methoxy-N-[4-(trifluoromethyl)pyrimidin-2-yl]benzamide (1.5 g, 5.04 mmol, 1 eq.) in DCM (30 mL) was added boron tribromide (4.8 mL, 50.4 mmol, 10 eq.) at -20 °C. The reaction mixture was heated at 45 °C for 16 h. After completion, the reaction mixture was slowly quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get desired compound-6 (1.2 g, 84.5%).

[00301] The following compounds were prepared in an analogous manner as described for the preparation of 1-41: 4-hydroxy-N-(4-methylpyrimidin-2-yl)benzamide (1-42), 4-hydroxy-N- (pyrimidin-2-yl)benzamide (1-43), N-(5-Tert- butyl- l,2-oxazol-3-yl)-4-hydroxybenzamide (1-44).

Example 89 - Preparation of 4-[(6-Aminoquinolin-4-yl)oxyl-N-[4-(trifluoromethyl)pyrimidi n-2- yllbenzamide (1-45)

[00302] Preparation of 4-[(6-nitroquinolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyrimidi n-2- yl]benzamide. To a solution of 4-chloro-6-nitro-quinoline (1.0 g, 4.8 mmol, 1 eq.) in DMF (10 mL) was added potassium carbonate (2.0 g, 14.4 mmol, 3 eq.). Compound 1-41 (1.08 g, 3.84 mmol, 0.8 eq.) was added and the reaction mixture was heated at 100 ° for 2h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude mass that was purified by washing with DCM and pentane to get pure 4-[(6-nitroquinolin-4-yl)oxy]-N-[4- (trifluoromethyl)pyrimidin-2-yl]benzamide (1.6 g, 73.3 %) as light brown solid.

[00303] Preparation of 4-[(6-aminoquinolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyrimidi n-2- yl]benzamide. To a solution of 4-[(6-nitroquinolin-4-yl)oxy]-N-[4-(trifluoromethyl)pyrimidi n-2- yl]benzamide (1.0 g, 2.19 mmol, 1 eq.) in THF was added iron (1.45 g, 26.3 mmol, 12 eq.). Acetic acid (5 mL) was added and the reaction mixture was heated at 80 °C for 4 h. After completion, the reaction mixture was filtered through celite and washed with ethyl acetate. The organic layer was basified with saturated solution of sodium bicarbonate. The layers were separated; organic layer was dried over sodium sulfate and concentrated to get 1-45 (650 mg, 69.5 %) as a cream colored solid.

Example 90 - Preparation of 4-[(6-((4-methoxybut-2-vnoyl ' )amino ' )quinolin-4-yl ' )oxyl-N-[4- (trifluoromethyl)pyrimidin-2-yll benzamide (E- 124)

[00304] To a solution of compound 1-45 (200 mg, 0.47 mmol, leq.) in THF (5 mL) were added 4-methoxybut-2-ynoic acid (64 mg, 0.56 mmol, 1.2 eq.), EDC.HC1 (107 mg, 0.56 mmol, 1.2 eq.) and pyridine (0.1 mL, 1.17 mmol, 2.5 eq.) at 0 °C. The reaction mixture was heated at 70 °C for 16h. After completion, the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to get crude compound that was purified by prep purification to get compound E-124 (45 mg, 18.3%) as light yellow solid. LC-MS (Method B) Rt: 5.19 mm; m/z 522.1 (M+H)+; 1H NMR (400 MHz, DMSO-D 6 ): δ (ppm) = 1 1.55 (1H, s), 11.20 (1H, s), 9.10 (1H, d, J= 5.0 Hz), 8.69-8.68 (2H, m), 8.13 (2H, d, J= 8.6 Hz), 8.04 (1H, d, J= 9.1 Hz), 7.95-7.92 (1H, m), 7.74 (1H, d, J= 4.92 Hz), 7.39 (2H, d, J= 8.72 Hz), 6.80 (1H, d, J= 5.08 Hz), 4.36 (2H, s), 3.09(3H, s). HPLC (Method D) Rt: 7.987 mm. Example 91 - Preparation of BTK Inhibitors

[00305] The following compounds were synthesized following methods analog methods described for compound E-124:

Example 92 - Preparation of 5-[(6-aminoquinolin-4-yl)oxyl-N-(pyridin-2-yl)pyridine-2- carboxamide (1-46)

