Indazole, benzisoxazole, and benzisothiazole kinase inhibitors

ES 2 398 074 T3

DESCRIPTION

Indazole, benzisoxazole, and benzisothiazole kinase inhibitors

Technical field

The present invention relates to compounds that are useful for inhibiting protein tyrosine kinases, methods of preparing the compounds, compositions containing the compounds, and the compounds for use in treating diseases.

Background of the invention

Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes themselves, acts as a molecular switch that regulates cell proliferation, activation, and differentiation. Aberrant or excessive PTK activity has been observed in many pathologies including benign and malignant proliferative disorders as well as diseases that occur as a result of inappropriate activation of the immune system (eg, autoimmune disorders), allograft rejection, and graft disease. against host. Additionally, endothelial cell-specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process and are therefore involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity and infantile hemangiomas).

The identification of effective small compounds that specifically inhibit signal transduction and cell proliferation by modulating tyrosine kinase activity to regulate and modulate cell proliferation, differentiation or metabolism is therefore desirable. In particular, it would be beneficial to identify methods and compounds that specifically inhibit the function of a tyrosine kinase that is essential for angiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition. as well as associated disorders.

WO 02/055517 refers to 4-arylindolinones, as well as pharmaceutical compositions thereof, capable of modulating protein kinase signal transduction in order to regulate, modulate and / or inhibit abnormal cell proliferation.

WO 00/27627 relates to aryloxime linkers in the solid phase synthesis of 3-aminobencisoxazoles, to an intermediate compound attached to a solid support that can be optionally derivatized before a cyclization and displacement process yields a product; to a library, and their synthesis, of polycyclic heterocyclic compounds wherein said library contains a plurality of diverse library compounds and to a test kit for the identification of leading compounds from said library.

GB 816 382 relates to light sensitive layers for photomechanical reproduction and particularly to the use in the preparation of such light sensitive layers of diazo photosensitive derivatives of heterocyclic nitrogenous bases.

WO 03/051847 refers to (1-H-indazol-3-yl) -amide derivatives as gsk-3 inhibitors.

Document WO 03/097610 refers to aminoindazole derivatives active as kinase inhibitors, processes for their preparation and pharmaceutical compositions comprising them.

WO 2004/010995 relates to fused heteroaryl derivatives for use as p38 kinase inhibitors in the treatment of, inter alia, rheumatoid arthritis.

WO 2004/022544 refers to aminoindazole derivatives as medicines and pharmaceutical compositions containing such aminoindazole derivatives.

Document WO 03/087072 refers to a preventive and / or therapeutic agent for diseases associated with endothelial disorder, sepsis, severe sepsis or septic shock and diseases associated with signals through TLR, which comprises as an active ingredient a compound of 3 -amino-1,2-benzisothiazole or a derivative thereof.

WO 2004/062662 relates to aminoindazole derivatives and the use thereof for the treatment of diseases that can occur as a result of abnormal kinase activity.

Summary of the invention

ES 2 398 074 T3

The present invention relates to compounds of formula (II) according to attached claim 1.

The present invention relates to a pharmaceutical composition comprising a compound of formula (II) according to attached claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.

The present invention relates to a use of a compound of formula (II) according to appended claim 1 or a therapeutically acceptable salt thereof to prepare a medicament for inhibiting a protein kinase in a patient having a recognized need for such treatment. wherein the compound is to be administered to the patient in a therapeutically acceptable amount.

The present invention relates to a use of a compound of formula (II) according to appended claim 1 or a therapeutically acceptable salt thereof to prepare a medicament for treating cancer in a patient having a recognized need for such treatment in the that the compound is to be administered to the patient in a therapeutically acceptable amount.

The present invention relates to a compound of formula (II) according to appended claim 1 for use as a protein kinase inhibitor or as an anti-cancer agent.

Detailed description of the invention

The present description pertains to a compound of formula (I)

<img file="ES2398074T3_D0001.tif" />

or a therapeutically acceptable salt thereof, wherein

A is selected from the group consisting of indolyl, phenyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, and thienyl;

X is selected from the group consisting of O, S, and NR⁹;

R¹ and R² are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclyloxylalkoxy, hydrocyclyloxylalkyl, hydrocyclyloxyalkyl NR^toR^b) alkoxy, (NR⁸R^b) alkenyl, (NR^toR^b) alkyl, (NR^toR^b) alkynyl, (NR^toR^b) carbonylalkenyl and (NR^toR^b) carbonylalkyl;

each of R³, R⁴ and R⁵ is independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkyl, halo, haloalkoxy, haloalkyl, hydroxy, and LR⁶;

provided that at least two of R³, R⁴ and R⁵ are other than LR⁶;

L is selected from the group consisting of (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n and CH2C (O) NR⁷, where m and n are independently 0 or 1, and where each group is drawn with its left end attached to A;

R⁶ is selected from the group consisting of hydrogen, aryl, cycloalkyl, heterocyclyl, and 1,3-benzodioxolyl, wherein the 1,3-benzodioxolyl may be optionally substituted with one, two, or three substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second heterocyclyl group, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR^cR^d and (NR^cR^d)I rent;

R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl;

R⁹ is selected from the group consisting of hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylcarbonyl, aryl, heterocyclylalkyl, hydroxyalkyl, and (NR^toR^b)I rent;

R^to and R^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl; Y

R^c and R^d they are independently selected from the group consisting of hydrogen, alkyl alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl.

In its main embodiment, the present invention provides a compound of formula (II)

ES 2 398 074 T3

<img file="ES2398074T3_D0002.tif" />

or a therapeutically acceptable salt thereof, wherein

X is selected from the group consisting of O and S;

R¹ and R² are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkenyl, heterocyclylalkoxy, heterocyclylalkyl, heterocyclyloxy, hydroxyalkyl (hydrocyclyloxy, hydroxyalkyl^toR^b) alkoxy, (NR^toR^b) alkenyl, (NR^toR^b) alkyl, (NR^toR^b) carbonylalkenyl and (NR^toR^b) carbonylalkyl;

R³ and R⁴ independently selected from the group consisting of hydrogen, alkoxy, alkyl, halo, haloalkoxy, haloalkyl, and hydroxy;

L is selected from the group consisting of (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n and CH2C (O) NR⁷, where m and n are independently 0 or 1, and where each group is drawn with its left end attached to the R-substituted ring³ and R⁴; R⁷ and R⁸ are independently selected from the group consisting of hydrogen and alkyl;

R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl alkoxycarbonyl, alkyl, aryloxy, arylalkyl carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR^cR^d;

R^to and R^b are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, arylsulfonyl, haloalkylsulfonyl, and heterocyclylsulfonyl; Y

R^c and R^d are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl;

wherein the aryl is a phenyl group, or a bicyclic or tricyclic fused ring system in which one or more of the fused rings is a phenyl group, wherein said aryl is optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR^cR^d, (NR^cR^d) alkyl and oxo;

wherein the second aryl group, and the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl are optionally substituted with one, two, three, four, or five groups independently selected from the group that consists of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo;

Heterocyclyl is a monocyclic, bicyclic, or tricyclic ring system in which one or more rings are a four-, five-, six-, or seven-membered ring containing one, two, or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur;

wherein said heterocyclyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano , cycloalkyl, halo, haloalkoxy, haloalkyl, a second group heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR^cR^d, (NR^cR^d) alkyl and oxo;

wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl is optionally further substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.

Cycloalkyl is a monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring system having three to twelve carbon atoms, wherein said cycloalkyl is optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting in alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR^cR^d, (NR^cR^d) alkyl and

ES 2 398 074 T3 oxo.

In another embodiment, the present invention provides a compound of formula (II), wherein L is CH2C (O) NR⁷; and X, R¹, R², R³, R⁴, R⁷, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (II), wherein L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; ym, n, X, R¹, R², R³, R⁴, R⁷, R⁸, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (II), wherein R¹ and R² are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, aryloxy, aryloxyalkyl, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, (NR^toR^b) alkoxy, (NR^toR^b) alkenyl, (NR^toR^b) alkyl, (NR^toR^b) carbonylalkenyl and (NR^toR^b) carbonylalkyl; and X, L, R^to, R^b, R³, R⁴, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (ll), wherein X is O and L, R¹, R², R³, R⁴, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (II), wherein X is O; Les (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; ym, n, R¹, R², R³, R⁴, R⁷, R⁸, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (II), wherein X is O; Les (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹, R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR^toR^b; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is O; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹, R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR^toR^b, and aryloxy where the aryloxy is phenoxy; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is O; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹ is heterocyclylalkoxy; R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR^toR^b; and R^to and R^bthey are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is O; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹ is heterocyclylalkoxy, where the heterocyclyl is morpholinyl; R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR^toR^b and aryloxy, where the aryloxy is phenoxy; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is O; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹ is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR^toR^b and aryloxy, where the aryloxy is phenoxy; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (ll), wherein X is S and L, R¹, R², R³, R⁴, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; ym, n, R¹, R², R³, R⁴, R⁷, R⁸, R¹⁰ and R¹¹ are as defined in formula (II).

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹, R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR^toR^b; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹, R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are selected

ES 2 398 074 T3 independently from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR^toR^b and aryloxy, where the aryloxy is phenoxy; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹, R², R³, R⁴, R⁷ and R⁸ they are hydrogen; and R¹⁰ and R¹¹ they are independently selected from the group consisting of hydrogen, alkyl, halo, and haloalkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) nN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹ is heterocyclylalkoxy; R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, aryloxy, arylalkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and -NR^toRb^b; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹ is heterocyclylalkoxy, where the heterocyclyl is morpholinyl; R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, -NR^toR^b and aryloxy, where the aryloxy is phenoxy; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a compound of formula (II), wherein X is S; L is (CH2) mN (R⁷) C (O) N (R⁸) (CH2) n; m and n are 0; R¹ is selected from the group consisting of alkoxy, alkyl, halo, and haloalkoxy; R², R³, R⁴, R⁷ and R⁸ they are hydrogen; R¹⁰ and R¹¹ are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, NR^toR^b and aryloxy, where the aryloxy is phenoxy; and R^to and R^b they are independently selected from the group consisting of hydrogen and alkyl.

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (II), or a therapeutically acceptable salt thereof, together with a therapeutically acceptable carrier.

In another embodiment, the present invention provides a compound of formula (II), or a therapeutically acceptable salt thereof for use in inhibiting protein kinase in a patient with a recognized need for such treatment by administering to the patient a therapeutically acceptable amount. of said compound of formula (II), or said therapeutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula (II), or a therapeutically acceptable salt thereof for use in treating cancer in a patient with a recognized need for said treatment by administering to the patient a therapeutically acceptable amount of said compound of formula (II), or said therapeutically acceptable salt thereof.

Definitions

All publications, filed patents, and patent applications cited herein are hereby incorporated by reference.

As used herein, the singular forms a, an, and the, include the plural reference unless the context clearly indicates otherwise.

As used herein the following terms have the indicated meanings:

The term "alkenyl," as used herein, refers to a straight or branched chain group of one to six carbon atoms that contains at least one carbon-carbon double bond.

The term "alkoxy," as used herein, refers to an alkyl group attached to the starting molecular moiety through an oxygen atom.

The term "alkoxyalkoxy," as used herein, refers to an alkoxy group attached to the starting molecular moiety through another alkoxy group.

The term "alkoxyalkyl," as used herein, refers to an alkyl group substituted with at least one alkoxy group.

The term "alkoxycarbonyl," as used herein, refers to an alkoxy group attached to the starting molecular moiety through a carbonyl group.

The term "alkyl," as used herein, refers to a group derived from a straight or branched chain saturated hydrocarbon of one to six carbon atoms. The preferred alkyl groups of the present invention are of one to three carbon atoms. The most preferred alkyl groups are methyl and ethyl.

The term "alkylcarbonyl", as used herein, refers to an alkyl group attached to the starting molecular moiety through a carbonyl group.

ES 2 398 074 T3

The term "alkylsulfonyl", as used herein, refers to an alkyl group attached to the starting molecular moiety through a sulfonyl group.

The term aryl, as used herein, refers to a phenyl group, or a bicyclic or tricyclic fused ring system in which one or more of the fused rings is a phenyl group. Bicyclic fused ring systems are illustrated by a phenyl group fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Tricyclic fused ring systems are illustrated by a bicyclic fused ring system fused to a monocyclic cycloalkenyl group, as defined herein, a monocyclic cycloalkyl group, as defined herein, or another phenyl group. Aryl groups include, but are not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl. The aryl groups of the present invention may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, a second aryl group, arylalkoxy, arylalkyl , aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR^cR^d, (NR^cR^d) alkyl and oxo; wherein the second aryl group, and the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl may be optionally further substituted with one, two, three, four or five groups independently selected from among the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.

The term "arylalkyl," as used herein, refers to an alkyl group substituted with at least one aryl group.

The term "arylcarbonyl," as used herein, refers to an aryl group attached to the starting molecular moiety through a carbonyl group.

The term "arylalkoxy," as used herein, refers to an aryl group attached to the starting molecular moiety through an alkoxy group.

The term "aryloxy", as used herein, refers to an aryl group attached to the starting molecular moiety through an oxygen atom.

The term "aryloxyalkyl," as used herein, refers to an aryloxy group attached to the starting molecular moiety through an alkyl group.

The term "arylsulfonyl", as used herein, refers to an aryl group attached to the starting molecular moiety through a sulfonyl group.

The term "carbonyl," as used herein, refers to -C (O) -.

The term carboxy, as used herein, refers to -CO2H.

The term cyano, as used herein, refers to -CN.

The term "cycloalkenyl," as used herein, refers to a non-aromatic cyclic or bicyclic ring system having three to ten carbon atoms and one to three rings, in which each five-membered ring has a double bond, each six-membered ring has one or two double bonds, each seven- and eight-membered ring has one to three double bonds, and each nine to ten-membered ring has one to four double bonds. Examples of cycloalkenyl groups include, but are not limited to, cyclohexenyl, octahydronaphthalenyl, and norbornylenyl.

The term "cycloalkyl," as used herein, refers to a monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring system having from three to twelve carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, bicyclo [3,1,1] heptyl, and adamantyl.

The cycloalkyl groups of the present invention may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, -NR^cR^d, (NR^cR^d) alkyl and oxo.

The terms halo and halogen, as used herein, refer to F, CI, Br, and I.

The term "haloalkoxy", as used herein, refers to a haloalkyl group attached to the starting molecular moiety through an oxygen atom.

The term "haloalkyl," as used herein, refers to an alkyl group substituted with one, two, three, or four halogen atoms.

The term "haloalkylsulfonyl", as used herein, refers to a haloalkyl group attached to the starting molecular moiety through a sulfonyl group.

The term heterocyclyl, as used herein, represents a monocyclic, bicyclic, or tricyclic ring system in which one or more rings are a four, five, six, or seven membered ring containing one, two, or three independently selected heteroatoms. among the group consisting of nitrogen, oxygen and sulfur. Monocyclic ring systems are illustrated by any 3- or 4-membered ring containing a heteroatom independently selected from the group consisting of oxygen, nitrogen, and sulfur; or a 5-, 6-, or 7-membered ring containing one, two, or three heteroatoms wherein the heteroatoms are independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 3- and 4-membered rings have no double bonds, the 5-membered ring has 0-2 double bonds, and the 6- and 7-membered rings have 0-3 double bonds. Representative examples of monocyclic ring systems include, but are not limited to, azetidine, azepine, aziridine, diazepine, 1,3-dioxolane, dioxane, dithian, furan, imidazole, imidazoline, imidazolidine, isothiazole, isothiazoline, isothiazolidine, isoxazole, isoxazoline, isoxazoline isoxazolidine, morpholine, oxadiazole, oxadiazoline, oxadiazolidine, oxazole, oxazoline, oxazolidine, piperazine, piperidine, pyran,

ES 2 398 074 T3 pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridine, pyrimidine, pyridazine, pyrrole, pyrroline, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrazine, tetrazole, thiadiazole, thiadiazoline, thiadiazolidine, thiazole, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, thiazolidine, sulfone, thiopyran, triazine, triazole, and tritian. Bicyclic ring systems are illustrated by any of the above monocyclic ring systems fused to a phenyl ring, a monocyclic cycloalkyl group, as defined herein, a monocyclic cycloalkenyl group, as defined herein, another ring system monocyclic heterocyclyl. Representative examples of bicyclic ring systems include, but are not limited to, benzimidazole, benzothiazole, benzothiophene, benzoxazole, benzofuran, benzopyran, benzothiopyran, benzodioxine, 1,3-benzodioxole, cinnoline, dihydrobenzimidazole, indazole, indole, indoline, naphthyridizine, isobenzofuran, isobenzothiophene, isoindole, isoindoline, isoquinoline, phthalazine, pyranopyridine, quinoline, quinolizine, quinoxaline, quinazoline, tetrahydroisoquinoline, tetrahydroquinoline and thiopyranopyridine. Tricyclic ring systems are illustrated by any of the above bicyclic ring systems fused to a phenyl ring, a monocyclic cycloalkyl group, as defined herein, a monocyclic cycloalkenyl group, as defined herein, or another system of monocyclic heterocyclyl rings. Representative examples of tricyclic ring systems include, but are not limited to, acridine, carbazole, carboline, dibenzofuran, dibenzothiophene, naphthofuran, naphthothiophene, oxanthrene, phenarine, phenoxatin, phenoxazine, phenothiazine, thianthrene, thioxanthene, and xanthene. Heterocyclyl groups can be attached to the starting molecular moiety through a carbon atom or a nitrogen atom in the group.

The heterocyclyl groups of the present invention may be optionally substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, arylalkoxy, arylalkyl, aryloxy, carboxy, cyano, cycloalkyl, halo, haloalkoxy, haloalkyl, a second group heterocyclyl, heterocyclylalkyl, hydroxy, hydroxyalkyl, nitro, -NR^cR^d, (NR^cR^d) alkyl and oxo; wherein the aryl, the aryl part of the arylalkoxy, the arylalkyl, and the aryloxy, the second heterocyclyl group, and the heterocyclyl part of the heterocyclylalkyl may be optionally further substituted with one, two, three, four, or five groups independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, cyano, halo, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, nitro, and oxo.

The term "heterocyclylalkenyl", as used herein, refers to an alkenyl group substituted with at least one heterocyclyl group.

The term "heterocyclylalkoxy," as used herein, refers to a heterocyclyl group attached to the starting molecular moiety through an alkoxy group.

The term "heterocyclylalkyl," as used herein, refers to an alkyl group substituted with at least one heterocyclyl group. The term "heterocyclyloxy," as used herein, refers to a heterocyclyl group attached to the starting molecular moiety through an oxygen atom.

The term "heterocyclyloxyalkyl," as used herein, refers to an alkyl group substituted with at least one heterocyclyloxy group.

The term "heterocyclylsulfonyl", as used herein, refers to a heterocyclyl group attached to the starting molecular moiety through a sulfonyl group.

The term hydroxy, as used herein, refers to -OH.

The term "hydroxyalkoxy," as used herein, refers to a hydroxy group attached to the starting molecular moiety through an alkoxy group.

The term "hydroxyalkyl," as used herein, refers to an alkyl group substituted with at least one hydroxy group.

The term nitro, as used herein, refers to -NO2.

The term -NR^toR^b, as used in this document, represents two groups, R^to and R^b, which are attached to the starting molecular moiety through a nitrogen atom.

R^to and R^b are independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylcarbonyl, arylsulfonyl, haloalkylsulfonyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylsulfonyl, in which the aryl and aryl alkylallyl part arylcarbonyl, heterocyclyl, the heterocyclyl portion of the heterocyclylalkyl and the heterocyclylsulfonyl may optionally be further substituted with one, two, three, four, or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.

ab

The term (NR R) alkenyl, as used herein, represents an alkenyl group substituted with at least one -NR group^toR^b.

The term (NR^toR^b) alkoxy, as used herein, represents a group -NR^toR^b attached to the starting molecular moiety through an alkoxy group.

The term (NR^toR^b) alkyl, as used herein, represents an alkyl group substituted with at least one -NR group^toR^b.

The term (NR^toR^b) alkynyl, as used herein, represents an alkynyl group substituted with at least one -NR group^toR^b.

The term (NR^toR^b) carbonyl, as used herein, represents a group (NR^toR^b) attached to the starting molecular moiety through a carbonyl group.

The term (NR^toR^b) carbonylalkenyl, as used herein, represents an alkenyl group substituted with at least one group (NR^toR^b) carbonyl.

The term (NR^toR^b) carbonylalkyl, as used herein, represents an alkyl group substituted with

ES 2 398 074 T3 at least one group (NR^toR^b) carbonyl.

The term -NR^cR^d, as used in this document, represents two groups, R^c and R^d, which are attached to the starting molecular moiety through a nitrogen atom.

R^c and R^d are independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl, wherein the aryl, the aryl part of the arylalkyl, the heterocyclyl, and the heterocyclyl part of the heterocyclylalkyl may be optionally further substituted with one, two, three, four or five substituents independently selected from the group consisting of alkenyl, alkoxy, alkyl, cyano, halo, haloalkyl, haloalkoxy, nitro, and oxo.

The term (NR^cR^d) alkyl, as used herein, represents an alkyl group substituted with at least one -NR group^cR^d.

The term oxo, as used herein, refers to = O.

The term "sulfonyl," as used herein, refers to -SO2.

The compounds of the present invention may exist in the form of therapeutically acceptable salts. The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present invention that are soluble or dispersible in water or oil, which are suitable for the treatment of diseases without excessive toxicity, irritation and response. allergic; that they are consistent with a reasonable risk / benefit ratio, and that they are effective for their intended use. The salts can be prepared during the isolation and final purification of the compounds or separately by reacting an -NR group^toR^b with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydrochloride, hydrobromide, 2-hydroxyethanesulfonate, lactate, maleate, mesylene sulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate, trichloro-acetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para-toluenesulfonate and undecanoate. Furthermore, the -NR groups^toR^b in the compounds of the present invention they can be quaternized with methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl and steryl chlorides, bromides and iodides; and benzyl and phenethyl bromides. Examples of acids that can be used to form therapeutically acceptable addition salts include inorganic acids, such as hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids, such as oxalic, maleic, succinic, and citric.

The present compounds can also exist as therapeutically acceptable prodrugs. The term "therapeutically acceptable prodrug" refers to those prodrugs and zwitterions that are suitable for use in contact with patient tissues without excessive toxicity, irritation and allergic response, are consistent with a reasonable benefit / risk ratio, and are effective. for its intended use. The term "prodrug" refers to compounds that are rapidly transformed in vivo into precursors of formula (II) eg by hydrolysis in blood.

When it is possible that, for use in therapy, therapeutically effective amounts of a compound of formula (II) can be administered, as well as therapeutically acceptable salts thereof, such as the raw chemical, it is possible to present the active ingredient in the form of a pharmaceutical composition. Accordingly, the invention also provides pharmaceutical compositions, which include therapeutically effective amounts of compounds of formula (II), or therapeutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. The compounds of formula (II), and therapeutically acceptable salts thereof are as described above. The carrier, or vehicle, the diluent (s), the excipient, or excipients, must be acceptable in the sense of being compatible with the other ingredients of the formulation and not being detrimental to the recipient thereof. According to another aspect of the invention, there is also provided a process for the preparation of a pharmaceutical formulation that includes mixing a compound of formula (II), or a therapeutically acceptable salt thereof, with one or more pharmaceutically carriers, diluents or excipients. acceptable.

Pharmaceutical formulations can be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, more preferably 5 mg to 100 mg of a compound of formula (II), depending on the condition being treated. , the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound used, the duration of treatment and the age, gender, Weight and condition of the patient or pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of an active ingredient per dose. Preferred unit dose formulations are those containing a daily dose or sub-dose, as mentioned hereinbefore or an appropriate fraction thereof, of an active ingredient. Furthermore, such pharmaceutical formulations can be prepared by any of the methods well known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration by any appropriate route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous) routes. or intradermal). Such

ES 2 398 074 T3 formulations can be prepared by any method known in the art of pharmacy, for example by associating the active ingredient with the vehicle (s) or excipient (s). Additionally, the compounds of the present invention can be administered using delivery technology in a conventional manner, for example, intra-arterial stents.

Pharmaceutical formulations adapted for oral administration can be presented as separate units such as capsules or tablets, powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or shakes; or in liquid oil-in-water emulsions or water-in-oil emulsions.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an inert, oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water, and the like. Powders will be prepared by pulverizing the compound to a suitable fine size and mixing it with a similarly pulverized pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavoring, preservative, dispersing and coloring agent may also be present.

Capsules are prepared by preparing a powder mix, as described above, and filling formed gelatin shells. Emollients and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture prior to the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is swallowed.

In addition, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents may also be included in the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. The lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or tapping, adding a lubricant and disintegrant, and compressing to form tablets. A powder mixture is prepared by mixing the compound, suitably powdered, with a diluent or base as described above and optionally with a binder such as carboxymethylcellulose, an alginate, gelatin or polyvinylpyrrolidone, a retarding solution such as paraffin, an accelerator of resorption such as a quaternary salt and / or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, acacia mucilage, or solutions of cellulosic or polymeric materials and forcing it through a sieve. As an alternative to granulation, the powder mixture can be passed through the tablet machine and the result is imperfectly formed pastes that are broken into granules. The granules can be lubricated to prevent sticking to tableting dies by the addition of stearic acid, a stearate salt, talc, or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with an inert fluid carrier and compressed into tablets directly without going through the granulating or tapping steps. A protective transparent or opaque coating can be provided consisting of a shellac seal coating, a polymeric material or sugar coating, and a wax polish coating. Colorants can be added to these coatings to distinguish between different unit doses.

Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form such that a given amount contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavor additives such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or maintain release, for example, by coating or embedding the particulate material in polymers, wax, or the like.

The compounds of formula (II) and the therapeutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

The compounds of formula (II), and the therapeutically acceptable salts thereof, can also be delivered through the use of monoclonal antibodies as individual carriers to which the molecules of the compound are coupled. The compounds can also be coupled to soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer,

ES 2 398 074 T3 polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethylenexidepolylysine substituted with palmitoyl residues. In addition, the compounds can be coupled to a class of biodegradable polymers useful to achieve controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphipathic block copolymers. of hydrogels.

Pharmaceutical formulations adapted for transdermal administration can be presented as separate patches intended to remain in intimate contact with the epidermis of the recipient for an extended period of time. For example, the active ingredient can be administered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3 (6), 318 (1986).

Pharmaceutical formulations adapted for topical administration can be formulated as ointments; creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

The formulations are preferably applied as a topical ointment or cream for use in treatments of the eye or other external tissues, eg, mouth and skin. When formulated into an ointment, the active ingredient may be used with a paraffinic or a water-miscible ointment base. Alternatively, the active ingredient can be formulated in a cream with an oil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for topical administrations to the eye include eye drops in which the active ingredient is dissolved or suspended in a suitable vehicle, especially in an aqueous solvent.

Pharmaceutical formulations adapted for use in topical administration in the mouth include lozenges, lozenges, and mouthwashes.

Pharmaceutical formulations adapted for use in rectal administration can be presented as suppositories or as enemas.

Pharmaceutical formulations adapted for use in nasal administration in which the carrier is a solid include a coarse powder having a particle size for example in the range of 20 to 500 microns which is administered in the manner in which snuff is taken, that is, by rapidly inhaling the powder through the nasal passage from a container that is held very close to the nose. Suitable formulations in which the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous and oily solutions of the active ingredient.

Pharmaceutical formulations adapted for use in administration by inhalation include fine particle powders or mists, which can be generated by means of various types of pressurized metered dose aerosols, nebulizers or isolators.

Pharmaceutical formulations adapted for use in vaginal administration can be presented as vaginal suppositories, tampons, creams, gels, pastes, foams, or spray formulations.

Pharmaceutical formulations adapted for use in parenteral administration include aqueous and non-aqueous sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and sterile aqueous and non-aqueous suspensions which may include suspending agents and thickening agents. The formulations can be presented in unit dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dry (lyophilized) condition that requires only the addition of the sterile liquid carrier, for example water for injections, immediately prior to of use. Improvised injection solutions and suspensions can be prepared from sterile powders, granules and tablets.

It is to be understood that in addition to the ingredients mentioned above in particular, the formulations may include other agents conventional in the art taking into account the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

A therapeutically effective amount of a compound of the present invention will depend on various factors including, for example, the age and weight of the animal, the exact condition requiring treatment and its severity, the nature of the formulation and the route of administration, and, in Ultimately, it will be at the discretion of the treating physician or veterinarian. However, an effective amount of a compound of formula (II) for the treatment of neoplastic growth, for example colon or mammary carcinoma, will generally be in the range of 0.1 to 100 mg / kg body weight of the recipient (mammal ) per day and more usually in the range of 1 to 10 mg / kg of body weight per day.

The compounds of the present invention, and the therapeutically acceptable salts thereof, can be used alone or in combination with other therapeutic agents for use in treating the aforementioned conditions. In particular, in anti-cancer therapy, the combination with other

ES 2 398 074 T3 chemotherapeutic agents, hormonal or antibodies as well as the combination with surgical therapy and radiotherapy. Combination therapies according to the present invention therefore comprise the administration of at least one compound of formula (II) or a therapeutically acceptable salt thereof and the use of at least one additional cancer treatment method. Preferably, combination therapies according to the present invention comprise the administration of at least one different pharmaceutically active agent, preferably an antineoplastic agent. The compound (s) of formula (II) and the other pharmaceutically active agent (s) can be administered together or separately and when administered separately this can occur simultaneously or sequentially in any order. The amounts of the compound (s) of formula (II) and the other pharmaceutically active agent (s) and the relative times of administration will be selected in order to achieve the desired combined therapeutic effect.

The compounds of formula (II) or therapeutically acceptable salts thereof and at least one additional cancer treatment therapy may be used in combination simultaneously or sequentially in any therapeutically appropriate combination with such different anti-cancer therapies. In one embodiment, the other anti-cancer therapy is at least one additional chemotherapeutic therapy that includes administration of at least one anti-cancer agent. The administration and combination of a compound of formula (II) or therapeutically acceptable salts thereof, with other antineoplastic agents may be in combination according to the invention by simultaneous administration in (1) a unitary pharmaceutical composition that includes both compounds or ( 2) separate pharmaceutical compositions each of which includes one of the compounds. Alternatively, the combination can be administered separately in a sequential manner in which one antineoplastic agent is administered first and the other second, or vice versa. Such sequential administration can be near in time or far in time.

Antineoplastic agents can induce antineoplastic effects in a cell cycle specific way, that is, they are phase specific and act in a specific phase of the cell cycle or they bind to DNA and act in a non-cell cycle specific way, that is, they are not cell cycle specific and work by other mechanisms.

Useful antineoplastic agents in combination with the compounds and salts of formula (II) include the following:

(1) cell cycle specific antineoplastic agents including, but not limited to, diterpenoids such as paclitaxel and its analog docetaxel; vinca alkaloids such as vinblastine, vincristine, vindesine, and vinorelbine; epipodophyllotoxins such as etoposide and teniposide; fluoropyrimidines such as 5-fluorouracil and fluorodeoxyuridine; antimetabolites such as allopurinol, fluduxabine, methotrexate, cladrabine, cytarabine, mercaptopurine, and thioguanine; and camptothecins such as 9-amino camptothecin, irinotecan, topotecan, CPT-11 and the various optical forms of 7- (4-methylpiperazino-methylene) -10,11-ethylenedioxy-20-camptothecin;

(2) cytotoxic chemotherapeutic agents including, but not limited to, alkylating agents, such as melphalan, chlorambucil, cyclophosphamide, mechlorethamine, hexamethylmelamine, busulfan, carmustine, lomustine, and dacarbazine; antitumor antibiotics such as doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactainomycin, and mithramycin; and platinum coordination complexes such as cisplatin, carboplatin, and oxaliplatin; and (3) other chemotherapeutic agents including, but not limited to, anti-estrogens such as tomixefene toremifene, raloxifene, droloxifene, and iodoxifene; progesterogens such as megastrol acetate; aromatase inhibitors such as anastrazole, letrazole, vorazol, and exemestane; antiandrogens such as flutamide, nilutamide, bicalutamide, and cyproterone acetate; LHRH agonists and antagonists such as goserelin acetate and luprolide, testosterone 5α-dihydroreductase inhibitors such as finasteride; metalloproteinase inhibitors such as marimastat; antiprogestogens; inhibitors of urokinase plasminogen activator receptor function; inhibitors of growth factor function such as inhibitors of hepatocyte growth factor functions; erb-B2, erb-B4, epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR and TIE-2 (other than VEGFR inhibitors) and TIE-2 described in the present invention)); and other tyrosine kinase inhibitors such as cDK2 inhibitors and CDK4 inhibitors.

Determination of biological activity

The in vitro potency of the compounds to inhibit these protein kinases can be determined by the procedures detailed below.

The potency of compounds can be determined by the amount of inhibition of phosphorylation of an exogenous substrate (eg, synthetic peptide (Z. Songyang et al., Nature. 373: 536-539) by a test compound relative to a control.

Production of KDR tyrosine kinase using baculovirus system:

The coding sequence for the intracellular domain of human KDR (aa 789-1354) was generated through PCR

ES 2 398 074 T3 using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into the transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through cotransfection using the BaculoGold Transfection Reagent (PharMingen). Recombinant BV was plaque purified and verified via Western analysis. For protein production, SF-9 cells were cultured in SF-900-II medium at 2 x 10⁶/ ml and infected at 0.5 plaque-forming units per cell (MOI). Cells were harvested 48 hours after infection.

KDR purification

SF-9 cells expressing (His) 6KDR (aa 789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, Triton X -100 to 1%, 1 mM PMSF, 10 mg / ml aprotinin, 1 mg / ml leupeptin) to the cell pellet from 1 µl of cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4 ° C. The cell lysate was applied to a 5 ml NiCl2 chelating sepharose column, equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) that measures kinase activity. The purified KDR was exchanged in 25 mM HEPEs, pH 7.5, 25 mM NaCl, 5 mM DTT buffer and stored at -80 ° C.

The compounds of the present invention inhibited KDR at IC50 between about 0.003mM and about 40mM. Preferred compounds inhibited KDR at IC50 between about 0.003mM and about 0.1mM.

Production and Purification of Human Tie-2 Kinase

The coding sequence for the intracellular domain of human Tie-2 (aa 775-1124) was generated via PCR using cDNA isolated from human placenta as a template. A poly-His6 sequence was introduced at the N terminus and this construct was cloned into a transfection vector pVL 1939 at the Xba 1 and Not 1 site. Recombinant BV was generated via cotransfection using BaculoGold Transfection Reagent (PharMingen). Recombinant BV was plaque purified and verified via Western analysis. For protein production, SF-9 insect cells were cultured in SF-900-II medium at 2 x 10⁶/ ml and were infected at a MOI of 0.5. The purification of the His-tagged kinase used in the screening was analogous to that described for KDR.

Production and purification of Flt-1 tyrosine kinase

The baculoviral expression vector pVL 1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5 'to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated via PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein in a manner analogous to KDR and ZAP70. SF-9 insect cells were infected at a multiplicity of 0.5 and harvested 48 hours after infection.

EGFR Tyrosine Kinase Source

EGFR was purchased from Sigma (Cat. No. E-3641; 500 units / 50 ml) and EGF ligand was purchased from Oncogene Research Products / Calbiochem (Cat. No. PF011-100).

ZAP70 expression

The baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.). The nucleotide sequence encoding amino acids M (H) 6 LVPR9S was placed 5 'to the region encoding ZAP70 in its entirety (amino acids 1-619). The nucleotide sequence encoding the ZAP70 coding region was generated via PCR using cDNA libraries isolated from immortalized Jurkat T cells. The histidine residues enabled affinity purification of the protein (see below). The LVPR9S bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, making it possible to remove the affinity tag of the enzyme. SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours after infection.

ZAP70 extraction and purification

SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X100, 1 mM PMSF, 1 mg / ml leupeptin, 10 mg / ml of aprotinin and 1 mM sodium orthovanadate. The soluble lysate was applied to a HiTrap chelating sepharose column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. Fusion protein was eluted with 250 mM imidazole. The enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl, and 5 mM DTT.

ES 2 398 074 T3

Protein kinase source

Lck, Fyn, Src, Blk, Csk, and Lyn and truncated forms thereof were obtained commercially (for example, from Upstate Biotechnology Inc. (Saranac Lake, N.Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca .)) or were purified from known natural or recombinant sources using standard methods.

Enzyme Linked Immunosorbent Assay (ELISA) for PTK

Enzyme-linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. The ELISA was conducted according to known protocols described in, for example, Voller, et al., 1980, "Enzyme-Linked Immunosorbent Assay", In: Manual of Clinical Immunology, 2^to ed., edited by Rose and Friedman, pp. 359-371 Am. Soc. Of Microbiology, Washington, DC

The disclosed protocol was adapted to determine activity with respect to a specific PTK. For example, preferred protocols for conducting ELISA experiments are provided below. Adaptation of these protocols to determine the activity of a compound for other members of the receptor PTK family, as well as non-receptor tyrosine kinases, is within the capabilities of those of skill in the art. For the purposes of determining inhibitory selectivity, a universal PTK substrate (e.g., poly (Glu4 Tyr) random copolymer, MW 20,000-50,000) was used together with ATP (typically 5 μΜ) at concentrations approximately twice the Apparent km in the test.

The following procedure was used to test the inhibitory effect of the compounds of the present invention on the tyrosine kinase activity of KDR, Flt-1, Flt-4, Tie-1, Tie-2, EGFR, FGFR, PDGFR, IGF-1 -R, c-Met, Lck, hck, Blk, Csk, Src, Lyn, fgr, Fyn and ZAP70:

Buffers and solutions:

PGTPoli (Glu, Tyr) 4: 1

Store powder at -20 ° C. Dissolve the powder in phosphate buffered saline (PBS) for 50 mg / ml of solution. Store 1 ml aliquots at -20 ° C. When preparing plates dilute to 250 mg / ml in Gibco PBS. Reaction Buffer: 100 mM Hepes, 20 mM MgCL, 4 mM MnCL, 5 mM DTT, 0.02% BSA, 200 mM NaVO4, pH 7.10

ATP: Store 100 mM aliquots at -20 ° C. Dilute to 20 mM in water.

Wash Buffer: PBS with 0.1% Tween 20

Antibody Dilution Buffer: 0.1% bovine serum albumin (BSA) in PBS

TMB Substrate: mix TMB Substrate and 9: 1 Peroxide solutions immediately before use or use Neogen K-Blue Substrate

Stop Solution: 1M Phosphoric Acid

Process

1. Plate Preparation:

Dilute PGT stock solution (50 mg / ml, frozen) in PBS to 250 mg / ml. Add 125 ml per well of Corning Modified Flat Bottom High Affinity ELISA plates (combing # 25805-96). Add 125 ml of PBS to empty wells. Cover with sealing tape and incubate overnight at 37 ° C. Wash 1x with 250 ml of wash buffer and dry for approximately 2 h in a dry incubator at 37 ° C. Store coated plates in sealed bag at 4 ° C until use.

2. Tyrosine Kinase Reaction:

- Prepare inhibitor solutions at a 4x concentration in 20% DMSO in water.

- Prepare reaction buffer

- Prepare enzyme solution so that the desired units are in 50 ml, for example to

Prepare KDR 1 ng / ml for a total of 50 ng per well in the reactions. Store on ice.

- Prepare 4x ATP solution at 20 mM from 10 mM stock solution in water. Store on ice.

- Add 50 ml of the enzyme solution per well (typically 5-50 ng of enzyme / well depending on the specific activity of the kinase)

- Add 25 ml of inhibitor 4 x

- Add 25 ml of ATP 4x for inhibitory assay

- Incubate for 10 minutes at room temperature

- Stop the reaction by adding 50 ml of 0.05 N HCl per well

- Wash plate

ES 2 398 074 T3 ** Final Reaction Concentrations: ATP 5pM, DMSO 5%

3. Antibody binding

- Dilute a 1 mg / ml aliquot of PY20-HRP antibody (Pierce) (a phosphotyrosine antibody) to 50 ng / ml in 0.1% BSA in PBS by a 2-step dilution (100x, then 200x)

- Add 100 ml of Ab per well. Incubate 1 h at room temperature. Incubate 1 h at 4 ° C

- Wash plate 4x

Four. Color reaction

- Prepare TMB substrate and add 100 ml per well

- Monitor DO at 650 nm until 0.6 is reached.

- Stop with 1 M phosphoric acid. Shake in plate reader.

- Read DO immediately at 450 nm

Optimal incubation times and enzyme reaction conditions vary slightly with enzyme preparations and are determined empirically for each batch.

For Lck, the Reaction Buffer used was 100 mM MOPSO, pH 6.5, 4 mM MnCl2, 20 mM MgCl2, 5 mM DTT, 0.2% BSA, 200 mM NaVO4 under similar assay conditions.

Compounds of formulas 1-109 may have therapeutic utility in the treatment of diseases involving both identified protein tyrosine kinases, including those not mentioned herein, as well as those not yet identified that are inhibited by compounds of formulas 1 -109.

Cdc2 source

The recombinant human enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods.

Cdc2 Assay

One protocol that can be used is that provided with the reagents purchased with minor modifications. Briefly, the reaction is carried out in a buffer consisting of final concentrations of Tris 50 mM pH

7.5, 100 mM NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl2 (commercial buffer) supplemented with fresh 300 mM ATP (31 mCi / ml) and 30 mg / ml histone type lllss. An 80 ml reaction volume, containing enzyme units, is run for 20 minutes at 25 degrees C in the presence or absence of inhibitor. The reaction is terminated by adding 120 ml of 10% acetic acid. The substrate is separated from the unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 minutes each with 75 mM phosphoric acid. Counts are measured by a beta counter in the presence of scintillation fluid.

PKC kinase source

The catalytic subunit of PKC is commercially available (Calbiochem).

PKC kinase assay

A radioactive kinase assay is employed following a published procedure (Yasuda, l., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3: 166, 1220-1227 (1990)). Briefly, all reactions were carried out in a kinase buffer consisting of 50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 100 mM ATP, 8 mM peptide, DMSO al 5% and³³P ATP (8 Ci / mM). Compound and enzyme are mixed in the reaction vessel and the reaction is started by adding the ATP and the substrate mixture. Following the termination of the reaction by adding 10 ml of stop buffer (5 mM ATP in 75 mM phosphoric acid), a part of the mixture is applied in a spot on phosphocellulose filters. Spot-applied samples are washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. The incorporation of radioactive labels is quantified by liquid scintillation counting.

Erk2 Enzyme Source

The recombinant murine enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using methods.

ES 2 398 074 T3 conventional.

Erk2 enzyme assay

Briefly, the reaction is carried out in a buffer consisting of 50 mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO, and 10 mM MgCl2 (commercial buffer) supplemented with freshly prepared 100 mM ATP (31 mCi / ml) and 30 mg / ml myelin basic protein under conditions recommended by the distributor. Reaction volumes and method of termination of incorporated radioactivity are as described for the PKC assay (see above).

Cell receptor PTK assays

The following cell assay was used to determine the level of activity and the effect of the different compounds of the present invention on KDR / VEGFR2. Similar receptor PTK assays employing a specific ligand stimulus can be designed along the same lines for other tyrosine kinases using techniques well known in the art.

VEGF-Induced KDR Phosphorylation in Human Umbilical Vein Endothelial Cells (HUVEC) Measured by Western Blot:

1. HUVEC cells (from pooled donors) can be purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer's directions. Only early passes (3-8) are used for this trial. Cells are grown in 100 mm plates (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using complete EBM medium (Clonetics).

2. To assess the inhibitory activity of a compound, cells are trypsinized and seeded at 0.51.0 x 10⁵ cells / well in each well of 6-well cluster plates (Costar; Cambridge, MA).

3. 3-4 days after seeding, the plates are typically 90-100% confluent. Medium is removed from all wells, cells are rinsed with 5-10 ml pBs and incubated 18-24 hr with 5 ml EBM base medium with no added supplements (ie, serum fasting).

Four. Serial dilutions of inhibitors in 1 ml of EBM medium (final concentration 25 mM, 5 mM or 1 mM are added to cells and incubated for one hour at 37 ° C. Recombinant human VEGF165 (R&amp;D Systems) is then added to all cells. wells in 2 ml EBM medium at a final concentration of 50 ng / ml and incubated at 37 ° C for 10 minutes. Untreated or VEGF-treated control cells are used only to assess background phosphorylation and induction of phosphorylation by VEGF.

All wells are then rinsed with 5-10 ml of cold PBS containing 1 mM Sodium Ortovanadate (Sigma) and the cells are lysed and scraped in 200 ml of RIPA buffer (50 mM Tris-HCI) pH 7, NaCl 150 mM, 1% NP-40, 0.25% sodium deoxycholate, 1mM EDTA) containing protease inhibitors (1 mM PMSF, 1 mg / ml aprotinin, 1 mg / ml pepstatin, 1 mg / ml leupeptin, 1 mM Na vanadate, 1 mM Na fluoride) and 1 mg / ml DNase (all chemicals from Sigma Chemical Company, St Louis, MO). The lysate is centrifuged at 14,000 rpm for 30 min, to remove the nuclei.

Equal amounts of protein are then precipitated by adding cold ethanol (-20 ° C) (2 volumes) for a minimum of 1 hour or a maximum of one night. The pellets are reconstituted in Laemli sample buffer containing 5% mercaptoethanol (BioRad; Hercules, CA) and boiled for 5 min. Proteins are resolved by polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Diego, CA) and transferred to a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), proteins are probed overnight with polyclonal anti-KDR antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with monoclonal anti-phosphotyrosine antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4 ° C. After washing and incubation for 1 hour with F (ab) 2 conjugated to HRP of goat anti-rabbit or goat anti-mouse IgG the bands are visualized using the emission chemiluminescence (ECL) system (Amersham Life Sciences, Arlington Heights, IL).

In vivo uterine edema model

This assay measures the ability of compounds to inhibit the acute increase in uterine weight in mice that occurs in the first hours following estrogen stimulation. This early onset of uterine weight gain is known to be due to edema caused by increased permeability of the uterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993), 133: 829-837) demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus. These results have been confirmed by the use of neutralizing monoclonal antibody to VEGF which significantly reduces the acute increase in uterine weight following estrogen stimulation (WO 97/42187). Thus, this system can serve as a model for in vivo inhibition of VEGF signaling and the associated hyperpermeability and edema.

ES 2 398 074 T3

Materials: All hormones can be purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to the supplier's instructions. Vehicle components (DMSO, Cremaphor El) are available from Sigma (St. Louis, MO). Mice (Balb / c, 8-12 weeks old) can be purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with the guidelines of the Institutional Committee for the Care and Use of Animals.

Method:

Day 1: Balb / c mice are given an intraperitoneal (ip) injection of 12.5 units of pregnant mare serum gonadotropin (PMSG).

Day 3: Mice receive 15 units of human chorionic gonadotropin (hCG) ip

Day 4: Mice are randomized and divided into groups of 5-10. Test compounds are administered by ip, iv or po routes depending on solubility and vehicle at doses ranging from 1-100 mg / kg. The vehicle control group receives vehicle only and two groups are left untreated.

Thirty minutes later, the experimental, vehicle and one untreated groups are given an ip injection of 17-estradiol (500 mg / kg). After 2-3 hours, the animals are sacrificed by CO2 inhalation. Following a midline incision, each uterus was isolated and removed by incision immediately below the cervix and at the junctions of the uterus and oviducts. Fat and connective tissue were removed with care not to alter the integrity of the uterus prior to weighing (wet weight). The uteri were dried to remove fluid by compression between two sheets of filter paper with a one-liter glass bottle filled with water. The uteri are weighed following drying (dry weight). The difference between the wet and dry weights is taken as the fluid content of the uterus. The mean fluid content of treated groups is compared to untreated or vehicle-treated groups. Significance is determined by Student's test. The unstimulated control group is used to monitor the estradiol response.

Certain compounds of the present invention that are angiogenic receptor tyrosine kinase inhibitors may also be shown to be active in the Matrigel implant model of neovascularization. Matrigel's model of neovascularization involves the formation of new blood vessels within a transparent marble of subcutaneously implanted extracellular matrix that is induced by the presence of tumor cells that produce proangiogenic factor (for example see: Passaniti, A., et al. , Lab. Investig. (1992), 67 (4), 519-528; Anat. Rec. (1997), 249 (1), 63-73; Int. J. Cancer (1995), 63 (5), 694 -701; See. Biol. (1995), 15 (11), 1857-6). The model preferably develops over 3-4 days and end points include gross visual / imaging assessment of neovascularization, microscopic microvessel density determinations, and hemoglobin quantification (Drabkin method) following removal of the implant versus to controls of animals not treated with inhibitors. The model can alternatively employ bFGF or HGF as the stimulus.

