Pyrazolopyrimidines as therapeutic agents

RELATED APPLICATION

BACKGROUND OF THE INVENTION

SUMMARY OF THE INVENTION

[0034] The present invention provides compounds of Formula (I)

[0036] G is

[0037] where Z¹⁰⁰ is
or a group optionally substituted with R₁ selected from the group consisting of alkyl; cycloalkyl; pyrrolidinyl; a bicyclic aromatic nitrogen containing heterocycle in which each ring has six atoms such as quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl and phthalazinyl; a bicyclic aromatic nitrogen containing heterocycle in which nitrogen is in a bridging position and one aromatic ring has five member and the other aromatic ring has six members such as imidazo[1,2-a]pyrimidinyl; 1H-imidazo[1,2-a]imidazolyl; imidazo[2,1-b][1,3]thiazolyl; naphthyl; tetrahydronaphthyl; benzothienyl; furanyl; thienyl; benzoxazolyl; benzoisoxazolyl; benzothiazolyl;
thiazolyl; benzofuranyl; 2,3-dihydrobenzofuranyl; indolyl; isoxazolyl; tetrahydropyranyl; tetrahydrofuranyl; piperidinyl; pyrazolyl; pyrrolyl; pyrrolopyridinyl; H-pyridinone; oxazolyl; isothiazolyl; oxadiazolyl; thiadiazolyl; indolinyl; indazolyl; imidazo[1,2-a]pyridinyl; benzoisothiazolyl; 1,1-dioxybenzoisothiazolyl; pyrido-oxazolyl; pyrido-thiazolyl; pyrimido-oxazolyl; pyrimido-thiazolyl; and benzimidazolyl;

[0070] In a first embodiment, R₂ in the compounds of formula I is a) hydrogen; b) substituted or unsubstituted trityl; c) substituted or unsubstituted cycloalkenyl; d) azaheteroaryl substituted with a substituted or unsubstituted alkyl; e) azacycloalkyl which is substituted with one or more substituents selected from substituted or unsubstituted —(C₁-C₆)-alkyl, substituted or unsubstituted —C₁-C₆-alkyl-OR, substituted or unsubstituted —C(O)—C₁-C₆-alkyl-N(R)₂, substituted or unsubstituted —C₁-C₆-alkyl-N(R)₂, substituted or unsubstituted C₁-C₆-alkyl-cycloalkyl, substituted or unsubstituted tetrahydrothienyl, and substituted or unsubstituted tetrahydrothiopyranyl; or f) a group of the formula (a):
wherein E₁ is piperidinyl, piperazinyl, imidazolyl, morpholinyl, pyrrolidinyl, amino, amido, or tetrahydrothiazolyl, and wherein E is optionally substituted with one or more substituents selected from —C₀-C₆-alkyl-OR, —C₁-C₆-alkyl-C(O)OR, -C₁-C₆-alkyl-heteroaryl, —C₁-C₆-alkyl-heterocycloalkyl, and —C₁-C₆-alkyl-N(R)₂.

[0074] In a fifth embodiment, G in the compounds of formula I or in any one of embodiments 1-4 is a group represented by the following structural formula

[0075] In a sixth embodiment, G in the compounds of formula I or in any one of embodiments 1-5 is a group represented by the following structural formula:

[0078] In a ninth embodiment, G in the compounds of formula I or in embodiments 7 or 8 is a group represented by the following formula:

[0080] In an eleventh embodiment, G in the compounds of formula I or in embodiment is a group represented by the following formula:

[0082] In a thirteenth embodiment, Z¹⁰⁰ in the compounds of formula I is pyrrolidinyl, quinolinyl, quinoxalinyl, quinazolinyl, isoquinolinyl, phthalazinyl, imidazo[1,2-a]pyrimidinyl, 1H-imidazo[1,2-a]imidazolyl, imidazo[2,1-b][1,3]thiazolyl, H-pyridinone, 1,1-dioxybenzoisothiazolyl, benzoisoxazolyl, alkyl, imidazo[1,2-a]pyridinyl, pyrrolopyridinyl or
wherein all of the foregoing Z¹⁰⁰ groups can be optionally substituted with R₁.

[0083] In a fourteenth embodiment, Z¹⁰⁰ in the compounds of formula I or in embodiment 13 is 2-pyrrolidinyl, 1,2-dihydro-2-oxopyridin-3-yl, benzoisoxazol-3-yl, 1,1-dioxybenzoisothiazol-3-yl, imidazo[1,2-a]pyridin-2-yl or
and R₂ is 4-(4-methylpiperazino)-cyclohexyl.