[00306] Preparation of methyl 5-[(6-nitroquinolin-4-yl)oxy]pyridine-2-carboxylate. To a suspension of 5-hydroxypyridine-2-carboxylic acid (19.0 g, 137 mmol, 1 eq.) in methanol (200 mL) was added thionyl chloride (49 mL, 683 mmol, 5 eq.) at 0-5 °C. The reaction mixture was heated to reflux for 24 h. After completion, the reaction mixture was quenched with saturated solution sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get methyl 5-hydroxypyridine-2-carboxylate (9.0 g, 43%) as off white solid. To a solution of methyl 5-hydroxypyridine-2-carboxylate (7.0 g, 45.8 mmol, 1 eq.) in DMF (100 mL) was added cesium carbonate (45 g, 137 mmol, 3 eq.), 4-chloro-6-nitro- quinoline (9.5 g, 45.8 mmol, 1 eq.) and copper (288 mg, 4.58 mmol, 0.1 eq.). The reaction mixture was heated at 100 °C for 45 min in microwave. After completion, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude compound that was purified by column chromatography (silica: 100-200; elution: 2% methanol in DCM) to get methyl 5-[(6- nitroquinolin-4-yl)oxy]pyridine-2-carboxylate (7.5 g, 50%) as off white solid.

[00307] Preparation of 5-[(6-nitroquinolin-4-yl)oxy]-N-(pyridin-2-yl)pyridine-2-car boxamide. To a solution 2-aminopyridine (650 mg, 6.9 mmol, 1.5 eq.) in toluene (30 mL) was added trimethyl aluminum (11.5 mL, 23 mmol, 5 eq.) at 0 °C and the reaction mixture was stirred at same temperature for 10 min. 5-[(6-Nitroquinolin-4-yl)oxy]pyridine-2-carboxylate (1.5 g, 4.6 mmol, 1 eq.) was added at 0 °C and the reaction mixture was heated at 70 °C for 16h. After completion, the reaction mixture was passed through celite bed, washed with ethyl acetate. Filtrate was washed with water and concentrated to get crude compound that was purified by column chromatography (silica: 100-200; elution: 1% methanol in DCM) to get 5-[(6- nitroquinolin-4-yl)oxy]-N-(pyridin-2-yl)pyridine-2-carboxami de (1.3 g, 73%) as off white solid.

[00308] Preparation of 5-[(6-Aminoquinolin-4-yl)oxy]-N-(pyridin-2-yl)pyridine-2-car boxamide. To a solution of 5-[(6-nitroquinolin-4-yl)oxy]-N-(pyridin-2-yl)pyridine-2-car boxamide (1.3 g, 3.36 mmol, 1 eq.) in DCM: methanol (15 mL; 15 mL) was added Pd/C (400 mg) under hydrogen atmosphere. The reaction mixture was stirred at room temperature for 24 h. After completion, the reaction mixture was filtered through celite and washed with DCM: methanol mixture. The filtrate was concentrated and purified by column chromatography (silica: 100-200; elution: 5% methanol in DCM) to obtain 1-46 (1.1 g, 91%) as light yellow solid

Example 93 - Preparation of 5-{[6-(acryloylamino)quinolin-4-ylloxy}-N-(pyridin-2-yl)pyri dine- 2-carboxamide (E-135)

[00309] To a solution of compound 1-46 (200 mg, 0.05 mmol, 1 eq.) in DCM (5 mL) and drops of DMF (1 mL) was added TEA (0.4 mL, 2.7 mmol 5 eq.), at 0 °C. The reaction mixture was stirred at same temperature for 2 min. Acrolyl chloride (0.04 mL, 0.8 mmol, 1.5 eq.) was added at 0 °C and the reaction mixture was stirred at same temperature for 30 min. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude mass that was purified by column chromatography (silica: 100-200; elution: 1% methanol in DCM) to get the title compound (30 mg, 14%) as light yellow solid. LC-MS (Method B) Rt : 5.20 min; m/z 412.3 (M+H) + ; 1H NMR (400 MHz, DMSO-D 6 ): δ (ppm) = 10.58 (1H, s), 10.35 (1H, s), 8.78 (1H, s), 8.69 (1H, s), 8.41 (1H, d, J= 4.4 Hz)), 8.32-8.27 (2H, m), 8.06 (1H, s), 8.01 (2H, d, J= 7.2 Hz), 7.92 (1H, s), 7.23 (1H, s), 6.96 (1H, s), 6.48 (2H, d, J=9.6 Hz), 6.33 (1H, d, J= 16.8 Hz), 5.80 (1H, s). HPLC Rt:

5.142.