The compounds of the present invention can be used in the treatment of conditions mediated by protein kinase, such as proliferative or benign and neoplastic diseases and disorders of the immune system. Such diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis, and systemic lupus erythematosus; psoriasis, organ transplant rejection (eg, kidney rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancers such as lung, breast, stomach, bladder, colon, pancreatic, ovarian cancer , prostate and rectal and hematopoietic malignancies (leukemia and lymphoma), glioblastoma, infantile hemangioma and diseases involving inappropriate vascularization (for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration and infantile hemangiomas in humans). Such inhibitors may be useful in the treatment of disorders involving VEGF-mediated edema, ascites, effusions and exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS). Additionally, the compounds of the invention may be useful in the treatment of pulmonary hypertension, particularly in patients with thromboembolic disease (J. Thorac. Cardiovasc. Surg. 2001, 122 (1), 65-73).

Synthetic Procedures

The abbreviations that have been used in the descriptions of the scheme and the examples that follow are: AIBN for 2,2'-azobis (2-methylpropionitrile); THF for tetrahydrofuran; MTBe for methyl tert-butyl ether, PPh3 for triphenylphosphine; o-tol3P for tri-o-tolylphosphine; dppf for diphenylphosphinoferrocene; dMf for N, N-dimethylformamide; DME for 1,2-dimethoxyethane; NBS for N-bromosuccinimide; NMP for N-methylpyrrolidinone; DMSO for dimethylsulfoxide; LDA for lithium diisopropylamide; TFA for trifluoroacetic acid; min for minutes; TBTU for O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium tetrafluoroborate; and DEAD for diethyl azodicarboxylate.

The compounds and processes of the present invention will be better understood in conjunction with the following schemes which illustrate the methods by which the compounds of the invention can be prepared. Starting materials can be obtained from commercial sources or prepared by established literature methods known to those of skill in the art. Groups A, X, R¹, R², R³, R⁴, R⁵ and R⁶ they are as they have

ES 2 398 074 T3 defined above unless otherwise indicated below.

This invention is intended to include compounds having formula (I) when they are prepared by synthetic processes or by metabolic processes. The preparation of the compounds of the invention by metabolic processes include those that take place in the human or animal body (in vivo) or processes that take place in vitro.

<img file="ES2398074T3_D0003.tif" />

Scheme 1 shows the synthesis of compounds of formula (4). Compounds of formula (3) can be reacted with an isocyanate (R⁶NCO) appropriately substituted to provide compounds of formula (4). Examples of solvents used in these reactions include THF, dichloromethane, and MTBE. The reaction is typically carried out at a temperature of from about 0 ° C to about 25 ° C for about 1 hour to about 14 hours.

Scheme 2 [comparative]

<img file="ES2398074T3_D0004.tif" />

Compounds of formula (la) can be prepared following the procedures described in Scheme 2. Compounds of formula (5) can be converted to compounds of formula (6) by treatment with hydrazine. Examples of solvents include n-butanol, ethanol, n-pentanol, and n-hexanol. The reaction is typically carried out at about 80 ° C to about 120 ° C for about 2 to about 12 hours. Compounds of formula (6), in which R⁹ is hydrogen can be converted into the compounds of formula (6), in which R⁹ is alkenyl, alkoxyalkyl, alkyl, heterocyclylalkyl, hydroxyalkyl or (NR^toR^b) alkyl by treatment with the appropriately substituted alkylating agent in the presence of a base under conditions known to those skilled in the art.

Conversion of compounds of formula (6) to compounds of formula (la) can be carried out by treatment with compounds of formula (7) in the presence of a palladium catalyst and a base. Representative palladium catalysts include Pd (PPh3) 4, Pd (o-tohP) 2Cl2, PdCh (dppf), and PdCh (dppf) .CH2Cl2. Examples of bases include sodium carbonate, cesium carbonate, and potassium carbonate. Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically carried out at temperatures between about 60 ° C and about 130 ° C (optionally in a microwave for about 5 to about 25 minutes) for about 4 to about 24 hours.

Scheme 3 [comparative]

<img file="ES2398074T3_D0005.tif" />

ES 2 398 074 T3

As shown in Scheme 3, compounds of formula (8) can be converted to compounds of formula (9) by treatment with NBS in the presence of a radical initiator, such as benzoyl peroxide, AIBN. Examples of solvents used in this reaction include CCl4, benzene, and CHCl. The reaction is typically carried out at about 60 to about 80 ° C for about 4 to about 48 hours.

Compounds of formula (9) can be converted to compounds of formula (5a) by treatment with a nucleophile (Z) (eg, an amine or an alcohol). Examples of solvents used in these reactions include THF, DMF, NMP, and DME. The reaction is typically carried out at about 20 ° C to about 60 ° C for about 12 to about 24 hours.

Conversion of compounds of formula (5a) to compounds of formula (6a) can be carried out by the methods described in Scheme 2.

Scheme 4 [comparative]

<img file="ES2398074T3_D0006.tif" />

Scheme 4 shows the synthesis of compounds of formula (Ib). Compounds of formula (6) (prepared by the methods described in Scheme 2) can be converted to compounds of formula (10) by treatment with a borane other appropriately substituted organometallic reagent, such as a stannane or stannane reagent. organozinc in the presence of a palladium catalyst and optionally a base. Representative palladium catalysts include Pd (PPh3) 4, Pd (o-tol3P) 2Cl2, PdCL (dppf), and PdCL (dppf) .CH2Cl2. Examples of bases include sodium carbonate, cesium carbonate, and potassium carbonate. Solvents typically used in these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically carried out at temperatures between about 60 ° C and about 130 ° C for about 4 to about 24 hours.

Compounds of formula (10) can be converted to compounds of formula (Ib) by treatment with the appropriately substituted electrophile to generate L (i.e., an isocyanate of formula R⁶NCO). Examples of solvents include dichloromethane, chloroform, THF, DMF, and MTBE. The reaction is typically carried out at about -5 ° C to about 25 ° C for about 12 to about 24 hours.

Scheme 5 [comparative]

<img file="ES2398074T3_D0007.tif" />

As shown in Scheme 5, compounds of formula (11) can be reacted with the compound of formula (12), a palladium catalyst and potassium acetate, then treated with compounds of formula (6) in the presence of a catalyst of palladium and a base to provide compounds of formula (Ib). Representative palladium catalysts include Pd (PPh3) 4, Pd (o-toLP) 2Cl2, PdCL (dppf), and PdCL (dppf) .CH2Cl2. Examples of bases include sodium carbonate, cesium carbonate, and potassium carbonate. Solvents typically used in

ES 2 398 074 T3 these reactions include DMF, DME, toluene, ethanol, water, and mixtures thereof. The reaction is typically carried out at temperatures between about 60 ° C and about 130 ° C for about 4 to about 24 hours.

Scheme 6 [comparative]

<img file="ES2398074T3_D0008.tif" />

(14)

<img file="ES2398074T3_D0009.tif" />

The synthesis of compounds of formula (Ic) is shown in Scheme 6. Compounds of formula (13) can be reacted with the compound of formula (12) and then with compounds of formula (6) using the 10 conditions that have been described in Scheme 5 to provide the compounds of formula (14). Compounds of formula (14) can be hydrolyzed to give compounds of formula (15) using conditions known to those skilled in the art (ie, KOH). Compounds of formula (15) can be converted to compounds of formula (Ic) by treatment with an appropriately substituted amine in the presence of a coupling agent under conditions known to those skilled in the art.

ES 2 398 074 T3

Scheme 7 [comparative]

<img file="ES2398074T3_D0010.tif" />

Compounds of formula (Id) can be prepared as described in Scheme 7. Compounds of formula (16) can be converted to compounds of formula (17) using the conditions described in Schemes 2 and 4. Compounds of formula (17) can be converted to compounds of formula (18) (where L² is an alkenyl group and R^d is (NR^toR^b) carbonyl or alkoxycarbonyl) by treatment with a palladium catalyst and a base such as triethylamine or diisopropylethylamine. Examples of solvents include THF and 1,4-dioxane. The reaction is typically carried out at about 80 to about 150 ° C for about 30 minutes to about 6 hours.

Conversion of compounds of formula (18) to compounds of formula (19) can be accomplished by methods known to those skilled in the art. Compounds of formula (19) can be converted to compounds of formula (Id) by the methods described in Scheme 4.

Scheme 8

This compound shows the synthesis of compounds according to the present invention, to the extent applicable.

<img file="ES2398074T3_D0011.tif" />

(21)

Scheme 8 shows the synthesis of compounds of formula (le). Compounds of formula (21) (where Q is Br or I) can be reacted with the compound of formula (22) in the presence of potassium tert-butoxide to provide compounds of formula (23). Examples of solvents used in this reaction include DMF, DME, and NMP. The reaction is typically carried out at about 20 ° C to about 35 ° C for about 15 minutes to about 12 hours.

ES 2 398 074 T3

Compounds of formula (23) can be coupled with compounds of formula (24) using the conditions described in Schemes 2, 4 and 7 to provide compounds of formula (le).

The present invention will now be described in conjunction with certain preferred embodiments. Therefore, the following examples, which include the preferred embodiments, will illustrate the preferred practice of the present invention, it being understood that the examples are for purposes of illustration of certain preferred embodiments and are presented to provide what is believed to be the further description. useful and easily understandable of its procedures and conceptual aspects.

Compounds of the invention will be named using ACD / ChemSketch version 5.0 software (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada).

Next, Examples 1-94; 117-260 and 332-380 are comparative.

Example 1

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 1A

4-Iodo-1H-indazol-3-amine

A mixture of 2-fluoro-6-iodobenzonitrile (2 g, 8.1 mmol) and hydrazine hydrate (4 ml) in n-butanol (40 ml) was heated at 105-110 ° C for 5 hours, cooled to temperature room, poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 1.88 g of the desired product. Fr = 0.25 (5% methanol / dichloromethane).

Example 1B

N- (3-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea

A mixture at 0 ° C of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (5.03 g, 23 mmol) and 1-isocyanato-3-methylbenzene (2 , 95 ml, 23 mmol) in THF (90 ml) was stirred at room temperature for 1 hour, concentrated, suspended in acetonitrile and filtered. The filter cake was dried to provide 8.09 g of the desired product.

Example 1C

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

A mixture of Example 1A (60mg, 0.24mmol), Example 1B (103mg, 0.29mmol) and Na2CO3 (64mg, 0.6mmol) under a nitrogen atmosphere was treated with DME (8ml) , water (2 ml) and Pd (PPh3) 4 (14 mg, 0.012 mmol). The mixture was purged with bubbling nitrogen for 2 minutes, heated at 80-90 ° C for approximately 18 hours, cooled to room temperature, poured into water, and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 5-8% methanol / dichloromethane to provide 56 mg (66% yield) of the desired product. MS (ESI (+)) m / e 358 (M + H)⁺; ¹H NMR (300 Mhz, DMSO-d6) δ 2.29 (s, 3H), 4.33 (s, 2H), 6.76-6.83 (m, 2H), 7.17 (t, J = 7.80 Hz, 1H), 7.23-7.28 (m, 3H), 7.32 (s, 1H),

7.39 (d, J = 8.48 Hz, 2H), 7.59 (d, J = 8.48 Hz, 2H), 8.64 (s, 1H), 8.79 (s, 1H), 11.70 (s, 1H).

Example 2

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3,5-dimethoxyphenyl) urea

The desired product was prepared by substituting 1-isocyanate-3-methylbenzene in Examples 1B-C for 1-isocyanato-

3,5-dimethoxybenzene. ¹H NMR (300 MHz, DMSO-d6) δ 3.73 (s, 6H), 4.33 (s, 2H), 6.15 (t, J = 2.20 Hz, 1H), 6.70 (d , J = 2.03 Hz, 2H), 6.78 (dd, J = 5.76, 2.37 Hz, 1H), 7.22-7.31 (m, 2H), 7.39 (d, J = 8.48 Hz, 2H), 7.58 (d, J = 8.81 Hz, 2H), 8.73 (s, 1H), 8.78 (s, 1H), 11.71 (s, 1 HOUR); MS (ESI (+)) m / e 404 (M + H)⁺.

Example 3

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene in Examples 1B-C for 1-chloro-3-isocyanatobenzene and purifying the crude product by preparative HPLC on a Waters Symmetry C8 column (25 mm x 100 mm, 7 mm particle size) using a gradient of 10% to 100% acetonitrile / 0.1% aqueous TFA over 8 minutes (10 minute run time) at a flow rate of 40

ES 2 398 074 T3 ml / min. ¹H NMR (300 MHz, DMSO-d6) δ 6.89 (dd, J = 6.44, 1.70 Hz, 1H), 7.03 (m, 1H), 7.28-7.38 (m, 4H), 7.42 (d, J = 8.81 Hz, 2H), 7.61 (d, J = 8.82 Hz, 2H), 7.74 (m, 1H), 9.00 (s, 1H), 9.03 (s, 1H); MS (ESl (+)) m / e 378 (M + H)⁺; Anal. calc. for C2₀H16ClN₅O-CF3CO2H: C, 52.76; H, 3.62; N, 13.98. Found: C, 52.40; H, 3.50; N, 13.86.

Example 4

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-3- (trifluoromethyl) benzene in Examples 1B-C and purifying the product by preparative HPLC using the conditions described in the Example 3. ¹H NMR (300 MHz, DMSO-d6) δ 6.86 (dd, J = 6.10, 2.03 Hz, 1H), 7.29-7.35 (m, 3H), 7.42 (d, J = 8.81 Hz, 2H), 7.53 (t, J = 7.97 Hz, 1H), 7.58-7.65 (m, 3H), 8.05 (s, 1H), 9, 01 (s, 1H),

9.16 (s, 1H); MS (ESl (+)) m / e 412 (M + H)⁺; Anal. calc. for C21H16F3N₅OO, 7CF3CO2H: C, 54.77; H, 3.43; N, 14.26. Found: C, 54.64; H, 3.32; N, 14.12.

Example 5

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

Example 5A

N- (2-fluoro-5-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea

A mixture at 0 ° C of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline (0.5 g, 2.28 mmol) and 1-fluoro-2 -isocyanato4-methylbenzene (0.297 ml, 2.28 mmol) in dichloromethane (15 ml) was allowed to gradually warm to room temperature and stirred overnight. The resulting suspension was diluted with hexanes resulting in the formation of more of the precipitate, which was collected by filtration to provide 0.68 g of the desired product. MS (ESl (+)) m / e 370.7 (M + H)⁺.

Example 5B

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

A mixture of Example 1A (80 mg, 0.32 mmol), Example 5A (144 mg, 0.39 mmol) and Na2CO3 (58 mg) in DME (3 ml) and water (1 ml) was degassed with nitrogen for 2 minutes, treated with Pd (PPh3) 4 (19 mg, 0.0161 mmol) and degassed with nitrogen for a further 2 minutes. The vial was capped and heated at 160 ° C for 10 minutes with shaking in a Smith Synthesizer microwave oven (300 W). The reaction was concentrated and the residue was purified by HPLC using the conditions of Example 3 to provide 63 mg of the desired product as the trifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 6.78-6.85 (m, 1H), 6.87 (dd, J = 6.10, 1.70 Hz, 1 HOUR),

7.12 (dd, J = 11.53, 8.48 Hz, 1H), 7.30-7.39 (m, 2H), 7.42 (d, J = 8.81 Hz, 2H), 7 , 60 (d, J = 8.48 Hz, 2H), 8.01 (dd, J = 7.80, 2.37 Hz, 1H), 8.54 (d, J = 2.71 Hz, 1H) , 9.23 (s, 1H); MS (ESl (+)) m / e 376 (M + H)⁺; Anal. calc. for C21H18FN₅OO, 8CF3CO2H: C, 58.17; H, 4.06; N, 15.01. Found: C, 58.17; H, 4.29; N, 15.12.

Example 6

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-2-isocyanate-4 (trifluoromethyl) benzene in Examples 5A-B and purifying the crude product as described in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.79 (dd, J = 5.26, 2.54 Hz, 1H), 7.24-7.31 (m, 2H), 7.42 (m, 3H),

7.52 (m, 1H), 7.61 (d, J = 8.48 Hz, 2H), 8.65 (dd, J = 7.29, 2.20 Hz, 1H), 8.96 (d , J = 3.05 Hz, 1H), 9.32 (s, 1H), 11.72 (s, 1H); MS (ESl (+)) m / e 430 (M + H)⁺.

Example 7

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-bromo-3-isocyanatobenzene in Examples 5A-B. ¹H NMR (300 MHz, DMSO-d6) δ 6.87 (dd, J = 6.10, 1.70 Hz, 1H),

7.13-7.18 (m, 1H), 7.25 (t, J = 7.97 Hz, 1H), 7.31-7.26 (m, 3H), 7.42 (d, J = 8.82 Hz, 2H), 7.61 (d, J = 8.48 Hz, 2H),

7.88 (t, J = 1.86Hz, 1H), 8.99 (s, 1H); MS (ESl (-)) m / e 420, 422 (MH) -.

Example 8

N- [4- (3-amino-1H-imidazol-4-yl) phenyl] -N '- (3-bromo-4-methylphenyl) urea

ES 2 398 074 T3

The desired product was prepared as the trifluoroacetate salt by substituting 2-bromo-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz, DMSO-d6) δ 2.33 (s, 3H), 6.88 (dd, J = 6.10, 1.70 Hz, 1H), 7.25-7.50 (m, 7H), 7.61 (d, J = 8.48Hz, 2H), 8.85 (s, 1H), 8.93 (s, 1H); MS (ESI (-)) m / e 434, 435 (MH) -.

Example 9

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N '- (3-ethylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-ethyl-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B. ¹H NMR (300 MHz, DMSO-d6) δ 1.19 (t, J = 7.63 Hz, 3H), 2.58 (c, J =

7.68 Hz, 2H), 6.81-6.88 (m, 2H), 7.19 (t, J = 7.80 Hz, 1H), 7.25-7.36 (m, 4H), 7.40 (d, J = 8.48 Hz, 2H), 7.60 (d, J =

8.81 Hz, 2H), 8.70 (s, 1H), 8.85 (s, 1H); MS (ESI (+)) m / e 372 (M + H)⁺.

Example 10

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N'-phenylurea

The desired product was prepared by substituting isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 4.33 (s, 2H), 6.78 (dd, J = 5.42, 2.37 Hz, 1H), 6.98 (t, J = 7, 29 Hz, 1H), 7.28 (m, 4H), 7.39 (d, J = 8.81 Hz, 2H), 7.48 (d, J =

7.46 Hz, 2H), 7.59 (d, J = 8.82 Hz, 2H), 8.72 (s, 1H), 8.81 (s, 1H), 11.70 (s, 1H) ; MS (ESI (+)) m / e 344 (M + H)⁺.

Example 11

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N '- (3-fluoro-4-methylphenyl) urea

The desired product was prepared by substituting 2-fluoro-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 2.17 (s, 3H), 4.33 (s, 2H), 6.78 (dd, J = 5.42, 2.71 Hz, 1H), 7 .05 (dd, J = 8.14, 2.03 Hz, 1H), 7.17 (t, J =

8.65 Hz, 1H), 7.23-7.30 (m, 2H), 7.39 (d, J = 8.48 Hz, 2H), 7.45 (dd, J = 12.54, 2 , 03Hz, 1H), 7.58 (d, J = 8.81Hz, 2H), 8.84 (s, 2H), 11.70 (s, 1H); MS ESI (+)) m / e 376 (M + H)⁺.

Example 12

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N '- (2-fluorophenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-2-isocyanatobenzene in Examples 5A-B and purifying the crude product as described in Example 1C. ¹H NMR (300 MHz, DMSOda) δ 4.33 (s, 2H), 6.79 (dd, J = 5.42, 2.71 Hz, 1H), 6.97-7.06 (m, 1H) , 7.16 (t, J = 7.63 Hz, 1H), 7.22-7.30 (m, 3H),

7.41 (d, J = 8.48 Hz, 2H), 7.60 (d, J = 8.48 Hz, 2H), 8.18 (m, 1H), 8.61 (d, J = 2 , 37 Hz, 1H), 9.22 (s, 1H), 11.71 (s, 1H); MS (ESI (+)) m / e 362 (M + H)⁺.

Example 13

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N '- (4-fluorophenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-4-isocyanatobenzene in Examples 5A-B and purifying the crude product as described in Example 1C. ¹H NMR (300 MHz, DMSOde) δ 4.33 (s, 2H), 6.78 (dd, J = 5.43, 2.37 Hz, 1H), 7.13 (t, J = 8.99 Hz , 2H), 7.22-7.29 (m, 2H), 7.39 (d, J = 8.48 Hz, 2H), 7.49 (m, 2H), 7.59 (d, J = 8.82 Hz, 2H), 8.80 (d, J = 15.50 Hz, 2H), 11.70 (s, 1H); MS (ESI (+)) 362 (M + H)⁺.

Example 14

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N '- (3-fluorophenyl) urea

The desired product was prepared by substituting 1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Examples 5A-B and purifying the crude product as described in Example 1C. ¹H NMR (300 MHz, DMSOds) δ 4.33 (s, 2H), 6.75-6.83 (m, 2H), 7.15 (m, 1H), 7.23-7.36 (m, 3H), 7.40 (d, J = 8.48 Hz, 2H), 7.52 (m, 1H), 7.59 (d, J = 8.48 Hz, 2H), 8.89 (s, 1H), 8.97 (s, 1H), 11.71 (s, 1H); MS (ESI (+)) m / e 362 (M + H)⁺.

Example 15

N- {4- [3-amino-7- (4-morpholinylmethyl) -1H-indazol-4-illphenyl} -N '- (3-fluorophenyl) urea

ES 2 398 074 T3

Example 15A 2-fluoro-6-iodo-3-methylbenzoic acid

A -78 ° C solution of 2-fluoro-4-iodo-1-methylbenzene (25 g, 105.9 mmol) in THF (200 ml) was treated dropwise with LDA (2 M solution in THF, 58, 5 ml, 116 mmol), stirred at -78 ° C for 1 hour, treated with excess dry ice powder, stirred at -78 ° C for 30 minutes and warmed to room temperature gradually over about 18 hours. The mixture was concentrated and the residue was partitioned between 4N NaOH and diethyl ether. The aqueous phase was adjusted to pH 2 with 2N HCl and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 19.4 g (66% yield) of the desired product. MS (ESI (+)) m / e 279 (M + H)⁺.

Example 15B

2-fluoro-6-iodo-3-methylbenzamide

A solution of Example 15A (19.3 g, 69.1 mmol) in thionyl chloride (60 ml) was heated at 80 ° C for 3 hours, cooled to room temperature, and concentrated. The residue was dissolved in THF (100 ml), cooled to 0 ° C, treated with concentrated NH4OH (80 ml), stirred at room temperature for approximately 18 hours, and concentrated. The concentrate was suspended in water and filtered. The filter cake was washed with water and dried to provide 18.67 g of the desired product. MS (CI / NH3) m / e 280 (M + H)⁺.

Example 15C

2- fluoro-6-iodo-3-methylbenzonitrile

A solution of Example 15B (18.6 g, 66.7 mmol) in DMF (190 ml) was treated dropwise with thionyl chloride (24 ml, 333 mmol), heated at 115 ° C for 16 hours, cooled to room temperature, poured into ice, and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 25% ethyl acetate / hexanes to provide 12.35 g (71% yield) of the desired product. MS (CI / NH3) m / e 279 (M + NH4)⁺.

Example 15D

3- (bromomethyl) -2-fluoro-6-iodobenzonitrile

A mixture of Example 15C (8.0 g, 30.6 mmol), NBS (6.54 g, 36.78 mmol), and benzoyl peroxide (0.5 g) in CCl4 (100 ml) was heated to reflux for 36 hours, during which time more of NBS (9 g) and benzoyl peroxide (1.5 g) were added in 3 portions. The suspension was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography on silica gel with 20% ethyl acetate / hexanes to provide 4.83 g (46% yield) of the desired product. Fr = 0.27 (20% ethyl acetate / hexanes).

Example 15E

2-fluoro-6-iodo-3- (4-morpholinylmethyl) benzonitrile

A solution of Example 15D (710 mg, 2.09 mmol) and morpholine (0.546 ml, 6.25 mmol) in DMF (8 ml) was stirred at room temperature overnight, poured into water and extracted twice with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated to provide 0.71 g of the desired product. Fr = 0.4 (ethyl acetate).

Example 15F

4- iodo-7- (4-morpholinylmethyl) -1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 15E in Example 1A. Fr = 0.18 (ethyl acetate).

Example 15G

4- (4-aminophenyl) -7- (4-morpholinylmethyl) -1H-indazol-3-amine

The desired product was prepared by substituting Example 1A and 1B for Example 15F and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 2.42 (d, J = 4.07 Hz, 4H), 3.58 (m, 4H), 3.65 (s, 2H), 4.36 (s , 2H), 5.24 (s, 2H), 6.66 (dd, J = 7.80, 4.41 Hz, 3H), 7.12 (m, 3H), 11.45 (s,

ES 2 398 074 T3

1 HOUR); MS (ESI (+)) m / e 324 (M + H)⁺.

Example 15H

N- {4- [3-amino-7- (4-morpholinylmethyl) -1H-indazol-4-yl] phenyl} -N '- (3-fluorophenyl) urea

A solution of Example 15G (50 mg, 0.155 mmol) in dichloromethane was cooled to 0 ° C, treated with 1-fluoro-3-isocyanatobenzene (0.021 ml), stirred at room temperature overnight, and concentrated. The concentrate was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, 7mm particle size) using a gradient of 10% to 100% acetonitrile / 0.1% aqueous TFA over 8 minutes ( 10 minute run time) at a flow rate of 40 ml / min to provide 24 mg of the desired product as the trifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d6) δ 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.79 (m, 1H), 6.92 (d, J = 7.12 Hz, 1H), 7.16 (m, 1H), 7.32 (m, 1H), 7.42 (m, 3H), 7.52 (m, 1H), 7.63 (d, J = 8.81 Hz, 2H), 9.12 (s, 1H), 9.16 (s, 1H); MS (ESI (+)) m / e 461 (M + H)⁺.

Example 16

N- {4- [3-amino-7- (4-morpholinylmethyl) -1H-indazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.20-4.20 (m, 8H), 4.56 (s, 2H), 6.80 (d, J = 7.12 Hz, 1H), 6.92 (d, J = 7.12 Hz, 1H), 7.17 (t, J = 7.80 Hz, 2H), 7.27 (d, J = 7, 23 Hz, 1H), 7.32 (s, 1H), 7.42 (m, 3H), 7.63 (d, J = 8.48 Hz, 2H), 8.79 (s, 1H), 8 , 98 (s, 1H).

Example 17

N- {4- [3-amino-7- (4-morpholinylmethyl) -1H-indazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene for 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 3.20-4.10 (m, 8H),

4.56 (s, 2H), 6.92 (d, J = 7.12 Hz, 1H), 7.38-7.47 (m, 4H), 7.52 (m, 1H), 7.64 (d, J = 8.81 Hz, 2H), 8.64 (dd, J = 7.46, 2.03 Hz, 1H), 9.00 (d, J = 2.71 Hz, 1H), 9 , 40 (s, 1H); MS (ESI (+)) m / e 529 (M + H)⁺.

Example 18

N- {4- [3-amino-7- (4-morpholinylmethyl) -1H-indazol-4-yl] phenyl} -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene for 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 3.15-4.05 (m, 8H),

4.56 (s, 2H), 6.92 (d, J = 7.12 Hz, 1H), 7.44 (m, 4H), 7.64 (d, J = 8.81 Hz, 2H), 7.66 (m, 1H), 8.05 (dd, J = 6.44, 2.71 Hz, 1H), 9.18 (s, 1H), 9.30 (s, 1H); MS (ESI (+)) m / e 529 (M + H)⁺.

Example 19

N- {4- [3-amino-7- (4-morpholinylmethyl) -1H-indazol-4-yl] phenyl} -N '- [3- (trifluoromethyl) phenyl] urea

A solution of Example 15F (80 mg, 0.22 mmol) and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [ 3 (trifluoromethyl) phenyl] urea (108 mg, 0.268 mmol) in toluene (2 ml) and ethanol (1.5 ml) was treated with a solution of Na2CO3 (58 mg) in water (1 ml), degassed with nitrogen for 2 minutes, it was treated with Pd (PPh3) 4 (13 mg, 0.011 mmol) and degassed with nitrogen for a further 2 minutes. The vial was capped and heated at 140-150 ° C for 8-10 minutes with shaking in a Smith Synthesizer microwave oven (300 W). The reaction was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by HPLC using the conditions of Example 15H to provide 55 mg of the desired product as the trifluoroacetate salt.¹H NMR (300 MHz, DMSOda) δ 3.10-4.08 (m, 8H), 4.55 (s, 2H), 6.92 (d, J = 7.12 Hz, 1H), 7.32 (d, J = 7.46 Hz, 1H), 7.38-7.47 (m, 3H), 7.53 (t, J = 7.80 Hz, 1H), 7.58-7.69 ( m, 3H), 8.06 (s, 1H), 9.17 (s, 1H), 9.30 (s, 1H); MS (ESI (+)) m / e 511 (M + H)⁺.

Example 20

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

Example 20A

4-iodo-7 - [(4-methyl-1-pjperazinyl) methyl] -1H-indazol-3-amine

ES 2 398 074 T3

The desired product was prepared by substituting 1-methylpiperazine for morpholine in Examples 15E-F. MS (ESI (+)) m / e 372 (M + H)⁺.

Example 20B

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [3 - (trifluoromethyl) phenyl] urea from Example 20a and N- (3-chlorophenyl) -N '- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea, respectively, in Example 19. ¹H NMR (300 MHz, DmSOda) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.97 (s, 2H), 6.85 (d, J = 7, 12 Hz, 1H), 7.03 (m, 1H), 7.25-7.33 (m, 3H), 7.40 (d, J = 8.48 Hz, 2H), 7.62 (d, J = 8.48 Hz, 2H), 7.74 (m, 1H), 9.14 (s, 1H), 9.17 (s, 1H); MS (ESI (+)) m / e 490 (M + H)⁺.

Example 21

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [3 - (trifluoromethyl) phenyl] urea from Example 20a and N- (3-methylphenyl) -N '- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea, respectively, in Example 19. ¹H NMR (300 MHz, DmSOde) δ 2.29 (s, 3H), 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (s, 2H), 6 , 80 (d, J = 7.46 Hz, 1H), 6.84 (d, J = 7.46 Hz, 1H),

7.17 (t, J = 7.63 Hz, 1H), 7.23-7.29 (m, 2H), 7.32 (s, 1H), 7.39 (d, J = 8.48 Hz , 2H), 7.61 (d, J = 8.81Hz, 2H), 8.76 (s, 1H), 8.94 (s, 1H); MS (ESI (+)) m / e 470 (M + H)⁺.

Example 22

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [3 - (trifluoromethyl) phenyl] urea by Example 20A and N- (3-fluorophenyl) -N '- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea, respectively, in Example 19. ¹H RmN (300 MHz, DmSOds) δ 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (s, 2H), 6.75-6.86 (m, 2H), 7.15 (m, 1H), 7.25-7.35 (m, 2H), 7.40 (d, J =

8.81 Hz, 2H), 7.52 (m, 1H), 7.62 (d, J = 8.48 Hz, 2H), 9.09 (s, 1H), 9.15 (s, 1H) ; MS (ESI (+)) m / e 474 (M + H)⁺.

Example 23

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 20A for Example 15F in Example 19. ¹H NMR (300 MHz, DMSO-d6) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.97 (s, 2H), 6.85 (d, J = 7.46 Hz, 1H), 7.28 (d, J = 7.12 Hz, 1H), 7.32 (d, J = 7.80 Hz, 1H), 7.41 (d, J = 8, 81 Hz, 2H), 7.58-7.66 (m, 3H), 8.06 (s, 1H), 8.06 (s, 1H), 9.18 (s, 1H), 9.32 ( s, 1H); MS (ESI (+)) m / e 524 (M + H)⁺.

Example 24

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- [2-fluoro-5- (trifluoromethyl) phenyl ]urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [3 - (trifluoromethyl) phenyl] urea per Example 20A and N- [2-fluoro-5 (trifluoromethyl) phenyl] -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl) phenyl] urea, respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d6) δ 2.80 (s, 3H), 3.00-3.50 (m, 8H), 3.95 (d, J = 2.37 Hz, 2H), 6 , 84 (d, J = 7.12 Hz, 1H),

7.28 (d, J = 7.12 Hz, 1H), 7.38-7.45 (m, 3H), 7.52 (m, 1H), 7.62 (d, J = 8.48 Hz , 2H), 8.64 (dd, J = 7.29, 2.20 Hz, 1H), 8.99 (d, J = 2.71 Hz, 1H), 9.38 (s, 1H); MS (ESI (+)) m / e 542 (M + H)⁺.

Example 25

N- (4- {3-amino-7 - [(4-methyl-1-piperazinyl) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [3 - (trifluoromethyl) phenyl] urea per Example 20A and N- (2-fluoro-5-methylphenyl) -N '[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) phenyl] urea, respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.79 (s, 3H), 3.00-3.50 (m, 8H), 3.96 (s, 2H) , 6.78-6.86 (m, 2H), 7.12 (dd, J = 11.36, 8.31 Hz, 1H), 7.27 (d, J = 7.46 Hz, 1H), 7.40 (d, J = 8.81 Hz, 2H), 7.60 (d, J = 8.48 Hz, 2H), 7.99 (dd, J = 7.97, 1.86 Hz, 1H ), 8.56 (d, J = 2.71Hz, 1H), 9.25 (s, 1H); MS (ESI (+)) m / e 488 (M + H)⁺.

ES 2 398 074 T3

Example 26

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

Example 26A

2,3-Difluoro-6-iodobenzonitrile

The desired product was prepared by substituting 1,2-difluoro-4-iodobenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C.

Example 26B

4- (4-aminophenyl) -7-fluoro-1H-indazol-3-amine

The desired product was prepared by substituting Example 15E for Example 26A in Examples 15F-G. MS (ESI (+)) m / e 243 (M + H)⁺.

Example 26C

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 26B and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J = 7.80, 4.07 Hz, 1H), 7.13 (dd, J = 11.19, 7.80 Hz, 1H) , 7.16 (m, 1H), 7.25 (t, J = 7.97 Hz, 1H), 7.34 (m, 1H), 7.38 (d, J = 8.48 Hz, 2H) , 7.59 (d, J = 8.48 Hz, 2H), 7.88 (t, J = 2.03 Hz, 1H), 8.91 (s, 1H), 8.94 (s, 1H) ; MS (ESI (+)) m / e 440, 442 (M + H)⁺.

Example 27

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 26B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 6.74 (dd, J = 7.80, 4.07 Hz, 1H), 7.03 (td, J = 4.41, 2.37 Hz, 1H) , 7.13 (dd, J = 11.19, 7.80 Hz, 1H), 7.27-7.35 (m, 2H), 7.38 (d, J = 8.48 Hz, 2H), 7.59 (d, J = 8.48Hz, 2H), 7.74 (m, 1H), 8.92 (s, 1H), 8.96 (s, 1H); MS (ESI (+)) m / e 396 (M + H)⁺.

Example 28

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 26B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 6.75 (dd, J = 7.80, 4.07 Hz, 1H), 7.14 (dd, J = 11.19, 7.80 Hz, 1H) , 7.32 (d, J = 7.46 Hz, 1H), 7.39 (d, J = 8.48 Hz, 2H), 7.53 (t, J = 7.80 Hz, 1H), 7 , 61 (m, 3H), 8.04 (s, 1H), 8.98 (s, 1H), 9.14 (s, 1H); MS (ESI (-)) m / e 615 (MH) -.

Example 29

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 26B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 6.75 (dd, J = 7.80, 4.41 Hz, 1H), 6.80 (d, J = 7, 46 Hz, 1H), 7.15 (m, 2H), 7.25 (m, 1H), 7.32 (s, 1H), 7.37 (d, J = 8.48 Hz, 2H), 7 , 59 (d, J = 8.48Hz, 2H), 8.66 (s, 1H), 8.82 (s, 1H); MS (ESI (+)) m / e 376 (M + H)⁺.

Example 30

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-cyanophenyl) urea

The desired product was prepared as the trifluoroacetate salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 26B and 3-isocyanatobenzonitrile, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 6.73 (dd, J = 7.80, 4.41 Hz, 1H), 7.12 (dd, J = 11.19, 7.80 Hz, 1H) , 7.39 (d, J = 8.81 Hz, 2H), 7.43

ES 2 398 074 T3 (dt, J = 7.71, 1.40 Hz, 1H), 7.51 (t, J = 7.97 Hz, 1H), 7.60 (d, J = 8.48 Hz , 2H), 7.70 (ddd, J = 8.22, 2.29, 1.36 Hz, 1H), 8.00 (t, J = 1.70 Hz, 1H), 9.00 (s, 1H), 9.09 (s, 1H); MS (ESI (+)) m / e 387 (M + H)⁺.

Example 31

N- (4- {3-amino-7 - [(dimethylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 31 A

7 - [(dimethylamino) methyl] -4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting N, N-dimethylamine for morpholine in Examples 15E-F. MS (ESI (+)) m / e 317 (M + H)⁺.

Example 31B

N- (4- {3-amino-7 - [(dimethylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [ 3- (trifluoromethyl) phenyl] urea per Example 31A and N- (2-fluoro-5-methylphenyl) -N '[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) phenyl] urea, respectively, in Example 19. ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.82 (s, 6H), 4.51 (s, 2H), 6.82 (m, 1H), 6.91 (d, J = 7.12 Hz, 1H), 7.12 (dd, J = 11.53, 8.48 Hz, 1H), 7.43 (d, J = 8.81 Hz, 2H), 7 , 43 (d, J = 6.78 Hz, 1H), 7.62 (d, J = 6.44 Hz, 2H), 7.99 (dd, J = 7.80, 2.03 Hz, 1H) , 8.56 (d, J = 2.71Hz, 1H), 9.26 (s, 1H); MS (ESI (+)) m / e 433 (M + H)⁺; Anal. calc. for C24H2₅FN6O-2,3CFaCO2H: C, 49.44; H, 3.96; H, 12.10. Found: C, 49.51; H, 3.78; N, 12.31.

Example 32

N- (4- {3-amino-7 - [(dimethylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15F and N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [ 3- (trifluoromethyl) phenyl] urea per Example 31A and N- (3-chlorophenyl) -N '- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ] urea, respectively, in Example 19. ¹H NMR (300 MHz, DmSOda) δ 2.82 (s, 6H), 4.50 (s, 2H), 6.91 (d, J = 7.12 Hz, 1H), 7.03 (m, 1H ), 7.28-7.36 (m, 2H), 7.40-7.45 (m, 3H), 7.63 (d, J = 8.82 Hz, 2H), 7.74 (m, 1H), 9.07 (s, 1H), 9.09 (s, 1H); MS (ESI (+)) m / e 435 (M + H)⁺; Anal. calc. for C23H23ClN6O-2,2CFaCO2H: C, 47.99; H, 3.70; N, 12.25. Found: C, 48.01; H, 3.41; N, 12.52.

Example 33

N- (4- {3-amino-7 - [(dimethylamino) methyl] -1H-indazol-4-yl} phenyl) -N'-3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15F for Example 31A in Example 19. ¹H NMR (300 MHz, DMSO-d6) δ 2.82 (s, 6H), 4.50 (s, 2H), 6.91 (d, J = 7.46 Hz, 1H), 7.33 (d , J = 7.46 Hz, 1H), 7.43 (d, J = 8.48 Hz, 2H), 7.43 (d, J = 7.46 Hz, 1H), 7.53 (t, J = 7.80 Hz, 1H), 7.61 (d, J = 8.82 Hz, 1H), 7.65 (d, J = 8.48 Hz, 2H), 8.06 (s, 1H), 9.13 (s, 1H), 9.26 (s, 1H); MS (ESI (+)) m / e 469 (M + H)⁺.

Example 34

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 34A

4-iodo-1-methyl-1H-indazol-3-amine

The desired product was prepared by substituting hydrazine hydrate for N-methylhydrazine in Example 1A. MS (ESI (+)) m / e 274 (M + H)⁺.

Example 34B

4- (4-aminophenyl) -1-methyl-1H-indazol-3-amine

The desired product was prepared by substituting Example 34A for Example 1A and 1B and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, respectively, in Example 1C. MS (ESI (+)) m / e 239 (M + H)⁺.

Example 34C

ES 2 398 074 T3

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-isocyanato-3-methylbenzene and Example 34B, respectively, in Example 15H. The resulting product was purified by flash column chromatography on silica gel with 5-8% methanol / dichloromethane to provide the desired product. MS (ESI (+)) m / e 372 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.79 (s, 3H), 4.39 (s, 2H), 6.79 (dd, J = 6.10, 1.70 Hz, 2H), 7.17 (t, J = 7.80 Hz, 1H), 7.24-7.40 (m, 6H), 7.59 (d, J = 8.48 Hz, 2H), 8.64 (s, 1H), 8.80 (s, 1H).

Example 35

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N'-phenylurea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for isocyanatobenzene and Example 34B, respectively, in Example 15H. MS (ESI (+)) m / e 372 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 6.80 (dd, J = 6.55, 0.94 Hz, 1H), 6.98 (t, J = 7, 49 Hz, 1H), 7.39 (d, J = 8.42 Hz, 2H), 7.28-7.36 (m, 4H), 7.47 (d, J = 7.49 Hz, 2H) , 7.59 (d, J = 8.42Hz, 2H), 8.70 (s, 1H), 8.80 (s, 1H).

Example 36

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (2-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-isocyanato-2-methylbenzene and Example 34B, respectively, in Example 15H. MS (ESI (+)) m / e 372 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.79 (s, 3H), 4.38 (s, 2H), 6.80 (d, J = 6.55 Hz , 1 HOUR),

6.96 (t, J = 7.96 Hz, 1H), 7.16 (t, J = 7.18 Hz, 1H), 7.19 (d, J = 7.49 Hz, 1H), 7, 30-7.36 (m, 2H), 7.39 (d, J = 8.42 Hz, 2H), 7.60 (d, J = 6.55 Hz, 2H), 7.84 (d, J = 7.18 Hz, 1H), 7.97 (s, 1H), 9.15 (s, 1H).

Example 37

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (4-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-isocyanato-4-methylbenzene and Example 34B, respectively, in Example 15H. MS (ESI (+)) m / e 372 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.25 (s, 3H), 3.79 (s, 3H), 6.80 (dd, J = 6.55,1.25 Hz, 1H), 7 , 10 (d, J = 8.11 Hz, 2H), 7.30-7.39 (m, 6H), 7.58 (d, J = 8.42 Hz, 2H), 8.59 (s, 1H), 8.76 (s, 1H).

Example 38

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (3-methoxyphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-isocyanate-3-methoxybenzene and Example 34B, respectively, in Example 15H. MS (ESI (+)) m / e 388 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.74 (s, 3H), 3.80 (s, 3H), 6.57 (dd, J = 8.11, 2.50 Hz, 1H), 6 .82 (dd, J = 6.71, 1.09 Hz, 1H), 6.96 (dd, J = 7.96, 1.09 Hz, 1H), 7.19 (t, J = 8.11 Hz, 1H), 7.21 (t, J = 2.18 Hz, 1H), 7.32-

7.40 (m, 4H), 7.59 (d, J = 8.42 Hz, 2H), 8.73 (s, 1H), 8.81 (s, 1H).

Example 39

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 34B for Example 15G in Example 15H. MS (ESI (+)) m / e 376 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.37 (s, 2H), 6.77-

6.81 (m, 1H), 6.80 (dd, J = 6.55, 1.25 Hz, 1H), 7.14 (dd, J = 8.11, 1.25 Hz, 1H), 7 , 29-7.36 (m, 3H), 7.40 (d, J = 8.42 Hz, 2H), 7.51 (dt, J = 11.85, 2.18 Hz, 1H), 7, 59 (d, J = 8.42 Hz, 2H), 8.87 (s, 1H), 8.94 (s, 1H).

Example 40

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-chloro-3-isocyanatobenzene and Example 34B, respectively, in Example 15H. MS (ESI (+)) m / e 376 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.22-4.56 (sa, 2H), 6.80 (dd, J = 6.55, 1.25 Hz, 1H), 7.03 (dt, J = 6.63, 2.14 Hz, 1H), 7.28-7.36 (m, 4H), 7.40 (d, J = 8.42 Hz, 2H ), 7.60 (d, J = 8.42 Hz, 2H), 7.73 (s, 1H),

8.89 (s, 1H), 8.93 (s, 1H).

ES 2 398 074 T3

Example 41

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-bromo-3-isocyanatobenzene and Example 34B, respectively, in Example 15H. MS (ESl (+)) m / e 384, 386 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.79 (s, 3H), 4.40 (s, 2H), 6.80 (dd, J = 6.71, 1.09 Hz, 1H),

7.16 (d, J = 8.11 Hz, 1H), 7.25 (t, J = 7.96 Hz, 1H), 7.30-7.36 (m, 3H), 7.39 (d , J = 8.42 Hz, 2H), 7.59 (d, J = 8.42 Hz, 2H), 7.88 (t, J = 1.87 Hz, 1H), 8.89 (s, 1H ), 8.91 (s, 1H).

Example 42

N- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-isocyanate-3- (trifluoromethyl) benzene and Example 34B, respectively, in Example 15H. MS (ESl (+)) m / e 426 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.80 (s, 3H), 6.81 (dd, J = 6.71, 1.09 Hz, 1H), 7.31-7.37 (m, 3H), 7.40 (d, J = 8.42 Hz, 2H), 7.53 (t, J = 7.80 Hz, 1H), 7.60 (d, J = 9.05 Hz, 1H) , 7.61 (d, J = 8.73Hz, 2H), 8.03 (s, 1H), 8.94 (s, 1H), 9.10 (s, 1H).

Example 43

N [4- (3-amino-1-methyl-1H-imidazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-3-isocyanatobenzene and Example 15G for 1-fluoro-2-isocyanato-4-methylbenzene and Example 34B, respectively, in Example 15H. MS (ESl (+)) m / e 390 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.80 (s, 3H), 6.81 (d, J = 5.93 Hz, 2H), 7.11 (dd , J = 11.39, 8.27 Hz, 1H), 7.31-7.37 (m, 2H), 7.40 (d, J = 8.73 Hz, 2H), 7.59 (d, J = 8.42 Hz, 2H), 8.00 (dd, J = 7.64, 1.72 Hz, 1H), 8.52 (d, J = 2.50 Hz, 1H), 9.20 ( s, 1H).

Example 44

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] N '- (3-methylphenyl) urea

Example 44A

N- (4-bromo-2-fluorophenyl) -N '- (3-methylphenyl) urea

A 0 ° C solution of 4-bromo-2-fluoroaniline (1 g, 5.26 mmol) in dichloromethane (10 ml) was treated dropwise with 1-isocyanate-3-methylbenzene (0.71 ml, 5.26 mmol ), warmed to room temperature, stirred for 18 hours, and filtered. The filter cake was washed with dichloromethane and dried to provide 0.62 g of the desired product. MS (ESl ()) m / e 321 (MH) -.

Example 44B

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-methylphenyl) urea

A mixture of Example 44A (100 mg, 0.31 mmol), bis (pinacholate) diboron (86 mg, 0.33 mmol), Pd (dppf) Cl2 (10 mg), and potassium acetate (270 mg) in DMF (3 ml) was heated at 80 ° C for 2 hours, treated with Example 1A (64 mg, 0.24 mmol), Pd (dppf) Cl2 (6 mg), Na2CO3 (78 mg) and water (1 ml), heated at 80 ° C for 18 hours, cooled to room temperature, and concentrated. The concentrate was purified by preparative HPLC using the conditions described in Example 15H to provide 27 mg of the desired product as the trifluoroacetate salt. MS (ESl (+)) m / e 376 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (d, J = 7.12 Hz, 3H), 6.82 (d, J = 6.78 Hz, 1H), 6.86 (t, J = 3.90 Hz, 1H), 7.18 (t, J = 7.63 Hz, 1H), 7.26 (d, J = 8.48 Hz, 2H), 7.31-7.34 (m , 3H), 7.37 (dd, J = 12.21,

1.70 Hz, 1H), 8.30 (t, J = 8.65 Hz, 1H), 8.66 (d, J = 2.37 Hz, 1H), 9.05 (s, 1H).

Example 45

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-3-isocyanatobenzene in Examples 44A-B. MS (ESl (+)) m / e 380 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ

6.82 (td, J = 8.42, 1.87 Hz, 1H), 6.86 (t, J = 3.90 Hz, 1H), 7.12 (dd, J = 8.11, 1, 25 Hz, 1H), 7.28 (dd, J = 8.27, 1.72 Hz, 1H), 7.32 (m, 3H), 7.38 (dd, J = 12.01, 2.03 Hz, 1H), 7.53 (dt, J = 11.55, 2.18 Hz, 1H), 8.26 (t, J = 8.42 Hz, 1H),

8.72 (d, J = 2.18Hz, 1H), 9.33 (s, 1H).