[0085] In a sixteenth embodiment, Z¹⁰⁰ in formula I or in embodiment 13 is a pyrrolopyridinyl selected from:

[0096] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula
wherein n is 1, 2 or 3.

[0097] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
wherein m is 0, 1, 2 or 3 and

[0099] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
wherein m is 0, 1, 2 or 3;

[0105] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
wherein n is 1, 2 or 3; and

• [0106] R₄ is H, azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, (CH₂)_q—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein q is an integer 0 to 6; and r is 0, 1 or 2; and Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group.

[0107] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
where m is 0, 1, 2 or 3;

• [0108] R₅ is H, azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of a covalent bond, —C(O)—, (CH₂)_q—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, —(CH₂)_qC(O)—, —C(O)(CH₂)_q— and —(CH₂)_qS(O)_r—, where the alkyl portion of —(CH₂)_q—, —(CH₂)_qO—, —(CH₂)_qNH—, —(CH₂)_qC(O)—, —C(O)(CH₂)_q— and —(CH₂)_qS(O)_r is optionally substituted by a halogen, hydroxy or an alkyl group; wherein q is an integer from 0 to 6; and r is 0, 1 or 2; and Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group;
• [0109] or Y and Z together are a natural or unnatural amino acid, which may be mono- or di-alkylated at the amine nitrogen; and
• [0110] R₆ represents one or more substituents each independently selected from the group consisting of hydrogen, hydroxy, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted heterocyclylcarbonyl, substituted or unsubstituted aminoalkyl and substituted or unsubstituted arylalkyl; provided that the carbon atoms adjacent to the nitrogen atom are not substituted by a hydroxy group.

[0111] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
wherein R₄ is H, substituted or unsubstituted alkyl, substituted or unsubstituted azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, —(CH₂)_q—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, —(CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein q is an integer from 0 to 6, and r is 0, 1 or 2; and Z is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.

[0112] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
wherein

• [0113] m is an integer from 1 to 6; and
• [0114] R₄ and R₅ are each, independently, H, substituted or unsubstituted azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, —(CH₂)_q—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, —(CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein q is an integer from 0 to 6; and r is 0, 1 or 2; and Z is a substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; or
• [0115] R₄, R₅ and the nitrogen atom to which they are attached together form a 3, 4, 5, 6 or 7-membered, substituted or unsubstituted heterocyclic or substituted or unsubstituted heterobicyclic group.

[0116] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:
where

• [0117] n is an integer from 0 to 4;
• [0118] r is 0 and m is an integer from 1 to 6; or
• [0119] r is 1 and m is an integer from 0 to 6;
• [0120] Q is —OR₆ or —NR₄R₅;
• [0121] each R₄ and R₅ is, independently, H, substituted or unsubstituted azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, —(CH₂)_q—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, —(CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; q is an integer from 0 to 6; and r is 0, 1 or 2; and Z is a substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; or
• [0122] R₄, R₅ and the nitrogen atom to which they are attached together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocyclic group; and
• [0123] R₆ is hydrogen or a substituted or unsubstituted alkyl group.

[0124] Another preferred compound of Formula (I) is wherein R₃ is H; R₂ is of the formula:

• [0125] n is an integer from 0 to 4;
• [0126] m is an integer from 0 to 6;
• [0127] R₄ is H, substituted or unsubstituted azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, —(CH₂)_q—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, —(CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein q is an integer from 0 to 6; and r is 0, 1 or 2; and Z is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; and
• [0128] R₆ is hydrogen or a substituted or unsubstituted alkyl group.

[0129] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocyclic group of the formula:
wherein

• [0130] R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are each, independently, lower alkyl or hydrogen; orat least one pair of substituents R₇ and R₈; R₉ and R₁₀; R₁₁ and R₁₂; or R₁₃ and R₁₄ together are an oxygen atom; or at least one of R₇ and R₉ is cyano, CONHR₁₅, COOR₁₅, CH₂OR₁₅ or CH₂NR₁₅(R₁₆), wherein R₁₅ and R₁₆ are each, independently, H, azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—,
• [0131] —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; or R₁₅, R₁₆ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered, substituted or unsubstituted heterocyclic or a substituted or unsubstituted heterobicyclic group;
• [0132] X is O, S, SO, SO₂, CH₂, CHOR₁₇ or NR₁₇, wherein R₁₇ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, —C(NH)NH₂, —C(O)R₁₇, or —C(O)OR₁₈, wherein R₁₈ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl; and t is 0 or 1.

[0133] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocycle of the formula:
wherein

• [0134] R₁₉ and R₂₀ are each, independently, hydrogen or lower alkyl; or R₁₉ and R₂₀ together are an oxygen atom;
• [0135] R₂₁ and R₂₂ are each, independently, H, substituted or unsubstituted azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; or
• [0136] R₂₁, R₂₂ and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocyclic group;
• [0137] m is an integer from 1 to 6; and
• [0138] n is an integer from 0 to 6.