Example 94 - Preparation of BTK Inhibitors

[00310] The following compounds were synthesized following methods analogous to the methods described for compound E-135:

Example 95 - Preparation of 6-[(6-aminoquinolin-4-yl)oxyl-N-(4-methylpyridin-2-yl)pyridi ne-3- carboxamide (1-47)

[00311] Preparation of 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylic acid. To a solution of 4-hydroxy-6-nitro-quinoline (5.5 g, 28.9 mmol, 1 eq.) in DMF (50 mL) was added potassium carbonate (7.9 g, 57.8 mmol, 2 eq.). Ethyl 6-chloropyridine-3-carboxylate (8.0 g, 43.3 mmol, 1.2 eq.) was added and the reaction mixture was heated at 100 °C for 2 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude mass that was purified by washing with DCM and pentane to get pure ethyl 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylate (5.5 g, 59.1%) light yellow solid. To a solution of ethyl 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3- carboxylate (5.0 g, 14.7 mmol, 1 eq.) in THF:MeOH: water (5:3:2) (40 mL) was added lithium hydroxide (1.2 g, 29.4 mmol, 2 eq.) and the reaction mixture was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated; water was added and neutralized with cone. HC1. The solids obtained was filtered off, washed with water and ether and dried to get 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylic acid (4.0 g, 88.8%), a light green solid.

[00312] Preparation of N-(4-methylpyridin-2-yl)-6-[(6-nitroquinolin-4-yl)oxy]pyridi ne-3- carboxamide. To a solution of 6-[(6-nitroquinolin-4-yl)oxy]pyridine-3-carboxylic acid (1.0 g, 3.2 mmol, 1 eq.) and 4-methylpyridin-2-amine (378 mg, 3.5 mmol, 1.1 eq.) in acetonitrile (15 mL) were added CMPI (1.2 g, 4.8 mmol, 1.5 eq.) and DIPEA (1.7 mL, 9.6 mmol, 3 eq.). The reaction mixture was heated at 80 °C for 16h. After completion, the reaction mixture was cooled, water was added. The solids obtained were filtered off and washed with ether to give N-(4- methylpyridin-2-yl)-6-[(6-nitroquinolin-4-yl)oxy]pyridine-3- carboxamide (800 mg, 66.6%) as light brown solid.

[00313] Preparation of 6-[(6-Aminoquinolin-4-yl)oxy]-N-(4-methylpyridin-2-yl)pyridi ne-3- carboxamide. To a solution of N-(4-methylpyridin-2-yl)-6-[(6-nitroquinolin-4-yl)oxy]pyridi ne- 3-carboxamide (800 mg, 1.9 mmol, 1 eq.) in ethanol: water (1 : 1) (20 rriL) was added iron powder (1.0 g, 19 mmol, 10 eq.) and ammonium chloride (1.0 g, 19 mmol, 10 eq.). The reaction mixture was heated at 80 °C for 16 h. After completion, the reaction mixture was filtered through celite bed and washed with ethanol. The filtrate was concentrated to give crude mass which was diluted with water and extracted with 25% IPA in chloroform. The organic layer was dried over sodium sulfate and concentrated to give 1-47 (380 mg, 51.6%)

Example 96 - Preparation of 6-{[6-(4-methoxybut-2-vnoylamino')quinolin-4-ylloxyl-N-(4- methylpyridin-2-yl)p ridine-3-carboxamide (E-143)

[00314] To a solution of compound 1-47 (200 mg, 0.53 mmol, 1 eq.) in THF (4 mL) was added DIPEA (0.97 mL, 1.59 mmol, 10 eq.), 4-methoxybut-2-ynoic acid (120 mg, 1.06 mmol, 2 eq.) and T3P (1.0 mL, 1.59 mmol, 3 eq.) at 0 °C. The reaction mixture was stirred at room

temperature for 16 h. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to get crude compound that was purified by prep purification to get the title compound (30 mg, 12.5%) as off white solid. LC-MS (Method B) Rt: 4.67 mm; m/z 468.3 (M+H) + ; 1H NMR (400 MHz, DMSO-D6): δ (ppm) = 11.17 (1H, s), 11.05 (1H, s), 9.24 (lH,s), 8.65 (1H, d, J= 7.6 Hz), 8.53 (1H, s), 8.28 (1H, d, J= 4.8 Hz), 8.15-8.13 (1H, m), 8.09 (1H, s), 7.89 (1H, m), 7.81 (1H, d, J=9.2 Hz), 7.36 (1H, d, J= 8.8 Hz), 7.06 (1H, d, J= 4.4 Hz), 6.22 (1H, d, J= 7.2 Hz), 4.35 (2H, s), 3.34 (3H, s), 2.49 (3H, s). HPLC Rt: 4.805.