ES 2 398 074 T3

Example 46

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3,5-dimethylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-3,5-dimethylbenzene in Examples 44A-B. MS (ESI (+)) m / e 390 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ

2.25 (s, 6H), 6.65 (s, 1H), 6.85 (t, J = 3.90 Hz, 1H), 7.10 (bs, 2H), 7.26 (d, J = 8.42 Hz, 1H), 7.30 (d, J = 4.06 Hz, 2H), 7.36 (dd, J = 12.32, 1.72 Hz, 1H), 8.29 (t , J = 8.42 Hz, 1H), 8.63 (d, J = 2.50 Hz, 1H), 8.96 (s, 1H).

Example 47

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-ethylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-3-ethylbenzene in Examples 44A-B. MS (ESI (+)) m / e 390 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J = 7.49 Hz, 3H), 2.59 (c, J = 7.80 Hz, 2H), 6.85-6.87 (m, 2H), 7.21 (t, J = 7.80 Hz, 1H), 7.28 (m, J = 4.06 Hz, 2H),

7.31 (bs, 1H), 7.32 (bs, 1H), 7.34 (bs, 1H), 7.37 (dd, J = 12.17, 1.87 Hz, 1H), 8.30 (t, J = 8.42 Hz, 1H), 8.64 (d, J =

2.18 Hz, 1H), 9.06 (s, 1H).

Example 48

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-chloro-4-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-fluoro-4-isocyanatobenzene for 2-chloro-1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI (+)) m / e 414 (M + H)⁺; ¹H NMR (500 MHz, DMSOda) δ 6.83 (dd, J = 4.68, 3.12 Hz, 1H), 7.24-7.40 (m, 6H), 7.84 (dd, J = 6.55, 2.50 Hz, 1H), 8.23 ​​(t, J = 8.58 Hz, 1H),

8.71 (s, 1H), 9.28 (s, 1H).

Example 49

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-fluoro-4-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 2-fluoro-4-isocyanato-1-methylbenzene for 1-isocyanato-3-methylbenzene in Examples 44A-B. MS (ESI (+)) m / e 394 (M + H)⁺; ¹H NMR (500 MHz, DMSOde) δ 2.18 (s, 3H), 6.85 (m, 1H), 7.03 (dd, J = 8.11, 1.87 Hz, 1H), 7.19 (t, J = 8.58 Hz, 1H), 7.27 (dd, J = 8.27, 1.72 Hz, 1H), 7.30 (bs, 1H), 7.31 (s, 1H) , 7.37 (dd, J = 12.17, 2.18 Hz, 1H), 7.46 (dd, J = 12.48, 2.18 Hz, 1H), 8.26 (t, J =

8.58 Hz, 1H), 8.67 (d, J = 2.18 Hz, 1H), 9.20 (s, 1H).

Example 50

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 1-isocyanato-3-methylbenzene for 1-chloro-3-isocyanatobenzene in Examples 44A-B. MS (ESI (-)) m / e 394 (MH) -;¹H NMR (500 MHz, DMSO-d6) δ 6.85 (t, J = 3.84 Hz, 1H), 7.05 (d, J = 7.80, 1H), 7.26-7.35 ( m, 5H), 7.38 (dd, J = 12.17, 1.87 Hz, 1H), 7.75 (t, J = 2.03 Hz, 1H), 8.25 (t, J = 8 , 42Hz, 1H), 8.72 (d, J = 2.18Hz, 1H), 9.30 (s, 1H).

Example 51

N- [4- (3-amino-7-bromo-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting 3-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile in Examples 1A-C. MS (ESI (-)) m / e 434, 436 (MH) -;¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.46 (s, 2H), 6.73 (d, J = 7.46 Hz, 1H), 6.80 (d , J = 6.78 Hz, 1H), 7.17 (t, J = 7.63 Hz, 1H), 7.24-7.32 (m, 2H), 7.39 (d, J = 8, 48Hz, 2H), 7.50 (d, J = 7.80Hz, 1H), 7.60 (d, J = 8.14Hz, 2H), 8.64 (s, 1H), 8.82 (s, 1H), 12.08 (s, 1H).

Example 52

N- {4- [3-amino-1- (2-hydroxyethyl) -1H-indazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared by substituting 2-hydrazinoethanol for hydrazine hydrate in Examples 1A-C. MS (ESI (+)) m / e 402 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.74 (t, J = 5.76 Hz, 2H), 4.20 (t, J = 5.59 Hz, 2H ), 6.79 (d, J = 6.78 Hz, 1H), 6.80 (d, J = 7.12 Hz, 1H), 7.17 (t, J = 7.63 Hz, 1H), 7.23-7.40 (m, 6H), 7.59 (d, J =

8.81 Hz, 2H), 8.65 (s, 1H), 8.80 (s, 1H).

ES 2 398 074 T3

Example 53

2- [4- (3-amino-1H-indazol-4-yl) phenyl-N-phenylacetamide

Example 53A

Methyl [4- (3-amino-1H-indazol-4-yl) phenylacetate

The desired product was prepared by substituting methyl (4-bromophenyl) acetate and K3PO4 for Example 44A and Na2CO3, respectively, in Example 44B. Furthermore, the reaction was carried out under anhydrous conditions. MS (ESI (+)) m / e 304 (M + H)⁺.

Example 53B [4- (3-amino-1H-indazol-4-yl) phenylacetic acid

A solution of Example 53A (140 mg) in 1: 1 methanol / 10% NaOH (1 ml) was stirred at room temperature for 2 hours and adjusted to pH 3 with 10% HCl. The resulting precipitate was collected by filtration to provide 108 mg of the desired product. MS (ESI (+)) m / e 268 (M + H)⁺.

Example 53C

2- [4- (3-amino-1H-indazol-4-yl) phenyl-N-phenylacetamide

A mixture of Example 53B (40 mg, 015 mmol), diisopropylethylamine (0.078 ml, 0.45 mmol), TBTU (57 mg, 0.18 mmol) and aniline in THF (1 ml) was stirred for 18 hours at room temperature and concentrated. The residue was purified by preparative HPLC using the conditions described in Example 15H to provide 15 mg of the desired product as the trifluoroacetate salt. MS (ESI (+)) m / e 343 (M + H)⁺; ¹H RmN (300 MHz, DMSO-d6) δ 3.74 (s, 2H), 6.84 (dd, J = 5.09, 3.05 Hz, 1H), 7.02-7.07 (m, 1H), 7.28-7.33 (m, 4H), 7.43-7.50 (m, 4H),

7.62 (d, J = 7.80Hz, 2H).

Example 54

2- [4- (3-amino-1H-indazol-4-yl) phenyl-N- (3-chlorophenyl) acetamide

The desired product was prepared as the trifluoroacetate salt by substituting 3-chloroaniline for aniline in Example 53C. MS (ESI (+)) m / e 377 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.75 (s, 1H), 6.84 (dd, J = 5.30, 2.50 Hz, 1H), 7.11 (dd, J = 7, 96, 2.03 Hz, 1H), 7.31-7.36 (m, 3H), 7.44-7.49 (m, 6H), 7.85 (d, J = 1.87 Hz, 1H ), 10.39 (s, 1H).

Example 55

2- [4- (3-amino-1H-indazol-4-yl) phenyl-N- (4-fluoro-3-methylphenyl) acetamide

The desired product was prepared as the trifluoroacetate salt by substituting 4-fluoro-3-ethylaniline for aniline in Example 53C. MS (ESI (+)) m / e 375 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.20 (d, J = 1.56 Hz, 3H), 3.71 (s, 2H), 6.84 (dd, J = 5.46, 2, 34 Hz, 1H), 7.07 (t, J = 9.20 Hz, 1H), 7.31 (s, 1H), 7.32 (d, J = 3.43 Hz, 1H), 7.40 -7.60 (m, 3H),

7.45 (d, J = 4.99Hz, 2H), 7.54 (dd, J = 7.02, 2.34Hz, 1H), 10.16 (s, 1H).

Example 56

2- [4- (3-amino-1H-indazol-4-yl) phenyl-N- [3- (trifluoromethyl) phenylacetamide

The desired product was prepared by substituting 3- (trifluoromethyl) aniline for aniline in Example 53C, then purifying the resulting product by flash column chromatography on silica gel with 58% methanol / dichloromethane. MS (ESI (+)) m / e 411 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 3.77 (s, 2H), 4.29 (s, 2H), 6.79 (dd, J = 4.41, 3.39 Hz, 1H), 7 , 27 (s, 1H), 7.28 (d, J = 1.36 Hz, 1H), 7.40-7.49 (m, 3H), 7.46 (d, J = 3.39 Hz, 2H), 7.56 (t, J = 7.63 Hz, 1H), 7.81 (d, J = 9.83 Hz, 1H), 5.14 (s, 1H), 10.57 (s, 1H), 11.74 (s, 1H).

Example 57

2- [4- (3-amino-1H-indazol-yl) phenyl-N- (3-methylphenyl) acetamide

The desired product was prepared as the trifluoroacetate salt by substituting 3-methylaniline for aniline in the

Example 53C. MS (ESI (+)) m / e 357 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.72 (s, 2H), 6.83 (dd, J =

4.75, 3.05 Hz, 1H), 6.86 (d, J = 7.46 Hz, 1H), 7.18 (t, J = 7.80 Hz, 1H), 7.30 (s, 1H), 7.32 (d, J = 2.03 Hz, 1H), 7.3933

ES 2 398 074 T3

7.49 (m, 6H), 10.13 (s, 1H).

Example 58

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 58A

2-fluoro-6-iodo-3-methoxybenzonitrile

The desired product was prepared by substituting 2-fluoro-4-iodo-1-methylbenzene for 2-fluoro-4-iodo-1-methoxybenzene in Examples 15A-C.

Example 58B

4- (4-aminophenyl) -7-methoxy-1H-indazol-3-amine

The desired product was prepared by substituting Example 15E for Example 58A in Examples 15F-G. MS (ESI (+)) m / e 290 (M + H)⁺.

Example 58C

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 58B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H, and then purifying the resulting product by flash column chromatography on silica gel. with 5-8% methanol / dichloromethane. MS (ESI (+)) m / e 388 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.92 (s, 3H), 4.30 (s, 2H), 6.69 (d, J = 7.80 Hz , 1H), 6.78 (d, J = 7.79 Hz, 1H), 6.80 (d, J = 7.46 Hz, 1H), 7.1.6 (t, J = 7.80 Hz , 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J = 8.48 Hz, 2H), 7.55 (d, J = 8.82 Hz , 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.86 (s, 1H).

Example 59

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 58B and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H, and then purifying the resulting product by chromatography Flash column on silica gel with 5-8% methanol / dichloromethane. MS (ESI (-)) m / e 458 (MH) -;¹H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.30 (s, 2H), 6.71 (d, J = 7.80 Hz, 1H), 6.79 (d , J = 7.80 Hz, 1H), 7.38 (d, J = 8.48 Hz, 2H), 7.41 (m, 1H), 7.50 (d, J = 10.85 Hz, 1H ), 7.58 (d, J = 8.82 Hz, 2H), 8.65 (dd, J = 7.46, 2.03 Hz, 1H), 8.95 (d, J = 2.71 Hz , 1H), 9.29 (s, 1H), 11.88 (s, 1H).

Example 60

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N'-phenylurea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 58B and isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 374 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.75 (d, J = 7.49 Hz, 1H), 6.84 (d, J = 7.80 Hz, 1H ), 6.98 (t, J = 7.33 Hz, 1H), 7.29 (t, J = 7.95 Hz, 2H), 7.36 (d, J = 8.74 Hz, 2H), 7.47 (d, J = 7.49 Hz, 2H), 7.57 (d, J = 8.42 Hz, 2H), 8.71 (s, 1H), 8.79 (s, 1H).

Example 61

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 58B and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 452 and 454 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.73 (d, J = 7.80 Hz, 1H), 6.82 (d, J =

7.80 Hz, 1H), 7.16 (d, J = 8.73 Hz, 1H), 7.25 (t, J = 8.11 Hz, 1H), 7.33 (d, J = 9, 36 Hz, 1H), 7.36 (d, J = 8.73 Hz, 2H),

7.56 (d, J = 8.74Hz, 2H), 7.88 (t, J = 1.87Hz, 1H), 8.87 (s, 1H), 8.92 (s, 1H).

Example 62

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-ethylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-334

ES 2 398 074 T3 isocyanatobenzene by Example 58B and 1-isocyanato-3-ethylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 402 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J = 7.64 Hz, 3H), 2.58 (c, J = 7.70 Hz, 2H), 3.94 (s, 3H ), 6.73 (d, J = 7.49 Hz, 1H), 6.82 (t, J = 7.80 Hz, 2H), 7.19 (t, J = 7.80 Hz, 1H), 7.27 (d, J = 7.80 Hz, 1H), 7.34 (s, 1H), 7.35 (d, J = 8.42 Hz, 2H), 7.56 (d, J = 8 , 42 Hz, 2H), 8.64 (s, 1H), 8.75 (s, 1H).

Example 63

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-fluoro-4-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 58B and 2-fluoro-4-isocyanate-1-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 406 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.17 (s, 3H), 3.94 (s, 3H), 6.75 (d, J = 7.49 Hz, 1H),

6.83 (d, J = 7.80 Hz, 1H), 7.05 (dd, J = 8.27, 2.03 Hz, 1H), 7.17 (t, J = 8.58 Hz, 1H ), 7.36 (d, J = 8.73 Hz, 2H), 7.45 (dd, J = 12.48, 1.87 Hz, 1H), 7.56 (d, J = 8.73 Hz , 2H), 8.82 (s, 1H), 8.83 (s, 1H).

Example 64

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 58B and 1-fluoro-4-isocyanate-2- (trifluoromethyl) benzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 460 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.95 (s, 3H), 6.79 (d, J = 7.80 Hz, 1H), 6.86 (d, J = 7.80 Hz, 1H ), 7.38 (d, J = 8.42 Hz, 2H), 7.44 (t, J = 9.67 Hz, 1H), 7.59 (d, J = 8.73 Hz, 2H), 7.67 (dt, J = 8.66, 3.78 Hz, 1H), 8.03 (dd, J = 6.40, 2.65 Hz, 1H), 9.01 (s, 1H), 9 , 17 (s, 1H).

Example 65

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 58B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 408 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.76 (d, J = 7.49 Hz, 1H), 6.84 (d, J = 7.80 Hz, 1H ), 7.02 (dt, J = 6.63, 2.14 Hz, 1H), 7.31 (m, 2H), 7.37 (d, J = 8.74 Hz, 2H), 7.57 (d, J = 8.42 Hz, 2H), 7.74 (m, 1H), 8.90 (s, 1H), 8.96 (s, 1H).

Example 66

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 58B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 442 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.76 (d, J = 7.80 Hz, 1H), 6.84 (d, J =

7.80 Hz, 1H), 7.32 (d, J = 7.80 Hz, 1H), 7.38 (d, J = 8.42 Hz, 2H), 7.52 (t, J = 7, 95Hz, 1H), 7.59 (d, J = 8.42Hz, 2H), 7.57-7.61 (m, 1H), 8.04 (s, 1H), 8.96 (s, 1H), 9.14 (s, 1H).

Example 67

N- [4- (3-amino-7-methoxy-1H-indazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 58B for Example 15G in Example 15H. MS (ESI (+)) m / e 392 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.94 (s, 3H), 6.77 (d, J = 7.80 Hz, 1H), 6.77-6.81 (m, 1H), 6 , 85 (d, J = 7.80 Hz, 1H), 7.14 (dd, J = 8.11, 0.94 Hz, 1H), 7.29-7.34 (m, 1H), 7, 37 (d, J =

8.73 Hz, 2H), 7.51 (dt, J = 11.93, 2.30 Hz, 1H), 7.57 (d, J = 8.73 Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).

Example 68

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-yl] phenyl} -N '- (3-methylphenyl) urea

Example 68A

2-fluoro-3-hydroxy-6-iodobenzonitrile

A -78 ° C solution of 2-fluoro-6-iodo-3-methoxybenzonitrile (1.48 mg, 0.53 mmol) in dichloromethane (5 ml) was treated dropwise with BBr3 (2.5 ml, 1 M in dichloromethane, 2.5 mmol), warmed to room temperature, stirred for 18 hours, poured into water and extracted with diethyl ether. The extract was dried (MgSO4), filtered and concentrated. The

ES 2 398 074 T3 residue was purified by flash column chromatography on silica gel with 20% ethyl acetate / hexanes to provide 110 mg of the desired product. MS (ESl (-)) m / e 262 (MH) -.

Example 68B

2-fluoro-6-iodo-3- (2-methoxyethoxy) benzonitrile

A mixture of Example 68A (104 mg, 0.39 mmol), 1-bromo-2-methoxyethane (0.088 ml) and K2CO3 (163 mg) in acetone (3 ml) was heated at 60 ° C for 18 hours, cooled at room temperature and partitioned between diethyl ether and water. The extract was dried (MgSO4), filtered, and concentrated to provide 122 mg of the desired product. MS (ESl (+)) m / e 334 (M + H)⁺.

Example 68C

4- (4-aminophenyl) -7- (2-methoxyethoxy) -1H-indazol-3-amine

The desired product was prepared by substituting Example 68B for Example 15E in Examples 15F-G. MS (ESl (+)) m / e 299 (M + H)⁺.

Example 68D

N- {4- [3-amino-7-2-methoxyethoxy-1H-indazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 68C and

1-isocyanato-3-methylbenzene, respectively, in Example 15, and then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol / dichloromethane. MS (ESl (+)) m / e 432 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.35 (s, 3H), 3.76 (dd, J = 5.09, 3.73 Hz, 2H), 4 , 27 (t, J = 3.05 Hz, 2H), 4.29 (s, 2H), 6.67 (d, J = 7.46 Hz, 1H), 6.79 (d, J = 7, 80 Hz, 2H), 7.16 (t, J = 7.63 Hz, 1H), 7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J = 8, 48Hz, 2H), 7.55 (d, J = 8.48Hz, 2H), 8.63 (s, 1H), 8.76 (s, 1H), 11.83 (s, 1H).

Example 69

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N'-phenylurea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 68C and isocyanatobenzene, respectively, in Example 15H. MS (ESl (+)) m / e 418 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.76 (t, J = 4.41 Hz, 2H), 4.30 (t, J = 4.75 Hz, 2H ), 6.74 (d, J = 7.80 Hz, 1H), 6.86 (d, J = 7.80 Hz, 1H), 6.98 (t, J = 7.29 Hz, 1H), 7.29 (t, J = 7.46 Hz, 2H), 7.36 (d, J = 8.82 Hz, 2H), 7.47 (d, J = 7.46 Hz, 2H), 7, 57 (d, J = 8.48Hz, 2H), 8.72 (s, 1H), 8.80 (s, 1H).

Example 70

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 68C for Example 15G in Example 15H. MS (ESl (+)) m / e 436 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.28-4.30 (m, 2H), 6.73 ( d, J = 7.80 Hz, 1H), 6.79 (td, J = 8.58, 2.18 Hz, 1H), 6.85 (d, J = 7.80 Hz, 1H), 7, 14 (dd, J = 8.27, 1.09 Hz, 1H), 7.31 (m, 1H), 7.37 (d, J = 8.74 Hz, 2H), 7.51 (dt, J = 11.93, 2.30 Hz, 1H), 7.57 (d, J = 8.42 Hz, 2H), 8.89 (s, 1H), 8.98 (s, 1H).

Example 71

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N '- (3-bromophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 68C and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. MS (ESl (+)) m / e 496 and 498 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.28-4.30 (m, 2H),

6.73 (d, J = 7.49 Hz, 1H), 6.84 (d, J = 7.80 Hz, 1H), 7.16 (d, J = 7.80 Hz, 1H), 7, 25 (t, J = 7.95 Hz, 1H), 7.33 (dd, J = 8.27, 1.09 Hz, 1H), 7.37 (d, J = 8.42 Hz, 2H), 7.57 (d, J = 8.42Hz, 2H), 7.88 (t, J = 1.87Hz, 1H), 8.87 (s, 1H), 8.92 (s, 1H).

Example 72

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-336

ES 2 398 074 T3 isocyanatobenzene from Example 68C and 1-chloro-3-isocyanatobenzene, respectively, from Example 15H. MS (ESI (+)) m / e 452 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.76 (t, J = 4.68 Hz, 2H), 4.29 (t, J = 4.68 Hz, 2H ), 6.74 (d, J = 7.80 Hz, 1H), 6.85 (d, J = 7.80 Hz, 1H), 7.02 (dt, J = 6.86,2.03 Hz , 1H), 7.30 (m, 2H), 7.37 (d, J =

8.42 Hz, 2H), 7.57 (d, J = 8.42 Hz, 2H), 7.73 (s, 1H), 8.89 (s, 1H), 8.95 (s, 1H) .

Example 73

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 68C and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 486 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.75-3.77 (m, 2H), 4.29-4.31 (m, 2H), 6.75 ( d, J = 7.80 Hz, 1H), 6.86 (d, J = 7.80 Hz, 1H), 7.32 (d, J = 8.11 Hz, 1H), 7.38 (d, J = 8.42 Hz, 2H), 7.52 (t, J = 7.95 Hz, 1H), 7.59 (d, J = 8.42 Hz, 2H), 7.58-7.61 ( m, 1H), 8.04 (s, 1H), 8.95 (s, 1H), 9.12 (s, 1H).

Example 74

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 68C and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 504 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.36 (s, 3H), 3.76 (t, J = 4.68 Hz, 2H),

4.29 (t, J = 4.68 Hz, 2H), 6.73 (d, J = 7.80 Hz, 1H), 6.85 (d, J = 7.80 Hz, 1H), 7, 39 (d, J = 8.74 Hz, 2H), 7.39-7.41 (m, 1H), 7.51 (m, 1H), 7.58 (d, J = 8.42 Hz, 2H ), 8.64 (dd, J = 7.18, 2.18 Hz, 1H), 8.93 (d, J = 2.81 Hz, 1H), 9.28 (s, 1H).

Example 75

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

Example 75A

2-fluoro-6-iodo-3- [2- (4-morpholinyl) ethoxy] benzonitrile

A mixture of Example 68A (250 mg, 0.95 mmol), 2- (4-morpholinyl) ethanol (0.19 ml) and triphenylphosphine on resin (630 mg, 3 mmol / g, 1.9 mmol) in THF ( 5 ml) was treated with DEAD (0.179 ml) and stirred at room temperature for approximately 18 hours. The mixture was filtered and the filtrate was concentrated. The residue was purified twice by flash column chromatography on silica gel, first eluting with 5% methanol / dichloromethane and then with 50% ethyl acetate / hexanes to provide 180 mg of the desired product. MS (ESI (+)) m / e 377 (M + H)⁺.

Example 75B

4- (4-aminophenyl) -7- [2- (4-morpholinyl) ethoxy] -1H-indazol-3-amine

The desired product was prepared by substituting Example 75A for Example 15E in Examples 15F-G. MS (ESI (+)) m / e 354 (M + H)⁺.

Example 75C

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H, and then purifying the resulting product by flash column chromatography on silica gel. with 5-8% methanol / dichloromethane. MS (ESI (+)) m / e 487 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.52-2.55 (m, 4H), 2.79 (t, J = 5.76 Hz, 2H), 3 , 57-3.60 (m, 4H),

4.26 (t, J = 5.76 Hz, 2H), 4.30 (s, 2H), 6.68 (d, J = 7.46 Hz, 1H), 6.80 (d, J = 7 , 80 Hz, 2H), 7.16 (t, J = 7.80 Hz, 1H),

7.25 (m, 1H), 7.31 (s, 1H), 7.34 (d, J = 8.48 Hz, 2H), 7.55 (d, J = 8.82 Hz, 2H), 8.64 (s, 1H), 8.77 (s, 1H), 11.81 (s, 1H).

Example 76

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N'-phenylurea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e

ES 2 398 074 T3

473 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.66 (m, 2H), 3.33-4.45 (ma, 8H), 4.54 (m, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.90 (d, J = 7.80 Hz, 1H), 6.98 (t, J = 7.33 Hz, 1H), 7.29 (t, J = 7, 80 Hz, 2H), 7.36 (d, J = 8.73 Hz, 2H), 7.48 (d, J = 7.49 Hz, 2H), 7.59 (d, J = 8.42 Hz , 2H), 8.86 (s, 1H), 8.95 (s, 1H).

Example 77

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 75B for Example 15G in Example 15H. MS (ESI (+)) m / e 491 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.66 (t, J = 4.37 Hz, 2H), 3.71 (ma, 8H), 4.53 (t, J = 4.99 Hz, 2H ), 6.75 (d, J = 7.80 Hz, 1H), 6.79 (td, J = 8.42,1.87 Hz, 1H), 6.89 (d, J = 7.80 Hz , 1 HOUR),

7.15 (dd, J = 8.27.1.09 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J = 8.74 Hz, 2H), 7.52 (dt , J = 12.09, 2.22 Hz, 1H), 7.58 (d, J =

8.74 Hz, 2H), 8.97 (s, 1H), 9.06 (s, 1H).

Example 78

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-bromophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 551 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.66 (t, J = 4.36 Hz, 2H), 3.30-4.32 (ma, 8H), 4.54 (t, J =

4.68 Hz, 2H), 6.75 (d, J = 7.49 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.16 (d, J = 8, 73 Hz, 1H), 7.25 (t, J = 7.95 Hz, 1H), 7.34-7.35 (m, 1H), 7.36 (d, J = 8.42 Hz, 2H) , 7.59 (d, J = 8.42 Hz, 2H), 7.89 (t, J = 1.87 Hz, 1H), 9.07 (s, 1H), 9.11 (s, 1H) .

Example 79

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-ethylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-ethyl-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 501 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J = 7.49 Hz, 3H), 2.58 (c, J = 7.49 Hz, 2H), 3.66 (m, 2H ), 3.31-4.01 (ma, 8H), 4.53 (m, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.83 (d, J = 7, 49 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.19 (t, J = 7.80 Hz, 1H), 7.27 (d, J = 8.42 Hz , 1H), 7.35 (m, J = 8.42 Hz, 3H), 7.58 (d, J = 8.73 Hz, 2H), 8.70 (s, 1H), 8.82 (s , 1 HOUR).

Example 80

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (-)) m / e 557 (MH);¹H NMR (500 MHz, DMSO-d6) δ 3.66 (t, J = 4.68 Hz, 2H), 3.32-4.20 (ma, 8H), 4.54 (t, J = 4, 68 Hz, 2H), 6.76 (d, J = 7.49 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.39 (d, J = 8.73 Hz , 2H), 7.41 (m, J = 4.06 Hz, 1H), 7.51 (t, J = 8.73 Hz, 1H), 7.59 (d, J = 8.73 Hz, 2H ), 8.64 (dd, J = 7.33, 2.03 Hz, 1H), 8.97 (d, J =

2.81 Hz, 1H), 9.34 (s, 1H).

Example 81

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-fluoro-4-isocyanate-2- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (-)) m / e 557 (MH);¹H NMR (500 MHz, DMSO-d6) δ 3.66 (m, 2H), 3.83 (m, 8H), 4.53 (m, 2H),

6.74 (d, J = 7.80 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.36 (d, J = 8.42 Hz, 2H), 7.45 ( t, J = 9.67 Hz, 1H), 7.59 (d, J = 8.73 Hz, 2H), 7.66 (dt, J = 8.74, 3.74 Hz, 1H), 8, 04 (dd, J = 6.40, 2.65 Hz, 1H), 9.08 (s, 1H), 9.25 (s, 1H).

Example 82

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 507 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.31-4.00 (ma, 8H), 3.65 (m, 2H), 4.53 (m, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.01 (td, J = 4.45, 2.03 Hz, 1H), 7.30 (d, J = 4.99 Hz, 2H), 7.35 (d, J = 8.42

ES 2 398 074 T3

Hz, 2H), 7.58 (d, J = 8.42 Hz, 2H), 7.73 (s, 1H), 9.10 (s, 1H), 9.15 (s, 1H).

Example 83

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (-)) m / e 539 (MH);¹H NMR (500 MHz, DMSO-d6) δ 3.66 (m, 2H), 3.32-4.11 (m, 8H), 4.54 (m, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.31 (d, J = 7.80 Hz, 1H), 7.37 (d, J = 8, 42 Hz, 2H), 7.52 (s, 1H), 7.61 (d, J = 8.42 Hz, 2H), 7.62 (m, 1H), 8.06 (s, 1H), 9 , 18 (s, 1H), 9.36 (s, 1H).

Example 84 (2E) -3- {3-amino-4- [4 - ({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} -N, N-dimethylacrylamide

Example 84A

7-bromo-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting 4-bromo-2-fluoro-6-iodobenzonitrile for 2-fluoro-6-iodobenzonitrile in Example 1A.

Example 84B

7-bromo-4- (4-nitrophenyl) -1H-indazol-3-amine

The desired product was prepared by substituting Example 1A and Example 1B for Example 84A and 4-nitrophenylboronic acid, respectively, in Example 1C. MS (ESI (+)) m / e 333, 335 (M + H)⁺.

Example 84C (2E) -3- [3-amino-4- (4-nitrophenyl) -1H-indazol-7-yl] -N, N-dimethylacrylamide

A mixture of Example 84B (165 mg), N, N-dimethylacrylamide (0.102 ml), triethylamine (0.207 ml) and Pd (o-tol3P) 2Cl2 (30 mg) in THF (2 ml) in a sealed tube was heated in a Smith Synthesizer microwave oven (300 W) at 150 ° C and concentrated. The residue was purified by flash column chromatography on silica gel with 3% methanol / dichloromethane to provide 163 mg of the desired product. MS (ESI (+)) m / e 352 (M + H)⁺.

Example 84D (2E) -3- [3-amino-4- (4-aminophenyl) -1H-indazol-7-yl] -N, N-dimethylacrylamide

A solution of Example 84C (113 mg, 0.32 mmol) in a mixture of ethanol (1 ml), methanol (1 ml) and THF (1 ml) was treated with iron powder (144 mg) and NH4Cl (17 mg ), heated at 85 ° C for 4 hours, cooled to room temperature and filtered. The filtrate was partitioned between water and ethyl acetate and the organic phase was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol / dichloromethane to provide 75 mg of the desired product. MS (ESI (+)) m / e 322 (M + H)⁺.

Example 84E (2E) -3- {3-amino-4- [4 - ({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazole-7-y} -N, N-dimethylacrylamide

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 84D and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 455 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.97 (s, 3H), 3.21 (s, 3H), 6.80 (d, J = 8.14 Hz , 1H), 6.86 (d, J = 7.46 Hz, 1H), 7.17 (m, 1H), 7.24 (m, 2H), 7.32 (s, 1H), 7.41 (d, J = 8.82 Hz, 2H), 7.61 (d, J =

8.81 Hz, 2H), 7.70 (d, J = 7.80 Hz, 1H), 7.85 (d, J = 15.60 Hz, 1H), 8.65 (s, 1H), 8 , 83 (s, 1H).

Example 85 (2E) -3- {3-amino-4- [4 - ({[(3-chlorophenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} -N, N-dimethylacrylamide

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 84D and

1-chloro-3-isocyanatobenzene, respectively, in Example 15H, and then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol / dichloromethane. MS (ESI (+)) m / e 475

ES 2 398 074 T3 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 3.21 (s, 3H), 4.44 (s, 2H), 6.86 (d, J = 7.46 Hz , 1H), 7.01-7.06 (m, 1H), 7.23 (d, J = 15.60 Hz, 1H), 7.30-7.32 (m, 2H), 7.43 ( d, J = 8.48 Hz, 2H), 7.61 (d, J = 8.82 Hz, 2H), 7.70 (d, J = 7.46 Hz, 1H), 7.74 (m, 1H), 7.85 (d, J = 15.60 Hz, 1H), 8.96 (s, 1H), 8.98 (s, 1H), 12.17 (s, 1H).

Example 86 (2E) -3- (3-amino-4- {4 - [({[3- (trifluoromethyl) phenylamino} carbonyl) aminolphenyl} -1H-indazol-7-yl) -N, N-dimethylacrylamide

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 84D and

1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H, and then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol / dichloromethane. MS (ESI (-)) m / e 507 (MH) -;¹H NMR (300 MHz, DMSO-d6) δ 2.97 (s, 3H), 3.21 (s, 3H), 4.44 (s, 2H), 6.86 (d, J = 7.12 Hz , 1H), 7.23 (d, J = 15.60 Hz, 1H), 7.32 (d, J = 7.80 Hz, 1H), 7.43 (d, J = 8.48 Hz, 2H ), 7.53 (t, J = 7.97 Hz, 1H), 7.59 (s, 1H), 7.63 (d, J = 8.81 Hz, 2H), 7.70 (d, J = 7.80 Hz, 1H), 7.85 (d, J = 15.26 Hz, 1H), 8.04 (s, 1H), 8.99 (s, 1H), 9.13 (s, 1H ), 12.17 (s, 1H).

Example 87

N- (4- {3-amino-7- [2- (dimethylamino) ethoxyl-1H-indazol-4-yl} phenyl) -N'-phenylurea

Example 87A

4- (4-aminophenyl) -7- [2- (dimethylamino) ethoxyl-1H-indazol-3-amine

The desired product was prepared by substituting 2- (4-morpholinyl) ethanol for 2- (dimethylamino) ethanol in Example 75A-B. MS (ESI (+)) m / e 312 (M + H)⁺.

Example 87B

N- (4- {3-amino-7- [2- (dimethylamino) ethoxyl-1H-indazol-4-yl} phenyl) -N'-phenylurea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 87A and isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 431 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 6H), 3.61 (sa, 2H), 4.49 (m, 2H), 6.77 (d, J = 7.63 Hz , 1 HOUR),

6.90 (d, J = 7.63 Hz, 1H), 6.98 (t, J = 7.32 Hz, 1H), 7.29 (t, J = 7.93 Hz, 2H), 7, 36 (d, J = 8.54 Hz, 2H), 7.48 (d, J =

7.93Hz, 2H), 7.59 (d, J = 8.54Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).

Example 88

N- (4- {3-amino-7- [2- (dimethylamino) ethoxyl-1H-indazol-4-yl} phenyl) -N '- (3-bromophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 87A and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 509 and 511 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 6H), 3.61 (s, 2H), 4.50 (m, 2H), 6.77 (d, J =

7.63 Hz, 1H), 6.90 (d, J = 7.63 Hz, 1H), 7.16 (d, J = 8.85 Hz, 1H), 7.25 (t, J = 8, 09 Hz, 1H), 7.35 (m, J = 10.68 Hz, 1H), 7.37 (d, J = 8.54 Hz, 2H), 7.60 (d, J = 8.54 Hz , 2H), 7.90 (t, J = 1.83 Hz, 1H), 9.17 (s, 1H), 9.21 (s, 1H).

Example 89

N- (4- {3-amino-7- [2- (dimethylamino) ethoxyl-1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 87A and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 445 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.95 (s, 6H), 3.61 (sa, 2H), 4.50 (m, 2H), 6.77 (d, J = 7.63 Hz, 1H), 6.80 (d, J = 7.32 Hz, 1H), 6.90 (d, J = 7.63 Hz, 1H), 7.16 (t , J = 7.78 Hz, 1H), 7.26 (d, J = 8.54 Hz, 1H), 7.33 (s, 1H), 7.36 (d, J = 8.54 Hz, 2H ), 7.59 (d, J = 8.54 Hz, 2H), 8.81 (s, 1H), 8.97 (s, 1H).

Example 90

N- (4- {3-amino-7- [2- (dimethylamino) ethoxyl-1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 87A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (-)) m / e 463 (MH) -;¹H NMR (500 MHz, DMSO-d6) δ 2.95 (s, 6H), 3.61 (bs, 2H), 4.50 (m, 2H), 6.77 (d, J = 7.63

Hz, 1H), 6.90 (d, J = 7.93 Hz, 1H), 7.02 (td, J = 4.42, 2.14 Hz, 1H), 7.31 (m, 2H), 7.37 (d, J = 8.85 Hz, 2H), 7.60 (d, J

ES 2 398 074 T3 = 8.54 Hz, 2H), 7.75 (s, 1H), 9.14 (s, 1H), 9.20 (s, 1H).

Example 91

N- (4- {3-amino-7- [2- (2-oxo-1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

Example 91A

1- (2 - {[3-amino-4- (4-aminophenyl) -1H-indazol-7-yl] oxy} ethyl) -2-pyrrolidinone

The desired product was prepared by substituting 1- (2-hydroxyethyl) -2-pyrrolidinone for 2- (4-morpholinyl) ethanol in Example 75A-B. MS (ESI (+)) m / e 352 (M + H)⁺.

Example 91B

N- (4- {3-amino-7- [2- (2-oxo-1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 91A and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 485 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 1.93 (m, 2H), 2.24 (t, J = 8.14 Hz, 2H), 2.29 (s, 3H), 3.55 (m , 2H), 3.62 (m, 2H), 4.27 (t, J = 5.43 Hz, 2H), 6.73 (d, J = 7.80 Hz, 1H), 6.80 (d , J = 7.12 Hz, 1H), 6.86 (d, J = 7.80 Hz, 1H), 7.16 (t, J = 7.80 Hz, 1H), 7.25 (m, 1H ), 7.32 (s, 1H), 7.35 (d, J = 8.48 Hz, 2H), 7.56 (d, J = 8.48 Hz, 2H), 8.64 (s, 1H ), 8.78 (s, 1H).

Example 92

2- [4- (3-amino-1-methyl-1H-indazol-4-yl) phenyl] -N- (3-methylphenyl) acetamide

The desired product was prepared by substituting Example 1A and Example 1B for Example 34A and 2- [4- (4,4,5,5-tetramethyl- [1,3,2] dioxaborolan-2-yl) -phenyl] -Nm -tolyl-acetamide, respectively, in Example 53C. The crude product was purified by preparative HPLC using the conditions described in Example 3 to provide the desired product as the trifluoroacetate salt. MS (ESI (+)) m / e 371 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.27 (s, 3H), 3.72 (s, 2H), 3.80 (s, 3H), 6.82 (dd, J = 6.61, 1.19 Hz, 1H), 6.86 (d, J = 7.46 Hz, 1H),

7.18 (t, J = 7.80 Hz, 1H), 7.31-7.48 (m, 8H), 10.13 (s, 1H).

Example 93

N- [4- (3-amino-1H-indazol-4-yl) -2-methylphenyl] -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting 4-bromo-2-fluoroaniline for 4-bromo-

2-methylaniline in Example 44A-B. MS (ESI (-)) m / e 370 (MH) -;¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.33 (s, 3H), 6.80 (d, J = 7.46 Hz, 1H), 6.85 (dd , J = 6.10, 1.70 Hz, 1H), 7.17 (t, J = 7.80 Hz, 1H), 7.25-7.34 (m, 6H), 8.03 (m, 2H), 9.03 (s, 1H).

Example 94

N- (4- {3-amino-7- [2- (2-oxo-1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl-N'-3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 91A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 505 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 1.93 (m, 2H), 2.24 (t, J = 8.14 Hz, 2H), 3.55 (m, 2H), 3.62 (t , J = 5.43 Hz, 2H), 4.27 (t, J = 5.59 Hz, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.87 (d, J = 8.14 Hz, 1H), 7.03 (dt, J = 6.53,

2.33 Hz, 1H), 7.30 (s, 1H), 7.31 (d, J = 3.73 Hz, 1H), 7.37 (d, J = 8.48 Hz, 2H), 7 , 57 (d, J = 8.48 Hz, 2H), 7.74 (d, J =

1.70 Hz, 1H), 8.89 (s, 1H), 8.95 (s, 1H).

Example 95

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 95A

4-bromo-1,2-benzisoxazol-3-amine

A suspension of acetylhydroxamic acid (2.46 g, 32.8 mmol) and potassium tert-butoxide (3.68 g, 32.8 mmol) in DMF (40 ml) was stirred at room temperature for 30 minutes, treated with 2-Bromo-6-fluorobenzonitrile (4.36 g, 21.8 mmol), stirred for three hours, poured into water and extracted three times with ethyl acetate. The extracts

The combined ES 2 398 074 T3 were washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 5-20% ethyl acetate / hexanes to provide 2.5 g of the desired product. MS (ESI (+)) m / e 212.9, 214.9 (M + H)⁺.

Example 95B

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 1A for Example 95A in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 5.22 (s, 2H), 6.81 (d, J = 7.12 Hz, 1H), 7.10-7 , 70 (m, 10H), 8.66 (s, 1H), 8.85 (s, 1H); MS (ESI (+)) m / e 359 (M + H)⁺.

Example 96

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- [2- (trifluoromethyl) phenyl] urea

Example 96A

N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [2- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-2- (trifluoromethyl) benzene in Example 1B.

Example 96B

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- [2- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and Example 1B for Example 95A and Example 96A, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 5.22 (s, 2H), 7.00-7.75 (m, 10H), 7.95 (d, J =

7.80 Hz, 1H), 8.16 (s, 1H), 9.57 (s, 1H); MS (ESI (+)) m / e 413 (M + H)⁺.

Example 97

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 1A and Example 1B for Example 95A and Example 5A, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 5.22 (s, 2H), 6.75-6.85 (m, 1H), 7.06-7.18 ( m, 2H), 7.40-7.66 (m, 6H), 8.00 (dd, J = 7.97, 1.86 Hz, 1H), 8.55 (d, J = 2.37 Hz , 1H), 9.25 (s, 1H); MS (ESI (+)) m / e 377 (M + H)⁺.

Example 98

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

Example 98A

N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-3- (trifluoromethyl) benzene in Example 1B.

Example 98B

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and Example 1B for Example 95A and Example 98A, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 5.22 (s, 2H), 7.14 (d, J = 6.78 Hz, 1H), 7.33 (d, J = 7.12 Hz, 1H ), 7.40-7.75 (m, 8H), 8.04 (s, 1H), 9.00 (s, 1H), 9.12 (s, 1H); MS (ESI (+)) m / e 413 (M + H)⁺.

Example 99

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

Example 99A

N- [2-fluoro-5- (trifluoromethyl) phenyl] -N '- [4 - (' 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea

ES 2 398 074 T3

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-2-isocyanato-4 (trifluoromethyl) benzene in Example 1B.

Example 99B

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and Example 1B for Example 95A and Example 99A, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-d6) δ 5.22 (s, 2H), 7.15 (d, J = 7.12 Hz, 1H), 7.40-

7.70 (m, 8H), 8.64 (d, J = 7.46 Hz, 1H), 8.98 (s, 1H), 9.38 (s, 1H); MS (ESl (+)) m / e 431 (M + H)⁺.

Example 100

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

Example 100A

2-fluoro-6-iodo-3-methoxybenzonitrile

The desired product was prepared by substituting 2-fluoro-4-iodo-1-methylbenzene for 2-fluoro-4-iodo-1-methoxybenzene in Examples 15A-C.

Example 100B

4-iodo-7-methoxy-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 100A for 2-bromo-6-fluorobenzonitrile in Example 95A.

Example 100C

4- (4-aminophenyl) -7-methoxy-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 15F for Example 100B in Example 15G. ¹H NMR (300 MHz, DMSO-d6) δ 3.93 (s, 3H), 5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d, J = 8.48 Hz , 2H), 6.94 (d, J = 8.14 Hz, 1H), 7.10 (m, 3H); MS (ESl (+)) m / e 256.0 (M + H)⁺.

Example 100D

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H rMn (300 MHz, DMSO-d6) δ 3.97 (s, 3H), 5.21 (s, 2H), 7.05 (d, J = 8.14 Hz, 1H), 7.17 (d , J = 8.14 Hz, 1H), 7.41 (d, J = 8.82 Hz, 3H), 7.45-7.56 (m, 1H), 7.61 (d, J = 8, 48 Hz, 2H), 8.64 (dd, J = 7.12.2.37 Hz, 1H), 8.96 (d, J = 2.71 Hz, 1H), 9.34 (s, 1H) ; MS (ESl (+)) m / e 461 (M + H)⁺.

Example 101

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl] phenyl] -N'-3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

1-isocyanato-3-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.96 (s, 3H), 5.21 (s, 2H), 6.80 (d, J = 7.46 Hz , 1H), 7.04 (d, J = 8.14 Hz, 1H), 7.10-7.35 (m, 4H), 7.37 (d, J =

8.48Hz, 2H), 7.59 (d, J = 8.82Hz, 2H), 8.64 (s, 1H), 8.81 (s, 1H); MS (ESl (+)) m / e 389 (M + H)⁺.

Example 102

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl] phenyl] -N'-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ

3.96 (s, 3H), 5.21 (s, 2H), 7.05 (d, J = 7.80 Hz, 1H), 7.17 (d, J = 8.14 Hz, 1H), 7.32 (d, J = 7.46 Hz, 1H), 7.39 (d, J =

ES 2 398 074 T3

8.48 Hz, 2H), 7.53 (t, J = 7.80 Hz, 1H), 7.61 (m, 3H), 8.04 (s, 1H), 8.96 (s, 1H) , 9.10 (s, 1H); MS (ESI (+)) m / e 443.0 (M + H)⁺.

Example 103

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

1-chloro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 3.96 (s, 3H), 5.20 (s, 2H), 7.00-7.06 (m, 2H), 7.16 (d, J = 8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.39 (d, J = 8.81 Hz, 2H), 7.60 (d, J = 8.48 Hz, 2H), 7.73 (t, J = 2.03 Hz, 1H), 8.92 (s, 1H), 8.94 (s, 1H); MS (ESI (+)) m / e 409 (M + H)⁺.

Example 104

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl] phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ

2.28 (s, 3H), 3.96 (s, 3H), 5.21 (s, 2H), 6.75-6.90 (m, 1H), 7.00-7.20 (m, 3H), 7.39 (d, J = 8.81 Hz, 2H), 7.59 (d, J =

8.48 Hz, 2H), 8.00 (dd, J = 7.63, 1.86 Hz, 1H), 8.53 (d, J = 2.37 Hz, 1H), 9.22 (s, 1 HOUR); MS (ESI (+)) m / e 407.0 (M + H)⁺.

Example 105

N- {4- [3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

Example 105A

4-iodo-7- (4-morpholinylmethyl) -1,2-benzisoxazol-3-amine

The desired product was prepared by substituting 2-bromo-6-fluorobenzonitrile for Example 15E in Example 95A.

Example 105B

4- (4-aminophenyl) -7- (4-morpholinylmethyl) -1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 15F for Example 105A in Example 15G. ¹H NMR (300 MHz, DMSO-d6) δ 2.38-2.45 (m, 4H), 3.55-3.63 (m, 4H), 3.70 (s, 2H), 5.21 ( s, 2H), 5.38 (s, 2H), 6.69 (d, J = 8.48 Hz, 2H), 7.02 (d, J = 7.46 Hz, 1H), 7.15 ( d, J = 8.48 Hz, 2H), 7.45 (d, J = 7.46 Hz, 1H).

Example 105C

N- {4- [3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H rMn (300 MHz, DMSO-d6) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 7.13 (d, J = 7.46 Hz, 1H), 7.35-7.55 (m, 5H), 7.64 (d, J = 8.81 Hz, 2H), 8.64 (dd, J = 7.29, 2.20 Hz, 1H), 8.99 (d, J = 2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI (+)) m / e 530 (M + H)⁺.

Example 106

N- {4- [3-amino-7- (4-morpholinylmethyl] -1,2-benzisoxazol-4-yl] phenyl} -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, CF3CO2D) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 7.12 (d , J = 7.46 Hz, 1H), 7.33 (d, J = 7.46 Hz, 1H), 7.44 (d, J =

8.48 Hz, 2H), 7.50-7.68 (m, 5H), 8.04 (s, 1H), 9.04 (s, 1H), 9.16 (s, 1H); MS (ESI (+)) m / e 512 (M + H)⁺.

Example 107

N- {4- [3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- (3-chlorophenyl) urea

ES 2 398 074 T3

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.22 (s, 2H), 6.95 -7.06 (m, 1H), 7.12 (d, J = 7.46 Hz, 1H), 7.25-7.38 (m, 2H), 7.44 (d, J = 8.48 Hz, 2H), 7.52 (d, J = 7.80 Hz, 1H), 7.62 (d, J = 8.48 Hz, 2H), 7.70-7.78 (m, 1H), 8.99 (s, 2H); MS (ESI (+)) m / e 478 (M + H)⁺.

Example 108

N- {4- [3-amino-7- (4-morpholinylmethyl) -1-1,2-benzisoxazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.23 (s, 2H), 6.80 (d, J = 7.80 Hz, 1H), 7.05-7.35 (m, 5H), 7.42 (d, J =

8.48 Hz, 1H), 7.52 (d, J = 7.12 Hz, 1H), 7.62 (d, J = 8.48 Hz, 2H), 8.67 (s, 1H), 8 , 86 (s, 1H); MS (ESI (+)) m / e 458 (M + H)⁺.