Example 97 - Preparation of BTK Inhibitors

[00315] The following compounds were synthesized following methods analogous to the methods described for compound E-143.

Example 98 - Preparation of 4-(2.3-dihvdro-lH-[1.4loxazino[3.2-glquinolin-9-yloxyVN- (pyridin-2-yl)benzamide (1-48

[00316] Preparation of 4-[(6-Amino-7-hydroxyquinolin-4-yl)oxy]-N-(pyridin-2-yl)benz amide. To a solution of compound 1-15 (4.0g , 9.95 mmoles) in EtOH (60 rriL), Fe-powder (11.1 g, 199.0 mmoles) and cone. HC1 (9.0 mL, 99.5 mmoles) were added and reaction mixture was stirred at room temperature. The reaction mixture was poured into ice cold water, basified with NaHC03 and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give 4-[(6-Amino-7-hydroxyquinolin-4-yl)oxy]-N-(pyridin-2-yl)benz amide (2.0 g, 54%) as light green solid.

[00317] Preparation of 4-(2,3-dihydro-lH-[l,4]oxazino[3,2-g]quinolin-9-yloxy)-N-(py ridin-2- yl)benzamide: To a solution of 4-[(6-Amino-7-hydroxyquinolin-4-yl)oxy]-N-(pyridin-2- yl)benzamide (1.2 g, 3.2 mmoles) and 1 ,2-dibromo-ethane (0.96 mL, 10.6 mmoles) in DMF (60 mL), K 2 CO 3 (1.3 g, 9.6 mmoles) was added and reaction mixture was heated at 80 °C for 12h. Reaction mixture was cooled, water was added and extracted with ethyl acetate. The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-40% ethyl acetate in hexane to give 1-48 (0.500 g, 41%) as light yellow solid.

Example 99 - Preparation of 4-[(l-(but-2-vnoyl)-2,3-dihydro-lH-[l,41oxazino[3,2-glquinol in-9- yl)oxyl-N-(pyridin-2-yl)benzamide (E-147)

[00318] A solution of compound 1-48 (0.100 g, 0.25 mmoles) and ethyl but-2-ynoate (0.084g, 0.75 mmoles) in THF (5 ml) was cooled at 0°C, trimethyl aluminium (0.6 mL, 1.2 mmoles) was added dropwise and reaction mixture was heated at 80°C for 5h. Reaction mixture was poured into saturated NH 4 C1 solution and extracted with 25% IPA in CHCI 3 . The organic part was dried over Na 2 S0 4 , filtered and concentrated to give crude which was further purified by column chromatography using silica gel (100-200 mesh) and 0-3% MeOH in DCM to give the title compound (0.030 g , 25%) as light yellow solid. LC-MS (Method B) Rt: 5.42 min; m/z 465.4 (M+H) + ; 1H NMR (400 MHz, DMSO-D 6 ): δ (ppm) = 10.86 (s, 1H), 9.15 (s, 1H), 8.62 (d, 1H, J = 5.0 Hz), 8.39 (d, 1H, J = 3.72 Hz), 8.20-8.17 (m, 3H), 7.87-7.83 (m, 1H), 7.47 (s, 1H), 7.36 (d, 2H, J = 8.60 Hz), 7.19-7.16 (m, 1H), 6.62 (d, 1H, J = 4.52 Hz), 4.46 (s, 2H), 4.30 (s, 2H) and 2.12 (s, 3H).

Example 100 - Preparation of 4-[(l-(4-methoxybut-2-vnoyl)-2,3-dihydro-lH-[l,41oxazino[3,2 - gl quinolin-9-yl)oxyl -N-(pyridin-2-yl)benzamide (E-148)

[00319] This compound was prepared, in an analogous manner as described in compound E- 147, from compound 1-48 and methyl 4-methoxybut-2-ynoate to afford the title compound (30 mg, 25%) as an off white solid. LC-MS (Method B) Rt: 5.40 mm; m/z 495.4 (M+H) + ; 1H NMR (400 MHz, DMSO-D 6 ): δ (ppm) = 10.87 (s, 1H), 9.18 (s, 1H), 8.63 (d, 1H, J = 5.0 Hz), 8.39 (d, 1H, J = 3.4 Hz), 8.21-8.17 (m, 3H), 7.87-7.83 (m, 1H), 7.48 (s, 1H), 7.38-7.35 (m, 2H), 7.19- 7.16 (m, 1H), 6.64-6.62 (m, 1H), 4.50 (s, 3H), 4.43-4.40 (m, 4H) and 3.16 (s, 2H). HPLC (Method D) Rt: 6.610 min.