Example 109

N- {4- [3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ

2.28 (s, 3H), 2.35-2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.74 (s, 2H), 5.23 (s, 2H), 6.75-6.85 (m, J = 2.37 Hz, 1H), 7.05-

7.18 (m, 2H), 7.44 (d, J = 8.48 Hz, 2H), 7.52 (d, J = 7.80 Hz, 1H), 7.62 (d, J = 8 , 48 Hz, 2H), 8.00 (dd, J = 7.80, 1.70 Hz, 1H), 8.55 (d, J = 2.37 Hz, 1H), 9.25 (s, 1H ); MS (ESI (+)) m / e 476 (M + H)⁺.

Example 110

N- {4- [3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- (3,5-dimethylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-isocyanato-3,5-dimethylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.24 (s, 6H), 2.44 (s, 4H), 3.59 (s, 4H), 3.73 (s, 2H), 5.23 (s, 2H), 6.63 (s, 1H), 7.05-7.15 (m, 3H), 7.42 (d, J = 8.48 Hz, 2H),

7.52 (d, J = 7.46Hz, 1H), 7.61 (d, J = 8.81Hz, 2H), 8.59 (s, 1H), 8.84 (s, 1H); MS (ESI (+)) m / e 472 (M + H)⁺.

Example 111

N- {4 - [- 3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- (3-phenoxyphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-isocyanato-3-phenoxybenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.40-

2.48 (m, 4H), 3.55-3.64 (m, 4H), 3.73 (s, 2H), 5.21 (s, 2H), 6.60-6.68 (m, 1H), 7.00-7.20 (m, 5H), 7.25-7.32 (m, 2H), 7.35-7.45 (m, 4H), 7.51 (d, J = 7.46 Hz, 1H), 7.59 (d, J = 8.82 Hz, 2H), 8.84 (s, 1H), 8.87 (s, 1H); MS (ESI (+)) m / e

536.1 (M + H)⁺.

Example 112

N- {4- [3-amino-7- (4-morpholinylmethyl) -1,2-benzisoxazol-4-yl] phenyl} -N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 105B and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.40-

2.48 (m, 4H), 3.50-3.65 (m, 4H), 3.73 (s, 2H), 5.22 (s, 2H), 7.10-7.35 (m, 4H), 7.43 (d, J = 8.48 Hz, 2H), 7.52 (d, J =

7.46 Hz, 1H), 7.62 (d, J = 8.48 Hz, 2H), 7.88 (t, J = 1.86 Hz, 1H), 8.96 (s, 2H); MS (ESI (+)) m / e 524 (M + H)⁺.

Example 113

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1,2-bencisoxazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenylurea

Example 113A

ES 2 398 074 T3

4-iodo-7- [2- (4-morpholinyl) ethoxy] -1,2-benzisoxazol-3-amine

The desired product was prepared by substituting 2-bromo-6-fluorobenzonitrile for Example 75A in Example 95A.

Example 113B

4- (4-aminophenyl) -7- [2- (4-morpholinyl) ethoxy] -1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 15F for Example 113A in Example 15G. ¹H NMR (300 MHz, DMSO-d6) δ 2.45-2.60 (m, 4H), 2.76 (t, J = 5.59 Hz, 2H), 3.50-3.70 (m, 4H), 4.28 (t, J = 5.59 Hz, 2H), 5.19 (s, 2H), 5.31 (s, 2H), 6.67 (d, J = 8.48 Hz, 2H), 6.92 (d, J = 7.80 Hz, 1H), 7.05-7.18 (m, 3H); MS (ESI (+)) m / e 355.0 (M + H)⁺.

Example 113C

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1,2-bencisoxazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 113B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.45-2.60 (m, 4H), 2.78 (t, J = 5.59 Hz, 2H), 3.50-3.65 (m, 4H), 4.31 (t, J = 5.59 Hz, 2H), 5.21 (s, 2H), 7.03 (d, J = 8.14 Hz, 1H), 7.19 (d, J = 8.14 Hz, 1H), 7.32 (d, J = 7.46 Hz, 1H), 7.39 (d, J = 8.81 Hz, 2H), 7.53 (t, J = 7.80 Hz, 1H), 7.57-7.66 (m, 3H), 8.04 (s, 1H), 8.96 (s, 1H), 9.10 (s, 1H); MS (ESI (+)) m / e 542.1, 540.1,

Example 114

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1,2-benzisoxazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 113B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ

2.28 (s, 3H), 2.45-2.55 (m, 4H), 2.78 (t, J = 5.59 Hz, 2H), 3.50-3.65 (m, 4H) , 431 (t, J = 5.76 Hz, 2H), 5.21 (s, 2H), 6.75-6.84 (m, 1H), 7.03 (d, J = 8.14 Hz, 1H), 7.11 (dd, J = 11.36, 8.31 Hz, 1H), 7.19 (d, J = 8.14 Hz, 1H), 7.39 (d, J =

8.48 Hz, 2H), 7.59 (d, J = 8.48 Hz, 2H), 8.00 (dd, J = 7.80, 2.03 Hz, 1H), 8.53 (d, J = 2.37 Hz, 1H), 9.22 (s, 1H); MS (ESI (+)) m / e 506.1 (M + H)⁺.

Example 115

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1,2-bencisoxazol-4-yl} phenyl) -N '- [2-fluoro-5- (trifluoromethyl) phenyl ]urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 113B and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H rMn (300 MHz, DMSO-d6) δ 2.45-2.55 (m, 4H), 2.78 (t, J = 5.26 Hz, 2H), 3.50-3.67 (m, 4H), 4.31 (t, J = 5.09 Hz, 2H), 5.21 (s, 2H), 7.03 (d, J =

7.80 Hz, 1H), 7.19 (d, J = 7.80 Hz, 1H), 7.35-7.70 (m, 6H), 8.64 (dd, J = 6.78, 1 , 36 Hz, 1H), 8.96 (d, J = 2.37 Hz, 1H),

9.34 (s, 1H); MS (ESI (+)) m / e 560.1 (M + H)⁺.

Example 116

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1,2-benzisoxazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 113B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product.¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 2.45-2.55 (m, 4H), 2.78 (t, J = 5.26 Hz, 2H), 3 , 50-3.70 (m, 4H), 4.31 (t, J = 4.92 Hz, 2H), 5.21 (s, 2H), 6.80 (d, J =

7.46 Hz, 1H), 7.02 (d, J = 7.80 Hz, 1H), 7.10-7.30 (m, 4H), 7.37 (d, J = 8.48 Hz, 2H), 7.59 (d, J = 8.48 Hz, 2H), 8.66 (s, 1H), 8.83 (s, 1H); MS (ESI (+)) m / e 488 (M + H)⁺.

Example 117

N- {4- [3-amino-7- (2-methoxyethoxy) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 68C and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. The crude suspension was filtered and the collected solid was washed with dichloromethane to provide the desired product. MS (ESI (+)) m / e 450 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.36 (s, 3H), 3.76 (t, J = 4.75 Hz, 2H), 4.26-4 , 29, (m, 2H), 4.29 (s, 2H),

ES 2 398 074 T3

6.68 (d, J = 7.80 Hz, 1H), 6.80 (d, J = 7.80 Hz, 1H), 6.82 (m, 1H), 7.11 (dd, J = 11 , 53, 8.14 Hz, 1H), 7.36 (d, J = 8.82 Hz, 2H), 7.56 (d, J = 8.48 Hz, 2H), 8.01 (dd, J = 7.80, 2.03 Hz, 1H), 8.52 (d, J = 2.37 Hz, 1H), 9.16 (s, 1H).

Example 118

N- (4- {3-amino-7- [2- (4-morpholinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (' 2-fluoro-5-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 75B and 1-fluoro-2-isocyanate-4-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 505 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.73 (m, 2H), 3.71 (m, 6H), 4.04 (m, 2H),

4.53 (m, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.81 (m, 1H), 6.88 (d, J = 7.80 Hz, 1H), 7.12 (dd, J = 11.36, 8.31 Hz, 1H),

7.36 (d, J = 8.82 Hz, 2H), 7.57 (d, J = 8.48 Hz, 2H), 8.01 (s, 1H), 8.52 (d, J = 2 , 71 Hz, 1H), 9.18 (s, 1H).

Example 119

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

Example 119A

2-fluoro-6-iodo-3- (methoxymethoxy) benzonitrile

A 0 ° C solution of Example 68A (250 mg, 0.95 mmol) in THF (5 ml) at room temperature was treated with NaH (25 mg, 95%, 1.05 mmol), stirred for 5 minutes, It was treated with chloromethyl methyl ether (0.108 ml, 1.4 mmol), stirred overnight and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2% ethyl acetate / hexanes to provide 0.21 g of the desired product. Fr = 0.4 (10% ethyl acetate / hexanes).

Example 119B

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N '(2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile and 1-isocyanato-3-methylbenzene for Example 119A and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Examples 1A-1C. MS (ESI (+)) m / e 436 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 3.46 (s, 3H), 4.33 (s, 2H), 5.34 (s, 2H), 6.69 (d, J = 7.80 Hz, 1H), 6.78-6.83 (m, 1H), 6.92 (d, J = 7.80 Hz, 1H), 7.11 (dd, J = 11.36, 8.31 Hz, 1H), 7.36 (d, J = 8.48 Hz, 2H), 7.56 (d, J = 8.48 Hz, 2H), 8.01 (dd, J = 7.80, 1.70 Hz, 1H), 8.52 (d, J = 2.71 Hz, 1H), 9.17 (s, 1H), 11.90 (s, 1H).

Example 120

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

A mixture of Example 119B (90 mg) and a 1: 1: 1 mixture of 3N HCl / methanol / THF (3 ml) was heated at 50 ° C for 3 hours, concentrated to half its original volume, and It was partitioned between saturated NaHCO3 and ethyl acetate. The organic extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 5% methanol / dichloromethane to provide 30 mg of the desired product. MS (ESI (+)) m / e 392 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.25 (s, 2H), 6.60 (d, J = 5.76 Hz, 2H), 6.82 (m , J = 5.09, 3.05 Hz, 1H), 7.11 (m, 2H), 7.33 (d, J = 8.48 Hz, 1H), 7.54 (d, J = 8, 81 Hz, 2H), 8.01 (dd, J = 7.97, 2.20 Hz, 1H), 8.51 (d, J = 2.71 Hz, 1H), 9.14 (s, 1H) , 9.84 (s, 1H), 11.58 (s, 1H).

Example 121

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

Example 121A

4- (4-aminophenyl) -7- (methoxymethoxy) -1H-indazol-3-amine

The desired product was prepared by substituting Example 15E for Example 119A in Examples 15F-G. MS (ESI (+)) m / e 285 (M + H)⁺.

Example 121B

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 121A for Example 15G in Example 15H.

ES 2 398 074 T3

Example 121C

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 119B for Example 121b in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (+)) m / e 378 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 6.68-6.72 (m, 2H), 6.79 (td, J = 8.34, 2.34 Hz, 1H), 7.14 (d, J = 8.11 Hz, 1H), 7.31 (m, 1H), 7.35 (d, J = 8.42 Hz, 2H), 7.51 (dt, J = 12.01, 2.26 Hz, 1H), 7.56 (d, J = 8.42 Hz, 2H), 8.88 (s, 1H), 8.97 (s, 1H).

Example 122

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

Example 122A

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H.

Example 122B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 119B for Example 122A in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (+)) m / e 438 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 6.69-6.73 (m, 2H), 7.16 (d, J = 7.80 Hz, 1H), 7.25 (t, J = 7, 95 Hz, 1H), 7.32-7.34 (m, 1H), 7.35 (d, J = 8.42 Hz, 2H), 7.56 (d, J = 8.73 Hz, 2H) ,

7.88 (t, J = 1.87Hz, 1H), 8.90 (s, 1H), 8.95 (s, 1H).

Example 123

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- (3-ethylphenyl) urea

Example 123A

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N '- (3-ethylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and 1-ethyl-3-isocyanatobenzene, respectively, in Example 15H.

Example 123B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N'-3- (ethylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 123a for Example 119B in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (+)) m / e 388 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.19 (t, J = 7.49 Hz, 3H),

2.58 (c, J = 7.49 Hz, 2H), 6.65-6.70 (m, 2H), 6.83 (d, J = 7.49 Hz, 1H), 7.19 (t , J = 7.80 Hz, 1H), 7.27 (d, J = 8.11 Hz, 1H), 7.33-7.34 (m, 3H), 7.55 (d, J = 8, 42 Hz, 2H), 8.64 (s, 1H), 8.74 (s, 1H).

Example 124

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

Example 124A

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H.

Example 124B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

ES 2 398 074 T3

The desired product was prepared as the trifluoroacetate salt by substituting Example 124a for Example 119B in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (+)) m / e 446 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 6.68-6.72 (m, 2H), 7.37 (d, J = 8.42 Hz, 2H), 7.38-7.40 (m, 1H), 7.51 (m, 1H), 7.57 (d, J = 8.73 Hz, 2H), 8.64 (dd, J = 7.17, 2.18 Hz, 1H), 8, 93 (d, J = 2.81 Hz, 1H), 9.28 (s, 1H).

Example 125

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl-) phenyl-N '- [4-fluoro-3- (trifluoromethyl) phenyl urea

Example 125A

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-illphenyl} -N '- [4-fluoro-3- (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H.

Example 125B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl-N '- [4-fluoro-3- (trifluoromethyl) phenylurea

The desired product was prepared as the trifluoroacetate salt by substituting Example 119B for Example 125a in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (-)) m / e 444 (MH) -;¹H NMR (500 MHz, DMSO-d6) δ 6.72-6.76 (m, 2H), 7.36 (d, J = 8.42 Hz, 2H), 7.44 (t, J = 9, 67 Hz, 1H), 7.58 (d, J = 8.73 Hz, 2H), 7.65-7.68 (m, 1H), 8.03 (dd, J = 6.39, 2.65 Hz, 1H), 9.02 (s, 1H), 9.19 (s, 1H).

Example 126

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl-N '- (3-chlorophenyl) urea

Example 126A

N- {4- [3-amino-7- (methoxyethoxy) -1H-indazol-4-illphenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H.

Example 126B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl-N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 119B for Example 126a in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (-)) m / e 392 (MH) -;¹H NMR (500 MHz, DMSO-d6) δ 6.69-6.73 (m, 1H), 7.017.03 (m, 1H), 7.30-7.31 (m, 2H), 7.35 ( d, J = 8.73 Hz, 2H), 7.56 (d, J = 8.73 Hz, 2H), 7.74 (d, J = 1.87 Hz, 1H), 8.91 (s, 1H), 8.98 (s, 1H).

Example 127

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl-N '- [3- (trifluoromethyl) phenylurea

Example 127A

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-illphenyl} -N '- [3- (trifluoromethyl) phenyl urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H.

Example 127B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl-N '- [3- (trifluoromethyl) phenylurea

The desired product was prepared as the trifluoroacetate salt by substituting Example 127a for Example 119B in Example 120, and then purifying the resulting product by HpLC using the conditions described in Example 15H. MS (ESI (+)) m / e 428 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 6.70-6.74 (m, 2H), 7.32 (d, J = 7.49 Hz, 1H), 7.36 (d, J = 8, 42 Hz, 2H), 7.52 (t, J = 7.95 Hz, 1H), 7.58 (d, J = 8.42 Hz, 2H), 7.60 (d, J = 9.04

ES 2 398 074 T3

Hz, 1H), 8.04 (s, 1H), 8.96 (s, 1H), 9.14 (s, 1H).

Example 128

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N'-phenylurea

Example 128A

N- {4- [3-amino-7- (methoxymethoxy) -1H-indazol-4-yl] phenyl} -N-phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 121A and isocyanatobenzene, respectively, in Example 15H.

Example 128B

N- [4- (3-amino-7-hydroxy-1H-indazol-4-yl) phenyl] -N'-phenylurea

The desired product can be prepared by substituting Example 128A for Example 119B in Example 120. MS (ESl (-)) m / e 358 (MH) -; ¹H NMR (300 MHz, DMSO-d6) δ 6.57-6.64 (m, 2H), 6.97 (t, J = 7.29 Hz, 1H), 7.29 (t, J = 8, 13 Hz, 2H), 7.32 (d, J = 8.82 Hz, 2H), 7.47 (d, J = 7.46 Hz, 2H), 7.54 (d, J = 8.82 Hz , 2H), 8.71 (s, 1H), 8.77 (s, 1H).

Example 129

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N'-phenylurea

Example 129A

4- (4-aminophenyl) -7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-3-amine

The desired product was prepared by substituting 2- (1-pyrrolidinyl) ethanol for 2- (4-morpholinyl) ethanol in Examples 75A and 75B. MS (ESl (+)) m / e 338 (M + H)⁺.

Example 129B

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N'-phenylurea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 129A and isocyanatobenzene, respectively, in Example 15H. MS (ESl (+)) m / e 457 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.08 (bs, 2H), 3.25 (bs, 4H), 3.68 (bs, 2H), 4.46 (t, J =

4.80 Hz, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 6.98 (t, J = 7, 33 Hz, 1H), 7.29 (t, J = 7.80 Hz, 2H),

7.36 (d, J = 8.73 Hz, 2H), 7.47 (d, J = 7.49 Hz, 2H), 7.58 (d, J = 8.42 Hz, 2H), 8, 74 (s, 1H), 8.82 (s, 1H).

Example 130

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxyl] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 129A for Example 15G in Example 15H. MS (ESl (+)) m / e 475 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.92 (bs, 2H), 2.07 (bs, 2H), 3.24 (bs, 2H), 3.68 (bs, 4H), 4.47 (t, J = 4.80 Hz, 2H), 6.75 (d, J = 7.49 Hz, 1H), 6.79 (td, J = 8.50, 2.34 Hz, 1H), 6 , 89 (d, J = 7.80 Hz, 1H), 7.15 (dd, J = 5.11, 1.25 Hz, 1H), 7.29-7.34 (m, 1H), 7, 37 (d, J = 8.73 Hz, 2H), 7.52 (dt, J = 12.01,2.26 Hz, 1H), 7.58 (d, J = 8.73 Hz, 2H), 9.00 (s, 1H), 9.08 (s, 1H).

Example 131

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 129A and 1-fluoro-2-isocyanate-4-methylbenzene, respectively, in Example 15H. MS (ESl (+)) m / e 489 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.07 (bs, 2H), 2.28 (s, 3H), 3.25 (bs, 2H), 3.69 (bs, 4H), 4.47 (t, J = 4.80 Hz, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.80-6.82 (m, 1H) , 6.88 (d, J = 7.80 Hz, 1H), 7.11 (dd, J = 11.38, 8.26 Hz, 1H), 7.37 (d, J = 8.42 Hz, 2H), 7.58 (d, J = 8.73 Hz, 2H), 7.99 (dd, J = 7.80,1.56 Hz, 1H), 8.53 (d, J = 2.49 Hz, 1H), 9.20 (s, 1H).

Example 132

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

ES 2 398 074 T3

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 129A and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 471 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.07 (bs, 2H), 2.29 (s, 3H), 3.25 (bs, 2H),

3.69 (bs, 4H), 4.48 (t, J = 4.80Hz, 2H), 6.77 (d, J = 7.80Hz, 1H), 6.80 (d, J = 7 , 49 Hz, 1H), 6.90 (d, J = 7.80 Hz, 1H), 7.16 (t, J = 7.80 Hz, 1H), 7.26 (d, J = 8.11 Hz, 1H), 7.33 (s, 1H), 7.36 (d, J = 8.73 Hz, 2H), 7.59 (d, J = 8.73 Hz, 2H), 8.79 ( s, 1H), 8.95 (s, 1H).

Examples 133

N- (4- {3-amino-7- [2 '- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N' - (3-bromophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 129A and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 535 and 537 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.07 (bs, 2H), 3.25 (bs, 2H), 3.68 (bs, 4H), 4.47 (t, J = 4.80 Hz, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.15 (d , J = 8.11 Hz, 1H), 7.25 (t, J = 8.11 Hz, 1H), 7.34 (d, J = 9.36 Hz, 1H), 7.37 (d, J = 8.42 Hz, 2H), 7.59 (d, J = 8.42 Hz, 2H), 7.89 (t, J = 1.87 Hz, 1H), 9.06 (s, 1H), 9.10 (s, 1H).

Example 134

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxyl] -1H-indazol-4-yl} phenyl) -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 129A and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 543 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.08 (bs, 2H), 3.25 (bs, 2H), 3.69 (bs, 4H), 4.47 (t, J = 4.80 Hz, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 7.39 (d , J = 8.42 Hz, 2H), 7.41 (m, 1H), 7.51 (t, J = 9.67 Hz, 1H), 7.59 (d, J = 8.42 Hz, 2H ), 8.64 (dd, J = 7.33, 2.34 Hz, 1H), 8.94 (d, J = 2.49 Hz, 1H), 9.30 (s, 1H).

Example 135

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 129A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 491 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.07 (bs, 2H), 3.25 (bs, 2H), 3.68 (bs, 4H), 4.47 (t, J = 4.80 Hz, 2H), 6.76 (d, J = 7.49 Hz, 1H), 6.90 (d, J = 7.80 Hz, 1H), 7.02 (m , 1H), 7.31 (d, J = 5.30 Hz, 2H), 7.37 (d, J = 8.42 Hz, 2H), 7.59 (d, J = 8.73 Hz, 2H ), 7.74 (s, 1H), 9.10 (s, 1H), 9.15 (s, 1H).

Example 136

N- (4- {3-amino-7- [2- (1-pyrrolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 129A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 525 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.93 (bs, 2H), 2.07 (bs, 2H), 3.25 (bs, 2H), 3.68 (bs, 4H), 4.47 (t, J = 4.80 Hz, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 7.32 (d , J = 7.80 Hz, 1H),

7.37 (d, J = 8.42 Hz, 2H), 7.52 (t, J = 7.80 Hz, 1H), 7.60 (d, J = 8.42 Hz, 2H), 7, 60 (d, J = 6.55 Hz, 1H), 8.05 (s, 1H),

9.10 (s, 1H), 9.28 (s, 1H).

Example 137

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N'-phenylurea

Example 137A

4- (4-aminophenyl) -7- [2- (diethylamino) ethoxy] -1H-indazol-3-amine

The desired product was prepared by substituting 2- (diethylamino) ethanol for 2- (4-morpholinyl) ethanol in Examples 75A and 75B. MS (ESI (+)) m / e 340 (M + H)⁺.

Example 137B

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N'-phenylurea

ES 2 398 074 T3

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 459 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.17 Hz, 6H), 3.33 (bs, 4H), 3.62 (bs, 2H), 4.49 (t , J = 4.80 Hz, 2H), 6.74 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 6.98 (t, J = 7.49 Hz, 1H), 7.29 (t, J = 7.95 Hz, 2H), 7.36 (d, J = 8.42 Hz, 2H), 7.48 (d, J = 7 , 80Hz, 2H), 7.58 (d, J = 8.73Hz, 2H), 8.83 (s, 1H), 8.91 (s, 1H).

Example 138

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N- (3-fluorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 137A for Example 15G in Example 15H. MS (ESI (+)) m / e 477 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.33 Hz, 6H), 3.34 (bs, 4H), 3.60 (bs, 2H), 4.49 (t , J = 4.80 Hz, 2H), 6.76 (d, J = 7.80 Hz, 1H), 6.79 (t, J = 8.58 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.15 (d, J = 8.11 Hz, 1H), 7.31 (c, J = 7.61 Hz, 1H), 7.37 (d, J = 8 , 42 Hz, 2H), 7.52 (dt, J = 11.93, 2.14 Hz, 1H),

7.59 (d, J = 8.42 Hz, 2H), 9.02 (s, 1H), 9.11 (s, 1H).

Example 139

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and 1-fluoro-2-isocyanate-4-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 491 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.33 Hz, 6H), 2.28 (s, 3H), 3.33 (da, J =

8.42 Hz, 4H), 3.62 (bs, 2H), 4.49 (t, J = 4.80 Hz, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6 , 80-6.82 (m, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.11 (dd, J = 11.38, 8.26 Hz, 1H), 7, 37 (d, J = 8.42 Hz, 2H), 7.58 (d, J = 8.42 Hz, 2H), 7.99 (dd, J = 7.95,

1.72 Hz, 1H), 8.54 (d, J = 2.50 Hz, 1H), 9.22 (s, 1H).

Example 140

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. MS (ESI (+)) m / e 473 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.33 Hz, 6H), 2.29 (s, 3H), 3.34 (sa, 4H), 3.61 (sa , 2H), 4.49 (t, J = 4.80 Hz, 2H), 6.74 (d, J = 7.49 Hz, 1H), 6.80 (d, J = 7.17 Hz, 1H ), 6.88 (d, J = 7.80 Hz, 1H),

7.16 (t, J = 7.80 Hz, 1H), 7.26 (d, J = 8.11 Hz, 1H), 7.32 (s, 1H), 7.35 (d, J = 8 , 42 Hz, 2H), 7.58 (d, J = 8.42 Hz, 2H),

8.72 (s, 1H), 8.87 (s, 1H).

Example 141

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-bromophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. MS (ESI (+)) m / e 537 and 539 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.33 Hz, 6H), 3.30-3.35 (m, 4H), 3.61 (bs, 2H), 4 , 49 (t, J = 4.80 Hz, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 7.16 (d, J = 7.80 Hz, 1H), 7.25 (t, J = 7.95 Hz, 1H), 7.33-7.35 (m, 1H), 7.36 (d, J = 8.42 Hz, 2H), 7.59 (d, J = 8.42 Hz, 2H), 7.89 (m, 1H), 9.05 (s, 1H), 9.09 (s, 1H) .

Example 142

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 545 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.17 Hz, 6H), 3.33 (bs, 4H), 3.62 (bs, 2H), 4.50 (t , J = 4.80 Hz, 2H), 6.77 (d, J = 7.80 Hz, 1H), 6.89 (d, J = 7.80 Hz, 1H), 7.39 (m, J = 8.42 Hz, 3H), 7.51 (t, J = 9.85 Hz 1H), 7.60 (d, J = 8.73 Hz, 2H), 8.64 (dd, J = 7, 17, 2.18 Hz, 1H), 8.97 (d, J = 2.81 Hz, 1H),

9.35 (s, 1H).

Example 143

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. MS

ES 2 398 074 T3 (ESI (+)) m / e 493 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.17 Hz, 6H), 3.34 (bs, 4H), 3.62 (bs, 2H), 4.49 (t , J = 4.80 Hz, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.80 Hz, 1H), 7.02 (td, J = 4.37, 2.18 Hz, 1H), 7.30-

7.31 (m, 2H), 7.37 (d, J = 8.42 Hz, 2H), 7.58 (d, J = 8.42 Hz, 2H), 7.74 (s, 1H), 9.01 (s, 1H), 9.06 (s, 1H).

Example 144

N- (4- {3-amino-7- [2- (diethylamino) ethoxy] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 137A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+)) m / e 527 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 1.27 (t, J = 7.33 Hz, 6H), 3.32-3.34 (bs, 4H), 3.61 (bs, 2H), 4 , 49 (t, J = 4.80 Hz, 2H), 6.75 (d, J = 7.80 Hz, 1H), 6.88 (d, J = 7.49 Hz, 1H), 7.31 (d, J = 7.80 Hz, 1H), 7.37 (d, J = 8.42 Hz, 2H), 7.52 (t, J = 7.95 Hz, 1H), 7.60-7 , 61 (m, 3H), 8.05 (s, 1H), 9.12 (s, 1H), 9.30 (s, 1H).

Example 145

N- (4- {3-amino-7- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N ' - (3-methylphenyl) urea

Example 145A

3- (2 - {[3-amino-4- (4-aminophenyl) -1H-indazol-7-yl] oxy} ethyl) -1,5,5-trimethyl-2,4-imidazolidinedione

The desired product was prepared by substituting 3- (2-hydroxyethyl) -1,5,5-trimethyl-2,4imidazolidinedione for 2- (4-morpholinyl) ethanol in Examples 75A and 75B. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.80 (s, 3H), 3.81 (t, J =

6.27 Hz, 2H), 4.32 (t, J = 6.27 Hz, 2H), 5.19 (s, 2H), 6.57 (d, J = 7.80 Hz, 1H), 6 , 65 (d, J = 8.14 Hz, 2H), 6.76 (d, J =

7.80 Hz, 1H), 7.07 (d, J = 8.14 Hz, 2H), 11.59 (s, 1H); MS (ESI (+)) m / e 409 (M + H)⁺.

Example 145B

N- (4- {3-amino-7- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethoxyl] -1H-indazol-4-yl} phenyl) -N ' - (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 145A and 1-isocyanato-3-methylbenzene, respectively, in Example 15H, and then purifying the resulting product by flash column chromatography on gel. silica with 5-8% methanol / dichloromethane. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.29 (s, 3H), 2.81 (s, 3H), 3.83 (t, J = 5.93 Hz , 2H), 4.35 (t, J = 5.93 Hz, 2H), 6.68 (d, J =

7.80 Hz, 1H), 6.81 (t, J = 7.46 Hz, 2H), 7.05-7.45 (m, 5H), 7.56 (d, J = 8.48 Hz, 2H), 8.62 (s, 1H), 8.75 (s, 1H), 11.75 (s, 1H); MS (ESI (+)) m / e 542 (M + H)⁺.

Example 146

N- (4- {3-amino-7- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N ' - (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 145A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H),

2.81 (s, 3H), 3.83 (t, J = 6.27 Hz, 2H), 4.35 (t, J = 6.44 Hz, 2H), 6.68 (d, J = 7 , 80 Hz, 1H), 6.82 (d, J = 7.80 Hz, 1H), 6.95-7.06 (m, 1H), 7.25-7.40 (m, 4H), 7 , 56 (d, J = 8.81 Hz, 2H), 7.73 (s, 1H), 8.86 (s, 1H), 8.93 (s, 1H), 11.74 (s, 1H) ; MS (ESI (+)) m / e 562 (M + H)⁺.

Example 147

N- (4- {3-amino-7- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N ' - (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 145A and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H, and then purifying the resulting product by chromatography on Flash column on silica gel with 5-8% methanol / dichloromethane. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (s, 6H), 2.28 (s, 3H), 2.81 (s, 3H), 3.83 (t, J = 6.27 Hz , 2H), 4.35 (t, J = 6.27 Hz, 2H), 6.67 (d, J = 7.80 Hz, 1H), 6.70-6.90 (m, 2H), 7 , 11 (dd, J = 11.36, 8.31 Hz, 1H), 7.36 (d, J = 8.48 Hz, 2H), 7.56 (d, J =

8.48 Hz, 2H), 7.90-8.10 (dd, J = 7.97,1.86 Hz, 1H), 8.52 (d, J = 2.71 Hz, 1H), 9, 17 (s, 1H), 11.72 (s, 1H); MS (ESI (+)) m / e 560 (M + H)⁺.

Example 148

N- (4- {3-amino-7- [2- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) ethoxy] -1H-indazol-4-yl} phenyl) -N ' - [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 145A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (s,

ES 2 398 074 T3

6H), 2.81 (s, 3H), 3.83 (t, J = 6.27 Hz, 2H), 4.35 (t, J = 6.44 Hz, 2H), 6.68 (d, J = 7.80 Hz, 1H), 6.82 (d, J = 8.14 Hz, 1H), 7.25-7.45 (m, 3H), 7.45-7.65 (m, 4H ), 8.04 (s, 1H), 8.90 (s, 1H), 9.09 (s, 1H), 11.73 (s, 1H); MS (ESI (+)) m / e 596 (M + H)⁺.

Example 149

N- [4- (3-amino-1H-indazol-4-yl) -2-ethylphenyl] -N '- (2-fluoro-5-methylphenyl) urea

Example 149A

N- (4-bromo-2-ethylphenyl) -N '- (2-fluoro-5-methylphenyl) urea

A solution of 4-bromo-2-ethylaniline (200 mg) in dichloromethane (10 ml) was treated with 1-fluoro-2-isocyanate-4-methylbenzene (151 mg), stirred at room temperature overnight, diluted with hexanes and leaked. The filter cake provided 227 mg of the desired product. MS (ESI (+)) m / e 351.353 (M + H)⁺.

Example 149B

N- [2-ethyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

A mixture of Example 149A (219 mg, 0.62 mmol), 4,4,4 ', 4', 5,5,5 ', 5'-octamethyl-2,2'-bi-1,3,2- Dioxaborolane (190 mg, 0.75 mmol), potassium acetate (183 mg) and PdCl2 (dppf) -CH2Cl2 (15 mg) in DMF (6 ml) was degassed and then heated at 80 ° C for 2 hours. The mixture was used directly in the next reaction.

Example 149C

N- [4- (3-amino-1H-indazol-4-yl) -2-ethylphenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 1B and Pd (PPh3) 4 for Example 149B and PdCh (dppf) .CH2Cl2, respectively, in Example 1C. Furthermore, DMF was used instead of DME.¹H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J = 7.46 Hz, 3H), 2.28 (s, 3H), 2.71 (c, J = 7.46 Hz, 2H ), 4.35 (s, 2H), 6.75-6.85 (m, 2H), 7.12 (dd, J = 11.53, 8.14 Hz, 1H), 7.25-7, 35 (m, 4H), 7.99 (d, J = 8.14 Hz, 1H), 8.06 (dd, J = 7.80, 2.03 Hz, 1H), 8.44 (s, 1H ), 8.99 (d, J = 2.03 Hz, 1H), 11.71 (s, 1H); MS (ESI (+)) m / e 404 (M + H)⁺.

Example 150

N- [4- (3-amino-1H-indazol-4-yl) -2-ethylphenyl '] - N' - [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3 (trifluoromethyl) benzene in Examples 149A-C. ¹H NMR (300 MHz, DMSO-d6) δ 1.24 (t, J = 7.46 Hz, 3H), 2.71 (c, J = 7.69 Hz, 2H), 4.35 (s, 2H ), 6.75-6.90 (m, 1H), 7.20-7.40 (m, 4H), 7.45-7.60 (m, 3H), 7.94 (d, J = 8 , 14 Hz, 1H), 8.07 (s, 1H), 8.13 (s, 1H), 9.43 (s, 1H), 11.72 (s, 1H); MS (ESI (+)) m / e 440 (M + H)⁺.

Example 151

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 26B and 1-fluoro-2-isocyanate-4-methylbenzene, respectively, in Example 15H. ¹H NMR (400 MHz, DMSO-d6) δ 2.27 (s, 3H), 6.74-6.83 (m, 2H), 7.13 (m, 2H), 7.38 (d, J = 8.29 Hz, 2H), 7.58 (d, J =

8.59Hz, 2H), 7.99 (d, J = 6.44Hz, 1H), 8.52 (d, J = 2.45Hz, 1H), 9.21 (s, 1H); MS (ESI (+)) m / e 394 (M + H)⁺.

Example 152

N- {4- [3-amino-7-fluoro-6- (hydroxymethyl) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

Example 152A

2,3-Difluoro-4- (hydroxymethyl) -6-iodobenzonitrile

A -78 ° C solution of Example 26A (5.0 g, 18.9 mmol) in THF was treated with LDA (2 M in hexanes, 11.5 ml, 22.6 mmol), stirred for 1 hour at -78 ° C, treated with methyl formate (2.34 ml, 37.8 mmol), stirred at -78 ° C for 30 minutes, heated at 0 ° C for 1 hour, quenched with saturated NH4Cl and it was extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was immediately dissolved in ethanol (100 ml), cooled to 0 ° C and treated in portions with NaBH4 (1.08 g). The reaction was stirred at 0 ° C for 2 hours, quenched with acetone, stirred for 5 minutes,

ES 2 398 074 T3 was poured into water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash column chromatography on silica gel with 2: 1 hexanes / ethyl acetate to give 1.02 g of the desired product. Fr = 0.84 (ethyl acetate).

Example 152B (3-amino-7-fluoro-4-iodo-1H-indazol-6-yl) methanol

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 152A in Example 1A. Fr = 0.53 (ethyl acetate).

Example 152C

N- {4- [3-amino-7-fluoro-6- (hydroxymethyl) -1H-indazol-4-illphenyl} -N '- (2-fluoro-5-methylphenyl) urea

A mixture of Example 152B (50 mg, 0.16 mmol), Example 5A (66 mg, 0.18 mmol), Pd (PPh3) 4 (9 mg, 0.008 mmol) and Na2CO3 (43 mg, 0.4 mmol) in toluene (2 ml), ethanol (1 ml) and water (1 ml) it was degassed and heated at 140 ° C for 8 minutes with shaking using a Smith Synthesizer in a 300 W septum capped process vial. The samples were cooled using pressurized air to 275.79 kPa (40 psi). The mixture was concentrated and the residue was purified by preparative HPLC on a Waters Symmetry C8 column (25mm x 100mm, particle size 7mm) using a 10% to 100% acetonitrile / 0.1 aqueous TFA gradient. % for 8 minutes (10 minute run time) at a flow rate of 40 ml / min to provide 26 mg of the desired product as the trifluoroacetate salt. ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 4.65 (d, J = 1.36 Hz, 2H), 6.81 (m, 1H), 6.86 (d , J = 5.76 Hz, 1H), 7.11 (dd, J = 11.36, 8.31 Hz, 1H), 7.39 (d, J = 8.48 Hz, 2H), 7.59 (d, J = 8.48 Hz, 2H), 8.01 (dd, J = 7.80,2.03 Hz, 1H), 8.53 (d, J = 2.37 Hz, 1H), 9 , 21 (s, 1H); MS (ESI (+)) m / e 424 (M + H)⁺.

Example 153

N- {4- [3-amino-7-fluoro-6- (hydroxymethyl) -1H-indazol-4-illphenyl} -N '- [3- (trifluoromethyl) phenylurea

The desired product was prepared as the trifluoroacetate salt by substituting Example 98A for Example 5A in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 4.65 (d, J = 1.70 Hz, 2H), 6.87 (d, J = 5.76 Hz, 1H), 7.32 (d, J =

7.46 Hz, 1H), 7.39 (d, J = 8.48 Hz, 2H), 7.53 (t, J = 7.97 Hz, 1H), 7.58-7.64 (m, 3H), 8.04 (s, 1H), 8.99 (s, 1H), 9.14 (s, 1H); MS (ESI (+)) m / e 460 (M + H)⁺; Anal. calc. for Cz&gt; H17F4N5O2-1.0CF3CO2H: C, 50.27; H, 3.15; N, 12.21; Found: C, 50.15; H, 3.15; N, 12.41.

Example 154

N- {4- [3-amino-7-fluoro-6- (hydroxymethyl) -1H-indazol-4-illphenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 5A for N- (3-chlorophenyl) -N '[4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) phenyl urea in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 4.65 (d, J = 1.36 Hz, 2H), 6.86 (d, J = 5.76 Hz, 1H), 7.03 (td, J = 4.41, 2.03 Hz, 1H.), 7.27-7.36 (m, 2H), 7.39 (d, J = 8.48 Hz, 2H), 7.60 (d, J = 8.48 Hz, 2H), 7.74 (m, 1H), 8.93 (s, 1H), 8.96 (s, 1H); MS (ESI (+)) m / e 426 (M + H)⁺.

Example 155

N- {4- [3-amino-7-fluoro-6- (hydroxymethyl) -1H-indazol-4-yl-lphenyl} -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 5A for Example 1B in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.65 (d, J = 1.36 Hz, 2H), 6.80 (d, J = 7.46 Hz, 1H ),

6.84 (d, J = 5.76 Hz, 1H), 7.17 (t, J = 7.80 Hz, 1H), 7.25 (d, J = 7.80 Hz, 1H), 7, 32 (s, 1H), 7.37 (d, J = 8.48 Hz, 2H),

7.59 (d, J = 8.48Hz, 2H), 8.64 (s, 1H), 8.80 (s, 1H); MS (ESI (+)) m / e 406 (M + H)⁺,

Example 156

N- {4- [3-amino-7-fluoro-6- (hydroxymethyl) -1H-indazol-4-illphenyl} -N '- (3-fluorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 5A for N- (3-fluorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl) phenyl urea in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 4.65 (d, J = 1.02 Hz, 2H), 6.80 (td, J = 8.65, 2.71 Hz, 1H), 6.84 (d, J = 5.76 Hz, 1H), 7.14 (d, J = 9.16 Hz, 1H), 7.32 (m, 1H), 7.38 (d, J = 8.48 Hz , 2H), 7.51 (dt, J = 11.87, 2.20 Hz, 1H), 7.59 (d, J = 8.48 Hz, 2H), 12.13 (s, 1H); MS (ESI (+)) m / e 410 (M + H)⁺.

ES 2 398 074 T3

Example 157

N- (4- {3-amino-6 - [(diethylamino) methyl] -7-fluoro-1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 157A

4 - [(diethylamino) methyl] -2,3-difluoro-6-iodobenzonitrile

A 0 ° C solution of Example 152A (350 mg, 1.18 mmol) in dichloromethane (10 ml) was treated with triethylamine (0.25 ml, 1.78 mmol) and methanesulfonyl chloride (0.1 ml, 1 , 3 mmol), stirred at 0 ° C for 1 hour, treated with diethylamine (0.245 ml, 2.37 mmol), and overnight at room temperature. The mixture was partitioned between 1N NaOH and dichloromethane and the organic extract was dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography on silica gel with 3: 1 hexanes / ethyl acetate to provide 0.263 g of the desired product. MS (ESI (+)) 351 (M + H)⁺.

Example 157B

6 - [(diethylamino) methyl] -7-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 157A in Example 1A. MS (ESI (+)) 363 (M + H)⁺.

Example 157C

N- (4- {3-amino-6 - [(diethylamino) methyl] -7-fluoro-1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 157B for Example 152B in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J = 7.29 Hz, 6H), 2.28 (s, 3H), 3.18 (m, 4H), 4.48 (d , J = 4.75 Hz, 2H), 6.82 (ddd, J = 7.71, 5.17, 2.03 Hz, 1H), 6.94 (d, J = 5.76 Hz, 1H) , 7.12 (dd, J = 11.36, 8.31 Hz, 1H), 7.44 (d, J = 8.48 Hz, 2H), 7.63 (d, J = 8.82 Hz, 2H), 7.99 (dd, J = 7.97, 1.87 Hz, 1H), 8.56 (d, J = 2.71 Hz, 1H),

9.27 (s, 1H), 9.36 (brs, 1H); MS (ESI (+) 477 (M + H)⁺.

Example 158

N- (4- {3-amino-6 - [(diethylamino) methyl] -7-fluoro-1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 152B and Example 5A for Example 157B and Example 98A, respectively, in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J = 7.29 Hz, 6H), 3.18 (m, 4H), 4.48 (d, J = 4.75 Hz, 2H ), 6.94 (d, J = 5.76 Hz, 1H), 7.33 (d, J = 7.80 Hz, 1H), 7.44 (d, J = 8.48 Hz, 2H), 7.53 (t, J = 7.80 Hz, 1H), 7.60 (m, 1H), 7.65 (d, J = 8.48 Hz, 2H), 8.06 (s, 1H), 9.14 (s, 1H), 9.27 (s, 1H), 9.34 (brs, 1H); MS (ESI (+)) m / e 515 (M + H)⁺.

Example 159

N- (4- {3-amino-6 - [(diethylamino) methyl] -7-fluoro-1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 152B and Example 5A for Example 157B and N- (3-chlorophenyl) -N '- [4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaboralan-2-yl) phenyl] urea, respectively, in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J = 7.29 Hz, 6H), 3.19 (m, 4H), 4.48 (d, J = 4.75 Hz, 2H ),

6.94 (d, J = 5.76 Hz, 1H), 7.03 (dt, J = 6.44, 2.20 Hz, 1H), 7.27-7.37 (m, 2H), 7 , 44 (d, J = 8.82 Hz, 2H), 7.63 (d, J =

8.48 Hz, 2H), 7.75 (m, 1H), 9.06 (s, 1H), 9.32 (brs, 1H); MS (ESI (+)) m / e 481 (M + H)⁺.

Example 160

N- (4- {3-amino-6 - [(diethylamino) methyl] -7-fluoro-1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by substituting Example 152B and Example 5A for Example 157B and Example 1B, respectively, in Example 152C. ¹H NMR (300 MHz, DMSO-d6) δ 1.27 (t, J =

7.12 Hz, 6H), 2.29 (s, 3H), 3.18 (m, 4H), 4.48 (d, J = 4.75 Hz, 2H), 6.81 (d, J = 7.12 Hz, 1H), 6.94 (d, J = 5.76 Hz, 1H), 7.17 (t, J = 7.80 Hz, 1H), 7.26 (m, 1H), 7 , 32 (s, 1H), 7.42 (d, J = 8.48 Hz, 2H), 7.63 (d, J = 8.48 Hz, 2H), 8.74 (s, 1H), 8 , 93 (s, 1H), 9.34 (brs, 1H); MS (ESI (+)) m / e 461 (M + H)⁺.

Example 161

N- (4- {3-amino-7 - [(3-pyridinyloxy) methyl] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

ES 2 398 074 T3

Example 161A

4-iodo-7 - [(3-pyridinyloxy) methyl] -1H-indazol-3-amine

The desired product was prepared by substituting 3-pyridinol for morpholine in Examples 15E-F.

Example 151B

N- (4- {3-amino-7 - [(3-pyridinyloxy) methyl] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 152B and Example 5A for Example 161A and Example 98A, respectively, in Example 152C and then purifying the resulting product by flash column chromatography on silica gel with 5-8% methanol. / dichloromethane. ¹H NMR (500 MHz, DMSO-d6) δ 4.38 (s, 2H), 5.40 (s, 2H), 7.32 (d, J = 7.17 Hz, 1H), 7.34-7 , 38 (m, 2H), 7.42 (d, J = 8.42 Hz, 2H), 7.52 (dd, J = 15.59.7.80 Hz, 2H), 7.58-7, 64 (m, 4H), 8.04 (s, 1H), 8.19 (d, J = 4.68 Hz, 1H), 8.39 (d, J = 2.50 Hz, 1H), 8, 96 (s, 1H), 9.12 (s, 1H), 11.92 (s, 1H); MS (ESl (+)) m / e 519 (M + H)⁺.

Example 162

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 162A

2- (4-iodo-1H-indazol-3-yl) -1H-isoindolo-1,3 (2H) -dione

A mixture of Example 1A (1.09 g) and phthalic anhydride (0.75 g) in dioxane (15 ml) was stirred overnight at 120 ° C and concentrated. The residue was triturated in diethyl ether (15 ml) to provide 0.51 g of the desired product. MS (ESl (+)) m / e 388 (M + H)⁺.

Example 1628

2- {4-iodo-1- [2- (4-morpholinyl) ethyl] -1H-indazol-3-yl} -1H-isoindolo-1,3 (2H) -dione

A mixture of Example 162A (100 mg), 4- (2-chloroethyl) morpholine (48 mg), and Na2CO3 (82 mg) in DMF (5 ml) was heated overnight at 80 ° C, cooled to room temperature and partitioned between 1N HCl and ethyl acetate. The aqueous layer was basified with 1N KOH and extracted with ethyl acetate. The extract was dried (MgSO4), filtered and concentrated to provide 45 mg of the desired product. MS (ESl (+)) m / e 503 (M + H)⁺.

Example 162C

4-iodo-1- [2- (4-morpholinyl) ethyl] -1H-indazol-3-amine

A mixture of hydrazine hydrate (0.058 ml) and Example 162B (120 mg, 0.24 mmol) in ethanol (5 ml) was stirred at 0 ° C for 3 hours and concentrated. The residue was purified by flash column chromatography on silica gel with 5-8% methanol / dichloromethane to provide 95 mg of the desired product.

Example 162D

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 162C for Example 152B in Example 152C. MS (ESl (+)) m / e 489 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.45 (d, J = 4.07 Hz, 4H), 2.68 (t, J = 6.61 Hz, 2H ), 3.54 (t, J = 4.05 Hz, 4H), 4.26 (t, J = 6.44 Hz, 2H), 4.41 (s, 2H), 6.78-6.83 (d, J = 6.78 Hz, 2H), 7.11 (dd, J = 11.36, 8.31 Hz, 1H), 7.31 (t, J = 8.48 Hz, 1H), 7 , 36-7.41 (m, 3H), 7.59 (d, J = 8.48 Hz, 2H), 8.01 (d, J = 7.46 Hz, 1H), 8.54 (s, 1H), 9.21 (s, 1H).

Example 163

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 162C for Example 15F in Examples 15G-H. MS (ESl (+)) m / e 475 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.58 (t, J = 5.77 Hz, 2H), 3.32-3.83 (ma, 8H), 4.55 (t, J = 6, 24 Hz, 2H), 6.79 (td, J = 8.42,1.87 Hz, 1H), 6.88 (d, J = 6.55 Hz, 1H), 7.15 (dd, J = 8.26.1.09 Hz, 1H), 7.29-7.34 (m, 1H), 7.38-7.42 (m, J = 8.11, 8.11 Hz, 3H), 7 , 48 (d, J = 8.11 Hz, 1H), 7.52 (dt, J =

11.85.2.18 Hz, 1H), 7.62 (d, J = 8.73 Hz, 2H), 9.06 (s, 1H), 9.12 (s, 1H).

Example 164

ES 2 398 074 T3

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 162C and 1-chloro-3-isocyanatobenzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H. MS (ESI (+)) m / e 491 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.58 (t, J = 5.92 Hz, 2H), 3.38-3.92 (ma, 8H), 4.55 (t, J = 6, 39 Hz, 2H), 6.88 (d, J = 6.86 Hz, 1H), 7.02-7.04 (m, 1H), 7.31-7.32 (m, 2H), 7, 38-7.41 (m, J = 7.95, 7.95 Hz, 3H),

7.48 (d, J = 8.11 Hz, 1H), 7.62 (d, J = 8.73 Hz, 2H), 7.74 (s, 1H), 9.09 (s, 1H), 9.11 (s, 1H).

Example 165

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 162C and 1-isocyanate-3 (trifluoromethyl) benzene for Example 15F and 1-fluoro-3-isocyanatobenzene, respectively, in Examples 15G-H. MS (ESI (+)) m / e 525 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 3.32-3.83 (ma, 8H), 3.58 (t, J = 5.77 Hz, 2H), 4.55 (t, J = 6, 39 Hz, 2H), 6.88 (d, J = 7.17 Hz, 1H), 7.32 (d, J = 7.80 Hz, 1H), 7.39-7.42 (m, 3H) , 7.48 (d, J = 8.42 Hz, 1H),

7.53 (t, J = 7.95 Hz, 1H), 7.61 (d, J = 8.73 Hz, 1H), 7.64 (d, J = 8.73 Hz, 2H), 8, 05 (s, 1H), 9.15 (s, 1H), 9.29 (s, 1H).

Example 166

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 15F and 1-fluoro-3-isocyanatobenzene for Example 162C and 1-isocyanato-3-methylbenzene, respectively, in Examples 15G-H. MS (ESI (+)) m / e 471 (M + H)⁺; ¹H NMR (500 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.58 (t, J = 5.77 Hz, 2H), 3.39-3.88 (ma, 8H), 4 , 55 (t, J = 6.39 Hz, 2H), 6.80 (d, J = 7.49 Hz, 1H), 6.87 (d, J = 6.86 Hz, 1H), 7.17 (t, 3 = 7.80 Hz, 1H), 7.26 (d, J = 8.42 Hz, 1H), 7.32 (s, 1H), 7.37-7.41 (m, 3H) , 7.48 (d, J = 8.11 Hz, 1H), 7.61 (d, J = 8.42 Hz, 2H), 8.75 (s, 1H), 8.93 (s, 1H) .

Example 167-I and 167-II

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea and N- [4- ( 3-amino-4-bromo-1H-indazol6-yl) phenyl] -N '- (3-methylphenyl) urea

Example 167A

2,4-dibromo-6-fluorobenzonitrile

The desired product was prepared by substituting 2,4-dibromo-6-fluorobenzoic acid for Example 15A (prepared as described in Tetrahedron Lett. 1996, 37, 6551-6554) in Examples 15B and 15C.

Example 167B

4,6-dibromo-1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 167A in Example 1A. ¹H NMR (DMSO-d6) δ 11.99 (1H, sa), 7.48 (1H, d, J = 1.6 Hz), 7.24 (1H, s), 5.22 (1H, d, J = 8.0 Hz).

Example 167-I and 167-II

N- (4- {3-amino-1- [2- (4-morpholinyl) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea and N- [4- { 3-amino-1- [2- (4-morpholinyl) ethyl] 1H-indazol-4-yl} phenyl] -N '- (3-methylphenyl) urea

A mixture of Example 167B (0.060 g, 0.021 mmol), Example 1B (0.073 g, 0.21 mmol), Na2CO3 (0.052 g, 0.49 mmol) and Pd (PPh3) 4 (0.014 g, 0.012 mmol) in 2 : 1 DME / water (1.2 ml) was heated to 85 ° C in a sealed tube overnight. The reaction was treated with more Pd (PPh3) 4 (0.028 g, 0.024 mmol), heated for two days, treated with more catalyst (0.028 g, 0.024 mmol), heated at 160 ° C for 2 hours and cooled to room temperature. The mixture was diluted with ethyl acetate and dichloromethane, cooled, and concentrated. The concentrate was purified by flash column chromatography on silica gel with methanol / dichloromethane (2: 100 to 5: 100), then purified by preparative HPLC with 30100% CH3CN / 5mM ammonium acetate buffer for 9 minutes to provide the desired products.

Example 167-I: LC / MS 434.2 (MH), LC retention time 3.00 min. ¹H NMR (DMSO-d6) δ 7.508 (2H, d, J = 8.4 Hz), 7.454 (1H, d, J = 1.2 Hz), 7.407 (2H, d, J = 8.4 Hz), 7.325 (1H, s), 7.257 (1H, d, J = 6.0 Hz), 7.166 (1H, m), 6.888 (1H, s), 6.799 (1H, d, J = 7.6 Hz), 4.397 (2H, s), 2.328 (3H, s).

ES 2 398 074 T3

Example 167-II: LC / MS 434.0 (MH), LC retention time 2.87 min. ¹H NMR (DMSO-d6) δ 11.88 (1H, sa), 8.961 (1H, sa), 8.782 (1H, sa), 7.637 (2H, d, J = 8.8 Hz), 7.560 (1H, d , J = 8.8 Hz), 7.414 (2H, d, J = 1.2 Hz), 7.352 (1H, d, J = 1.2 Hz), 7.319 (1H, s), 7.252 (1H, d, J = 7.6 Hz), 7.181-7.142 (1H, m), 6.796 (1H, d, J = 7.6 Hz), 5.147 (2H, d, J = 9.2 Hz), 2.285 (3H, s ).

Example 168

N- (4- {3-amino-1- [2- (dimethylamino) ethyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting 4- (2-chloroethyl) morpholine for N- (2-chloroethyl) -N, N-dimethylamine in Example 162. MS (ESI (+)) m / e 447 ( M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H), 2.87 (s, 3H), 2.88 (s, 3H), 3.54 (q, J = 5.65 Hz , 2H), 4.52 (t, J = 6.10 Hz, 2H), 6.79-6.84 (m, 1H), 6.58 (d, J =

6.10 Hz, 1H), 7.12 (dd, J = 11.36, 8.31 Hz, 1H), 7.37-7.42 (m, 3H), 7.50 (d, J = 7 , 79 Hz, 2H), 7.61 (d, J = 8.48 Hz, 2H), 7.99 (dd, J = 8.14,2.03 Hz, 1H), 8.55 (d, J = 2.37 Hz, 1H), 9.24 (s, 1H).

Example 169

N- (4- {3-amino-1- [2- (dimethylamino) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

Example 169A

1- [2- (dimethylamino) ethyl] -4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting N- (2-chloroethyl) -N, N-dimethylamine for 4- (2-chloroethyl) morpholine in Example 162A-C.

Example 169B

N- (4- {3-amino-1- [2- (dimethylamino) ethyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared as the bis (trifluoroacetate) salt by substituting Example 152B (50 mg, 0.16 mmol) and Example 5A for Example 169A and N- (3-chlorophenyl) -N '- [4- (4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea, respectively, in Example 152C. MS (ESI (+)) m / e 449 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.87 (s, 3H)

2.88 (s, 3H) 3.55 (c, J = 5.65 Hz, 2H) 4.52 (t, J = 6.27 Hz, 2H) 6.87 (dd, J = 6.95, 0.85 Hz, 1H) 7.01-7.05 (m, 1H) 7.30-7.32 (m, 2H) 7.38-7.42 (m, 3H) 7.50 (d, J = 8.48 Hz, 1H) 7.61 (d, J = 8.48 Hz, 2H) 7.73-7.75 (m, 1H) 9.01 (s, 1H) 9.04 (s, 1H ).

Example 170

N- [2 - ({3-amino-4- [4 - ({[(2-fluoro-5-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] methanesulfonamide

Example 170A

Tert-butyl 2- (3-cyano-2-fluoro-4-iodophenoxy) ethylcarbamate

The desired product was prepared by substituting tert-butyl 2-hydroxyethylcarbamate for 2- (4-morpholinyl) ethanol in Example 75A. Fr = 0.8 (1: 1 ethyl acetate / hexanes).

Example 170B

N- [2- (3-cyano-2-fluoro-4-iodophenoxy) ethyl] methanesulfonamide

A mixture of Example 170A (317 mg, 0.78 mmol) in TFA (1 mL) and CH2CL (1 mL) was stirred at room temperature for 10 minutes and concentrated. The residue was partitioned between saturated NaHCO3 and dichloromethane. The aqueous phase was extracted twice with dichloromethane and the combined organic extracts were dried (Na2SO4), filtered and concentrated. The concentrate was dissolved in pyridine (5 ml), treated with methanesulfonyl chloride (0.07 ml), stirred at room temperature for 6 hours, concentrated, and partitioned between ethyl acetate and 1N HCl. The organic extract dried (Na2SO4), filtered, and concentrated to provide the desired product. MS (ESI) m / e 383 (MH). Example 170C

N- {2 - [(3-amino-4-iodo-1H-indazol-7-yl) oxy] ethyl} methanesulfonamide

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 170B in Example 1A.

Example 170D

ES 2 398 074 T3

N- [2 - ({3-amino-4- [4 - ({[(2-fluoro-5-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] methanesulfonamide

The desired product was prepared as the trifluoroacetate salt by substituting Example 170C for Example 152B in Example 152C. MS (APCI (+)) m / e 513 (M + H)⁺; ¹H NMR (300 MHz, DMSO-d6) δ 2.28 (s, 3H) 2.99 (s, 3H)

3.43 (c, J = 5.76 Hz, 2H) 4.22 (t, J = 5.42 Hz, 2H) 4.35 (s, 2H) 6.70 (d, J = 7.46 Hz , 1H) 6.80 (d, J = 7.80 Hz, 1H) 6.80-6.83 (m, 1H) 7.08-7.19 (m, 2H) 7.37 (d, J = 8.81 Hz, 2H) 7.56 (d, J = 8.81 Hz, 2H) 8.01 (dd, J = 7.97, 1.86 Hz, 1H) 8.52 (d, J = 2 , 37 Hz, 1H) 9.17 (s, 1H) 11.77 (s, 1H).

Example 171

4- (1H-indol-5-yl) -1H-indazol-3-amine

The desired product was prepared by substituting 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) amylin and Example 15F for 5-indolylboronic acid and Example 1A, respectively, in the Example 15G. ¹H NMR (300 MHz, DMSO-d6) δ

4.28 (s, 2H), 6.50 (ddd, J = 3.05, 2.03, 0.68 Hz, 1H), 6.80 (dd, J = 6.27, 1.53 Hz, 1H), 7.18 (dd, J = 8.14, 1.70 Hz, 1H), 7.25 (m, 2H), 7.43 (m, 1H), 7.51 (d, J = 8 , 14 Hz, 1H), 7.60 (m, 1H), 11.23 (s, 1H), 11.63 (s, 1H); MS (ESI (+)) m / e 249 (M + H)⁺.

Example 172

N- {4- [3-amino-1- (2-methoxyethyl) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

Examples 172A and 172B

2- [4-iodo-2- (2-methoxyethyl) -2H-indazol-3-yl] -1H-isoindolo-1,3 (2H) -dione and 2- [4-iodo-1- (2-methoxyethyl ) -1H-indazol-3-yl] -1Hisoindole-1,3 (2H) -dione

A mixture of Example 162A (1.2 g, 3.1 mmol), 1-bromo-2-methoxyethane (0.35 ml, 3.7 mmol) and K2CO3 (857 mg, 6.2 mmol) in DMF (15 ml) was stirred overnight at rt and then concentrated to dryness. The residue was partitioned between EtOAc and H2O. The extract was dried (Na2SO4), concentrated, and the residue was purified by flash chromatography on silica gel, eluting with 2% MeOH / CH2Cl2. The product was obtained as a mixture of Examples 172A and 172B (3: 1).

Example 172C and 172D

4-iodo-1- (2-methoxyethyl) -1H-imidazol-3-amine and 4-iodo-2- (2-methoxyethyl) -1H-indazol-3-amine

A mixture of isomers 172A and 172B (970 mg, 2.2 mmol) was dissolved in EtOH (10 ml), and the solution was cooled to 0 ° C, treated dropwise with hydrazine monohydrate (0.58 ml) , and then stirred for 3 h at rt. The mixture was concentrated to dryness and the residue was purified by flash chromatography on silica gel, eluting with 0-4% MeOH / CH2Cl2. A mixture of the 172C and 172D isomers was obtained. MS (ESI (+)) m / e 317.8 (M + H)⁺.

Example 172E and 172F

4- (4-aminophenyl) -1- (2-methoxyethyl) -1H-indazol-3-amine and 4- (4-aminophenyl) -2- (2-methoxyethyl) -1H-indazol-3-amine

A mixture of Examples 172E and 172F was prepared by substituting Example 15F for a mixture of Examples 172C and 172D in Example 15G. MS (ESI (+)) m / e 283.0 (M + H)⁺.

Example 172G

N- {4- [3-amino-1- (2-methoxyethyl) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was obtained by replacing Example 15G with a mixture of Examples 172E and 172F and 1-fluoro-3-isocyanatobenzene with 1-fluoro-2-isocyanato-4-methylbenzene in Example 15H. Also, DMF was used instead of CH2CL. The mixture was concentrated and the residue was purified by preparative HPLC as in Example 3 to provide the desired product as the trifluoroacetate salt.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 3.21 (s, 3H) 3.69 (t, J = 5.4 Hz, 2H) 4.32 ( t, J = 5.4 Hz, 2H) 6.79-6.84 (m, 2H) 7.12 (dd, J = 11.4, 8.3 Hz, 1H)

7.31 (dd, J = 8.5, 6.8 Hz, 1H) 7.38-7.43 (m, 3H) 7.59 (d, J = 8.5 Hz, 2H) 8 .01 (dd, J = 7.8, 2.0 Hz, 1H) 8.54 (d, J =

2.4 Hz, 1H) 9.21 (s, 1H) MS (ESI (+)) m / e 434.0 (M + H)⁺.

Example 174

N- (4- {3-amino-7- [2- (3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl) ethoxy] -1H-indazol-4-yl} phenyl) -N ' - (3,5-dimethylphenyl) urea

The desired product was prepared by substituting Example 145A for Example 15G and 1-fluoro-3-isocyanatobenzene and

ES 2 398 074 T3

1-isocyanato-3,5-dimethylbenzene, respectively, in Example 15H. The product was purified by preparative HPLC as in example 3.¹H NMR (300 MHz, DMSO-D6) δ ppm 1.27 (s, 6H) 2.24 (s, 6H) 2.81 (s, 3H) 3.83 (t, J = 6.4 Hz, 2H) 4.35 (t, J = 6.4 Hz, 2H) 6.62 (s, 1H) 6.68 (d, J = 7.8 Hz, 1H) 6.83 ( d, J = 7.8 Hz, 1H) 7.09 (s, 2H) 7.34 (d, J = 8.8 Hz, 2H) 7.55 (d, J = 8.8 Hz, 2H) 8.54 (s, 1H) 8.74 (s, 1H) 11.75-11.85 (br, 1H) MS (ESI (+)) m / e 556.3 (M + H)⁺.

Example 175

N- [4- (3-amino-1H-indazol-4-yl) -2,6-dimethylphenyl-N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 4-bromo-2,6-dimethylaniline for 4-bromo-2-ethylaniline in Examples 149A-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3H) 2.30 (s, 6H) 6.77-6.80 (m, 1H) 6.87 (dd, J = 5.8, 2.4 Hz, 1H) 7.10 (dd, J = 11.5, 8.5 Hz, 1H) 7.20 (s, 2H) 7.33 (s, 1H ) 7.35 (d. J = 3.4 Hz, 1H) 7.95 (d, J = 6.8 Hz, 1H) 8.23 ​​(s, 1H) 8.54-8.65 ( bs, 1H) 11.99-12.20 (bs, 1H) MS (ESI (+)) m / e 404.2 (M + H)⁺.

Example 176

N- [4- (3-amino-1H-indazol-4-yl) -2,6-dimethylphenyl-N '- [3- (trifluoromethyl) phenylurea

The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylaniline for 1-isocyanato-3- (trifluoromethyl) benzene and 4-bromo-2,6-dimethylaniline, respectively, in the Examples. 149A-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.30 (s, 6H) 6.84 (dd, J = 5.3, 2.5 Hz, 1H) 7.21 (s, 2H) 7.27-7.32 (m, 3H) 7.50 (t, J = 8.0 Hz, 1H) 7.62 (d, J = 8.5 Hz, 1H) 7.96 (s , 1H) 8.03 (s, 1H) 9.17 (s, 1H) 11.88-11.99 (m, 1H) MS (ESI (+)) m / e

440.2 (M + H)⁺.

<img file="ES2398074T3_D0012.tif" />

Example 177

N- [4- (3-amino-1H-indazol-4-yl) phenyl-N '- (3-hydroxyphenyl) urea

The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzene and 4-bromo-2-ethylamine for 4-iodo-1-isocyanatobenzene and 3-hydroxyaniline, respectively, in Examples 149A-C. ¹H NMR (300 MHz, DMSOD6) δ ppm 6.38 (ddd, J = 8.1, 2.3, 0.9 Hz, 1 H) 6.82 (ddd, J = 8.0, 2.0, 0.9 Hz, 1H) 6.86 (dd, J = 6.4, 1.7 Hz, 1H) 7.03-7.08 (m, 2H) 7.29-7.35 (m , 2H) 7.40 (d, J = 8.5 Hz, 2H) 7.59 (d, J = 8.8 Hz, 2H) 8.65 (s, 1H) 8.80 (s , 1H) 9.12-9.53 (br, 1H) 11.80-12.39 (br, 1H) MS (ESI (+)) m / e 360.2 (M + H)⁺.

Example 178

N- [2 - ({3-amino-4- [4 - ({[(3-methylphenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethylmethanesulfonamide

Example 178A

N- (2 - {[3-amino-4- (4-aminophenyl) -1H-indazol-7-yloxy} ethyl) methanesulfonamide

The desired product was prepared by substituting Examples 1A and 1B for Example 170C and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, respectively, in Example 1C.

Example 178B

N- [2 - ({3-amino-4- [4 - ({[(3-methylphenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethylmethanesulfonamide

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 178A and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 2.99 (s, 3H) 3.44 (c, J = 5.8 Hz, 2H) 4.23 ( t, J = 5.4 Hz, 2H) 6.73 (d, J = 7.8 Hz, 1H) 6.80 (d, J = 7.8 Hz, 1H)

6.84 (d, J = 7.8 Hz, 1H) 7.12-7.19 (m, 2H) 7.25 (d, J = 8.1 Hz, 1H) 7.31 (s , 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.56 (d, J

ES 2 398 074 T3 = 8.5 Hz, 2H) 8.63 (s, 1H) 8.77 (s, 1H), 11.91-12.07 (bs, 1H) MS (ESl ( +)) m / e 495.1 (M + M)⁺.

Example 179

N- {2 - [(3-amino-4- {4 - [({[2-fluoro-5- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenyl} -1H-indazol-7-yl) oxy] ethyl} methanesulfonamide

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 178A and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 2.99 (s, 3H) 3.44 (c, J = 6.1 Hz, 2H) 4.22 (t, J = 5.4 Hz, 2H) 6.72 (d, J = 7.8Hz, 1H) 6.82 (d, J = 7.8Hz, 1H)

7.17 (t, J = 6.1 Hz, 1H) 7.38-7.42 (m, 3H) 7.48-7.54 (m, 1H) 7.58 (d, J = 8.8 Hz, 2H) 8.65 (dd, J = 7.5, 2.0 Hz, 1H)

8.94 (d, J = 3.1 Hz, 1H) 9.29 (s, 1H) 11.87 (s, 1H) MS (ESl (+)) m / e 567.2 (M + H)⁺.

Example 180

N- [2 - ({3-amino-4 - ({[(3-chlorophenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] methanesulfonamide

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 178A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.99 (s, 3H) 3.43 (c, J = 5.8 Hz, 2H) 4.22 (t, J = 5.4 Hz, 2H) 6.71 (d, J = 7.8 Hz, 1H) 6.81 (d, J = 7.8 Hz, 1H) 7.03 (dt, J = 6.7, 2.3 Hz, 1H) 7.15-7.19 (m, 1H) 7.27-7.32 (m, 2H) 7.37 (d, J = 8.5 Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 7.73 (t, J = 1.9 Hz, 1H) 8.86 (s, 1H) 8.93 (s, 1H) 11.84 (s, 1H) MS (ESl (+)) m / e 515.1 (M + H)⁺.

Example 181

N- {2 - [(3-amino-4- {4 - [({3- (trifluoromethyl) phenyl] amino} carbonyl) amino] phenyl} -1H-indazol-7-yl) oxyl] ethyl} methanesulfonamide

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 178A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.99 (s, 3H) 3.43 (c, J = 5.8 Hz, 2H) 4.22 (t, J = 5.4 Hz, 2 H) 6.71 (d, J = 7.5 Hz, 1 H) 6.81 (d, J = 7.8 Hz, 1 H) 7.17 (t, J = S. 8 Hz, 1 H ) 7.30-7.34 (m, 1H) 7.37 (d, J = 8.5 Hz, 2H) 7.50-7.61 (m, 4H) 8.04 (t, J = 2.2 Hz, 1H) 8.91 (s, 1H) 9.09 (s, 1H) 11.82 (s, 1H) MS (ESl (-)) m / e 547.1 ( MH) -.

Example 182

N- [4- (3-amino-1H-indazol-6-yl) phenyl] -N '(- 3-methylphenyl) urea

Example 182A

6-broma-1H-indazol-3-amine

The desired product was prepared by substituting 4-bromo-2-fluorobenzonitrile for 2-fluoro-6-iodobenzonitrile in Example 1A .. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.44 (s, 2H) 7.02 (dd, J = 8.48,1.70 Hz, 1H) 7.41 (d, J = 1 , 70Hz, 1H) 7.63 (d, J = 8.48Hz, 1H) 11.49 (s, 1H).

Example 182C

N '- [4- (3-amino-1H-indazol-6-yl) phenyl] -N' - (3-methylphenyl) urea

The desired product was prepared by substituting 1A and 5A for Example 182A and 1B, respectively, in Example 5B. MS (ESl (+) Q1MS m / z 358 (M + H)⁺; ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 5.34 (s, 2H) 6.79 (d, J = 7.32 Hz, 1H) 7.15- 7.20 (m, 2H) 7.25 (d, J = 8.24 Hz, 1H) 7.31 (s, 1H) 7.38 (s, 1H) 7.55 (d, J = 8.85 Hz, 2H) 7.62 (m, 2H) 7.72 (d, J = 8.54 Hz, 1H) 8.75 (s, 1H) 8.89 (s, 1 H) 11.38 (s, 1H)

Example 183

3-amino-N- (3-methylphenyl) -6- [4 - ({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazole-1-carboxamide

Example 183A

6- (4-aminophenyl) -1H-indazol-3-amine

The desired product was prepared by substituting Example 1A for Example 182A and Example 5A for 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.19 (s, 2H) 5.27 (s, 2H) 6.64 (d, J = 8.48 Hz, 2H) 7.10 ( dd, J = 8.48, 1.36 Hz, 1H) 7.25 (s, 1H) 7.37 (d, J = 8.48 Hz, 2H) 7.64 (d, J =

8.48 Hz, 1H) 11.25 (s, 1H).

ES 2 398 074 T3

Example 183B

3- amino-N- (3-methylphenyl) -6- [4 - ({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazole-1-carboxamide

The desired product was prepared by substituting 15G and 1-fluoro-3-isocyanatobenzene for Example 183A and 1-isocyanato-3-methylbenzene, respectively for Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H)

2.32 (s, 3H) 6.37 (s, 2H) 6.80 (d, J = 7.1 Hz, 1H) 6.9 (d, J = 7.5 Hz, 1H) 7.17 (t, J = 7.8 Hz, 1H) 7.22 (t, J = 7.8 Hz, 1H) 7.25 (d, J = 8.5 Hz, 1H) 7, 33 (s, 1H) 7.46-7.50 (m, 1H) 7.55-7.61 (m, 4H) 7.68 (d, J = 8.8 Hz, 2H) 7 , 95 (d, J =

8.1 Hz, 1H) 8.39 (d, J = 0.7 Hz, 1H) 8.62 (s, 1H) 8.83 (s, 1H) 9.37 (s, 1H) MS (ESI (+)) m / e 490.0 (M + H)⁺.

Example 184

N- [3- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 184A

N- (3-methylphenyl) -N '- [3- (4,4,5,5-tetramethyl-1-1,3,2-dioxaborolan-2-yl) phenyl] urea

The desired product was prepared by substituting 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline for 3- (4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl) aniline in Example 1B. MS (ESI (+)) m / e 352.9 (M + H)⁺.

Example 184B

N- [3- (3-amino-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 184A for Example 5A in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3H) 6.78-6.83 (m, 2H) 7.05-7.09 (m, 1H) 7.15 (t, J = 7.8 Hz, 1H) 7.22 (d, J = 8.1 Hz, 1H) 7.28-7.31 (m, 3H) 7.38-7.43 (m , 2H) 7.63 (s, 1H) 8.63 (s, 1H) 8.81 (s, 1H) 11.74 (s, 1H) MS (ESI (+)) m / e

358.1 (M + H)⁺.

Example 185

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 185A

4- iodo-7-methyl-1H-indazol-3-amine

The desired compound was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 15C in Example 1A. MS (ESI (+)) m / e 273.8 (M + H)⁺.

Example 185B

4- (4-aminophenyl) -7-methyl-1H-indazol-3-amine

The desired product was prepared by substituting Examples 1A and 1B for Example 185A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, respectively, in Example 1C. MS (eSi (+)) m / e 239.0 (M + H)⁺.

Example 185C

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 185B and 1-isocyanato-3-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 2.42 (s, 3H) 6.70 (d, J = 7.1 Hz, 1H) 6.80 ( d, J = 7.5 Hz, 1H) 7.05 (dd, J = 7.1, 1.0 Hz, 1H) 7.16 (t, J = 7.8 Hz, 1H) 7, 25 (d, J = 8.5 Hz, 1H) 7.32 (s, 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 8.63 (s, 1H) 8.77 (s, 1H) 11.75 (s, 1H) MS (ESI (+)) m / e 371.6 (M + H)⁺.

Example 186

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 185B and 1-chloro-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 6.80 (d, J = 7.1 Hz, 1H) 7.00-7.06 (m, 1H) 7.15 (dd, J = 7.1, 1.0 Hz, 1H) 7.28-7.32 (m, 2H) 7.39 (d, J = 8.8 Hz, 2H) 7 , 60 (d, J = 8.8 Hz, 2H) 7.73-7.75 (m, 1H) 8.98 (s, 1H) 9.01 (s, 1H) 12.01- 12.46 (bs, 1H) MS (ESI (+)) m / e 382.0 (M + H)⁺.

ES 2 398 074 T3

Example 187

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 185B and 1-isocyanato-3- (trifluoromethyl) benzene in Example 15H, respectively. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ p ± 2.43 (s, 3 H) 6.73 (d, J = 7.1 Hz, 1 H) 7.08 (d, J = 7.1 Hz , 1H) 7.32 (d, J = 8.1 Hz, 1H) 7.39 (d, J = 8.5 Hz, 2H) 7.53 (t, J = 7.8 Hz, 1 H) 7.58-7.61 (m, 3H) 8.04 (s, 1H) 8.94 (s, 1H) 9.1 (s,

H) 11.87 (s, 1H) MS (ESI (+)) m / e 426.0 (M + H)⁺.

Example 188

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 185B and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.43 (s, 3H) 6.71 (d, J = 7.1 Hz, 1H) 7.06 (d, J = 7.8 Hz, 1H) 7.38-7.43 (m, 3H) 7.48-7.55 (m, 1H) 7.59 (d, J = 8.5 Hz, 2H) 8.65 (dd , J = 7.3, 2.2 Hz, 1H) 8.95 (d, J = 2.7 Hz, 1H)

9.30 (s, 1H) 11.78 (s, 1H) MS (ESI (+)) m / e 444.1 (M + H)⁺.

Example 189

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 185B and 1-bromo-3-isocyanatobenzene for Example 15G and 1-fluoro-3-isocyanatobenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.44 (s, 3 H) 6.76 (d, J = 7.1 Hz, 1 H) 7.11 (dd, J = 7.3, 0 , 9 Hz, 1H) 7.16 (ddd, J = 7.8, 2.0, 1.0 Hz, 1H) 7.25 (t, J = 8.0 Hz, 1H) 7.33 (ddd, J = 8.1, 2.0, 1.0 Hz, 1H) 7.39 (d, J = 8.5 Hz, 2H) 7.59 (d, J = 8.8 Hz, 2H) 7.88 (t, J = 1.9 Hz, 1H) 8.94 (s, 1H) 8.97 (s, 1H) 12.06 (s, 1H) MS (ESI ( +)) m / e 463.0, 438.0 (M + H)⁺.

Example 190

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 185B for Example 15G in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 6.76-6.82 (m, 2H) 7.13-7.17 (m, 2H) 7.32 (td, J = 8.5, 6.8 Hz, 1H) 7.39 (d, J = 8.8 Hz, 2H) 7.52 (dt, J = 12.1, 2.3 Hz, 1H) 7.60 (d, J = 8.5 Hz, 2H)

8.96 (s, 1H) 9.03 (s, 1H) 12.08-12.44 (br, 1H) MS (ESI (+)) m / e 376.1 (M + H)⁺.

Example 191

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 185B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 2.45 (s, 3H) 6.78 (d, J = 6.8 Hz, 1H) 6.79- 6.84 (m, 1H) 7.08-7.15 (m, 2H) 7.39 (d, J = 8.5 Hz, 2H) 7.59 (d, J = 8.8 Hz , 2H) 8.01 (dd, J = 7.8, 1.7Hz, 1H) 8.53 (d, J = 2.4Hz, 1H) 9.21 (s, 1H) 12 0.00-12.33 (bs, 1H) MS (ESI (+)) m / e 390.0 (M + H)⁺.

Example 192

N- [4- (3-amino-7-methyl-1H-indazol-4-yl) phenyl] -N '- (3-cyanophenyl) urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 185B and

3-isocyanatobenzonitrile, respectively, in Example 15H. Also, DMF was used instead of C ^ Ch¹H NMR (300 MHz, DMSO-D6) δ ppm 2.44 (s, 3H) 6.77 (d, J = 7.1 Hz, 1H) 7.12 (dd, J = 7.1, 1 , 0 Hz, 1H) 7.40 (d, J = 8.5 Hz,

H) 7.43 (dt, J = 7.8, 1.4 Hz, 1 H) 7.51 (t, J-8.0 Hz, 1 H) 7.60 (d, J = 8.5 Hz , 2H) 7.70 (ddd, J = 8.3, 2.2, 1.0 Hz, 1H) 8.01 (t, J = 1.7 Hz, 1H) 9.05 (s, 1H) 9.14 (s, 1H) 11.98-12.22 (br, 1H) MS m / e (ESI (+)) 383.1 (M + H)⁺.

Example 193

N- [4- (3-amino-1H-indazol-4-yl) -2- (trifluoromethoxy) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline for 4-bromo-2- (trifluoromethoxy) aniline in Examples 149A-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.82-6.91 (m, 2H) 7.14 (dd, J = 11.5, 8.1 Hz , 1

ES 2 398 074 T3

H) 7.32 (d, J = 1.0 Hz, 1H) 7.34 (s, 1H) 7.47-7.52 (m, 2H) 8.03 (dd, J = 8, 0.19Hz, 1H) 8.42 (d, J = 8.8Hz, 1H) 9.03 (s, 1H) 9.24 (d, J = 2.4Hz, 1H ) 11.83-12.13 (brs, 1H) MS (ESI (+)) m / e 460.1 (M + H)⁺.

Example 194

N- [5- (3-amino-1H-indazol-4-yl) pyridin-2-yl] -N '- (2-fluoro-5-methylphenyl) urea

Example 194A

N- (5-bromopyridin-2-yl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 2-amino-5-bromopyridine and 1-fluoro-2-isocyanato-4-methylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene in Example 15H, respectively. MS (ESI (+)) m / e 324.0 (M + H)⁺.

Example 194B

N- [5- (3-amino-1H-indazol-4-yl) pyridin-2-yl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 194A for Example 44A in Example 44B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.30 (s, 3H) 6.83-6.92 (m, 2H) 7.15 (dd, J = 11.2, 8.5 Hz , 1H) 7.34 (s, 1H) 7.35 (s, 1H)

7.54 (d, J = 8.5 Hz, 1H) 7.90 (dd, J = 8.7, 2.5 Hz, 1H) 8.07 (dd, J = 7.5, 2, 0 Hz, 1H) 8.38 (d, J = 2.4 Hz, 1H) 9.95 (s, 1H) 10.88 (s, 1H) 12.02 (s, 1H) MS (ESI (+)) m / e 377.1 (M + H)⁺.

Example 195

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

Example 195A

7-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 26A in Example 1A.

Example 195B

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N'-2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 195A for Example 1A and Example 5A for N- (2-fluoro-5 (trifluoromethyl) phenyl) -N '- [4- (4,4,5,5-tetramethyl-1 , 3,2-dioxaborolan-2-yl) phenyl] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.74 (dd, J = 7.8, 4.1 Hz, 1 H) 7.13 (dd, J = 11.5, 7.8 Hz, 1 H) 7.37-7.43 (m, 3H) 7.51 (dd, J =

10.9, 8.5 Hz, 1H) 7.61 (d, J = 8.5 Hz, 2H) 8.64 (dd, J = 7.3, 2.2 Hz, 1H) 8, 96 (d, J = 3.1 Hz, 1H) 9.32 (s, 1H) 12.25 (s, 1H) MS (ESI (+)) m / e 448.0 (M + H)⁺.

Example 196

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl-N '- (4-fluorophenyl) urea

The desired product was prepared by substituting Example 195A for Example 1A and Example 5A for N- (4fluorophenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) phenyl] urea in Example 5B. ¹H RmN (300 MHz, DMSOD6) δ ppm 6.74 (dd, J = 7.8, 4.1 Hz, 1 H) 7.11 (dd, J = 7.8, 1.4 Hz, 1 H) 7.15 (d, J = 8.5 Hz, 2H) 7.37 (d, J = 8.5 Hz, 2H) 7.49 (dd, J = 9.3, 4.9 Hz, 2 H) 7.58 (d, J = 8.5 Hz, 2H) 8.77 (s, 1H) 8.83 (s, 1H) 12.29 (s, 1H) MS (ESI (+ )) m / e 380.0 (M + H)⁺.

Example 197

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (2-fluorophenyl) urea

The desired product was prepared by substituting Example 195A for Example 1A and Example 5A for N- (2-fluorophenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) phenyl] urea in Example 5B. ¹H RmN (300 MHz, DMSOD6) δ ppm 6.98-7.06 (m, 1H) 7.14 (dd, J = 11.2, 7.8 Hz, 1H) 7.16 (dt, J = 7.5, 1.4 Hz, 1H) 7.25 (ddd, J = 11.5, 8.1,

1.4 Hz, 1H) 7.33-7.38 (m, 1H) 7.39 (d, J = 8.5 Hz, 2H) 7.59 (d, J = 8.5 Hz, 2H) 8.17 (td, J = 8.3, 1.7Hz, 1H) 8.61 (d, J = 2.7Hz, 1H) 9.23 (s, 1H) 11, 99-12.62 (bs, 1H) MS (ESI (+)) m / e 380.0 (M + H)⁺.

Example 198

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-fluoro-4-methylphenyl) urea

ES 2 398 074 T3

The desired product was prepared by substituting Example 195A for Example 1A and Example 5A for N- (3-fluoro-4-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenyl] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.17 (d, J = 1.4 Hz, 3H) 6.73 (dd, J = 7.8, 4.1 Hz, 1H) 7, 05 (dd, J = 8.3, 2.2 Hz, 1 H) 7.13 (dd, J = 11.2, 7.8 Hz, 1 H) 7.17 (t, J = 8.7 Hz , 1H) 7.37 (d, J = 8.5 Hz, 2H) 7.45 (dd, J = 12.5, 2.0 Hz, 1H) 7.58 (d, J = 8, 5 Hz, 2H)

8.84 (s, 1H) 8.86 (s, 1H) 12.11-12.41 (br, 1H) MS (ESI (+)) m / e 394.1 (M + H)⁺.

Example 199

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N'-phenylurea

The desired product was prepared by substituting Example 1A for Example 195A and Example 5A for N-phenyl-N '- [4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.74 (dd, J = 7.8, 4.4 Hz, 1 H) 6.98 (t, J = 7.3 Hz, 1 H) 7, 13 (dd, J = 11.2, 7.8 Hz, 1H) 7.26-7.32 (m, 2H) 7.37 (d, J = 8.5 Hz, 2H) 7.46 -7.49 (m, 2H) 7.59 (d, J = 8.5 Hz, 2H) 8.74 (s, 1H) 8.84 (s, 1H) 11.99-12, 59 (bs, 1H) MS (ESI (+)) m / e 362.0 (M + H)⁺.

Example 200

N- [2 - ({3-amino-4-4 - ({(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] -1,1,1-trifluoromethanesulfonamide

Example 200A

N- {2 - [(3-amino-4-iodo-1H-indazole-7-oxy] ethyl} -1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substituting anhydrous trifluoromethanesulfonic chloride for methanesulfonyl chloride in Example 170B.

Example 200B

N- [2 - ({3-amino-4- [4 - ({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] -1,1, 1-trifluoromethanesulfonamide

The desired product was prepared by substituting Example 200A and Example 1B for Example 1A and Example 5A, respectively, in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 3.65 (c, J = 6.1 Hz, 2H) 4.24 (t, J = 5.3 Hz, 2H) 6.73 (d, J = 7.8Hz, 1H) 6.80 (d, J = 6.8Hz, 1H) 6.85 (d, J = 7.8Hz, 1H ) 7.16 (t, J = 7.6 Hz, 1H)

7.25 (d, J = 8.5 Hz, 1H) 7.31 (s, 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.57 (d, J = 8 , 5 Hz, 2H) 8.63 (s, 1H) 8.78 (s, 1H) 9.52 (t, J = 5.6 Hz, 1H) 11.83 (s, 1H) MS (ESI (+)) m / e 549.1 (M + H)⁺.

Example 201

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-2-isocyanato-4-methylbenzene in Examples 44A-B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.80-6.87 (m, 2H) 7.13 (dd, J = 11.4, 8.3 Hz , 1H) 7.26-7.40 (m, 4H) 8.04 (dd, J = 8.1, 1.7 Hz, 1H) 8.32 (t, J = 8.5 Hz, 1H) 9.04 (d, J = 2.4Hz, 1H) 9.16 (d, J = 2.7Hz, 1H) 11.90 (s, 1H) MS (ESI (+) ) m / e 394.2 (M + H)⁺.

Example 202

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 5A for N- (4-fluoro-3-trifluoromethylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.83 (dd, J = 5.8, 2.3 Hz, 1H) 7.27-7.34 (m, 2H) 7.40-7 , 48 (m, 3H) 7.61 (d, J = 8.8 Hz, 2H) 7.63-7.69 (m, 1H) 8.03 (dd, J = 6.4, 2 , 7 Hz, 1H) 8.99 (s, 1H) 9.13 (s, 1H) 11.94 (s, 1H) MS (ESI (+)) m / e 430.0 (M + H)⁺.

Example 203

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting N- (2-fluoro-3-trifluoromethylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl for Example 5A ] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.85 (dd, J = 5.8, 2.0 Hz, 1H) 7.29-7.39 (m, 4H) 7.43 (d , J = 8.5 Hz, 2H) 7.62 (d, J = 8.5 Hz, 2H) 8.45-8.50 (m, 1H) 8.90 (d, J = 2, 7 Hz, 1H) 9.31 (s, 1H) 12.01 (m, 1H) MS (ESI (+)) m / e 430.1 (M + H)⁺.

ES 2 398 074 T3

Example 204

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (4-bramo-2-fluorophenyl) urea

The desired product was prepared by substituting Example 5A for N- (4-bromo-2-fluorophenyl) N '- [4- (4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl) phenyl] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.83 (dd, J = 5.8, 2.0 Hz, 1 H) 7.30 (d, J = 0.7 Hz, 1 H) 7, 31 (dd, J = 13.2, 8.1 Hz, 1H) 7.37 (ddd, J = 8.8, 2.0, 1.4 Hz, 1H) 7.42 (d, J = 8.8 Hz, 2H) 7.56-7.61 (m, 3H) 8.16 (t, J = 8.8 Hz, 1H) 8.71 (d, J = 2.4 Hz, 1H) 9.25 (s, 1H) 11.97 (s, 1H) MS (ESI (+)) m / e 440.0, 440.9 (M + H)⁺.

Example 205

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (5-fluoro-2-methylphenyl) urea

The desired product was prepared by substituting Example 5A for N- (5-fluoro-2-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl) phenyl] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 3 H) 6.76 (td, J =

8.5, 2.7 Hz, 1H) 6.87 (dd, J = 6.1, 1.7 Hz, 1H) 7.16-7.24 (m, 1H) 7.30-7 , 38 (m, 2H) 7.43 (d, J = 8.5 Hz, 2H) 7.62 (d, J = 8.5 Hz, 2H) 7.87 (dd, J = 12, 2, 2.7 Hz, 1H) 8.12 (s, 1H) 9.34 (s, 1H) 11.94-12.25 (br, 1H) MS (ESI (+)) m / and

376.1 (M + H)⁺.

Example 206

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 5A for N- (4-fluoro-3-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl) phenyl] urea in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J = 1.7 Hz, 3 H)

6.84 (dd, J = 6.1, 1.7 Hz, 1H) 7.06 (t, J = 9.2 Hz, 1H) 7.25-7.34 (m, 3H) 7 , 37-7.41 (m, 3H) 7.59 (d, J = 8.5 Hz, 2H)

8.69 (s, 1H) 8.84 (s, 1H) 11.86-12.20 (br, 1H) MS (ESI (+)) m / e 376.1 (M + H)⁺.

Example 207

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N'-phenylurea

Example 207A

2-fluoro-6-iodo-3- (3-morpholin-4-ylpropoxy) benzonitrile

The desired product was prepared by substituting 3- (4-morpholinyl) -propan-1-ol for 2- (4-morpholinyl) ethanol in Example 75A. MS (ESI (+)) m / e 391 (M + H)⁺.

Example 207B

4- (4-aminophenyl) -7- (3-morpholin-4-ylpropoxy) -1H-indazol-3-amine

The desired product was prepared by substituting Example 207A for Example 15E in Examples 15F-G.

Example 207C

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N'-phenylurea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 207B and isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2H) 3.08-3.20 (m, 4H) 3.51-3.53 (m, 2H ) 3.65-3.70 (m, 2H) 4.02-4.05 (m, 2H) 4.24 (t, J = 5.9 Hz, 2H) 6.72 (d, J = 7.8 Hz, 1H) 6.82 (d, J = 7.8 Hz, 1H) 6.98 (t, J = 7.3 Hz, 1H) 7.27-7.31 (m , 2H) 7.35 (d, J = 8.4 Hz, 2H) 7.48 (d, J = 7.8 Hz, 2H) 7.57 (d, J = 8.4 Hz, 2 H) 8.76 (s, 1H) 8.84 (s, 1H) 9.68 (s, 1H) 11.86 (s, 1H) MS (ESI (+)) m / e 487, 2 (M + H)⁺.

Example 208

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 207 for Example 15G in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2H) 3.08-3.18 (m, 4H) 3.51-3.53 (m, 2H ) 3.65-3.70 (m, 2H) 4.02-4.05 (m, 2H) 4.23 (t, J = 5.8 Hz, 2H) 6.72 (d, J = 7.8 Hz, 1H) 6.78 (dt, J = 8.1, 2.5 Hz, 1H) 6.82 (d, J = 7.8 Hz, 1H) 7.15 (dd , J = 8.1, 1.3 Hz, 1H) 7.31 (dd, J = 15.3, 8.4 Hz, 1H) 7.36 (d, J = 8.7 Hz, 2H ) 7.52 (dt, J = 11.9, 2.2 Hz, 1H) 7.57 (d, J

ES 2 398 074 T3 = 8.7 Hz, 2H) 8.96 (s, 1H) 9.06 (s, 1H) 9.71 (s, 1H) 11.86 (s, 1H) MS (ESI (+)) m / e 505.1 (M + H)⁺.

Example 209

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 207B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.19-2.24 (m, 2H) 2.28 (s, 3H) 3.08-3.18 (m, 2H) 3.42 -3.45 (m, 2H) 3.50-3.55 (m, 2H) 3.68-3.72 (m, 2H) 4.03-4.08 (m, 2H) 4 , 24 (t, J = 5.8 Hz, 2H) 6.75 (d, J = 7.8 Hz, 1H) 6.80-6.84 (m, 1H) 6.84 (d, J = 7.8 Hz, 1H) 7.11 (dd, J =

11.2, 8.4 Hz, 1H) 7.37 (d, J = 8.4 Hz, 2H) 7.58 (d, J = 8.4 Hz, 2H) 7.99 (dd, J = 7.8, 1.9 Hz, 1H) 8.56 (d, J = 2.5 Hz,

H) 9.24 (s, 1H) 9.76-10.28 (br, 1H) MS (ESI (+)) m / e 519.2 (M + H)⁺.

Example 210

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 207B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.19-2.23 (m, 2H) 2.29 (s, 3H) 3.08-3.17 (m, 2H) 3.43 -3.51 (m, 4H) 3.66-3.70 (m, 2H) 4.02-4.05 (m, 2H) 4.24 (t, J = 5.8 Hz,

H) 6.72 (d, J = 7.8 Hz, 1 H) 6.80 (d, J = 8.1 Hz, 1 H) 6.82 (d, J = 7.8 Hz, 1 H) 7.16 (t, J = 7.6 Hz, 1H) 7.26 (d, J =

8.1 Hz, 1H) 7.32 (s, 1H) 7.35 (d, J = 8.4 Hz, 2H) 7.57 (d, J = 8.4 Hz, 2H) 8 , 70 (s, 1H) 8.84 (s, 1H) 9.72 (s, 1H)

11.88 (s, 1H) MS (ESI (+)) m / e 501.2 (M + H)⁺.

Example 211

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 207B and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (500 mHz, DMSO-D6) δ ppm 2.18-2.24 (m, 2H) 3.08-3.18 (m, 2H) 3.42-3.45 (m, 2H ) 3.51-3.57 (m, 2H) 3.65-3.71 (m, 2H) 4.02-4.05 (m, 2H) 4.24 (t, J = 5, 8Hz, 2H) 6.73 (d, J = 7.5Hz, 1H) 6.83 (d, J = 7.8Hz, 1H) 7.37-7.41 (m, 3H ) 7.49-7.53 (m, 1H)

7.59 (d, J = 8.7 Hz, 2H) 8.64 (dd, J = 7.3, 2.0 Hz, 1H) 8.96 (d, J = 2.8 Hz, 1 H) 9.32 (s, 1H) 9.77 (s, 1H) 11.92 (s, 1H) MS (ESI (+)) m / e 573.1 (M + H)⁺.

Example 212

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 207B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2H) 3.08-3.18 (m, 4H) 3.66-3.70 (m, 4H ) 4.02-4.05 (m, 2H) 4.24 (t, J = 5.8 Hz, 2H) 6.73 (d, J = 7.8 Hz, 1H)

6.82 (d, J = 7.8 Hz, 1H) 7.01-7.03 (m, 1H) 7.29-7.33 (m, 2H) 7.36 (d, J = 8.4 Hz, 2H) 7.58 (d, J = 8.7 Hz, 2H) 7.74 (s, 1H) 9.00 (s, 1H) 9.07 (s, 1H ) 9.74 (s, 1H) 11.89 (s, 1H) MS (ESI (+)) m / e 521.1 (M + H)⁺.

Example 213

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 207B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.24 (m, 2H) 3.08-3.19 (m, 4H) 3.42-3.44 (m, 2H ) 3.66-3.70 (m, 2H) 4.02-4.04 (m, 2H) 4.24 (t, J = 5.8 Hz, 2H) 6.74 (d, J = 7.8 Hz, 1H) 6.83 (d, J = 7.8 Hz, 1H) 7.32 (d, J = 7.8 Hz, 1H) 7.37 (d, J = 8 , 4 Hz, 2H) 7.52 (t, J = 8.0 Hz, 1H) 7.59-7.61 (m, 3H) 8.05 (s, 1H) 9.10 (s , 1H) 9.28 (s, 1H) 9.78 (s, 1H) 11.94 (s, 1H) MS (ESI (+)) m / e 555.2 (M + H)⁺.

Example 214

N- [2 - ({3-amino-4- [4 - ({[(2-fluoro-5-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] - 1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substituting Example 200A for Example 1A in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 3.65 (c, J = 4.9 Hz, 2 H) 4.24 (t, J = 5.3 Hz, 2H) 6.73 (d, J = 7.8 Hz, 1H) 6.78-

6.82 (m, 1H) 6.84 (d, J = 7.5Hz, 1H) 7.11 (dd, J = 11.4, 8.3Hz, 1H) 7.37 (d , J = 8.5 Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 8.01 (dd, J = 8.0, 2.2 Hz, 1H) 8.52 (d, J = 2.7 Hz, 1H) 9.17 (s, 1H) 9.52 (t, J = 5.8 Hz, 1H) 11.79 (s, 1H) MS

ES 2 398 074 T3 (ESI (+)) 567.0 m / e (M + H)⁺.