Example 101 - Preparation of 4-{[6-(Amino')cinnolin-4-ylloxyl-N-(4-ethylpyridin-2- vDbenzamide (1-49)

[00320] Preparation of 4-chloro-6-nitrocinnoline. To a solution of 4-hydroxy-6-nitrocinnoline (170 mg; 0.89 mmol) in DMF (1 ml) was added dropwise thionylchloride (194 μΕ; 2.67 mmol). The reaction mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, taken up in ethyl acetate and washed with water. The organic layer was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure, to give 110 mg of 4-chloro-6-nitrocinnoline as a black solid. LC-MS (Method A) Rt: 6.47 min; m/z 210.0 (M+H) + .

[00321] Preparation of 4-{[6-(nitro)cinnolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benza mide. Compound 1-4 (40 mg; 0.17 mmol) and cesium carbonate (65 mg; 0.20 mmol) were

coevaporated twice with toluene. The mixture was taken up in dry THF (2 ml) and stirred for 30 minutes at 60 °C. 4-chloro-6-nitrocinnoline (35 mg; 0.17 mmol) in DCM (1 ml) was added and the reaction mixture was stirred under a nitrogen atmosphere at 60oC for 1 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified using silica gel chromatography (0-5% methanol in dichloromethane) to give 45 mg 4- { [6-(nitro)cinnolin-4- yl]oxy}-N-(4-ethylpyridin-2-yl)benzamide (64%). LC-MS (Method A) Rt: 7.01 min; m/z 416.2

(M+H) .

[00322] Preparation of 4-{[6-(amino)cinnolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benza mide. The title compound was synthesized using the method described for Compound 1-20, yielding 24 mg 4-{[6-(amino)cinnolin-4-yl]oxy}-N-(4-ethylpyridin-2-yl)benza mide (62%). LC-MS (Method A) Rt : 5.35 mm; m/z 386.2 (M+H) + .

Example 102 - Preparation of 4-{[6-(Acryloylamino)cinnolin-4-ylloxy}-N-(4-ethylpyridin-2- vDbenzamide (E-149)

[00323] The title compound was synthesized using the method described for E-20, yielding 1.4 mg 4-{[6-(Acryloylamino)cinnolin-4-yl]oxy}-N-(4-ethylpyridin-2- yl)benzamide (14%). HPLC (Method C) Rt: 7.04 mm; LC-MS (Method A) Rt: 6.17 mm; m/z 440.2 (M+H) + .

Example 103 - Preparation of 4-[(6-{[(2E)-4-methoxy-but-2-vnoyllamino}cinnolin-4-ylloxy}- N-(4-ethylpyridin-2-yl)benzamide (E-150)

[00324] The title compound was synthesized using the method described for E-149, yielding 1.4 mg of the title compound (14%) Data: HPLC (Method C) Rt: 7.17 mm; LC-MS (Method A) Rt: 6.44 mm; m/z 482.2 (M+H) + .

Example 104 - Preparation of BTK Inhibitors

[00325] The following compounds were synthesized following essentially the methods described above:

E-151: 3-{[6-(acryloylamino)quinazolin-4-yl]amino}-N-(pyridin-2-yl) benzamide;

E-152: 3-{[6-(but-2-ynoylamino)quinazolin-4-yl]amino}-N-(pyridin-2- yl)benzamide;

E-153: 4-[(6-((2£ ' )-4-methoxybut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-me thoxypyridin-2- yl)benzamide;

E-154: 4-[(6-((2£ ' )-4-methoxybut-2-enoylamino)quinolin-4-yl)oxy]-N-(4-me thoxypyridin-2- yl)benzamide;

E-155: 4-[(6-{[(i?/Z)-4-(4-ethylpiperazin-l-yl)-2-enoyl]amino}quino lin-4-yl)oxy]-N-(pyridin-2- yl)benzamide;

E- 156: 4- [(6-aminoquinolin-4-y l)oxy] -N-(4-propylpyridin-2-yl)benzamide;

E- 157: 4- [ [6-(but-2-ynoylamino)-7- [3 -(1 -pyrrolidyl)propoxy ] quinolin-4-yl] oxy] -N-(2- pyridyl)benzamide;

E- 158: 4- [ [6-(acryloylamino)-7- [3 -(1 -pyrrolidyl)propoxy ] quinolin-4-yl] oxy ] -N-(2- pyridyl)benzamide.