Example 215

N- [2 - ({3-amino-4- [4 - ({[(3-fluorophenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethyl-1,1,1-trifluoromethanesulfonamide

The desired product was prepared by substituting Example 200A for Example 1A and Example 5A and N- (3-fluorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl urea, respectively, in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.65 (c, J = 5.3 Hz, 2H) 4.23 (t, J = 5.3 Hz, 2H) 6.71 (d, J = 7.8 Hz, 1H) 6.78 (td, J = 8.5, 2.0 Hz, 1H) 6.83 (d, J = 7.8 Hz, 1H) 7.13 ( m, 1H) 7.30 (m, 1H) 7.37 (d, J = 8.5 Hz, 2H) 7.44-7.54 (m, 1H) 7.57 (d, J = 8.5 Hz, 2H) 8.86 (s, 1H) 8.95 (s, 1H) 9.52 (t, J = 5.3 Hz, 1H) 11.72 (s, 1 H) MS (ESI (-)) m / e 550.9 (MH) -.

Example 216

N- [2 - ({3-amino-4- [4 - ({[(2-fluoro-5-methylphenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethylbenzenesulfonamide

Example 216A

N- {2 - [(3-amino-4-iodo-1H-imidazol-7-yl) oxylethyl} benzenesulfonamide

The desired product was prepared by substituting phenylsulfonyl chloride for methanesulfonyl chloride in Example 170B. MS (ESI (+)) m / e 459 (M + H)⁺.

Example 216B

N- [2 - ({3-amino-4- (4 - ({[(2-fluoro-5-methylphenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethylbenzenesulfonamide

The desired product was prepared by substituting Example 1A and Example 5A for Example 216A and N- (2-fluoro-5-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenylurea, respectively, in Example 5B. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 3.26 (c, J = 5.6 Hz, 2H) 4.08 (t, J = 5.6 Hz, 2H) 6.67 (d, J = 7.8 Hz, 1H)

6.70 (d, J = 7.8 Hz, 1H) 6.79-6.82 (m, 1H) 7.11 (dd, J = 11.2, 8.4 Hz, 1H) 7 , 36 (d, J = 8.5 Hz, 2H) 7.55 (t, J = 7.6 Hz, 2H) 7.56 (d, J = 8.5 Hz, 2H) 7.61 (t, J = 7.2 Hz, 1H) 7.78 (t, J = 6.1 Hz, 1H) 7.84 (d, J = 7.2 Hz, 2H) 8.00 (dd , J = 8.0, 1.7 Hz, 1H) 8.50 (d, J = 2.5 Hz, 1H) 9.16 (s, 1H) 11.84 (s, 1H) MS (ESI (-)) m / e 573.2 (MH) -.

Example 217

N- {2 - [(3-amino-4- {4 - [({[3- (trifluoromethyl) phenylamino} carbonyl) aminolphenyl} -1H-indazol-7-yl) oxylethyl} benzenesulfonamide

The desired product was prepared by substituting Example 1A and Example 5A for Example 216A and N- (3-trifluoromethylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -il) phenyl urea, respectively, in Example 5B. ¹H NMR (500 MHz, DMSO-D6) δ ppm 3.26 (c, J = 5.8 Hz, 2H) 4.10 (t, J = 5.6 Hz, 2H) 6.70 (d, J = 7.8 Hz, 1 H) 6.73 (d, J = 7.8 Hz, 1 H) 7.32 (d, J = 7.5 Hz, 1 H) 7.37 (d, J = 8.4 Hz, 2H) 7.51-7.63 (m, 7H) 7.78 (t, J = 6.1 Hz, 1H) 7.84 (d, J = 8.7 Hz, 2H) 8.04 (s, 1H) 8.93 (s, 1H) 9.1 (s, 1H) 12.01 (s, 1H) MS (ESI (+)) m / e 611 , 1 (M + H)⁺.

Example 218

N- [2 - ({3-amino-4- [4 - ({[(3-fluorophenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethylbenzenesulfonamide

The desired product was prepared by substituting Example 1A and Example 5A for Example 216A and N- (3-fluorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl urea, respectively, in Example 5B. ¹H NMR (500 MHz, DMSO-D6) δ ppm 3.26 (c, J = 5.6 Hz, 2H) 4.09 (t, J = 5.6 Hz, 2H) 6.70 (d, J = 7.8 Hz, 1H) 6.73 (d, J = 7.8 Hz, 1H) 6.79 (td, J = 8.4, 1.9 Hz, 1H) 7.14 ( dd, J = 8.3, 1.1 Hz, 1H) 7.29-7.34 (m, 1H) 7.37 (d, J = 8.7 Hz, 2H) 7.49-7 , 58 (m, 5H) 7.61 (t, J = 7.3Hz, 1H) 7.78 (t, J = 6.1Hz, 1H) 7.83-7.85 (m, J = 8.4 Hz, 2H) 8.88 (s, 1H) 8.97 (s, 1H) 12.00 (s, 1H) MS (ESI (-)) m / e 559.0 (MH) -.

Example 219

N- [2 - ({3-amino-4- (4 - ({[(3-chlorophenyl) aminolcarbonyl} amino) phenyl-1H-indazol-7-yl} oxy) ethylbenzenesulfonamide

The desired product was prepared by substituting Example 216A for Example 1A and Example 5A and N- (3-chlorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl urea, respectively, in Example 5B. ¹H RmN (300 MHz, DMSO-D6) δ ppm 3.26 (c, J = 5.6 Hz, 2 H) 4.10 (t, J = 5.6 Hz, 2 H) 6.70-6, 75 (m, 2H) 7.03 (td, J = 4.3, 2.2 Hz, 1H) 7.27-7.32 (m, 2H) 7.37 (d, J = 8, 5 Hz, 2H) 7.52-7.64 (m, 5H) 7.74-7.75 (m, 1H) 7.78-7.85 (m, 3H) 8.92 (s , 1H) 8.98 (s, 1H) 12.09 (s, 1H) MS (ESI (+)) m / e 577.0 (M + H)⁺.

ES 2 398 074 T3

Example 220

N- (4- {3-amino-7 - [(isopropylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 220A

2-fluoro-3-formyl-6-iodobenzonitrile

LDA (24.3 mL, 2.0 M solution in THF) was added dropwise to a stirred solution of 2-fluoro-6-iodobenzonitrile (10.0 g, 40.5 mmol) in THF (200 mL) at -78 ° C, and the mixture was stirred for 1 hr. Methyl formate (5.0 mL, 81.0 mmol) was added via syringe and the resulting mixture was stirred at -78 ° C for 30 min and then at rt for

h. H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 2025% EtOAc / hexanes to give the desired product (8.01 g). MS (ESl (+)) m / e 274.9 (M + H)⁺.

Example 220B

2-fluoro-6-iodo-3 - [(isopropylamino) methyl] benzonitrile

A solution of Example 220A (1.00 g, 3.6 mmol) in MeOH (15 ml) was treated with isopropylamine (0.31 ml, 3.6 mmol) and sodium cyanoborohydride (227 mg, 3.6 mmol), and the mixture was stirred overnight at rt. HOAc (1 mL) was added and the reaction was stirred for 5 h, then treated with 1N NaOH and extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 8% MeOH / CH2Cl2 to give the desired product (372 mg). MS (ESl (+)) m / e 318.9 (M + H)⁺.

Example 220C

4-iodo-7 - [(isopropylamino) methyl] -1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 220B in Example 1A. MS (ESl (+)) m / e 330.9 (M + H)⁺.

Example 220D

N- {4- {3-amino-7 - [(isopropylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 220C and N- (2-fluoro-5-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenyl] urea, respectively, in Example 5B. Furthermore, DME / water as solvent was replaced by toluene / EtOH / H2O (2: 1: 1).¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J = 6.4 Hz, 6H) 2.28 (s, 3H) 3.39-3.51 (m, 1H) 4.39 (t, J = 6.1 Hz, 2H) 6.79-6.84 (m, 1H) 6.90 (d, J = 7.1 Hz, 1H)

7.12 (dd, J = 11.4, 8.3 Hz, 1H) 7.39-7.45 (m, 3H) 7.61 (d, J = 8.5 Hz, 2H) 7 .99 (dd, J = 7.8, 2.0 Hz, 1H) 8.55 (d, J =

2.4 Hz, 1H) 8.65-8.73 (m, 1H) 9.25 (s, 1H) 12.03 (s, 1H) MS (ESl (+)) m / e 447 , 1 (M + H)⁺.

Example 221

N- (4- {3-amino-7 - [(isopropylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 220C and N- (3-chlorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J = 6.8 Hz, 6H) 3.37-3.49 (m, 1H) 4.38 (t, J = 5 , 9 Hz, 2H) 6.90 (d, J = 7.5 Hz, 1H) 7.03 (dt, J = 6.4, 2.4 Hz, 1H) 7.28-7.35 (m,

H) 7.39-7.45 (m, 3H) 7.62 (d, J = 8.5 Hz, 2H) 7.74-7.75 (m, 1H) 8.63-8, 73 (m, 2H) 9.03 (s, 1H) 9.04 (s, 1H) 12.03 (s, 1H) MS (ESl (+)) m / e 449.1 (M + H)⁺.

Example 222

N- (4- {3-amino-7 - [(isopropylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 220C and N- (3-trifluoromethylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J = 6.4 Hz, 6 H) 3.39-3.51 (m, 1 H) 4.39 (t, J = 5 , 8Hz, 2H) 6.91 (d, J = 7.1Hz, 1H) 7.32 (d, J = 7.5Hz, 1H) 7.39-7.45 (m, 3 H) 7.53 (t, J = 8.0 Hz, 1H) 7.59-7.66 (m, 3H) 8.05 (s, 1H) 8.67-8.73 (m, 2H) 9.14 (s, 1H) 9.28 (s, 1H) 12.05 (s, 1H) MS (ESl (-)) m / e 481.0 (MH) -.

Example 223

ES 2 398 074 T3

N- (4- {3-amino-7 - [(isopropylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 220C and N- (3-methylphenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J = 6.4 Hz, 6H) 2.29 (s, 3H) 3.39-3.51 (m, 1H) 4.36-4.40 (m, 2H) 6.80 (d, J = 7.8 Hz, 1H) 6.90 (d, J = 7.1 Hz, 1H) 7.17 (t , J =

7.8 Hz, IH) 7.26 (d, J = 8.5 Hz, 1H) 7.32 (s, 1H) 7.39 (d, J = 8.8 Hz, 2H) 7, 44 (d, J = 7.5 Hz, 1H) 7.62 (d, J = 8.8 Hz, 2H) 8.69 (m, 2H) 8.75 (s, 1H) 8, 94 (s, 1H) 12.03 (s, 1H) MS (ESI (+)) m / e 429.1 (M + H)⁺.

Example 224

N- (4- {3-amino-7 - [(isopropylamino) methyl] -1H-indazol-4-yl} phenyl) -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 220C and N- (4-fluoro-3-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (d, J = 6.4 Hz, 6 H) 2.22 (d, J = 1.7 Hz, 3 H) 3.39-3, 51 (m, 1H) 4.36-4.40 (m, 2H) 6.90 (d, J = 7.1 Hz, 1H) 7.06 (t, J = 9.2 Hz, 1 H) 7.28 (ddd, J = 8.4, 4.8, 3.1 Hz, 1H) 7.37-7.45 (m, 4H) 7.61 (d, J = 8.5 Hz, 2H) 8.64-8.74 (m, 2H) 8.79 (s, 1H) 8.95 (s, 1H) 12.04 (s, 1H) MS (ESI (+ )) m / e 447.1 (M + H)⁺.

Example 225

N- (4- {3-amino-7 - [(4-chlorophenoxy) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 225A

2- fluoro-3- (hydroxymethyl) -6-iodobenzonitrile

A solution of Example 220A (5.0 g, 18 mmol) in MeOH (100 ml) at 0 ° C was treated with NaBH4 (822 mg, 22 mmol) and the mixture was stirred for 1 hr at 0 ° C. Acetone was added and the mixture was stirred for 5 min, and then concentrated to dryness. The residue was partitioned between H2O and EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 3: 2 hexanes / EtOAc to give the desired product (3.14 g). Fr = 0.38 (3: 2 hexane: EtOAc).

Example 225B

3- [(4-chlorophenoxy) methyl] -2-fluoro-6-iodobenzonitrile

The desired product was prepared by substituting Example 68A and 2- (4-morpholinyl) ethanol for Example 225A and 4-chlorophenol, respectively, in Example 75A. Furthermore, DEAD was replaced by diisopropyl azodicarboxylate. MS (ESI (-)) m / e 385.8 (MH) -.

Example 225C

7 - [(4-chlorophenoxy) methyl] -4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 225B in Example 1A. MS (ESI (+)) m / e 399.9 (M + H)⁺.

Example 225D

N- (4- {3-amino-7 - [(4-chlorophenoxy) methyl] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 225C for Example 1A and Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 5.33 (s, 2H) 6.79-6.83 (m, 2H) 7.09 (d, J = 9.2 Hz, 2H) 7.06-7.15 (m, 1H) 7.33-7.38 (m, 3H) 7.41 (d, J = 8.5 Hz, 2H ) 7.60 (d, J = 8.5 Hz, 2H) 8.01 (dd, J = 7.8, 2.0 Hz, 1H) 8.54 (d, J = 2.7 Hz, 1H) 9.22 (s, 1H) 12.00 (s, 1H) MS (ESI (+)) m / e 516.1 (M + H)⁺.

Example 226

N- (4- {3-amino-7 - [(4-chlorophenoxy) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 226C and N- (3-chlorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 5.33 (s, 2H) 6.82

ES 2 398 074 T3 (d, J = 7.5 Hz, 1H) 7.01-7.05 (m, 1H) 7.08 (d, J = 8.8 Hz, 2H) 7.28 -7.32 (m, 2H) 7.33-7.38 (m, 3H) 7.41 (d, J = 8.8 Hz, 2H) 7.60 (d, J = 8.8 Hz, 2H) 7.73-7.74 (m, 1H) 8.93 (s, 1H) 8.96 (s, 1H) 12.01 (s, 1H) MS (ESI (+ )) m / e 518.5 (M + H)⁺.

Example 227

N- (4- {3-amino-7 - [(4-chlorophenoxy) methyl] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 225C and N- (3-trifluoromethylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 5.32 (s, 2H) 6.82 (d, J = 7.1 Hz, 1H) 7.08 (d, J = 8.8 Hz, 2H) 7.31-7.37 (m, 4H) 7.41 (d, J = 8.5 Hz, 2H) 7.53 (t, J = 8.0 Hz, 1H) 7, 59-7.63 (m, 3H) 8.04 (s, 1H) 8.96 (s, 1H) 9.11 (s, 1H) 11.96 (s, 1H) MS (ESI (+)) m / e 522.0 (M + H)⁺.

Example 228

N- (4- {3-amino-7 - [(4-chlorophenoxy) methyl] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 225C and N- (3-methylphenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 5.33 (s, 2H) 6.80 (d, J = 7.5 Hz, 1H) 6.83 ( d, J = 7.1 Hz, 1H) 7.08 (d, J = 8.8 Hz, 2H) 7.17 (t, J = 7.8 Hz, 1H) 7.25 (d, J = 8.5 Hz, 1H) 7.32 (s, 1H) 7.33-7.41 (m, 5H) 7.60 (d, J = 8.8 Hz, 2H) 8, 65 (s, 1H) 8.82 (s, 1H) 12.08 (s, 1H) MS (ESI (+)) m / e 498.1 (M + H)⁺.

Example 229

N- (4- {3-amino-7 - [(4-chlorophenoxy) methyl] -1H-indazol-4-yl} phenyl) -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 225C and N- (4-fluoro-3-methylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl) phenyl] urea, respectively, in Example 5B. Also, DME / water was replaced by toluene / EtOH / H2O (2: 1: 1) as the solvent.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J = 1.7 Hz, 3H) 5.33 (s, 2H) 6.83 (d, J = 7.1 Hz, 1H) 7.01-7.11 (m, 3H) 7.25-7.31 (m, 1H) 7.33-7.41 (m, 6H) 7.59 (d, J = 8.8 Hz, 2H) 8.68 (s, 1H) 8.82 (s, 1H) 12.05 (s, 1H) MS (ESI (+)) m / e 516.1 (M + H)⁺.

Example 230

N- (4- {3-amino-7- [3- (1H-pyrrol-1-yl) propoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 230A

2-fluoro-6-iodo-3- [3- (1H-pyrrol-1-yl) propoxy] benzonitrile

The desired product was prepared by substituting 2- (4-morpholinyl) ethanol for 3-pyrrol-1-yl-propan-1-ol in Example 75A.

Example 230B

4-iodo-7- [3- (1H-pyrrol-1-yl) propoxy] -1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 230A in Example 1A. MS (ESI (+)) m / e 383 (M + H)⁺.

Example 230C

N- (4- {3-amino-7- [3- (1H-pyrrol-1-yl) propoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 230B for Example 1A in Example 5B. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.14-2.23 (m, 2H) 2.27 (s, 3H) 4.01 (t, J = 6.1 Hz, 2H) 4.19 (t, J = 6.9 Hz, 2H) 4.31 (s, 2H)

5.97 (t, J = 2.2 Hz, 2H) 6.66 (d, J = 7.5 Hz, 1H) 6.71 (d, J = 7.8 Hz, 1H) 6, 76 (t, J = 2.2 Hz, 2H) 6.78-6.81 (m, 1H)

7.10 (dd, J = 11.2, 8.4 Hz, 1H) 7.35 (d, J = 8.4 Hz, 2H) 7.55 (d, J = 8.4 Hz, 2 H) 7.99 (dd, J = 8.0, 2.0 Hz, 1H) 8.49 (d, J = 2.2 Hz, 1H) 9.14 (s, 1H) 11.90 (s, 1H) MS (ESI (+)) m / e 499.1 (M + H)⁺.

Example 231

4- (1H-indol-5-yl) -7- [3- (1H-pyrrol-1-yl) propoxy] -1H-indazol-3-amine

ES 2 398 074 T3

The desired product was prepared by substituting Example 1A and Example 5A for Example 230B and indole-5-boronic acid, respectively, in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.16-2.24 (m, 2H) 4.02 (t, J =

6.1 Hz, 2H) 4.21 (t, J = 6.6 Hz, 2H) 4.29 (s, 2H) 5.98 (t, J = 2.0 Hz, 2H) 6.47 -6.49 (m, 1H) 6.67 (d, J = 7.5 Hz, 1H)

6.72 (d, J = 7.8 Hz, 1H) 6.78 (t, J = 2.0 Hz, 2H) 7.14 (dd, J = 8.3, 1.5 Hz, 1 H) 7.41 (t, J = 2.7 Hz, 1 H) 7.49 (d, J =

8.1 Hz, 1H) 7.56 (s, 1H) 11.19 (s, 1H) 11.86 (s, 1H). MS (ESI (+)) m / e 372.1 (M + H)⁺.

Example 232

N- (4- {3-amino-7- [3- (1H-pyrrol-1-yl) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 230B for Example 1A and Example 5A and N- (3-methylphenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. ¹RmN (300 MHz, DMSO-D6) δ ppm 2.16-2.24 (m, 2H) 2.29 (s, 3H) 4.02 (t, J = 5.9 Hz, 2H) 4 , 20 (t, J = 6.8 Hz, 2H) 5.98 (t, J = 2.2 Hz, 2H) 6.68 (d, J = 7.8 Hz, 1H) 6.74 (d, J = 7.8 Hz, 1H) 6.77 (t, J = 2.0 Hz, 2H) 6.80 (d, J = 7.1 Hz, 1H) 7.16 (t , J = 7.6 Hz, 1H) 7.25 (d, J = 8.1 Hz, 1H) 7.32 (s, 1H) 7.35 (d, J = 8.8 Hz, 2 H) 7.56 (d, J = 8.8 Hz, 2H) 8.63 (s, 1H) 8.76 (s, 1H) 12.05 (s, 1H) MS (ESI (+ )) m / e 481.1 (M + H)⁺.

Example 233

N- (4- {3-amino-7- [3- (1H-pyrrol-1-yl) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 1A and Example 5A for Example 230B and N- (3-chlorophenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. ¹H RmN (300 MHz, DMSO-D6) δ ppm 2.15-2.23 (m, 2H) 4.01 (t, J = 5.9 Hz, 2H) 4.20 (t, J = 6 , 8 Hz, 2H) 4.33 (s, 2H) 5.98 (t, J = 2.2 Hz, 2H) 6.66 (d, J = 7.5 Hz, 1H) 6, 72 (d, J = 7.8 Hz, 1H) 6.77 (t, J = 2.2 Hz, 2H) 7.02 (dt, J = 6.4, 2.2 Hz, 1H) 7.28 (m, 2H) 7.36 (d, J = 8.5 Hz, 2H) 7.56 (d, J = 8.5 Hz, 2H) 7.72-7.74 (m , 1H) 8.85 (s, 1H) 8.92 (s, 1H) 11.93 (s, 1H) MS (ESI (-)) m / e 499.3 (MH) -.

Example 234

N- [2 - ({3-amino-4- [4 - ({[(2-fluoro-5-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] thiophene -2-sulfonamide

Example 234A

N- {2 - [(3-amino-4-iodo-1H-indazol-7-yl) oxy] ethyl} thiophene-2-sulfonamide

The desired product was prepared by substituting 2-thiophenesulfonyl chloride for methanesulfonyl chloride in Example 170B. MS (ESI (+)) m / e 465 (M + H)⁺.

Example 234B

N- [2 - ({3-amino-4- [4 - ({[(2-fluoro-5-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] thiophene -2-sulfonamide

The desired product was prepared by substituting Example 234A for Example 1A in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 3.30-3.34 (m, 2H) 4.14 (t, J = 5.9 Hz, 2H) 6.68 (d, J = 7.5 Hz, 1H) 6.74 (m, J =

7.5 Hz, 1H) 6.79-6.83 (m, 1H) 7.11 (dd, J = 11.4, 8.3 Hz, 1H) 7.17 (dd, J = 5 , 1, 3.7 Hz, 1H) 7.36 (d, J = 8.8 Hz, 2H) 7.56 (d, J = 8.8 Hz, 2H) 7.65 (dd, J = 3.7, 1.4 Hz, 1H) 7.92-8.02 (m, 3H) 7.98 (d, J = 6.4 Hz, 1H) 8.01 (dd, J = 7.8, 2.0 Hz, 1H) 8.51 (d, J = 2.4 Hz, 1H) 9.17 (s, 1H) 11.84 (s, 1H) MS (ESI ( +)) m / e 580.6 (M + H)⁺.

Example 235

N- [2 - ({3-amino-4- [4 - ({[(3-methylphenyl) amino] carbonyl} amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] thiophene-2-sulfonamide

The desired product was prepared by substituting Example 234A for Example 1A and Example 5A and N- (3-methylphenyl) N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl) phenyl] urea, respectively, in Example 5B. ¹H RmN (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3 H) 3.33 (c, J = 5.8 Hz, 2 H) 4.14 (t, J = 5.8 Hz, 2H) 6.66-6.84 (m, 3H) 7.16 (t, J = 7.8

Hz, 1H) 7.17 (dd, J = 5.1, 3.7 Hz, 1H) 7.25 (d, J = 8.8 Hz, 1H) 7.31 (s, 1H) 7.35 (d, J = 8.5 Hz, 2H) 7.56 (d, J = 8.5

Hz, 2H) 7.65 (dd, J = 3.7, 1.4 Hz, 1H) 7.93 (dd, J = 5.1, 1.4 Hz, 1H) 7.97 (t , J = 5.9 Hz, H) 8.63 (s, 1H) 8.77 (s, 1H)

11.91 (s, 1H) MS (ESI (+)) m / e 563.0 (M + H)⁺.

Example 236

N- (2 - {[3-amino-4- (1H-indol-5-yl) -1H-indazol-7-yl] oxy} ethyl) thiophene-2-sulfonamide

The desired product was prepared by replacing Example 1A and Example 5A with Example 234A and indole-5-boronic acid, respectively, in Example 5B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.33 (c, J = 5.4 Hz, 2 H) 4.16 (t,

ES 2 398 074 T3

J = 5.6 Hz, 2H) 6.49-6.49 (m, 1H) 6.74 (d, J = 7.8 Hz, 1H) 6.78 (d, J = 7.8 Hz, 1H) 7.15 (dd, J = 8.5, 1.7 Hz, 1H)

7.1.8 (dd, J = 4.8, 3.7 Hz, 1H) 7.41 (t, J = 2.7 Hz, 1H) 7.49 (d, J = 8.1 Hz, 1 H) 7.57 (d, J = 1.4 Hz, 1 H) 7.65 (dd, J = 3.7, 1.4 Hz, 1 H) 7.94 (dd, J = 5.1, 1.4 Hz, 1H) 7.98 (t, J = 5.9 Hz, 1H) 11.20 (s, 1H) 11.98 (s, 1H) MS (ESI (+)) m / e 454.0 (M + H)⁺.

Example 237

N- (4- {3-amino-7- [3- (diethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

Example 237A

3- [3- (diethylamino) propoxy] -2-fluoro-6-iodobenzonitrile

The desired product was prepared by substituting 3- (diethylamino) propan-1-ol for 2- (4-morpholinyl) ethanol in Example 75A.

Example 237B

4- (4-aminophenyl) -7- [3- (diethylamino) propoxy] -1H-indazol-3-amine

The desired product was prepared by substituting Example 237A for Example 15E in Examples 15F-G. MS (ESI (+)) m / e 354 (M + H)⁺.

Example 237C

N- (4- {3-amino-7- [3- (diethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 237B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

1.25 (t, J = 7.3 Hz, 6H) 2.11-2.20 (m, 2H) 2.28 (s, 3H) 3.16-2.35 5 (m, 4 H) 3.31-3.41 (m, 2H) 4.24 (t, J = 5.8 8 Hz, 2 H) 6.71 (d, J = 7.5 Hz, 1 H) 6, 79-6.84 (m, 2H) 7.11 (dd, J = 11.4, 8.3 Hz, 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.57 (d, J =

8.5 Hz, 2H) 8.00 (dd, J = 7.8, 2.0 Hz, 1H) 8.52 (d, J = 2.4 Hz, 1H) 9.07 (s, 1H ) 9.18 (s, 1H) 11.93 (s, 1H) MS (APCI (+)) m / e 505.4 (M + H)⁺.

Example 238

N- (4- {3-amino-7- [3- (diethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 237B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.25 (t, J =

7.29 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.25 (m, 4H) 3.34-3.14 (m, 2H) 4.24 (t, J = 5.8 Hz, 2H) 6.71 (d, J = 7.8 Hz, 1H) 6.81 (d, J = 7.8 Hz, 1H) 7.03 (dt , J = 6.4, 2.4 Hz, 1H) 7.26-7.32 (m, 2H) 7.36 (d, J = 8.8 Hz, 2H) 7.57 (d, J = 8.8 Hz, 2H) 7.73-7.74 (m, 1H) 8.92 (s, 1H) 8.98 (s, 1H) 9.05 (s, 1H) 11.92 (s, 1H) MS (ESI (+)) m / e 506.9 (M + H)⁺.

Example 239

N- (4-3- {amino-7- [3- (diethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N'-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 237B and 1-isocyanato-3- (trifluoromethyl) benzene for Example 15G and 1-fluoro-3-isocyanatobenzene in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.24 (t, J = 7.3 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.25 (m , 4H) 3.31-3.37 (m, 2H) 4.24 (t, J = 5.6 Hz, 2H) 6.71 (d, J =

7.8 Hz, 1H) 6.81 (m, J = 7.8 Hz, 1H) 7.32 (d, J = 7.1 Hz, 1H) 7.36 (d, J = 8.5 Hz , 2H) 7.50-7.61 (m, 4H) 8.04 (s, 1H) 8.95 (s, 1H) 9.04 (s, 1H) 9.13 (s, 1H) 11.92 (s, 1H) MS (ESI (+)) m / e 541.2 (M + H)⁺.

Example 240

N- (4- {3-amino-7- [3- (diethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 237B for Example 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.25 (t, J = 7.3 Hz, 6H) 2.11-2.20 (m, 2H) 3.16-3.24 (m , 4H) 3.34-3.43 (m, 2H) 4.24 (t, J =

5.6 Hz, 2H) 6.72 (d, J = 7.8 Hz, 1H) 6.76-6.82 (m, 1H) 6.81 (d, J = 7.8 Hz, 1H ) 7.14 (ddd, J = 8.1, 2.0, 0.7 Hz, 1H) 7.28-7.35 (m, 1H) 7.36 (d, J = 8.8 Hz , 2H) 7.52 (dt, J = 12.0, 2.3Hz, 1H) 7.57 (d, J = 8.8Hz, 2H) 8.92 (s, 1H) 9 .01 (s, 1H) 9.06 (s, 1H) 11.94 (s, 1H) MS (APCI (-)) m / e 489.3 (MH) -.

Example 241

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N '- [3- (trifluoromethyl) phenyl] urea

ES 2 398 074 T3

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-3- (trifluoromethyl) benzene in Examples 44A-B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 4.37 (s, 2H) 6.80-6.86 (m, 1H) 7.26-7.35 (m, 4H) 7.39 (dd, J = 12.2, 1.7 Hz, 1H) 7.54-7.56 (m, 2H) 8.06 (s, 1H) 8.26 (t, J = 8.5 Hz, 1H) 8.76 (d, J = 2.4 Hz, 1H) 9.47 (s, 1H) 11.77 (s, 1H) MS (ESI (+)) m / e 430 , 0 (M + H)⁺.

Example 242

N- [4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl-N '- [4-fluoro-3- (trifluoromethyl) phenyl urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-4-isocyanato-2 (trifluoromethyl) benzene in Examples 44A-B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 4.37 (s, 2H) 6.83 (dd, J = 4.4,

3.7 Hz, 1H) 7.25-7.29 (m, 3H) 7.38 (dd, J = 12.0, 1.9 Hz, 1H) 7.46 (t, J = 9 , 8 Hz, 1H) 7.61-7.66 (m, 1H) 8.05 (dd, J = 6.4, 2.7 Hz, 1H) 8.23 ​​(t, J = 8, 5Hz, 1H) 8.75 (d, J = 1.7Hz, 1H) 9.45 (s, 1H) 11.77 (s, 1H) MS (ESI (+)) m / e 448.0 (M + H)⁺.

Example 243

N- [4- (3-amino-7-pyridin-3-yl-1H-indazol-4-yl) phenyl-N '- (4-fluoro-3-methylphenyl) urea

Example 243A

3-fluoro-1,1'-biphenyl-2-carbonitrile

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 1A and phenylboronic acid for Example 1B in Example 1C. Also, DME / H2O was replaced by toluene / EtOH / H2O (3: 2: 1) as solvent.

Example 243B

3-fluoro-4-iodo-1,1'-biphenyl-2-carbonitrile

A solution of Example 243A (6.8 g, 34.5 mmol) in THF (110 ml) at -78 ° C under a nitrogen atmosphere was treated dropwise with lDa (2.0 M solution in THF) and stirred for 1 hr, then a solution of iodine in THF (30 mL) was added via cannula over approximately 10 min. The thick mixture was allowed to warm to rt, stirred for 1h and then treated with a saturated aqueous Na2S2O3 solution (10 mL). The mixture was concentrated to remove tHf, then H2O was added and the mixture was extracted with EtOAc. The extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel, eluting with EtOAc / hexanes (1: 7), and the resulting solid was triturated with hexanes and EtOAc to give the desired product (6.8 g). Fr = 0.44 (7: 1 hexane: EtOAc)

Example 243C

3-fluoro-4-iodo-4'-nitro-1,1'-biphenyl-2-carbonitrile

A solution of Example 243B (2.77 g, 8.6 mmol) in 1,2-dichloroethane (50 mL) under a nitrogen atmosphere was treated with nitronium tetrafluoroborate (85% technical grade, 2.0 g, 12 , 9 mmol) and the mixture was stirred for 3.5 h at which time a further portion of nitronium tetrafluoroborate (700 mg, 5.3 mmol) was added. The reaction was stirred for an additional 2 h, then was poured onto ice, and once the mixture had melted it was neutralized with a sat. Solution. NaHCO3. The mixture was extracted with EtOAc, and the extracts were washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography on silica gel, eluting with hexanes / EtOAc (4: 1) to give the desired product (1.84 g). MS (ESI (-)) m / e 367.9 (MH) -.

Example 243D

3- fluoro-4'-nitro-4-pyridin-3-yl-1,1'-biphenyl-2-carbonitrile

The desired product was prepared by substituting Examples 1A and 1B for Example 243C and pyridine-3-boronic acid, respectively, in Example 1C. Furthermore, PdCL (dppf) was used instead of Pd (PPh3) 4. MS (ESI (+)) m / e 320.0 (M + H)⁺.

Example 243E

4- (4-aminophenyl) -7-pyridin-3 -yl-1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for Example 243D in Example 1A. In addition to the cyclization of the pyrazole, a nitro reduction was also performed in this reaction. MS (ESI (+)) m / e 302.0

ES 2 398 074 T3 (M + H)⁺.

Example 243F

N-4- (3-amino-1H-indazol-4-yl) -2-fluorophenyl] -N'-4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 243E and 1-fluoro-4-isocyanato-2-methylbenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.23 (d, J = 1.7 Hz, 3H) 6.97 (d, J = 7.5 Hz, 1H) 7.06 (t, J = 9.2 Hz, 1H) 7.29 (ddd, J = 8.7, 4.5, 3.1 Hz, 1H) 7.39 (dd, J = 6.8, 2.8 Hz , 1H) 7.43-7.47 (m, 3H) 7.62 (d, J = 8.5 Hz, 2H) 7.69-7.80 (m, 1H) 8.32 ( d, J = 7.8 Hz, 1H) 8.67-8.80 (m, 1H) 8.71 (s, 1H) 8.87 (s, 1H) 8.90-9.15 (m, 1H) 11.8112.42 (br, 1H) MS (ESI (+)) m / e 453.1 (M + H)⁺.

Example 244

N- [4- (3-amino-7-pyridin-3-yl-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 243E and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 6.96 (d, J = 7.5 Hz, 1H) 7.02-7.05 (m, 1H) 7.28-7.35 (m , 2H) 7.44-7.47 (m, 3H)

7.63 (d, J = 8.8 Hz, 2H) 7.66-7.72 (m, 1H) 7.74-7.75 (m, 1H) 8.27 (d, J = 7.5 Hz, 1H) 8.61-8.85 (m, 1H) 8.93-9.04 (m, 3H) 11.73-12.36 (bs, 1H) MS (ESI (+)) m / e 455.1 (M + H)⁺.

Example 245

N- [4- (3-amino-7-pyridin-3-yl-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 243E and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 6.97 (d, J = 7.1 Hz, 1 H) 7.33 (d, J = 7.5 Hz, 1 H) 7.44-7, 47 (m, 3H) 7.53 (t, J = 7.8 Hz, 1H) 7.60-7.70 (m, 4H) 8.05 (s, 1H) 8.26 (d , J = 8.1 Hz, 1H) 8.61-8.81 (m, 1H) 8.89-9.08 (m, 2H) 9.15 (s, 1H) 11.79- 12.29 (brs, 1H) MS (ESI (+)) m / e 489.1 (M + H)⁺.

Example 246

N- [4- (3-amino-7-pyridin-3-yl-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 243E and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.79-6.84 (m, 1H) 6.96 (d, J = 7.5 Hz, 1H) 7.12 (dd, J = 11.4, 8.3 Hz, 1H) 7.44-7.47 (m, 3H) 7.63 (d, J = 8.8 Hz, 2H) 7 , 65-7.73 (m, 1H) 8.01 (dd, J = 8.0, 1.9 Hz, 1H) 8.26 (d, J = 7.8 Hz, 1H) 8, 55 (d, J = 2.4 Hz, 1H) 8.63-8.82 (m, 1H) 8.88-9.11 (m, 1H) 9.24 (s, 1H) 11 , 79-12.33 (bs, 1H) MS (ESI (+)) m / e 453.1 (M + H)⁺.

Example 247

N- [4- (3-amino-7-pyridin-3-yl-1H-indazol-4-yl) phenyl] -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 243E and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 6.95 (d, J = 7.5 Hz, 1H) 7.40-7.49 (m, 4H) 7.61-7.70 (m , 4H) 8.04 (dd, J = 6.4, 2.7 Hz, 1H) 8.19-8.23 (m, 1H) 8.67 (dd, J = 4.8, 1 , 4 Hz, 1H) 8.94-8.97 (m, 1H) 9.00 (s, 1H) 9.12 (s, 1H) 12.02 (s, 1H) MS (ESI (+)) m / e 507.1 (M + H)⁺.

Example 248

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

Example 248A

3- [3- (dimethylamino) propoxy] -2-fluoro-6-iodobenzonitrile

The desired product was prepared by substituting 3- (dimethylamino) -propan-1-ol for 2- (4-morpholinyl) ethanol in Example 75A. MS (ESI (+)) m / e 349 (M + H)⁺.

Example 248B

ES 2 398 074 T3

4- (4-aminophenyl) -7- [3- (dimethylamino) propoxy] -1H-indazol-3-amine

The desired product was prepared by substituting Example 248A for Example 15E in Examples 15F-G. MS (ESl (+)) m / e 326 (M + H)⁺.

Example 248C

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 248B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H) 2.28 (s, 3H) 2.86 (d, J = 5.1 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J = 5.8 Hz, 2H) 6.72 (d, J = 7.8 Hz, 1H)

6.80 (d, J = 7.1 Hz, 1H) 6.82 (d, J = 7.8 Hz, 1H) 7.16 (t, J = 7.8 Hz, 1H) 7, 25 (d, J = 8.5 Hz, 1H) 7.32 (s, 1H) 7.34 (d, J = 8.5 Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 8.68 (s, 1H) 8.83 (s, 1H) 9.40 (s, 1H) 11.94 (s, 1H) MS (ESl (+)) m / and

459.2 (M + H)⁺.

Example 249

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 248B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.13-2.22 (m, 2H) 2.28 (s, 3H) 2.86 (d, J = 4.8 Hz, 6H) 3.34-3.42 (m, 2H ) 4.22 (t, J = 5.9 Hz, 2H) 6.72 (d, J = 7.8 Hz, 1H) 6.79-6.83 (m, 2H) 7.12 ( dd, J = 11.2, 8.5 Hz, 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 8, 00 (dd, J = 8.0, 1.9 Hz, 1H) 8.53 (d, J = 2.4 Hz, 1H) 9.19 (s, 1H) 9.41 (s, 1 H) 11.94 (s, 1H) MS (ESl (+)) m / e 477.1 (M + H)⁺.

Example 250

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3'-fluorophenyl) urea

The desired product was prepared by substituting Example 248B for Example 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H) 2.86 (d, J = 4.8 Hz, 6H) 3.34-3.41 (m , 2H) 4.22 (t, J = 5.9 Hz, 2H) 6.73 (d, J = 7.5 Hz, 1H) 6.79 (td, J = 8.6, 2, 5Hz, 1H) 6.83 (d, J = 7.8Hz, 1H) 7.14 (ddd, J = 8.1, 2.0, 1.0Hz, 1H) 7.26-

7.37 (m, 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.52 (dt, J = 12.0.2.3 Hz, 1H) 7.58 (d , J = 8.5 Hz, 2H) 8.98 (s, 1H) 9.07 (s, 1H) 9.44 (s, 1H) 11.99 (s, 1H) MS (ESl (+)) m / e 463.2 (M + H)⁺.

Example 251

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 248 and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H) 2.86 (d, J = 4.8 Hz, 6H) 3.34-3.41 (m , 2H) 4.22 (t, J = 5.8 Hz, 2H) 6.73 (d, J = 7.8 Hz, 1H) 6.82 (d, J = 7.8 Hz, 1 H) 7.03 (ddd, J = 6.1, 3.1, 2.4 Hz, 1H) 7.27-7.32 (m, 2H) 7.36 (d, J = 8.5 Hz, 2H) 7.58 (d, J = 8.5 Hz, 2H) 7.73-

7.75 (m, 1H) 8.98 (s, 1H) 9.04 (s, 1H) 9.41 (s, 1H) 11.96 (s, 1H) MS (ESl (+ )) m / e 479.1 (M + H)⁺.

Example 252

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 248B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.13-2.22 (m, 2H) 2.86 (d, J = 4.8 Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J = 5, 9Hz, 2H) 6.72 (d, J = 7.8Hz, 1H) 6.82 (d, J = 7.8Hz, 1H) 7.32 (d, J = 7.5Hz , 1H) 7.36 (d, J = 8.8 Hz, 2H) 7.50-7.61 (m, 4H) 8.05 (s, 1H) 8.98 (s, 1H )

9.16 (s, 1H) 9.38 (s, 1H) 11.92 (s, 1H) MS (ESl (+)) me / 513.1 (M + H)⁺.

Example 253

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 248B and 1-fluoro-4-isocyanato-2-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.13-2.19 (m, 2H) 2.22 (d, J = 1.7Hz, 3H) 2.86 (d, J = 5.1Hz, 6H) 3.34-3.41 (m, 2H) 4.22 (t, J = 5.9 Hz, 2H) 6.72 (d, J = 7.8 Hz, 1H) 6.81 (d, J = 7.8 Hz , 1H) 7.05 (t, J = 9.2 Hz, 1H) 7.28 (ddd, J = 8.8, 4.1, 2.7 Hz, lH) 7.33-7, 39 (m, 3H) 7.56 (d, J = 8.5 Hz, 2H) 8.72 (s, 1H) 8.83 (s, 1H) 9.41 (s, 1H) 11, 95 (s, 1H) MS (ESl (+)) m / e 477.2 (M + H)⁺.

ES 2 398 074 T3

Example 254

N- {4- [3-amino-7- (3-morpholin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 207B and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.18-2.23 (m, 2H) 3.06-3.19 (m, 4H) 3.42-3.46 (m, 2H ) 3.65-3.70 (m, 2H) 4.00-4.07 (m, 2H) 4.24 (t, J = 5.8 Hz, 2H) 6.73 (d, J = 7.8 Hz, 1H) 6.83 (d, J = 7.8 Hz, 1H) 7.16 (ddd, J = 8.1, 1.9, 0.9 Hz, 1H) 7 , 25 (t, J = 8.1 Hz, 1H) 7.32-7.38 (m, 3H) 7.58 (d, J = 8.7 Hz, 2H) 7.88 (t, J = 1.9 Hz, 1H) 8.99 (s, 1H) 9.04 (s, 1H) 9.73 (s, 1H) 11.91 (s, 1H) MS (ESI ( +)) m / e 565.1, 567.1 (M + H)⁺.

Example 255

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl] -N'-methylphenyl) urea

Example 255A

3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylamine

The desired product was prepared by substituting 4-bromo-3-fluoro-phenylamine for Example 149A in Example 149B. The mixture was heated to 85 ° C overnight and the desired product was purified by flash chromatography using 30% ethyl acetate in hexanes. MS (ESI (+) m / e 238 (M + H)⁺.

Example 255B

N- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene for Example 255A and 1-isocyanato-3-methylbenzene, respectively, in Example 149A. MS (ESI (+) m / e 371 (M + H)⁺.

Example 255C

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 255B for Example 1B in Example 1C. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.29 (s, 3H), 6.81-6.85 (m, 2H), 7.18 (t, J = 7.83 Hz, 1H), 7.25 (d, J = 1.84 Hz, 1H), 7.27 (d, J = 1.84 Hz, 1H), 7.30-7.34 (m, 4H), 7.64 (dd , J = 12.73, 1.99 Hz, 1H), 8.74 (s, 1H), 9.04 (s, 1H); MS (ESI (+) m / e 376 (M + H)⁺.

Example 256

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline for Example 255A in Example 149A and then substituting Example 1B for the product in Example 1C. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.49 (s, 3H), 7.02-7.05 (m, 1H), 7.08 (t, J = 3.84 Hz, 1H), 7.32 (dd, J = 11.20, 8.44 Hz, 1H), 7.43-7.45 (m, 1H), 7.52-7.57 (m, 3H), 7.85 ( dd, J = 12.43.1.69 Hz, 1H), 8.17 (d, J = 7.98 Hz, 1H), 8.80 (d, J = 2.15 Hz, 1H), 9, 61 (s, 1H); MS (ESI (+) m / e 394 (M + H)⁺.

Example 257

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene for Example 255A and 1-chloro-3-isocyanatobenzene, respectively, in Example 149A and then substituting Example 1B by the product in Example 1C. ¹H NMR (400 MHz, DMSO-D6) δ ppm 6.81 (dd, J = 4.91, 2.46 Hz, 1H), 7.03-7.06 (m, 1H), 7.27-7 , 35 (m, 6H), 7.62 (dd, J = 12.43.1.99 Hz, 1H), 7.72 (t, J = 1.99 Hz, 1H), 9.02 (s, 1H), 9.12 (s, 1H); MS (ESI (+) m / e 396 (M + H)⁺.

Example 258

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl] -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene for Example 255A and 1-fluoro-4-isocyanate-2-methylbenzene, respectively, in Example 149A and after substituting

ES 2 398 074 T3 Example 1B by the product in Example 1C. ¹H NMR (400 MHz, DMSO-D6) δ ppm 2.22 (s, 3H), 6.87 (t, J = 3.84 Hz, 1H), 7.06 (t, J = 9.05 Hz, 1H), 7.27-7.38 (m, 6H), 7.63 (dd, J = 12.58.1.53 Hz, 1H), 8.79 (s, 1H), 9.07 (s , 1 HOUR); MS (ESI (+) m / e 394 (M + H⁺.

Example 259

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl [-N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene for Example 255A and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene, respectively, in Example 149A and then substituting Example 1B for the product in Example 1C. ¹H NMR (400 MHz, DMSO-D6) δ ppm 6.89 (t, J = 3.84 Hz, 1H), 7.28 (dd, J = 8.44, 1.99 Hz, 1H), 7, 34-7.38 (m, 3H), 7.42-7.45 (m, 1H), 7.50-7.54 (m, 1H), 7.66 (dd, J = 12.43, 1 , 99 Hz, 1H), 8.61 (dd, J = 7.21, 1.99 Hz, 1H), 9.03 (d, J = 2.15 Hz, 1H), 9.54 (s, 1H ); MS (ESI (+) m / e 448 (M + H)⁺.

Example 260

N- [4- (3-amino-1H-indazol-4-yl) -3-fluorophenyl] -N '- [4-fluoro-3- (trifluoromethyl) phenyl] phenyl] urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene for Example 255A and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 149A and then substituting Example 1B for the product in Example 1C. ¹H NMR (400 MHz, DMSO-D6) δ ppm 6.84 (t, J = 3.99 Hz, 1H), 7.29-7.36 (m, 4H), 7.46 (t, J = 9 , 82 Hz, 1H), 7.62 (dd, J = 12.73, 1.69 Hz, 1H), 7.68 (m, 1H), 8.02 (dd, J = 6.60, 2, 92 Hz, 1H), 9.21 (s, 2H); MS (ESI (+) m / e 448 (M + H)⁺.

Example 261

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl) -N '- (3,5-dimethylphenyl) urea

Example 261A

4- (4-aminophenyl) -1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Examples 1A and 1B for Example 95A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, respectively, in Example 1C. mS (ESI (+)) m / e 226 (M + H)⁺.

Example 261B

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3,5-dimethylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-isocyanato-3,5-dimethylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6H) 5.22 (s, 2H) 6.63 (s, 1H) 7.10 (s, 2H) 7, 14 (d, J = 6.8 Hz, 1H) 7.43 (d, J = 8.5 Hz, 2H) 7.48 (d, J-8.1 Hz, 1H) 7.56- 7.64 (m, 3H) 8.57 (s, 1H) 8.83 (s, 1H) MS (ESI (+)) m / e 373.1 (M + H)⁺.

Example 262

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N'-phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2 H) 6.99 (t, J = 7.5 Hz, 1 H) 7.14 (d, J = 7.1 Hz, 1H) 7.30 (t, J = 8.0 Hz, 2H) 7.44 (d, J = 8.5 Hz, 2H) 7.46-7.50 (m, 3H) 7, 58 (dd, J = 8.3, 7.3 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 8.74 (s, 1H) 8.87 (s, 1 H) MS (ESI (+)) m / e 345.0 (M + H)⁺.

Example 263

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (4-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3H) 5.22 (s, 2H) 7.10 (d, J = 8.5 Hz, 2H) 7.13 ( d, J = 6.8 Hz, 1H) 7.36 (d, J = 8.5 Hz, 2H) 7.43 (d, J = 8.5 Hz, 2H)

7.48 (d, J = 8.1 Hz, 1H) 7.55-7.63 (m, 3H) 8.62 (s, 1H) 8.83 (s, 1H) MS (ESI (+)) m / e 359.0 (M + H)⁺.

ES 2 398 074 T3

<img file="ES2398074T3_D0013.tif" />

Example 264

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl-N '- (3-cyanophenyl) urea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

3-isocyanatobenzonitrile, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2H) 7.14 (dd, J = 7.1, 0.7 Hz, 1H) 7.42-7.50 (m, 4 H) 7.51 (t, J = 8.0 Hz, 1 H) 7.59 (dd, J = 8.5, 7.5 Hz, 1 H) 7.64 (d, J =

8.5 Hz, 2H) 7.71 (ddd, J = 8.2, 2.1, 1.2 Hz, 1H) 8.00 (t, J = 1.9 Hz, 1H) 9.05 ( s, 1H) 9.09 (s, 1H) MS (ESI (+)) m / e 370.0 (M + H)⁺.

Example 265

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl-N '- [4-fluoro-3- (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 5.22 (s, 2H) 7.14 (d, J = 7.1 Hz, 1H) 7.45 (d, J = 8.5 Hz, 2H) 7.45 (t, J = 9.7 Hz, 1H) 7.49 (dd, J = 8.1, 0.7 Hz, 1H) 7.59 (dd, J = 8.5 , 7.5 Hz, 1H) 7.62-7.70 (m, 3H) 8.03 (dd, J = 6.4, 2.7 Hz, 1H) 9.01 (s, 1H ) 9.11 (s, 1H) MS (ESI (+)) m / e 431.0 (M + H)⁺.

Example 266

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl-N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2H) 7.13-7.18 (m, 2H) 7.26 (t, J = 8.0 Hz, 1H) 7.34 (ddd, J = 8.1, 2.0, 1.4 Hz, 1H) 7.44 (d, J = 8.5 Hz, 2H) 7.49 (dd, J = 8, 5, 0.9 Hz, 1H) 7.59 (dd, J = 8.5, 7.1 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 7.88 ( t, J = 1.9 Hz, 1H) 8.95 (s, 1H) 8.96 (s, 1H) MS (ESI (+)) m / e 422.9, 424.8 (M + H)⁺.

Example 267

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl-N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.75 (s, 2H) 7.03 (dt, J = 6.4, 2.7 Hz, 1H) 7.14 (dd, 1 = 7 , 1.0.7 Hz, 1H) 7.28-7.35 (m, 2H) 7.44 (d, J = 8.5 Hz, 2H) 7.48 (d, J =

8.1 Hz, 1H) 7.59 (dd, J = 8.1, 7.5 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 7.73 (t, J = 2.0 Hz, 1H) 8.96 (s ap., 2H) MS (ESI (+)) m / e 379.0 (M + H)⁺.

Example 268

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl-N '- (3-ethylphenyl) urea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

3-ethyl-1-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (t, J =

7.5 Hz, 3H) 2.59 (c, J = 7.5 Hz, 2H) 5.22 (s, 2H) 6.84 (d, J = 7.5 Hz, 1H) 7.14 (d, J = 7.1 Hz, 1H) 7.19 (t, J = 7.6 Hz, 1H) 7.27 (d, J = 7.8 Hz, 1H) 7.34 (s , 1H) 7.43 (d, J = 8.5 Hz, 2H) 7.48 (d, J = 8.1 Hz, 1H) 7.56-7.64 (m, 3H) 8 , 67 (s, 1H) 8.84 (s, 1H) MS (ESI (+)) m / e 373.0 (M + H)⁺.

Example 269

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl-N '- (trifluoromethyl) phenylurea

ES 2 398 074 T3

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

5.22 (s, 2H) 7.15 (d, J = 7.1 Hz, 1H) 7.44-7.50 (m, 3H) 7.59 (dd, J = 8.5, 7.1 Hz, 1H) 7.63-7.71 (m, 6H) 9.02 (s, 1H) 9.18 (s, 1H) MS (ESI (+)) m / e 413 , 0 (M + H)⁺.

Example 270

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- (3-fluoro-4-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-fluoro-5-isocyanato-2-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.17 (d, J = 1.4 Hz, 3H) 5.22 (s, 2H) 7.05 (dd, J = 8.3, 2.2 Hz, 1H) 7.12-7 , 21 (m, 2H) 7.42-7.50 (m, 4H) 7.56-7.64 (m, 3H) 8.84 (s, 1H) 8.90 (s, 1 H) MS (ESI (+)) m / e 377.1 (M + H)⁺.

Example 271

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 15G for Example 261A in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2H) 6.77-6.83 (m, 1H) 7.13-7.18 (m, 2H) 7.32 (td, J = 8.1, 7.1 Hz, 1H) 7.44 (d, J =

8.8 Hz, 2H) 7.48 (dd, J = 8.5, 1.0 Hz, 1H) 7.52 (dt, J = 11.9, 2.4 Hz, 1H) 7, 59 (dd, J = 8.1, 7.5 Hz, 1H) 7.63 (d, J =

8.8 Hz, 2H) 8.94 (s, 1H) 8.98 (s, 1H) MS (ESI (+)) m / e 363.0 (M + H)⁺.

Example 272

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3,5-difluorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1,3-difluoro-5-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2H) 6.81 (tt, J = 9.4, 2.3 Hz, 1H) 7.14 (dd, J = 7 , 1, 0.7 Hz, 1H) 7.22 (dd, J = 10.0, 2.3 Hz, 2H) 7.45 (d, J = 8.5 Hz, 2H) 7.49 (dd, J = 8.5, 0.7 Hz, 1H) 7.59 (dd, J = 8.5, 7.1 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 9.05 (s, 1H) 9.16 (s, 1H) MS (ESI (+)) m / e 381.0 (M + H)⁺.

Example 273

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methoxyphenyl) urea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

3-isocyanate-1-methoxybenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.74 (s, 3H) 5.22 (s, 2H) 6.57 (dd, J = 8.0, 2.2 Hz, 1H) 6.96 (dd, J = 8.1, 1.4 Hz, 1H) 7.14 (d, J = 6.8 Hz, 1H) 7.19 (t, J = 8.1 Hz, 1 H) 7.21 (t, J = 2.2 Hz, 1 H) 7.43 (d, J = 8.5 Hz, 2 H) 7.48 (d, J = 7.8 Hz, 1 H) 7.58 (dd, J = 8.1, 7.1 Hz, 1H) 7.62 (d, J = 8.5 Hz, 2H) 8.75 (s, 1H) 8.86 (s , 1H) MS (ESI (+)) m / e 375.1 (M + H)⁺.

Example 274

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (4-methoxyphenyl) urea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

4-isocyanate-1-methoxybenzene, respectively, in Example 15H. ¹H NNM (300 MHz, DMSO-D6) δ ppm 3.72 (s, 3H) 5.22 (s, 2H) 6.88 (d, J = 8.8 Hz, 2H) 7.13 ( dd, J = 7.1, 0.7 Hz, 1H) 7.38 (d, J = 8.8 Hz, 2H) 7.42 (d, J = 8.5 Hz, 2H) 7, 48 (dd, J = 8.5, 0.7 Hz, 1H) 7.58 (dd, J = 8.5, 7.5 Hz, 1H) 7.62 (d, J = 8.5 Hz , 2H) 8.54 (s, 1H) 8.79 (s, 1H) MS (ESI (+)) m / e 375.1 (M + H)⁺.

Example 275

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] urea

A solution of Example 261A (45 mg, 0.2 mmol) and sodium isocyanate (26 mg, 0.4 mmol) in HOAc (0.5 ml) and H2O (0.5 ml) was stirred overnight at rt, and then diluted with water. The precipitated solid was collected by filtration and recrystallized from THF / hexanes to give an off-white solid (35 mg, 65%).¹H NMR (300 MHz, DMSOD6) δ ppm 5.20 (s, 2H) 5.92 (s, 2H) 7.11 (dd, J = 7.3, 0.9 Hz, 1H) 7, 37 (d, J = 8.5 Hz, 2H) 7.46 (dd, J = 8.5, 1.0 Hz, 1H) 7.57 (d, J = 8.5 Hz, 2H) 7.57 (dd, J = 8.1, 7.1 Hz, 1H) 8.72 (s, 1H) MS (ESI (+)) m / e 269.0 (M + H)⁺.

Example 276

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-nitrophenyl) urea

ES 2 398 074 T3

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-nitro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2H) 7.15 (d, J = 6.8 Hz, 1H) 7.45-7.50 (m, 3H) 7.57-7.62 (m, 2H) 7.66 (d, J = 8.5 Hz, 2H) 7.75 (dd, J = 7.8, 1.7 Hz, 1H) 7 , 84 (dd, J-8.1, 2.4 Hz, 1H) 8.59 (t, J = 2.2 Hz, 1H) 9.09 (s, 1H) 9.34 (s, 1 H) MS (ESI (+)) m / e 390.0 (M + H)⁺.

Example 277

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- (4-fluorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-fluoro-4-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2H) 7.11-7.17 (m, 3H) 7.40-7.51 (m, 5H) 7.58 (dd, J = 8.1, 7.1 Hz, 1H) 7.63 (d, J = 8.8 Hz, 2H) 8.80 (s, 1H) 8.90 (s, 1H ) MS (ESI (+)) m / e 363.0 (M + H)⁺.

Example 278

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl] -N '- (2-fluorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-fluoro-2-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2H) 6.99-7.06 (m, 1H) 7.13-7.19 (m, 2H) 7.25 (ddd, J = 11.7, 8.1, 1.5 Hz, 1H) 7.45 (d, J = 8.8 Hz, 2H) 7.49 (dd, J =

8.5, 1.0 Hz, 1H) 7.59 (dd, J = 8.5, 7.5 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 8, 17 (td, J = 8.3, 1.7 Hz, 1H) 8.62 (d, J = 2.4 Hz, 1H) 9.27 (s, 1H) MS (ESI (+)) m / e 363.0 (M + H)⁺.

Example 279

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-chloro-4-fluorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-chloro-2-fluoro-5-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

5.22 (s, 2H) 7.14 (dd, J = 7.3, 0.9 Hz, 1H) 7.34 (m, 2H) 7.44 (d, J = 8.5 Hz , 2H) 7.48 (dd, J = 8.3, 0.9 Hz, 1H) 7.58 (dd, J = 8.5, 7.1 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 7.81-7.84 (m, 1H) 8.95 (s, 1H) 8.97 (s, 1H) MS (ESI (+)) m / e 397.0 (M + H)⁺.

Example 280

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-chloro-4-methoxyphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-chloro-5-isocyanato-2-methoxybenzene, respectively, in Example 15H.¹H NMR (300 MHz, DMSO-D6) δ ppm

3.82 (s, 3H) 5.22 (s, 2H) 7.10 (d, J = 9.2 Hz, 1H) 7.14 (dd, J = 7.1, 1.0 Hz , 1H) 7.29 (dd, J = 9.2, 2.5 Hz, 1H) 7.43 (d, J = 8.5 Hz, 2H) 7.48 (dd, J = 8, 3, 1.0 Hz, 1H) 7.58 (dd, J = 8.1, 7.1 Hz, 1H) 7.62 (d, J = 8.5 Hz, 2H) 7.68 ( d, J =

2.5 Hz, 1H) 8.71 (s, 1H) 8.87 (s, 1H) MS (ESI (+)) m / e 409.0 (M + H)⁺.

Example 281

N- [4- (3-amino-1,2-benzisoxazol-4-yl) phenyl] -N '- [4- (dimethylamino) phenyl] urea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

4-dimethylamino-1-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.84 (s, 6H) 5.21 (s, 2H) 6.71 (d, J = 9.2 Hz, 2H) 7.13 (dd, J = 7.1, 1.0 Hz , 1H) 7.28 (d, J = 9.2 Hz, 2H) 7.41 (d, J =

8.5 Hz, 2H) 7.47 (dd, J = 8.5, 1.0 Hz, 1H) 7.58 (dd, J = 8.5, 7.1 Hz, 1H) 7.61 ( d, J = 8.5 Hz, 2H) 8.36 (s, 1H) 8.73 (s, 1H) MS (ESI (+)) m / e 388.1 (M + H)⁺.

Example 282

N- [4-3-amino-1,2-bencisoxazol-4-yl) phenyl-N'-1,3-benzodioxol-5-ylurea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

5-isocyanatobenzo [1,3] dioxole, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.21 (s, 2H) 5.98 (s, 2H) 6.78 (dd, J = 8.5, 2.0 Hz, 1H) 6.84 (d, J = 8.5 Hz, 1H) 7.13 (dd, J = 7.1, 1.0 Hz, 1H) 7.22 (d, J = 2.0 Hz, 1 H) 7.42 (d, J = 8.5 Hz, 2H) 7.48 (dd, J = 8.1, 1.0 Hz, 1H) 7.58 (dd, J = 8.1, 7.5 Hz, 1H) 7.61 (d, J = 8.5 Hz, 2H) 8.62 (s, 1H) 8.80 (s, 1H) MS (ESI (+)) m / e 389.0 (M + H)⁺.

Example 283

ES 2 398 074 T3

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl-N '- [4- (trifluoromethoxy) phenylurea

The desired product was prepared by substituting Example 261A for Example 15G and 1-fluoro-3-isocyanatobenzene and

4-isocyanate-1- (trifluoromethoxy) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

5.22 (s, 2H) 7.14 (dd, J = 7.1, 1.0 Hz, 1H) 7.30 (d, J = 8.8 Hz, 2H) 7.44 (d, J = 8.5 Hz, 2H) 7.48 (dd, J = 8.5, 0.7 Hz, 1H) 7.59 (dd, J = 8.3, 7.3 Hz, 1H) 7 , 59 (d, J = 8.8 Hz, 2H) 7.63 (d, J = 8.5 Hz, 2H) 8.93 (s, 1H) 8.96 (s, 1H) MS (ESI (-)) m / e 426.9 (MH) -.

Example 284

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl-N '- [2- (trifluoromethoxy) phenylurea

The desired product was prepared by substituting Example 261A and 2-isocyanato-1- (trifluoromethoxy) benzene for Example 15G and 1-fluoro-3-isocyanatobenzene in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

5.23 (s, 2H) 7.11 (td, J = 7.6, 2.0 Hz, 1H) 7.15 (d, J = 7.1 Hz, 1H) 7.36 (td, J = 8.1, 1.4 Hz, 1H) 7.39 (ddd, J = 6.6, 3.1, 1.5 Hz, 1H) 7.44-7.50 (m, 3H) 7.59 (dd, J = 8.5, 7.1 Hz, 1H) 7.65 (d, J = 8.5 Hz, 2H) 8.28 (dd, J = 8.3, 1, 5 Hz, 1H) 8.55 (s, 1H) 9.48 (s, 1H) MS (ESI (+)) m / e 429.0 (M + H)⁺.

Example 285

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl-N '- [3,5-bis (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-isocyanato-3,5-bis (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.22 (s, 2H) 7.15 (dd, J = 7.1, 1.0 Hz, 1H) 7.45-7.51 (m , 3H) 7.59 (dd, J = 8.5, 7.1 Hz, 1H) 7.65-7.69 (m, 3H)

8.16 (s, 2H) 9.20 (s, 1H) 9.47 (s, 1H) MS (ESI (+)) m / e 481.0 (M + H)⁺.

Example 286

N- [4- (3-amino-1,2-bencisoxazol-4-yl) phenyl-N '- (3-chloro-4-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 261A and 1-chloro-5-isocyanato-2-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3H) 5.22 (s, 2H) 7.14 (dd, J = 7.1, 1.0 Hz, 1H) 7.21 (dd, J = 8.5, 2.0 Hz, 1H) 7.26 (d, J = 8.5 Hz, 1H) 7.44 (d, J = 8.8 Hz, 2 H) 7.48 (dd, J = 8.5, 0.7 Hz, 1 H) 7.58 (dd, J = 8.5, 7.5 Hz, 1 H) 7.63 (d, J = 8.8 Hz, 2H) 7.71 (d, J = 2.0 Hz, 1H) 8.84 (s, 1H) 8.91 (s, 1H) MS (ESI (+)) m / e 393.1 (M + H)⁺.

Example 287

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl-N '- [3,5-bis (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-isocyanato-3,5-bis (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.97 (s, 3H) 5.21 (s, 2H) 7.06 (d, J = 8.1 Hz, 1H) 7.17 ( d, J = 8.1 Hz, 1H) 7.41 (d, J = 8.5 Hz, 2H) 7.63 (d, J =

8.5 Hz, 2H) 7.66 (s, 1H) 8.16 (s, 2H) 9.16 (s, 1H) 9.45 (s, 1H) MS (ESI (+) ) m / e 511.0 (M + H)⁺.

Example 288

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl-N '- [4- (trifluoromethoxy) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

4-isocyanate-1- (trifluoromethoxy) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 7.04 (d, J = 8.1 Hz, 1H) 7.16 ( d, J = 8.1 Hz, 1H) 7.30 (d, J = 8.8 Hz, 2H) 7.39 (d, J = 8.5 Hz, 2H) 7.58 (d, J = 8.8 Hz, 2H) 7.60 (d, J = 8.5 Hz, 2H) 8.89 (s, 1H) 8.94 (s, 1H) MS (ESI (+) ) m / e 459.0 (M + H)⁺.

Example 289

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl-N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 15G for Example 100C in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3H) 5.21 (s, 2H) 6.80 (td, J = 8.5, 2.4 Hz, 1H) 7.05 (d, J = 7.8 Hz, 1H) 7.12-7.18 (m, 2H) 7.28-7.36 (m, 1H) 7.39 (d, J = 8.5 Hz, 2H) 7.51 (dt, J = 11.9, 2.2 Hz, 1H) 7.60 (d, J = 8.5 Hz, 2H) 8.91 (s, 1H) 8.96 (s, 1H) MS (ESI (+)) m / e 393.0 (M + H)⁺.

Example 290

ES 2 398 074 T3

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

3-isocyanate-1-methoxybenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.74 (s, 3H) 3.96 (s, 3H) 5.21 (s, 2H) 6.57 (dd, J = 8.3 , 2.5 Hz, 1H) 6.95 (dd, J = 7.8, 1.5 Hz, 1H) 7.04 (d, J = 7.8 Hz, 1H) 7.15-7 , 22 (m, 3H) 7.38 (d, J = 8.5 Hz, 2H) 7.59 (d, J = 8.5 Hz, 2H) 8.73 (s, 1H) 8 , 82 (s, 1H) MS (ESI (+)) m / e 405.0 (M + H)⁺.

Example 291

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (3,5-difluorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1,3-difluoro-5-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 6.80 (tt, J = 9.3, 2.4 Hz, 1H) 7.05 (d, J = 8.1 Hz, 1H) 7.17 (d, J = 8.1 Hz, 1H) 7.19-7.26 (m, 2H) 7.40 (d , J = 8.5 Hz, 2H) 7.60 (d, J = 8.5 Hz, 2H) 9.01 (s, 1H) 9.14 (s, 1H) MS (ESI (+ )) m / e 411.1 (M + H)⁺.

Example 292

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (4-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3H) 3.96 (s, 3H) 5.20 (s, 2H) 7.04 (d, J = 8.1 Hz, 1H) 7.09 (d, J = 8.1 Hz, 2H) 7.16 (d, J = 8.1 Hz, 1H) 7.35 (d, J =

8.1 Hz, 2H) 7.37 (d, J = 8.5 Hz, 2H) 7.58 (d, J = 8.5 Hz, 2H) 8.60 (s, 1H) 8.78 (s, 1H) MS (ESI (+)) m / e 389.1 (M + H)⁺.

Example 293

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 7.05 (d, J = 7.8 Hz, 1H) 7.14- 7.18 (m, 2H) 7.25 (t, J = 8.0 Hz, 1H) 7.33 (ddd, J = 8.0, 2.0, 1.2 Hz, 1H) 7 .39 (d, J = 8.5 Hz, 2H) 7.60 (d, J = 8.5 Hz, 2H) 7.88 (t, J = 1.9 Hz, 1H) 8.91 (s, 1H) 8.92 (s, 1H) MS (ESI (+)) m / e 451.0, 453.0 (M + H)⁺.

Example 294

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (3,5-dimethylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-isocyanato-3,5-dimethylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6H) 3.96 (s, 3H) 5.20 (s, 2H) 6.63 (s, 1H) 7, 04 (d, J = 8.1 Hz, 1H) 7.09 (s, 2H) 7.16 (d, J = 8.1 Hz, 1H) 7.37 (d, J = 8.5 Hz, 2H) 7.59 (d, J = 8.5 Hz, 2H) 8.55 (s, 1H) 8.79 (s, 1H) MS (ESI (+)) m / e 403 , 1 (M + H)⁺.

Example 295

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl-N '- [4- (dimethylamino) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

4-dimethylamino-1-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.84 (s, 6H) 3.96 (s, 3H) 5.20 (s, 2H) 6.71 (d, J = 9.2 Hz, 2H) 7.03 (d, J = 8.1 Hz, 1H) 7.16 (d, J = 8.1 Hz, 1H)

7.28 (d, J = 9.2 Hz, 2H) 7.35 (d, J = 8.5 Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 8, 35 (s, 1H) 8.68 (s, 1H) MS (ESI (+)) m / e

418.1 (M + H)⁺.

Example 296

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N'-1,3-benzodioxol-5-ylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and

5-isocyanatobenzo [1,3] dioxole, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 5.97 (s, 2H) 6.78 (dd, J = 8.5 , 2.0 Hz, 1H) 6.84 (d, J = 8.5 Hz, 1H) 7.04 (d, J = 8.1 Hz, 1H) 7.16 (d, J = 8 , 1Hz, 1H) 7.22 (d, J = 2.0Hz, 1H) 7.37 (d, J = 8.5Hz, 2H) 7.57 (d, J = 8.5 Hz, 2H) 8.60 (s, 1H) 8.76 (s, 1H) MS (ESI (+)) m / e 419.1 (M + H)⁺.

ES 2 398 074 T3

Example 297

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

Example 297A

4-iodo-7-methyl-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting 2-bromo-6-fluorobenzonitrile for Example 15C in Example 95A. MS (ESI (+)) m / e 274.8 (M + H)⁺.

Example 297B

4- (4-aminophenyl) -7-methyl-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Examples 1A and 1B for Example 297A and 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline, respectively, in Example 1C. MS (ESl (+)) m / e 240.0 (M + H)⁺.

Example 297C

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 2.45 (s, 3H) 5.20 (s, 2H) 6.80 (d, J = 7.5 Hz, 1H) 7.03 (d, J = 7.1 Hz, 1H) 7.17 (t, J = 7.8 Hz, 1H) 7.25 (d, J =

8.5 Hz, 1H) 7.31 (s, 1H) 7.38 (dd, J = 7.5, 1.0 Hz, 1H) 7.40 (d, J = 8.5 Hz, 2H) 7.61 (d, J = 8.5 Hz, 2H) 8.64 (s, 1H) 8.83 (s, 1H) MS (ESI (+)) m / e 373.1 (M + H)⁺.

Example 298

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.02-7.05 (m, 2H) 7.27-7.32 (m, 2H) 7.37-7.44 (m, 3H) 7.62 (d, J = 8.8 Hz, 2H) 7.73-7.74 (m, 1H)

8.94 (s, 1H) 8.95 (s, 1H) MS (ESI (+)) m / e 393.0 (M + H)⁺.

Example 299

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.28 (s, 3H) 2.45 (s, 3H) 5.20 (s, 2H) 6.79-6.84 (m, 1H) 7.04 (d, J = 7, 1 Hz, 1H) 7.11 (dd, J = 11.4, 8.3 Hz, 1H) 7.37-7.43 (m, 3H) 7.61 (d, J = 8.5 Hz, 2H) 8.00 (dd, J = 7.6, 1.9 Hz, 1H) 8.54 (d, J = 2.4 Hz, 1H) 9.24 (s, 1H) MS (ESI (+)) m / e 391.1 (M + H)⁺.

Example 300

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 2.46 (s, 3H) 5.20 (s, 2H) 7.05 (d, J = 7.5 Hz, 1H) 7.38- 7.45 (m, 4H) 7.48-7.55 (m, 1H) 7.63 (d, J = 8.5 Hz, 2H) 8.64 (dd, J = 7.3, 2 , 2 Hz, 1H) 8.97 (s, 1H) 9.37 (s, 1H) MS (ESI (+)) m / e 445.0 (M + H)⁺.

Example 301

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J = 7.1 Hz, 1H) 7.32 (d, J = 7.8 Hz, 1H) 7.38 (dd, J = 7.3, 0.9 Hz, 1H) 7.42 (d, J =

8.5 Hz, 2H) 7.53 (t, J = 8.0 Hz, 1H) 7.59-7.64 (m, 3H) 8.04 (s, 1H) 9.00 ( s, 1H) 9.13 (s, 1H) MS (ESI (+)) m / e 427.0 (M + H)⁺.

ES 2 398 074 T3

Example 302

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3,5-dimethylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-isocyanato-3,5-dimethylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6H) 2.45 (s, 3H) 5.20 (s, 2H) 6.63 (s, 1H) 7, 04 (d, J = 7.5 Hz, 1H) 7.09 (s, 2H) 7.38 (dd, J = 7.3, 0.9 Hz, 1H) 7.40 (d, J = 8.5 Hz, 2H) 7.60 (d, J = 8.5 Hz, 2H) 8.56 (s, 1H) 8.81 (s, 1H) MS (ESI (+)) m / e 387.1 (M + H)⁺.

Example 303

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-ethylphenyl) urea

The desired product was prepared by substituting Example 297B for Example 15G and 1-fluoro-3-isocyanatobenzene and

3-ethyl-1-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.19 (t, J =

7.5 Hz, 3H) 2.45 (s, 3H) 2.58 (c, J = 7.6 Hz, 2H) 5.20 (s, 2H) 6.84 (d, J = 7.5 Hz, 1H) 7.04 (d, J = 7.5 Hz, 1H) 7.1.9 (t, J = 7.8 Hz, 1H) 7.27 (ddd, J = 8.1, 2.0, 1.4 Hz, 1H) 7.33-7.35 (m, 1H) 7.38 (dd, J = 7.3, 0.9 Hz, 1H) 7 , 40 (d, J = 8.5 Hz, 2H) 7.61 (d, J = 8.5 Hz, 2H) 8.66 (s, 1H) 8.82 (s, 1H) MS (ESI (+)) m / e 387.1 (M + H)⁺.

Example 304

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (4-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.25 (s, 3H) 2.45 (s, 3H) 5.19 (s, 2H) 7.03 (d, J = 7.5 Hz, 1H) 7.10 (d, J = 8.5 Hz, 2H) 7.34-7.41 (m, 5H) 7.60 (d, J = 8.5 Hz, 2H) 8.61 (s, 1H) 8.80 (s, 1H) MS (ESI (+)) m / e 373.1 (M + H)⁺.

Example 305

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- [4- (trifluoromethoxy) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-trifluoromethoxy-4-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J = 7.5Hz, 1H) 7.30 (d, J = 8.5Hz, 2H) 7.37-7.42 (m, 3H) 7.57-7.63 (m, 4H)

8.91 (s, 1H) 8.95 (s, 1H) MS (ESI (+)) m / e 443.0 (M + H)⁺.

Example 306

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-fluoro-4-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-fluoro-5-isocyanato-2-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.17 (s, 3H) 2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J = 7.5 Hz, 1H) 7.05 (dd, J = 8.1, 2.0 Hz, 1H) 7.18 (t, J = 8.7 Hz, 1H) 7.37-7.39 (m, 1H) 7.41 (d, J = 8 , 5 Hz, 2H) 7.46 (dd, J = 12.6, 2.0 Hz, 1H) 7.60 (d, J = 8.5 Hz, 2H) 8.84 (s, 1 H)

8.88 (s, 1H) MS (ESI (+)) m / e 391.1 (M + H)⁺.

Example 307

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methoxyphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-methoxy-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 3.74 (s, 3H) 5.20 (s, 2H) 6.57 (dd, J = 8.1 , 2.4 Hz, 1H) 6.95 (dd, J = 7.5, 1.5 Hz, 1H) 7.04 (d, J = 7.5 Hz, 1H) 7.16-7 , 22 (m, 2H) 7.37-7.43 (m, 3H) 7.61 (d, J = 8.5 Hz, 2H) 8.74 (s, 1H) 8.84 ( s, 1H) MS (ES1 (+)) m / e 389.0 (M + H)⁺.

Example 308

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N'-phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 6.98 (tt, J = 7.1, 1.4 Hz, 1H) 7.04 (d, J = 7.5 Hz, 1H) 7.27-7.32 (m, 2H) 7.38 (dd, J = 7.5, 1.0 Hz, 1H) 7 , 40 (d, J = 8.8 Hz, 2H) 7.48 (dd, J = 8.8, 1.0 Hz, 2H) 7.61 (d, J = 8.8 Hz, 2H ) 8.72 (s, 1H) 8.85 (s, 1H) MS (ESI (+)) m / e

ES 2 398 074 T3

359.0 (M + H)⁺.

Example 309

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- [3,5-bis (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-isocyanato-3,5-bis (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.05 (d, J = 7.1 Hz, 1H) 7.39 ( dd, J = 7.5, 0.7 Hz, 1H) 7.43 (d, J = 8.5 Hz, 2H) 7.63-

7.66 (m, 3H) 8.16 (s, 2H) 9.18 (s, 1H) 9.45 (s, 1H) MS (ESl (+)) m / e 495.0 (M + H)⁺

Example 310

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 297B and 1-bromo-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 5.20 (s, 2H) 7.04 (d, J = 7.1 Hz, 1H) 7.16 ( ddd, J = 7.8, 1.9, 1.2 Hz, 1H) 7.25 (t, J = 8.0 Hz, 1H) 7.33 (ddd, J = 8.0, 2, 0.12 Hz, 1H) 7.38 (m, J = 7.5, 1.0 Hz, 1H) 7.41 (d, J = 8.5 Hz, 2H) 7.61 ( d, J = 8.5 Hz, 2H) 7.88 (t, J = 1.9 Hz, 1H) 8.93 (s ap., 2H) MS (ESl (+)) m / e 436 , 9, 438.9 (M + H)⁺.

Example 311

N- [4- (3-amino-7-methyl-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-fluorophenyl) urea

The desired product was prepared by substituting Example 297B for Example 15G in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.45 (s, 3H) 5.19 (s, 2H) 6.80 (tdd, J = 8.5, 2.7, 1.0 Hz , 1H) 7.04 (d, J = 7.5 Hz, 1H) 7.14 (ddd, J = 8.2, 2.0, 0.7 Hz, 1H) 7.32 (td, J = 8.2, 7.0 Hz, 1H) 7.37-7.44 (m, 3H) 7.51 (dt, J = 12.0, 2.3 Hz, 1H) 7.61 (d, J = 8.5 Hz, 2H) 8.92 (s, 1H) 8.96 (s, 1H) MS (ESl (+)) m / e 377.1 (M + H)⁺.

Example 312

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 3.96 (s, 3H) 5.20 (s, 2H) 7.05 (d, J = 8.1 Hz, 1H) 7.16 ( d, J = 8.1 Hz, 1H) 7.39 (d, J = 8.5 Hz, 2H) 7.45 (t, J = 9.8 Hz, 1H) 7.61 (d, J = 8.5 Hz, 2H) 7.64-7.69 (m, 1H) 8.02 (dd, J = 6.4, 2.7 Hz, 1H) 8.97 (s, 1 H) 9.09 (s, 1H) MS (ESl (+)) m / e 461.0 (M + H)⁺.

Example 313

N- [4- (3-amino-7-methoxy-1,2-benzisoxazol-4-yl) phenyl] -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 100C and 1-fluoro-4-isocyanato-2-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J = 2.0 Hz, 3H) 3.96 (s, 3H) 5.20 (s, 2H) 7.03- 7.09 (m, 2H) 7.16 (d, J = 8.1 Hz, 1H) 7.27 (ddd, J = 8.5, 4.1, 3.0 Hz, 1H) 7 , 35-7.39 (m, 3H) 7.59 (d, J = 8.5 Hz, 2H) 8.66 (s, 1H) 8.81 (s, 1H) MS (ESl ( +)) m / e 407.1 (M + H)⁺.

Example 314

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

Example 314A

7-fluoro-4-iodo-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting 2-bromo-6-fluorobenzonitrile for Example 26A in Example 95A. MS (ESl (+)) m / e 278.8 (M + H)⁺.

Example 314B

4- (4-aminophenyl) -7-fluoro-1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Examples 1A and 1B for Example 314A and 4- (4,4,5,5-tetramethyl-1,3,287

ES 2 398 074 T3 dioxaborolan-2-yl) aniline, respectively, in Example 1C. MS (ESI (+)) m / e 244.0 (M + H)⁺.

Example 314C

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 314B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

5.38 (s, 2H) 7.12 (dd, J = 8.3, 3.9 Hz, 1H) 7.33 (d, J = 7.8 Hz, 1H) 7.43 (d, J = 8.8 Hz, 2H) 7.52 (dd, J = 10.9, 8.1 Hz, 1H) 7.53 (t, J = 7.8 Hz, 1H) 7.59- 7.65 (m, 3H) 8.04 (s, 1H) 9.00 (s, 1H) 9.12 (s, 1H) MS (ESI (+)) m / e 431.0 ( M + H)⁺.

Example 315

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 314B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.38 (s, 2H) 7.03 (dt, J = 6.4, 2.2 Hz, 1H) 7.12 (dd, J = 8 , 1, 4.1 Hz, 1H) 7.27-7.35 (m, 2H) 7.42 (d, J = 8.5 Hz, 2H) 7.52 (dd, J = 10, 9, 8.1 Hz, 1H) 7.62 (d, J = 8.5 Hz, 2H) 7.72-7.74 (m, 1H) 8.95 (s, 1H) 8, 96 (s, 1H) MS (ESI (+)) m / e 397.0 (M + H)⁺.

Example 316

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 314B and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 5.37 (s, 2H) 7.12 (dd, J = 8.1, 4.1 Hz, 1H) 7.43 (d, J = 8 , 5 Hz, 2H) 7.43 (d, J = 9.2 Hz, 1H) 7.52 (dd, J =

10.9, 8.1 Hz, 1H) 7.63 (d, J = 8.5 Hz, 2H) 7.64-7.69 (m, 1H) 8.02 (dd, J = 6 , 4, 2.7 Hz, 1H) 9.01 (s, 1H) 9.10 (s, 1H) MS (ESI (+)) m / e 449.0 (M + H)⁺.

Example 317

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 314B and 1-isocyanato-3-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 5.38 (s, 2H) 6.81 (d, J = 7.5 Hz, 1H) 7.11 ( dd, J = 8.1, 4.1 Hz, 1H) 7.17 (t, J = 7.8 Hz, 1H) 7.25 (d, J = 8.5 Hz, 1H) 7, 32 (s, 1H) 7.41 (d, J = 8.5 Hz, 2H) 7.51 (dd, J = 10.9, 8.1 Hz, 1H) 7.62 (d, J = 8.5 Hz, 2H) 8.65 (s, 1H) 8.85 (s, 1H) MS (ESI (+)) m / e 377.1 (M + H)⁺.

Example 318

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 314B and 1-fluoro-2-isocyanate-4- (trifluoromethyl) benzene for Example 15G and 1-fluoro-3-isocyanatobenzene in Example 15H, respectively. ¹H NMR (300 mHz, DMSO-D6) δ ppm 5.38 (s, 2H) 7.12 (dd, J = 8.3, 3.9 Hz, 1H) 7.38-7.55 (m , 5H) 7.64 (d, J = 8.8Hz, 2H) 8.64 (dd, J = 7.3, 2.2Hz, 1H) 8.97 (d, J = 3, 1 Hz, 1H) 9.37 (s, 1H) MS (ESI (+)) m / e 449.0 (M + H)⁺.

Example 319

N- [4- (3-amino-7-fluoro-1,2-benzisoxazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 314B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.28 (s, 3H) 5.38 (s, 2H) 6.79-6.84 (m, 1H) 7.08-7.15 (m, 2H) 7.43 (d, J = 8.5 Hz, 2H) 7.52 (dd, J = 10.9, 8.1 Hz, 1H) 7.62 (d, J = 8.5 Hz, 2H) 8.00 ( dd, J = 7.6, 1.9 Hz, 1H) 8.55 (d, J = 2.4 Hz, 1H) 9.25 (s, 1H) MS (ESI (+)) m / e 395.0 (M + H)⁺.

Example 320

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

ES 2 398 074 T3

Example 320A

6-bromo-2-fluoro-3- (trifluoromethoxy) benzonitrile

The desired product was prepared by substituting 4-bromo-2-fluoro-1-trifluoromethoxybenzene for 2-fluoro-4-iodo-1-methylbenzene in Examples 15A-C. MS (ESI (-)) m / e 282 (MH) -.

Example 320B

4-bromo-7- (trifluoromethoxy) -1,2-benzisoxazol-3-amine

A solution of propan-2-one oxime (810 mg, 1.1 mmol) in THF (50 ml) was treated with potassium tert-butoxide (1.23 g), stirred at rt for 30 min and then treated with Example 320A (2.84 g, 10 mmol). The reaction mixture was stirred at rt for 30 min and then partitioned between EtOAc and water. The organic extract was washed with brine, dried (MgSO4), and concentrated. The residue was dissolved in ethanol (20 ml), treated with 5% HCl (20 ml) and refluxed for 2 h. The reaction was allowed to cool to rt and concentrated to half its volume resulting in a precipitate which was collected by filtration. The crude solid was purified by silica gel chromatography eluting with 0-10% EtOAc -hexanes to give 0.95 g of Example 320B. MS (ESI (+)) m / e 297, 299 (M + H)⁺.

Example 320C

4- (4-aminophenyl) -7- (trifluoromethoxy) -1,2-benzisoxazol-3-amine

The desired product was prepared by substituting Example 320B for Example 15H in Example 15G. MS (ESI (+)) m / e 310 (M + H)⁺.

Example 320D

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-yl] phenyl} -N '- [2-fluoro-5- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 320C and 1-fluoro-2-isocyanato-4- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 5.44 (s, 2H), 7.22 (d, J = 7.80 Hz, 1H), 7.35-7.46 (m, 1H), 7.45-7.52 (m, 3H), 7.62-7.72 (m, 3H), 8.64 (dd, J = 7.29, 2.20 Hz, 1H), 8.98 ( d, J = 2.71 Hz, 1H), 9.40 (s, 1H); MS (ESI (+)) m / e 515 (M + H)⁺.

Example 321

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-yl] phenyl} -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 320C and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

5.44 (s, 2H), 7.22 (d, J = 8.14 Hz, 1H), 7.33 (d, J = 7.80 Hz, 1H), 7.45-7.72 (m , 7H), 8.04 (s, 1H), 9.03 (s, 1H), 9.13 (s, 1H); MS (ESI (+)) m / e 497 (M + H)⁺.

Example 322

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 320C and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.28 (s, 3H), 5.44 (s, 2H), 6.75-6.90 (m, 1H), 7.12 (dd, J = 11.36, 8.31 Hz, 1H) , 7.21 (d, J = 8.14 Hz, 1H), 7.47 (d, J =

8.82 Hz, 2H), 7.55-7.75 (m, 3H), 8.00 (dd, J = 7.97,1.86 Hz, 1H), 8.56 (d, J = 2 , 71 Hz, 1H), 9.28 (s, 1H); MS (ESI (+)) m / e 461 (M + H)⁺.

Example 323

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-yl] phenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 320C and

3-chloro-1-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.43 (s, 2H), 7.95-7.06 (m, 1H), 7.21 (d, J = 8.14 Hz, 1H), 7.25-7.35 (m, 2H), 7.47 (d, J = 8.48 Hz, 2H), 7.6-7.9 (m, 4H), 8.97 (s, 1H) , 8.99 (s, 1H); MS (ESI (+)) m / e 463 (M + H)⁺.

Example 324

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-yl] phenyl} -N '- (3-bromophenyl) urea

ES 2 398 074 T3

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 320C and

3-bromo-1-isocyanatobenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.43 (s, 2H), 7.10-7.37 (m, 4H), 7.47 (d, J = 8.82 Hz, 2H), 7.60-7.72 (m, 3H), 7.88 (t, J = 2.03Hz, 1H), 8.96 (s, 1H), 8.99 (s, 1H); MS (ESI (+)) m / e 507 (M + H)⁺.

Example 325

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-illphenyl} -N '- [4-fluoro-3- (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 320C and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 mHz, DMSO-D6) δ ppm 5.43 (s, 2H), 7.21 (d, J = 8.14 Hz, 1H), 7.40-7.52 (m, J = 9 , 15.9.15 Hz, 3H), 7.60-7.75 (m, 4H), 7.90-8.10 (dd, J = 6.44, 2.71 Hz, 1H), 9, 04 (s, 1H), 9.12 (s, 1H); MS (ESI (+)) m / e 515 (M + H)⁺.

Example 326

N- {4- [3-amino-7- (trifluoromethoxy) -1,2-benzisoxazol-4-illphenyl} -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 320C and

1- fluoro-4-isocyanato-2-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.23 (s, 3H), 5.43 (s, 2H), 7.06 (t, J = 9.16 Hz, 1H), 7.21 (d, J = 8.14 Hz, 1H), 7.25-7.40 (m, 2H), 7.45 (d, J = 8.48 Hz, 2H), 7.58-7.78 (m, 3H), 8.69 (s, 1H) , 8.88 (s, 1H); MS (ESI (+)) m / e 461 (M + H)⁺.

Example 327

N- [4- (3-amino-1,2-benzisothiazol-4-yl) phenyl-N '- (3,5-dimethylphenyl) urea

Example 327A

2- (benzylthio) -6-iodobenzonitrile

A suspension of potassium tert-butoxide (1.12 g, 10.0 mmol) and phenylmethanethiol (1.24 g, 10 mmol) in THF (30 ml) at room temperature was stirred for 10 minutes before treatment with 2-fluoro -6-iodo-benzonitrile (2.47 g, 10 mmol). The solution was stirred for 1 hour at room temperature, poured into a saturated ammonium chloride solution and filtered. The filter cake was recrystallized from hexanes to provide 2.41 g (53% yield) of the desired product. MS (ESI (-)) m / e 350.0 (MH) -.

Example 327B

4- iodo-1,2-benzisothiazol-3-amine

Example 327A (2.5 g, 7.1 mmol) was treated with sulfuryl chloride (1.0 M in dichloromethane, 3.5 mL, 35.5 mmol), stirred at room temperature for 2 hours, and concentrated . The residue was dissolved in a minimal amount of THF, treated with ammonia (7.0M in methanol, 10 ml), stirred at room temperature for 1 hour, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was triturated in ethyl acetate / hexanes to provide 1.2 g (61% yield) of the desired product. MS (ESI (-)) m / e 274.8, 276.7 (MH) -.

Example 327C

N- [4- (3-amino-1,2-benzisothiazol-4-yl) phenyl-N '- (3,5-dimethylphenyl) urea

The desired product was prepared by substituting 1-isocyanato-3,5-dimethylbenzene for 1-isocyanato-3-methylbenzene in Example 1B and Example 1A for Example 327B in Example 1C. In addition, PdCl2.dppf.CH2Cl2 was used instead of Pd (PPha) 4.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.24 (s, 6H), 5.45 (s, 2H), 6.63 (s, 1H), 7.09 (s, 2H), 7, 35 (d, J =

8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.97 (d, J = 8.14 Hz, 1H), 8.59 (s, 1H), 8.85 ( s, 2H); MS (ESI (+)) m / e 389.0 (M + H)⁺.

Example 328

N- [4- (3-amino-1,2-benzisothiazol-4-yl) phenyl-N '- (3-chlorophenyl) urea

The desired product was prepared by substituting 3-chloro-1-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1B and Example 1a for Example 327B in Example 1C. In addition, PdCl2.dppf.CH2Cl2 was used instead of Pd (PPh3) 4.¹H NMR (300 MHz, DMSO-D6) δ ppm 5.45 (s, 2H), 7.01-7.10 (m, 1H), 7.17 (d, J = 7.80 Hz, 1H), 7.30-

7.40 (m, 3H), 7.50-7.65 (m, 4H), 7.70-7.80 (m, 1H), 7.97 (dd, J = 7.97, 0.85 Hz, 1H), 9.00 (s, 2H); MS (ESI (+)) m / e

ES 2 398 074 T3

395.0 (M + H)⁺.

Example 329

N- [4- (3-amino-1,2-benzisothiazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Example 1B and Example 1A for Example 327B in Example 1C. In addition, PdCl2.dppf.CH2Cl2 was used instead of Pd (PPha) 4.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 5.45 (s, 2H) 6.78-6.88 (m, 1H) 7.05-7.25 ( m, 2H), 7.37 (d, J = 8.48 Hz, 2H), 7.50-7.70 (m, 3H), 7.90-8.10 (m, 2H), 8.56 (d, J = 2.37 Hz, 1H), 9.28 (s, 1H); MS (ESI (+)) m / e 393.0 (M + H)⁺.

Example 330

N- [4- (3-amino-1,2-benzisothiazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 1A for Example 327B in Example 1C. In addition, PdCl2.dppf.CH2Cl2 was used instead of Pd (PPh3) 4.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H), 5.45 (s, 2H), 6.81 (d, J = 7.46 Hz, 1H), 7.20- 7.40 (m, 3H), 7.48-7.56 (m, 6H), 7.97 (d, J = 8.14 Hz, 1H), 8.67 (s, 1H), 8.87 (s, 1H); MS (ESI (+)) m / e 375.0 (M + H)⁺.

Example 331

N- [4- (3-amino-1,2-benzisothiazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-isocyanate-3- (trifluoromethyl) benzene in Example 1B and Example 1A for Example 327B in Example 1C. In addition, PdCl2.dppf.CH2Cl2 was used instead of Pd (PPh3) 4.¹H NMR (300 MHz, DMSO-D6) δ ppm 5.45 (s, 2H), 7.17 (d, J = 7.12 Hz, 1H), 7.25-7.45 (m, 3H), 7.50-

7.60 (m, 5H), 7.97 (d, J = 7.46 Hz, 1H), 8.04 (s, 1H), 9.02 (s, 1H), 9.14 (s, 1H ); MS (ESI (+)) m / e 429 (M + H)⁺.

Example 332

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) -2-fluorophenyl] -N '- (2-fluoro-5-methylphenyl) urea

Example 332A

2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylamine

The desired product was prepared by substituting 4-bromo-2-fluoro-phenylamine for Example 149A in Example 149B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 3.32 (s, 12H) 5.56 (s, 2H) 6.72 (dd, J = 8.82, 7.80 Hz, 1H) 7.13 (m, 1H) 7.18 (dd, J = 7.97, 1.19 Hz, 1H).

Example 332B

N- (2-fluoro-5-methylphenyl) -N '- [2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea

The desired product was prepared by substituting Example 332A for 4-bromo-2-ethylaniline in Example 149A. MS (ESI (+)) m / e 389 (M + H)⁺.

Example 332C

7-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting Example 15E for Example 26A in Example 15F. MS (ESI (+)) m / e 278 (M + H)⁺.

Example 332D

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) -2-fluorophenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 332B and Example 332C for Example 1B and Example 1A, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 6.77-6.81 (m, 2H), 7.09-7.17 (m, 2H), 7.24 (dd, J = 8.48, 2.03 Hz, 1H), 7.36 (dd, J = 12.21, 2.03 Hz, 1H), 8.03 (dd, J = 7.97, 2 , 20 Hz, 1H), 8.31 (t, J = 8.48 Hz, 1H), 9.03 (d, J = 2.37 Hz, 1H), 9.15 (d, J = 2.37 Hz, 1H); MS (ESI (+) m / e 412 (M + H)⁺.

ES 2 398 074 T3

Example 333

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-chlorophenyl) urea

Example 333A

N- (3-chlorophenyl) -N '- [3-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea

The desired product was prepared by substituting 4-bromo-2-ethylaniline and 1-fluoro-2-isocyanato-4-methylbenzene for Example 332A and 1-chloro-3-isocyanato-benzene, respectively, in Example 149A. MS (ESI (+)) m / e 391 (M + H)⁺.

Example 333B

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) -2-fluorophenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 333A and Example 332C for Example 1B and Example 1A, respectively, in Example 1C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.79 (dd, J = 7.80, 4.07 Hz, 1H), 7.03-7.07 (m, 1H), 7.14 (dd , J = 11.36, 7.97 Hz, 1H), 7.24-7.39 (m, 4H), 7.75 (t, J = 2.03 Hz, 1H), 8.25 (t, J = 8.48 Hz, 1H), 8.73 (d, J = 2.37 Hz, 1H), 9.31 (s, 1H); MS (ESI (+) m / e 414 (M + H)⁺.