Example 105 - BTK Enzyme Activity

[00326] BTK enzyme activity is measured using the IMAP (immobilized metal ion affinity- based fluorescence polarization) assay as outlined below.

[00327] BTK enzyme (His-BTK (Millipore catalog* 14-552)), is diluted to 0.4 U/mL in KR buffer (10 mM Tris-HCl, 10 mM MgCl 2 , 0.01% Tween-20, 0.05% NaN 3 , 1 mM DTT, 2 mM MnCl 2 , pH 7.2).

[00328] Serial dilutions loglO from 2 mM to 63.2 nM of test compounds are made in 100% DMSO. The dilutions in DMSO are then diluted 50-fold in KR-buffer. Final compound concentration range in the assay ranged from 10 μΜ to 0.316 nM.

[00329] 5 of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5 μΐ/well of 0.4 U/mL BTK enzyme (final concentration in the assay is 0.1 U/mL). Test compounds and BTK enzyme are pre-incubated 60 minutes at room temperature, before adding 5 of 200 nM Fluorescin labeled substrate peptide (Blk/Lyntide substrate, e.g. #R7188/#R7233, Molecular Devices) in KR-buffer. Final peptide substrate concentration in assay is 50 nM. The kinase assay is started by adding 5 of 20 μΜ ATP in KR-buffer (final ATP concentration is 5 μΜ ATP, Km ATP in BTK IMAP assay). Following incubation for 2h at room temperature the enzyme reaction is stopped by adding 40 IMAP Progressive Binding Solution (according to suppliers (Molecular Devices) protocol using 75% lx buffer A and 25% lx buffer B with 1 :600 Progressive Binding Solution). After 60 min incubation at room temperature in the dark the FP signal is read. Fluorescence at 535 nm is measured using parallel and perpendicular filters to determine differences in rotation due to binding of the

phosphorylated substrate peptide to the beads. Values are calculated as percentage of the difference in readout (AmPi) of the controls with and without ATP. IC 50 values are determined by curve fitting of the experimental results using Activity Base. The results are reported in Table 1.

Example 106 - EGFR enzyme activity

[00330] EGFR enzyme activity is measured using the IMAP (immobilized metal ion affinity- based fluorescence polarization) assay as outlined below.

[00331] EGFR enzyme (Invitrogen catalog* PR7295B), is diluted to 2.5 μg/mL in KR buffer (10 mM Tris-HCl, 10 mM MgC12, 0.01% Tween-20, 0.1% NaN 3 , 1 mM DTT, 2 mM MnCl 2 , pH 7.5).

[00332] Serial dilution logl 0 from 1 mM to 31.6 nM of test compounds are made in 100% DMSO. The dilutions in DMSO are then diluted 25-fold in KR-buffer of which 5 μΐ is used in the assay, leading to a final compound concentration range in the assay from 10 μΜ to 0.316 nM.

[00333] 5 μΕΛνβΙΙ of test compound in KR buffer (final DMSO concentration in the assay is 1%) is mixed with 5 μΐ/well of 2.5 μg/mL EGFR enzyme (final concentration in the assay is 625 ng/mL). Test compounds and EGFR enzyme are pre-incubated 60 min at room temperature, before adding 5 pL/well of 200 nM Fluorescein labeled substrate peptide (PDGFR-tide substrate peptide RP7084, Molecular Devices) in KR-buffer. Final peptide substrate concentration in assay is 50 nM. The kinase assay is started by adding 5 of 8 μΜ ATP in KR-buffer (final ATP concentration is 2 uM, Km ATP in EGFR IMAP assay). Following incubation for 60 min at room temperature in the dark the enzyme reaction is stopped by adding 40 pL/well IMAP Progressive Binding Solution (according to suppliers (Molecular Devices) protocol using 20% lx buffer A and 80% lx buffer B with 600x diluted beads). After 60 min incubation at room temperature in the dark the FP signal is read. Fluorescence at 535 nm is measured using parallel and perpendicular filters to determine differences in rotation due to binding of the

phosphorylated substrate peptide to the beads. Values are calculated as percentage of the difference in readout (AmPi) of the controls with and without ATP. IC 50 values are determined by curve fitting of the experimental results using GraphPad Prism6. The results are reported in Table 1.

Table 1. Enzyme Activity Data.

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