Example 334

N- (4- {3-amino-7 - [(1-methylpiperidin-4-yl) methoxy] -1H-indazol-4-yl} -2-fluorophenyl) -N '- (2-fluoro-5-methylphenyl )urea

Example 334A

2-fluoro-6-iodo-3 - [(1-methylpiperidin-4-yl) methoxy] benzonitrile

The desired product was prepared by substituting 1-methyl-4-piperidinemethanol for 2- (4-morpholinyl) ethanol in Example 75A. MS (ESI (+)) m / e 375 (M + H)⁺.

Example 334B

4-iodo-7 - [(1-methylpiperidin-4-yl) methoxy] -1H-indazol-3-amine

The desired product was prepared by substituting Example 334A for Example 15E in Example 15F. MS (ESI (+)) m / e 387 (M + H)⁺.

Example 334C

N- (4- {3-amino-7 - [(1-methylpiperidin-4-yl) methoxy] -1H-indazol-4-yl} -2-fluorophenyl) -N '- (2-fluoro-5-methylphenyl )urea

The desired product was prepared by substituting Example 334B and Example 5A for Example 1A and Example 1B in Example 1C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.42-1.58 (m, 2H), 2.08-2.18 (m, 3H), 2.28 (s, 3H), 2.79 (d, J =

4.75 Hz, 3H), 2.91-3.11 (m, 2H), 3.51 (d, J = 12.21 Hz, 2H), 4.03 (d, J = 6.44 Hz, 2H), 6.71 (d, J = 7.80 Hz, 1H), 6.81-

6.83 (m, 2H), 7.11 (dd, J = 11.36, 8.31 Hz, 1H), 7.36 (d, J = 8.48 Hz, 2H), 7.57 (d , J = 8.81 Hz, 2H), 8.00 (dd, J = 7.97.2.20 Hz, 1H), 8.53 (d, J = 2.71 Hz, 1H), 9.19 (s, 1H); MS (ESI (+) m / e 503 (M + H)⁺.

Example 335

N- (4- {3-amino-7 - [(1-methylpiperidin-4-yl) methoxy] -1H-indazol-4-yl} phenyl) -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 334B for Example 1A in Example 1C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.41-1.53 ​​(m, 2H), 2.07-2.18 (m, 3H), 2.29 (s, 3H), 2.79 (d, J = 4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J = 12.55 Hz, 2H), 4.03 (d, J = 6.44 Hz, 2H), 6.71 (d, J = 7.46 Hz, 1H), 6.81 (m, 2H), 7.16 (m, 1H), 7.25 (d, J = 8.14 Hz, 1H), 7.32 (s, 1H), 7.34 (d, J = 8.48 Hz, 2H), 7.57 (d, J = 8.48 Hz, 2H), 8 , 69 (s, 1H), 8.83 (s, 1H); MS (ESI (+) m / e 485 (M + H)⁺.

Example 336

N- (4- {3-amino-7 - [(1-methylpiperidin-4-yl) methoxy] -1H-indazol-4-yl} phenyl) -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 334B and 1-chloro-3-isocyanatobenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.41-1.53 ​​(m, 2H), 2.07-2.18 (m, 3H), 2.79 (d, J = 4.75 Hz , 3H), 2.92-3.05 (m, 2H), 3.51 (d, J = 12.55 Hz, 2H), 4.03 (d, J = 6.44 Hz, 2H), 6 , 72 (d, J = 7.80 Hz, 1H), 6.82 (d, J = 7.80 Hz, 1H), 7.01-7.04 (m, 1H), 7.30-7, 32 (m, 2H), 7.36 (d, J = 8.48

ES 2 398 074 T3

Hz, 2H), 7.57 (d, J = 8.48 Hz, 2H), 7.74 (m, 1H), 8.98 (s, 1H), 9.04 (s, 1H); MS (ESI (+) m / e 505 (M + H)⁺.

Example 337

N- (4- {3-amino-7 - [(1-methylpiperidin-4-yl) methoxy] -1H-indazol-4-yl} phenyl) -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 334B and 1-fluoro-2-methyl-4-isocyanatobenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 1.41-1.53 ​​(m, 2H), 2.07-2.18 (m, 3H), 2.22 (s, 3H) 2.79 ( d, J = 4.75 Hz, 3H), 2.92-3.05 (m, 2H), 3.51 (d, J = 12.55 Hz, 2H), 4.03 (d, J = 6 , 44 Hz, 2H), 6.72 (d, J = 7.46 Hz, 1H), 6.82 (d, J = 7.80 Hz, 1H), 7.05 (t, J = 9.16 Hz, 1H), 7.25-

7.40 (m, 2H), 7.34 (d, J = 8.48 Hz, 2H), 7.56 (d, J = 8.82 Hz, 2H), 8.73 (s, 1H), 8.85 (s, 1H); MS (ESI (+) m / e 503 (M + H)⁺.

Example 338

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-chlorophenyl) urea

Example 338A

2-fluoro-6-iodo-3- (3-pyridin-3-ylpropoxy) benzonitrile

The desired product was prepared by substituting 2- (4-morpholinyl) ethanol for 3-pyridinepropanol in Example 75A. MS (ESI (+)) m / e 383 (M + H)⁺.

Example 338B

4-iodo-7- (3-pyridin-3-ylpropoxy) -1H-indazol-3-amine

The desired product was prepared by substituting Example 338A for Example 15E in Example 15F. MS (ESI (+)) m / e 395 (M + H)⁺.

Example 338C

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 338B and 1-chloro-3-isocyanatobenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.13-2.22 (m, 2H), 3.05 (t, J = 7.12 Hz, 2H), 4.16 (t, J = 5 , 93 Hz, 2H), 6.73 (d, J = 7.80 Hz, 1H), 6.81 (d, J = 7.80 Hz, 1H), 7.017.04 (m, 1H), 7, 27-7.32 (m, 2H), 7.37 (d, J = 8.81 Hz, 2H), 7.58 (d, J = 8.81 Hz, 2H), 7.74 (t, J = 2.03 Hz, 1H), 7.83 (dd, J = 7.80, 5.42 Hz, 1H), 8.32 (d, J = 7.80 Hz, 1H), 8.69 (d , J = 4.07 Hz, 1H), 8.77 (d, J = 2.03 Hz, 1H), 8.97 (s, 1H), 9.03 (s, 1H); MS (ESI (+) m / e 513 (M + H)⁺.

Example 339

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 338B for Example 1A in Example 1C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.22 (m, 2H), 2.29 (s, 3H), 3.05 (t, J = 7.12 Hz, 2H), 4.16 (t, J = 5.93 Hz, 2H), 6.72 (d, J = 7.80 Hz, 1H), 6.79-6.82 (m, 2H), 7.16 (m , 1H), 7.25 (m, 1H), 7.32 (s, 1H), 7.35 (d, J = 8.81 Hz, 2H), 7.57 (d, J =

8.81 Hz, 2H), 7.83 (dd, J = 7.80, 5.42 Hz, 1H), 8.31 (d, J = 8.14 Hz, 1H), 8.69 (m, 2H), 8.77 (d, J = 1.69Hz, 1H), 8.82 (s, 1H); MS (ESI (+) m / e 493 (M + H)⁺.

Example 340

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 338B and 1-fluoro-4-isocyanate) -2- (trifluoromethyl) benzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DmSoD6) δ ppm 2.07-2.19 (m, 2H), 3.05 (t, J = 7.12 Hz, 2H), 4.15 (t, J = 5.93 Hz, 2H), 6.71 (d, J = 7.80 Hz, 1H), 6.80 (d, J = 7.80 Hz, 1H), 7.37 (d, J = 8.82 Hz, 2H), 7.45 (t, J = 9.16 Hz, 1H), 7.58 (d, J = 8.48 Hz, 2H), 7.66 (m, 1H), 7.78 (dd, J = 7.80, 5.42 Hz, 1H), 8.04 (dd, J = 6.78, 2.71 Hz, 1H), 8.25 (d, J = 8.14 Hz, 1H), 8.66 (d, J = 4.41 Hz, 1H), 8.74 (d, J = 1.70 Hz, 1H), 9.00 (s, 1H), 9.16 (s, 1H); MS (ESI (+) m / e 565 (M + H)⁺.

Example 341

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (4-fluoro-3-methylphenyl) urea

ES 2 398 074 T3

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 338B and 1-fluoro-4-isocyanato-2-methylbenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.22 (m, 2H), 2.22 (s, 3H), 3.05 (t, J = 7.12 Hz, 2H), 4.15 (t, J = 6.10 Hz, 2H), 6.72 (d, J = 7.80 Hz, 1H), 6.82 (d, J = 7.80 Hz, 1H), 7, 05 (t, J = 9.16 Hz, 1H), 7.19-7.40 (m, 4H), 7.56 (d, J = 8.48 Hz, 2H), 7.82 (dd, J = 7.97, 5.26 Hz, 1H), 8.30 (d, J = 7.12 Hz, 1H), 8.69 (dd, J = 5.43, 1.36 Hz, 1H), 8 , 73 (s, 1H), 8.76 (d, J = 1.70Hz, 1H), 8.85 (s, 1H); MS (ESl (+) m / e 511 (M + H)⁺.

Example 342

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-chloro-4-fluorophenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 338B and 1-fluoro-2-chloro-4-isocyanatobenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.13-2.22 (m, 2H), 3.05 (t, J = 7.12 Hz, 2H), 4.15 (t, J = 5.93 Hz, 2H), 6.71 (d , J = 7.80 Hz, 1H), 6.80 (d, J = 7.80 Hz, 1H), 7.33-7.38 (m, 4H), 7.57 (d, J = 8, 48 Hz, 2H), 7.77-7.84 (m, 2H), 8.27 (d, J = 7.80 Hz, 1H), 8.67 (dd, J = 5.42,

1.36 Hz, 1H), 8.75 (d, J = 1.70 Hz, 1H), 8.97 (s, 1H), 9.01 (s, 1H); MS (ESl (+) m / e 531 (M + H)⁺.

Example 343

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 338B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.13-2.22 (m, 2H), 3.05 (t, J = 7.12 Hz, 2H), 4.15 (t, J = 6.10 Hz, 2H), 6.72 (d , J = 7.80 Hz, 1H), 6.81 (m, 1H), 7.32 (d, J = 7.46 Hz, 1H), 7.37 (d, J = 8.48 Hz, 2H ), 7.53 (t, J = 7.97 Hz, 1H), 7.60 (m, 3H), 7.81 (dd, J = 8.14, 5.42 Hz, 1H), 8.05 (s, 1H), 8.28 (d, J = 8.14 Hz, 1H), 8.68 (dd, J = 5.26, 1.19 Hz, 1H), 8.76 (d, J = 1.70 Hz, 1H), 9.01 (s, 1H), 9.19 (s, 1H); MS (ESl (+) m / e 547 (M + H)⁺.

Example 344

N- {4- [3-amino-7- (3-pyridin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

Example 344A

2-fluoro-6-iodo-3- (3-pyridin-4-ylpropoxy) benzonitrile

The desired product was prepared by substituting 2- (4-morpholinyl) ethanol for 4-pyridinepropanol in Example 75A. MS (ESl (+) m / e 382.9 (M + H)⁺.

Example 344B

4-iodo-7- (3-pyridin-4-ylpropoxy) -1H-indazol-3-amine

The desired product was prepared by substituting Example 344A for Example 15E in Example 15F. MS (ESl (+) m / e 395 (M + H)⁺.

Example 344C

N- {4- [3-amino-7- (3-pyridin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 344B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.09-2.15 (m, 2H), 2.28 (s, 3H), 2.90 (t, J = 7.12 Hz, 2H), 4.13 (t, J = 6.10 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J = 7.80 Hz, 1H), 6.75 (d, J = 7 , 80 Hz, 1H), 6.78-6.82 (m, 1H), 7.11 (dd, J = 11.36, 8.31 Hz, 1H), 7.31 (d, J = 6, 10 Hz, 2H), 7.36 (d, J = 8.48 Hz, 2H), 7.56 (d, J = 8.48 Hz, 2H), 8.01 (dd, J = 7.97, 2.20 Hz, 1H), 8.47 (d, J = 5.76 Hz, 2H), 8.53 (d, J =

2.71 Hz, 1H), 9.18 (s, 1H), 11.90 (s, 1H); MS (ESl (+) m / e 511 (M + H)⁺.

Example 345

N- {4- [3-amino-7- (3-pyridin-4-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 344B for Example 1A in Example 1C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.07-2.16 (m, 2H), 2.29 (s, 3H), 2.90 (m, 2H), 4.13 (t, J = 5.93 Hz, 2H), 4.32 (s, 2H), 6.67 (d, J = 7.46 Hz, 1H), 6.75 (d, J = 7.80 Hz, 1H), 6.80 (d, J = 7.12 Hz, 1H), 7.16 (t, J = 7.80 Hz, 1H), 7.25 (d, J = 8.14 Hz, 1H), 7, 31 (dd, J = 4.07, 1.70 Hz, 3H), 7.35 (d, J = 8.48 Hz, 2H), 7.56 (d, J = 8.48 Hz, 2H), 8.47 (d, J = 6.10 Hz, 2H),

ES 2 398 074 T3

8.64 (s, 1H), 8.77 (s, 1H), 11.90 (s, 1H); MS (ESI (+) m / e 493 (M + H)⁺.

Example 346

N- {4- [3-amino-7- (3-pyridin-4-ylpropoxy) -1H-indazol-yl] phenyl} -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 344B and 1-chloro-3-isocyanatobenzene, respectively, in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.13 (m, 2H), 4.13 (t, J = 6.10 Hz, 2H), 4.32 (s, 2H), 6.67 ( d, J = 7.80 Hz, 1H), 6.75 (m, 1H), 7.02 (m, 1H), 7.31 (m, J = 6.10, 2.03 Hz, 5H), 7.36 (d, J = 8.81 Hz, 2H), 7.56 (m, J = 8.48 Hz, 3H), 7.73 (s, 1H), 8.47 (m, 2H), 8.90 (s, 1H), 8.97 (s, 1H), 11.90 (s, 1H); MS (ESI (+) m / e 513 (M + H)⁺.

Example 347

N- [4- (3-amino-1H-indazol-4-yl) -2- (methoxymethoxy) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

Example 347A

N- (4-bromo-2-hydroxyphenyl) -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 2-Amino-5-bromo-phenol for 4-bromo-2-ethylaniline in Example 149A. MS (ESI (+)) m / e 339 and 341 (M + H)⁺.

Example 347B

N- [4-bromo-2- (methoxymethoxy) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

A solution of Example 347A (68 mg, 0.2 mmol) in acetone (2 ml) was treated with K2CO3 (41 mg, 0.3 mmol) and MOMCl (0.023 ml, 0.3 mmol), stirred under reflux for 2 h, then allowed to cool to room temperature and treated with water. The resulting suspension was filtered and the filter cake was dried to give 58 mg of Example 347B.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.27 (s, 3H) 3.45 (s, 3H) 5.32 (s, 2H) 6.78-6.83 (m, 1 H) 7.12-7.15 (m, 2H) 7.29 (d, J =

2.37 Hz, 1H) 7.98 (dd, J = 7.97, 1.86 Hz, 1H) 8.13 (d, J = 8.82 Hz, 1H) 8.82 (s, 1H) 9.22 (d, J = 1.70Hz, 1H).

Example 347C

N- [4- (3-amino-1H-indazol-4-yl) -2- (methoxymethoxy) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 44A for Example 347B in Example 44B. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 3.47 (s, 3H) 4.42 (s, 2H) 5.37 (s, 2H) 6, 78-6.83 (m, 2H) 7.08 (dd, J = 8.3, 1.9 Hz, 1H) 7.11 (dd, J = 11.4, 8.3 Hz, 1H ) 7.24 (d, J = 2.0 Hz, 1H) 7.26 (s, 1H) 7.27 (d, J = 2.7 Hz, 1H) 8.04 (dd, J = 8.1, 2.0 Hz, 1H) 8.29 (d, J = 8.5 Hz, 1H) 8.89 (s, 1H) 9.26 (d, J = 1.7 Hz, 1H) 11.72 (s, 1H); MS (ESI (+)) m / e 436.2 (M + H)⁺.

Example 348

N- [4- (3-amino-1H-indazol-4-yl) -2-hydroxyphenyl] -N '- (2-fluoro-5-methylphenyl) urea

Example 348A

N- (4-bromo-2-tetrahydro-2H-pyran-2-ylphenyl) -N '- (2-fluoro-5-methylphenyl) urea

A solution of Example 347A (150 mg, 0.44 mmol) and dihydropyran (0.24 mL, 2.4 mmol) in CH2Cl2 (2 mL) was treated with TsOH (1 mg), stirred at room temperature for 1 hr. then it was partitioned between EtOAc and aq solution. sat. NaHCO3. The organic extract was washed with brine, dried (MgSO4), concentrated and purified by chromatography on silica gel eluting with 20% EtOAc -hexanes to give 190 mg of 348A.

Example 348B

N- [4- (3-amino-1H-indazol-4-yl) -2-hydroxyphenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 44A for Example 348A (190 mg, 0.4 mmol) in Example 44B, and then dissolving the crude product in methanol by treating it with a drop of 1N HCl and stirring at rt for 12 h. Purification by silica gel chromatography eluting with 5% methanol-methylene chloride gave 14 mg of 348B.¹H NMR (500 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 6.77-6.81 (m, 2H) 6.85 (dd, J = 8.4, 1.9 Hz , 1H) 6.94 (d, J = 2.2Hz, 1H) 7.09 (dd, J = 11.2, 8.4Hz, 1H) 7.24-7.29 (m, 2H) 8.02 (dd, J = 7.8, 1.3 Hz, 1H) 8.17 (d, J = 8.4 Hz, 1H) 8.81 (s, 1H) 9, 19 (d, J = 1.9 Hz, 1H) 10.14 (s, 1H) 11.74 (s, 1H); MS (ESI (+)) m / e 391.7 (M + H)⁺.

ES 2 398 074 T3

Example 349

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (hydroxymethyl) phenyl] urea

Example 349A

N- (4-bromophenyl) -N '- [2-fluoro-5- (hydroxymethyl) phenyl] urea

A solution of (3-amino-4-fluoro-phenyl) -methanol (0.61 g, 4.3 mmol) in CH2Cl2 (20 ml) was treated with 1-isocyanate-4-bromobenzene (0.85 g, 4.3 mmol), was stirred at room temperature overnight resulting in a thick suspension which was filtered to give 1.43 g of 349 as an off-white solid. MS (ESI (-)) m / e

336.9, 338.9 (MH)⁺.

Example 349B

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-5- (hydroxymethyl) phenyl] urea

The desired product was prepared by substituting 149A for Example 349A in Examples 149B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 4.33 (s, 2H) 4.46 (d, J = 5.8 Hz, 2H) 5.22 (t, J = 5.8 Hz, 1H) 6.79 (dd, J = 5.4, 2.4 Hz, 1H) 6.95 (ddd, J = 8.1, 4.8, 2.0 Hz, 1H) 7.11 -7.30 (m, 3H) 7.41 (d, J = 8.5 Hz, 2H) 7.60 (d, J = 8.5 Hz, 2H) 8.16 (dd, J = 7.8, 2.0 Hz, 1H) 8.58 (d, J = 2.4 Hz, 1H) 9.21 (s, 1H) 11.71 (s, 1H); MS (ESI (+)) m / e 392.0 (M + H)⁺.

Example 350

N- [4- (3-amino-7-thien-3-yl-1H-indazol-4-yl) phenyl-N '- [3- (trifluoromethyl) phenyl] urea

Example 350A

4- (4-aminophenyl) -7-thien-3-yl-1H-indazol-3-amine

The desired product was prepared by substituting thiophene-3-boronic acid for pyridine-3-boronic acid in Examples 243D-E, and then following the procedure of Example 352B. Fr = 0.24 (EtOAc).

Example 350B

N- [4- (3-amino-7-thien-3-yl-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 350A and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

6.92 (d, J = 7.1 Hz, 1H) 7.33 (d, J = 7.5 Hz, 1H) 7.44 (d, J = 8.8 Hz, 2H) 7, 48-7.68 (m, 6H) 7.73 (dd, J = 4.8, 2.7 Hz, 1H) 7.96 (d, J = 2.4 Hz, 1H) 8.05 (s, 1H) 9.01 (s, 1H) 9.15 (s, 1H) 11.96 (s, 1H); MS (ESI (+)) m / e 494.0 (M + H)⁺.

Example 351

N [4- (3-amino-7-thien-3-yl-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 350A and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. ¹H NMR (300 MHz, DMSO-D6) δ ppm

2.29 (s, 3H) 6.79-6.84 (m, 1H) 6.89 (d, J = 7.5 Hz, 1H) 7.12 (dd, J = 11.4, 8.3 Hz, 1H) 7.44 (d, J = 8.5 Hz, 2H) 7.54 (d, J = 7.1 Hz, 1H) 7.57-7.64 (m, 3H) 7.72 (dd, J = 4.9, 2.9 Hz, 1H) 7.95 (s, 1H) 8.02 (d, J = 6.8 Hz, 1H) 8, 55 (d, J = 2.0 Hz, 1H) 9.23 (s, 1H) 11.84 (s, 1H); MS (ESI (+)) m / e 458.1 (M + H)⁺

Example 352

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl] -N '- (4-fluoro-3-methylphenyl) urea

Example 352A

4- (4-nitrophenyl) -7-pyridin-4-yl-1H-indazol-3-amine

The desired product was prepared by substituting pyridine-3-boronic acid for pyridine-4-boronic acid in Examples 243D-E. Unlike example 243E, only a small amount (approx. 20%) of the reduced product 352A was obtained. MS (ESI (+)) m / e 332 (M + H)⁺.

Example 352B

ES 2 398 074 T3

4- (4-aminophenyl) -7-pyridin-4-yl-1H-indazol-3-amine

A mixture of 352A (370 mg, 1.1 mmol), iron (374 mg) and NH4Cl (60 mg, 1.1 mmol) in ethanol (20 ml), THF (10 ml) and water (4 ml) was heated at reflux for 5 h, it was diluted with THF (20 ml), filtered through a pad of celite, washing with ethanol. The filtrate was concentrated and the residue was triturated in water to give 313 mg of 352A as a light yellow solid. MS (ESI (+)) m / e 302 (M + H)⁺.

Example 352C

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl-N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 352B and 1-fluoro-4-isocyanato-2-methylbenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.23 (d, J = 2.0 Hz, 3H) 7.02 (d, J = 7.5 Hz, 1H) 7.06 (t, J = 9.2 Hz, 1H) 7.29 (ddd, J = 8.7, 4.3, 2.9 Hz, 1H) 7.39 (dd, J = 7.1, 2.4 Hz , 1H) 7.46 (d, J = 8.8 Hz, 2H) 7.64 (d, J = 8.8 Hz, 2H) 7.72 (d, J = 7.5 Hz, 1 H) 8.22 (d, J = 3.7 Hz, 2H) 8.78 (s, 1H) 8.85-8.92 (m, 2H) 8.96 (s, 1H); MS (ESI (+)) m / e

453.3 (M + H)⁺.

Example 353

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl-N '- [3- (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 352B and 1-isocyanato-3- (trifluoromethyl) benzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 7.02 (d, J = 7.1 Hz, 1 H) 7.33 (d, J = 7.5 Hz, 1 H) 7.48 (d, J = 8.5 Hz, 2H) 7.53 (t, J = 8.0 Hz, 1H) 7.62 (d, J = 8.5 Hz, 1H) 7.67 (d, J = 8.5 Hz, 2H) 7.71 (d, J = 7.8 Hz, 1H) 8.05 (s, 1H) 8.19 (d, J = 2.4 Hz, 2H) 8 , 87 (d, J = 2.4 Hz, 2H) 9.11 (s, 1H) 9.23 (s, 1H); MS (ESI (+)) m / e 489.1 (M + H)⁺.

Example 354

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl-N '- (3-chlorophenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 352B and 1-chloro-3-isocyanatobenzene, respectively, in Example 15H. Also, DMF was used instead of CH2CL.¹H NMR (300 MHz, DMSO-D6) δ ppm 7.00-7.05 (m, 2H) 7.29-7.33 (m, 2H) 7.47 (d, J = 8.8 Hz , 2H) 7.65 (d, J = 8.8 Hz, 2H) 7.70 (d, J = 7.5 Hz, 1H) 7.75 (dd, J = 2.5, 1, 2Hz, 1H) 8.17 (d, J = 3.7Hz, 2H) 8.86 (d, J = 3.7Hz, 2H) 9.08 (s.p., 2H); MS (ESI (+)) m / e 455.2 (M + H)⁺.

Example 355

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl-N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 352B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Example 15H. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 6.80-6.85 (m, 1H) 7.01 (d, J = 7.5 Hz, 1H) 7.12 (dd, J = 11.4, 8.3 Hz, 1H) 7.47 (d, J = 8.8 Hz, 2H) 7.64 (d, J = 8.8 Hz, 2 H) 7.69 (d, J = 7.5 Hz, 1H) 8.01 (dd, J = 8.0, 1.9 Hz, 1H) 8.14-8.19 (m, 2H ) 8.57 (d, J = 2.7 Hz, 1H) 8.82-8.89 (m, 2H) 9.28 (s, 1H); MS (ESI (+)) m / e 453.3 (M + H)⁺.

Example 356

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl-N '- [4-fluoro-3- (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 352B and 1-fluoro-4-isocyanato-2-trifluoromethylbenzene for Example 15G and 1-fluoro-3-isocyanatobenzene in Example 15H, respectively. Also, dMf was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 4.45 (s, 2H) 6.95 (d, J = 7.5 Hz, 1H) 7.42-7.47 (m, 1H) 7.45 (d, J =

8.5 Hz, 2H) 7.50 (d, J = 7.5 Hz, 1H) 7.64 (d, J = 8.5 Hz, 2H) 7.64-7.69 (m, 1H) 7.71 (d, J = 6.1 Hz, 2H) 8.03 (dd, J = 6.6, 2.5 Hz, 1H) 8.68 (d, J = 6.1 Hz, 2H) 8.99 (s, 1H) 9.11 (s, 1H) 11.98 (s, 1H); MS (ESI (+)) m / e 507.2 (M + H)⁺.

Example 357

N- [4- (3-amino-7-pyridin-4-yl-1H-indazol-4-yl) phenyl-N '- [2-fluoro-5- (trifluoromethyl) phenylurea

The desired product was prepared by substituting Example 352B and 1-fluoro-2-isocyanato-4-trifluoromethyl-benzene for Example 15G and 1-fluoro-3-isocyanatobenzene in Example 15H, respectively. Also, DMF was used instead of CH2Cl2.¹H NMR (300 MHz, DMSO-D6) δ ppm 7.01 (d, J = 7.5 Hz, 1H) 7.42-7.49 (m, 3H) 7.65-7.71 (m , 4H) 8.04

ES 2 398 074 T3 (dd, J = 6.4, 2.7 Hz, 1H) 8.14-8.21 (m, 2H) 8.82-8.90 (m, 2H) 9, 12 (s, 1H) 9.23 (s, 1H); MS (ESI (+)) m / e 507.7 (M + H)⁺.

Example 358

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

Example 358A

5-fluoro-4-iodo-1H-indazol-3-amine

The desired product was prepared by substituting 2,5-difluoro-benzonitrile for Example 243A in Example 243B, and then substituting 2-fluoro-6-iodo-benzonitrile for the product in Example 1A. MS (ESI (+) m / e 278 (M + H)⁺.

Example 358B

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-bromophenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-bromo-3-isocyanatobenzene and Example 358B during 1A, respectively and in Examples 1B-C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 7.15-7.38 (m, 7H) 7.61 (d, J = 8.8 Hz, 2H) 7.88 (t, J = 1 , 9 Hz, 1H) 8.95 (s, 1H)

8.95 (s, 1H) 11.82 (s, 1H); MS (ESI (+)) m / e 439.9, 441.9 (M + H)⁺.

Example 359

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-methylphenyl) urea

The desired product was prepared by substituting Example 358B for 1A in Examples 1C and purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 4.19 (s, 2H) 6.80 (d, J = 7.5 Hz, 1H) 7.14-

7.30 (m, 4H) 7.32 (s, 1H) 7.35 (d, J = 8.5 Hz, 2H) 7.61 (d, J = 8.5 Hz, 2H) 8.65 (s, 1H) 8.83 (s, 1H) 11.74 (s, 1H); MS (ESI (+)) m / e 376.1 (M + H)⁺.

Example 360

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N'-phenylurea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-isocyanatobenzene and 1A for Example 358B, respectively and in Examples 1B-C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 6.98 (t, J = 7.3 Hz, 1 H) 7.21 (t, J = 9.3 Hz, 1 H) 7.27-7, 32 (m, 3H) 7.36 (d, J = 8.1 Hz, 2H)

7.48 (d, J = 7.8 Hz, 2H) 7.61 (d, J = 8.5 Hz, 2H) 8.74 (s, 1H) 8.86 (s, IH) 11 , 81 (s, 1H).

Example 361

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- [2-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-2-isocyanato-4-trifluoromethylbenzene and 1A for Example 358B, respectively and in Examples 1B-C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 7.21 (t, J = 9.2 Hz, 1 H) 7.29 (dd, J = 9.2, 4.1 Hz, 1 H) 7, 37-3.40 (m, 4H) 7.63 (d, J = 8.5 Hz, 2H) 8.45-8.50 (m, 1H) 8.90 (d, J = 2.4 Hz, 1H) 9.32 (s, 1H) 11.81 (brs, 1H); MS (EBI (+)) m / e 448.1 (M + H)⁺.

Example 362

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 1A and 1B for Example 358B and 5A, respectively in Examples 1C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3 H) 6.82 (ddd, J =

8.5, 4.8, 2.0 Hz, 1H) 7.12 (dd, J = 11.5, 8.1 Hz, 1H) 7.25 (t, J = 9.3 Hz, 1 H) 7.33 (dd, J = 9.2, 4.1 Hz, 1 H) 7.38 (d, J = 8.5 Hz, 2 H) 7.62 (d, J = 8.5 Hz , 2H) 8.01 (dd, J = 7.8, 2.0 Hz, 1H) 8.55 (d, J = 2.4 Hz, 1H) 9.26 (s, 1H) 12 , 01 (brs, 1H); MS (ESI (+)) m / e 394.0 (M + H)⁺.

Example 363

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-isocyanato-3-trifluoromethylbenzene and 1A for Example 358B, respectively in Examples 1B-C and by purification as in Example 3. ¹H

ES 2 398 074 T3

NMR (300 MHz, DMSO-D6) δ ppm 7.22 (t, J = 9.5 Hz, 1H) 7.28-7.34 (m, 2H) 7.38 (d, J = 8, 1Hz, 2H) 7.53 (t, J = 8.0Hz, 1H) 7.59-7.65 (m, 3H) 8.04 (s, 1H) 9.01 (s, 1H) 9.14 (s, 1H) 11.85 (brs, 1H); MS (ESI (+)) m / e 430.0 (M + H)⁺.

Example 364

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- [4-fluoro-3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-4-isocyanato-3-trifluoromethylbenzene and 1A for Example 358B, respectively in Examples 1B-C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 7.23 (t, J = 9.5 Hz, 1 H) 7.32 (dd, J = 9.2, 4.1 Hz, 1 H) 7, 38 (d, J = 8.1 Hz, 2H) 7.45 (t, J = 9.5 Hz, 1H) 7.66 (m, 3H) 8.03 (dd, J = 6.4 , 2.7 Hz, 1H) 9.04 (s, 1H) 9.15 (s, 1H) 11.94 (brs, 1H); MS (ESI (+)) m / e 448.0 (M + H)⁺.

Example 365

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-chlorophenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-chloro-3-isocyanatobenzene and 1A for Example 3588, respectively in Examples 1B-C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 7.02-7.05 (m, 1H) 7.25 (t, J = 9.5 Hz, 1H) 7.29-7.35 (m , 3H) 7.38 (d, J = 8.5 Hz, 2H) 7.62 (d, J = 8.5 Hz, 2H) 7.73-7.75 (m, 1H) 9 0.00 (s, 1H) 9.01 (s, 1H) 12.01 (brs, 1H); MS (ESI (+)) m / e 396.0 (M + H)⁺.

Example 366

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (4-fluoro-3-methylphenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-4-isocyanato-3-methylbenzene and 1A for Example 358B, respectively in Examples 1B-C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.22 (d, J = 1.7 Hz, 3H) 7.06 (t, J = 9.2 Hz, 1H) 7.21-7, 40 (m, 6H) 7.61 (d, J =

8.5 Hz, 2H) 8.71 (s, 1H) 8.88 (s, 1H) 12.01 (brs, 1H); MS (ESI (+)) m / e 396.0 (M + H)⁺.

Example 3 67

N- [4- (3-amino-5-fluoro-1H-indazol-4-yl) phenyl] -N '- (3-chloro-4-fluorophenyl) urea

The desired product was prepared by substituting 1-isocyanato-3-methylbenzene for 1-fluoro-2-chloro-4-isocyanatobenzene and 1A for Example 358B, respectively in Examples 1B-C and by purification as in Example 3. ¹H NMR (300 MHz, DMSO-D6) δ ppm 7.24 (t, J = 9.5 Hz, 1H) 7.30-7.39 (m, 5H) 7.62 (d, J = 8 , 8 Hz, 2H) 7.82-7.85 (m, 1H) 9.00 (s, 1H) 9.01 (s, 1H) 11.99 (br, 1H); MS (ESI (+)) m / e 414.0 (M + H)⁺.

Example 368

N- [4- (3-amino-7-bromo-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting 2-fluoro-6-iodobenzonitrile for 3-bromo-2-fluoro-6-iodobenzonitrile and 1-isocyanato-3-methylbenzene for 1-fluoro-2-isocyanato-4-methylbenzene in Examples 1A- C. ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 6.73 (d, J = 7.5 Hz, 1H) 6.79-6.84 (m, 1H) 7.11 (dd, J = 11.4, 8.3 Hz, 1H) 7.40 (d, J = 8.8 Hz, 2H) 7.51 (d, J = 7.80 Hz, 1 H) 7.60 (d, J = 8.8 Hz, 2H) 8.01 (dd, J = 7.5, 2.0 Hz, 1H) 8.54 (d, J = 2.4 Hz , 1H) 9.22 (s, 1H) 12.08 (brs, 1H); MS (ESI (+)) m / e 453.9,455.9 (M + H)⁺.

Example 369 3 - [({[4- (3-amino-1H-indazol-4-yl) phenyl] amino} carbonyl) amino] -4-fluorobenzoic acid

Example 369A

4- (4-aminophenyl) -1H-indazol-3-amine

The desired product was prepared by substituting 2-fluoro-6-benzonitrile for 15F in Example 15G, and then substituting 2-fluoro-6-benzonitrile for the product in Example 1A. MS (ESI (+)) m / e 225 (M + H)⁺.

Example 369B

Tert-butyl 3-amino-4- (4-aminophenyl) -1H-indazole-1-carboxylate

ES 2 398 074 T3

A -78 ° C solution of 369A (100 mg, 0.45 mmol) in THF (6 ml) was treated with LDA (0.245 ml, 2M solution in heptane, 0.49 mmol), stirred at -50 ° C for 15 minutes, treated with solid (Boc) 2O (98 mg, 0.45 mmol). The reaction was allowed to gradually warm to room temperature over 2 h, concentrated in vacuo, and purified by chromatography on silica gel eluting first with 75 EtOAc: hexanes and then with 8% methanol: CH2Cl2 to give 62 mg of 369B. MS (ESI (+)) m / e 325 (M + H)⁺.

Example 369C

Methyl 3 - [({[4- (3-amino-1H-indazol-4-yl) phenyl] amino} carbonyl) amino] -4-fluorobenzoate

A 0 ° C solution of 3-amino-4-fluoro-benzoic acid methyl ester (29 mg, 0.17 mmol) in THF (4 ml) was treated with triethyl amine (0.026 ml) and 4-nitrophenyl chloroformate (38 mg), stirred at 0 ° C for 45 min, then treated with a solution of example 396B (56 mg, 0.17 mmol) in THF (3 ml) followed by an additional 0.026 ml of Et3N. The resulting mixture was allowed to warm to room temperature slowly, stirred overnight, diluted with water, and extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), concentrated and purified by chromatography on silica gel eluting with EtOAc to give 98 mg of 3-amino-4- {4- [acid tert-butyl ester]. 3- (2-fluoro-5-methoxycarbonyl-phenyl) ureido] -phenyl} -indazole-1-carboxylic. This compound was dissolved in CH2Cl2 (2 ml), cooled to 0 ° C, treated with TFA (1 ml), stirred at 0 ° C for 45 min and then at room temperature for 1 h. The reaction was quenched with aq NaHCO3. sat. adjusting pH to 8-9 and then extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried (MgSO4), concentrated and purified by chromatography on silica gel eluting first with EtOAc and then with 12% methanol: CH2Cl2 to give 30 mg of 369C as a white solid. MS (ESI (+)) m / e 420 (M + H)⁺.

Example 369D 3 - [{[4- (3-amino-1H-indazol-4-yl) phenyl] amino} carbonyl) amino] -4-fluorobenzoic acid

A solution of 369C (20 mg, 0.05 mmol) in methanol (1 ml) was treated with a solution of NaOH 911 mg) in water (1 ml), stirred under reflux for 7 h and concentrated. The residue was diluted with water, the pH was adjusted to pH 3 with 1N HCl, and the resulting solid was collected by filtration to give 17 mg of 369D. H NMR (300 MHz, DMSO-D6) δ ppm 4.34 (sa, 2H) 6.79 (dd, J = 5.3, 2.5 Hz, 1H) 7.24-7.28 (m , 2H) 7.34-7.43 (m, 3H) 7.60-7.64 (m, 3H) 8.77 (d, J = 2.7 Hz, 1H) 8.85 ( dd, J = 8.1, 2.0 Hz, 1H) 9.27 (s, 1H) 11.72 (brs, 1H) 13.00 (brs, 1H).

Example 370

N- [4- (3-amino-1H-indazol-6-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 182A for 1A in Example 5B. MS (ESI (+) Q1MS m / z 376 (M + H)⁺; ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 6.78-6.84 (m, 1H) 7.11 (dd, J = 11.36, 8.31 Hz , 1 HOUR)

7.33 (dd, J = 8.65, 1.19 Hz, 1H) 7.48 (s, 1H) 7.57 (d, J = 8.82 Hz, 2H) 7.67 (d , J-8.82 Hz, 2H) 7.84 (d, J = 8.48 Hz, 1H) 8.00 (dd, J = 7.80, 2.37 Hz, 1H) 8.51 (d, J = 2.71 Hz, 1H) 9.19 (s, 1H)

Example 371

N- [2 - ({3-amino-4- [4 - ({[(3-fluorophenyl) amino] carbonyl) amino) phenyl] -1H-indazol-7-yl} oxy) ethyl] methanesulfonamide

The desired product was prepared by substituting Example 178A for Example 15G in Example 15H. MS (ESI (+) Q1MS m / z 499 (M + H)⁺; ¹H NMR (500 MHz, DMSO-D6) δ ppm 2.99 (s, 3H) 3.44 (c, J = 5.61 Hz, 2H) 4.23 (t, J = 5.61 Hz, 2 H) 6.72 (d, J = 7.49 Hz, 1 H) 6.79 (td, J = 8.58, 2.18 Hz, 1 H) 6.83 (d, J = 7.80 Hz, 1H) 7.13-7.17 (m, 2H) 7.29-7.34 (m, 1H) 7.37 (d, J = 8.42 Hz, 2H) 7.51 (dt, J = 11.93, 2.30 Hz, 1H) 7.57 (d, J = 8.73 Hz, 2H) 8.85 (s, 1H) 8.94 (s, 1H )

Example 372

N- (4- {3-amino-7- [3- (dimethylamino) propoxy] -1H-indazol-4-yl} phenyl) -N '- [4-fluoro-3- (tritluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 15G and 1-fluoro-3-isocyanatobenzene for Example 248B and 1-fluoro-4-isocyanato-2- (trifluoromethyl) benzene, respectively, in Example 15H. MS (ESI (+) Q1MS m / z 531 (M + H)⁺; ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.15-2.20 (m, 2H) 2.86 (d, J = 5.09 Hz, 6H) 3.34-3.41 (m , 2H) 4.22 (t, J = 5.76 Hz, 2H) 6.72 (d, J = 7.46 Hz, 1H) 6.81 (d, J = 7.80 Hz, 1 H) 7.36 (d, J = 8.48 Hz, 2H) 7.45 (t, J = 9.83 Hz, 1H) 7.58 (d, J = 8.48 Hz, 2H) 7.63-7.69 (m, 1H) 8.04 (dd, J = 6.44, 2.71 Hz, 1H) 9.02 (s, 1H) 9.18 (s, 1H )

Example 373

N- [4- (1-acetyl-3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

100

ES 2 398 074 T3

Example 373A

-acetyl-4-iodo-1H-indazol-3-amine

A solution of Example 1A (215 mg, 0.83 mmol), acetic anhydride (0.086 ml) and 18-crown-6 (438 mg) in CH2Cl2 (5 ml) was stirred at room temperature overnight and then partitioned between EtOAc and water. The organic extract was dried (MgSO4), concentrated and purified by chromatography on silica gel eluting with 1: 1 hexane: EtOAc to give 110 mg of 373A.¹H NMR (300 MHz, DMSO-D6) δ ppm 2.53 (s, 3H) 6.01 (s, 2H) 7.26 (t, J = 7.46 Hz, 1H) 7.77 ( d, J = 7.46 Hz, 1H) 8.31 (d, J = 8.48 Hz, 1H).

Example 373B

N- [4- (1-acetyl-3-amino-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 373A for 1A in Example 5B. MS (ESI (-) QIMS m / z 416 (MH) -;¹H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 2.55 (s, 3H) 5.20 (s, 2H) 6.79-6.84 (m, 1 H) 7.12 (dd, J = 11.53, 8.48 Hz, 1 H) 7.18 (d, J = 7.46 Hz, 1 H) 7.42 (d, J = 8.48 Hz , 2H) 7.57-7.64 (m, 3H) 8.00 (dd, J = 7.63, 1.87 Hz, 1H) 8.29 (d, J = 8.14 Hz, 1H) 8.56 (d, J = 2.71Hz, 1H) 9.26 (s, 1H)

Example 374

N- [4- (3-amino-7-fluoro-1H-indazol-4-yl) phenyl] -N '- (4-bromo-3-methylphenyl) urea

The desired product was prepared as the trifluoroacetate salt by replacing Example 15G and 1-fluoro-3-isocyanatobenzene with Example 26B and 1-bromo-4-isocyanate-2-methylbenzene, respectively, in Example 15H. MS (ESI (+)): m / e 456 (M + H);¹H NMR (300 MHz, DMSO-D6) δ ppm 2.32 (s, 3H) 6.74 (dd, J = 7.80, 4.41 Hz, 1H)

7.13 (dd, J = 11.19, 7.80 Hz, 1 H) 7.27 (dd, J = 8.65, 2.54 Hz, 1 H) 7.37 (d, J = 8, 48Hz, 2H) 7.44-7.49 (m, 2H) 7.58 (d, J = 8.48Hz, 2H) 8.80 (s, 1H) 8.87 (s, 1 HOUR).

Example 375

N- [4- (3-amino-1-phenyl-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

Example 375A

2- (4-iodo-1-phenyl-1H-indazol-3-yl) -1H-isoindolo-1,3 (2H) -dione

A mixture of 162A (940 mg), phenyl boronic acid (590 mg), cupric acetate (440 mg), triethylamine (0.674 ml) in CH2Cl2 (20 ml) was stirred at room temperature overnight and then concentrated. The residue was purified by silica gel chromatography eluting with 20% EtOAc in hexane to give 770 mg of 375A. MS (ESI (+)) m / e 466.1 (M + H)⁺.

Example 375B

4-iodo-1-phenyl-1H-indazol-3-amine

The desired product was prepared by substituting 375A for 162B in Example 162C. MS (ESI (+)) m / e 336.1 (M + H)⁺.

Example 375C

N- [4- (3-amino-1-phenyl-1H-indazol-4-yl) phenyl] -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 375B for 1A in Example 5B. MS (ESI (+) Q1MS m / z 452 (M + H)⁺; ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.29 (s, 3H) 4.75 (s, 2H) 6.83 (m, 1H) 6.97 (d, J = 6.44 Hz, 1H) 7.12 (dd, J = 11.53, 8.48 Hz, 1H) 7.26 (t, J = 7.29 Hz, 1H) 7.43-7.47 (m , 3H) 7.50-7.55 (m, 2H) 7.61-7.74 (m, 5H) 8.01 (dd, J = 7.97, 2.20 Hz, 1H) 8.57 (d, J = 2.37 Hz, 1H) 9.26 (s, 1H)

Example 376

N- {4- [3-amino-7- (3-pyridin-3-ylpropoxy) -1H-indazol-4-yl] phenyl} -N '- (2-fluoro-5-methylphenyl) urea

The desired product was prepared by substituting Example 1A and 1-isocyanato-3-methylbenzene for Example 338B and 1-fluoro-2-isocyanato-4-methylbenzene, respectively, in Examples 1B-C. MS (ESI (+) Q1MS m / z 511 (M + H)⁺; ¹H NMR (300 MHz, DMSO-D6) δ ppm 2.14-2.1.8 (m, 2H) 2.28 (s, 3H) 3.01 (t, J = 7.4 Hz, 2 H) 4.14 (t, J = 6.10 Hz, 2 H)

6.70 (d, J = 7.80 Hz, 1H) 6.77-6.84 (m, 2H) 7.11 (dd, J = 11.36, 8.31 Hz, 1H) 7 , 37 (d, J = 8.82 Hz, 2H) 7.56 (d, J =

8.48 Hz, 2H) 7.70-7.73 (m, 1H) 8.01 (dd, J = 7.97, 2.20 Hz, 1H) 8.17 (d, J = 9 , 49 Hz, 1H) 8.52 (d, J = 3.05 Hz, 1H)

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ES 2 398 074 T3

8.62 (d, J = 5.09 Hz, 1H) 8.70 (s, 1H) 9.17 (s, 1H).

Example 377

N- [4- (3-amino-1H-indazol-6-yl) phenyl] -N'-phenylurea

The desired product was prepared by substituting Example 182A for 1A and 5A and N-phenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] urea respectively , in Example 5B. mS (ESI (+) Q1MS m / z 344 (M + H)⁺; ¹H NMR (300 MHz, DMSO-D6) δ ppm 5.33 (s, 2H) 6.97 (t, J = 7.29 Hz, 1H) 7.19 (dd, J = 8.31, 1 , 19 Hz, 1H) 7.28 (t, J = 7.97 Hz, 2H) 7.38 (s, 1H) 7.48 (d, J = 7.46 Hz, 2H) 7, 59 (m, 4H) 7.72 (d, J = 8.48 Hz, 1H) 8.90 (s, 1H) 8.96 (s, 1H) 11.38 (s, 1H)

Example 378

N- [4- (3-amino-1H-indazol-6-yl) phenyl] -N '- [3- (trifluoromethyl) phenyl] urea

The desired product was prepared by substituting Example 182A for 1A and 5A and N- (3-trifluoromethylphenyl) -N '- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl ] urea respectively, in Example 5B. MS (ESI (+) Q1MS m / z 412 (m + H)⁺; ¹H NMR (300 MHz, DMSO-D6) δ ppm 7.33 (dd, J = 7.97, 4.58 Hz, 2H) 7.55-7.58 (m, 3H) 7.58 (d , J = 8.82 Hz, 2 H)

7.67 (d, J = 8.82 Hz, 2H) 7.85 (d, J = 8.48 Hz, 1H) 8.04 (s, 1H) 8.95 (s, 1H) 9.11 (s, 1H).

Example 379

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N'-thien-3-ylurea

The desired product was prepared by substituting 3-isocyanate-thiophene for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 4.33 (s, 2H) 6.78 (dd, J = 5.59, 2.20 Hz, 1H) 7.07 (dd, J = 5 .09, 1.36 Hz, 1H) 7.24-7.28 (m, 2H) 7.29-7.33 (m, 1H) 7.39 (d, J = 8.48 Hz, 2H) 7.45 (dd, J = 5.09, 3.39 Hz, 1H) 7.59 (d, J =

8.48 Hz, 2H) 8.78 (s, 1H) 8.99 (s, 1H) 11.70 (s, 1H); MS (ESI (+)) m / e 350 (M + H)⁺.

Example 380

N- [4- (3-amino-1H-indazol-4-yl) phenyl] -N'-cyclopentylurea

The desired product was prepared by substituting isocyanate-cyclopentane for 1-isocyanato-3-methylbenzene in Examples 5A-B. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.31-1.45 (m, 2H) 1.47-1.71 (m, 4H) 1.77-1.93 (m, 2H ) 3.894.00 (m, 1H) 4.31 (s, 2H) 6.21 (d, J = 7.12 Hz, 1H) 6.75 (dd, J = 5.59, 2.20 Hz, 1H) 7.22-7.27 (m, 2H) 7.32 (d, J =

8.48 Hz, 2H) 7.50 (d, J = 8.48 Hz, 2H) 8.39 (s, 1H) 11.68 (s, 1H). MS (ESI (+)) m / e 336 (M + H)⁺.

102