[0139] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocyclic group of the formula:
wherein

• [0140] m is an integer from 1 to 6; and
• [0141] R₂₃ is CH₂OH, NRR′, C(O)NRR′ or COOR, wherein R and R′ are each, independently, hydrogen or substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl.

[0142] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocyclic group of the formula:
wherein R₂₄ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl, carboxyl, cyano, C(O)OR₂₅, CH₂OR₂₅, CH₂NR₂₆R₂₇ or C(O)NHR₂₆, wherein R₂₅ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic or substituted or unsubstituted heterocycloaryl; and R₂₆ and R₂₇ are each, independently, H, substituted or unsubstituted azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; or R₂₆, R₂₇ and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocyclic group.

[0143] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds at least one of R₄ and R₅ is of the formula Y-Z, wherein Z is of the formula:
wherein

• [0144] T is C(O), S, SO, SO₂, CHOR or NR, wherein R is hydrogen or a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl group; and
• [0145] n is 0, 1 or 2.

[0148] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocycle of the formula:
wherein

• [0149] R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃ and R₁₄ are each, independently, lower alkyl or hydrogen; or at least one pair of substituents R₇ and R₈; R₉ and R₁₀; R₁₁ and R₁₂; or R₁₃ and R₁₄ together are an oxygen atom; or at least one of R₇ and R₉ is cyano, CONHR₁₅, COOR₁₅, CH₂OR₁₅ or CH₂NR₁₅(R₁₆), wherein R₁₅ and R₁₆ are each, independently, H, substituted or unsubstituted azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; or R₁₆, R₁₆ and the nitrogen atom together form a 3, 4, 5, 6 or 7-membered, substituted or unsubstituted heterocyclic or heterobicyclic group;
• [0150] X is O, S, SO, SO₂, CH₂, CHOR₁₇ or NR₁₇, wherein R₁₇ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, —C(NH)NH₂, —C(O)R₁₈, or —C(O)OR₁₈, wherein R₁₈ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl; and
• [0151] t is 0 or 1.

[0152] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocycle of the formula:
wherein

• [0153] R₁₉ and R₂₀ are each, independently, hydrogen or lower alkyl; or R₁₉ and R₂₀ together are an oxygen atom;
• [0154] R₂₁ and R₂₂ are each, independently, H, substituted or unsubstituted azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; or
• [0155] R₂₁, R₂₂ and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocyclic group;
• [0156] m is an integer from 1 to 6; and
• [0157] n is an integer from 0 to 6.

[0158] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocyclic group of the formula:
wherein

• [0159] m is an integer from 1 to 6; and
• [0160] R₂₃ is CH₂OH, NRR′, C(O)NRR′ or COOR, wherein R is hydrogen or a substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl group.

[0161] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄, R₅ and the nitrogen atom together form a heterocyclic group of the formula:
wherein R₂₄ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl, carboxyl, cyano, C(O)OR₂₅, CH₂OR₂₅, CH₂NR₂₆R₂₇ or C(O)NHR₂₆, wherein R₂₅ is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocyclic or substituted or unsubstituted heterocycloaryl group; and R₂₆ and R₂₇ are each, independently, H, substituted or unsubstituted azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; or R₂₆, R₂₇ and the nitrogen atom together form a 3, 4, 5 or 6-membered, substituted or unsubstituted heterocyclic group.

[0162] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds at least one of R₄ and R₅ is of the formula Y-Z, wherein Z is of the formula:
wherein

• [0163] g is 0 or 1;
• [0164] T is C(O), O, S, SO, SO₂, CH₂, CHOR₁₇ or NR₁₇, wherein R₁₇ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, —C(NH)NH₂, —C(O)R₁₈, or —C(O)OR₁₈, wherein R₁₈ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl; and
• [0165] R₃₂ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted arylalkyl.

[0169] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₅ is Y-Z, wherein Z is of the formula:
wherein

• [0170] each X is, independently, CH or N; and
• [0171] R₃₂ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted arylalkyl group.

[0172] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₅ is Y-Z, wherein Z is of the formula:
wherein

• [0173] g is 0 or 1;
• [0174] T is O, S, SO, SO₂, CH₂, CHOR₁₇ or NR₁₇, wherein R₁₇ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, C(O)NH₂, —C(NH)NH₂, —C(O)R₁₇, or —C(O)OR₁₈, wherein R₁₈ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl; and
• [0175] R₃₂ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted arylalkyl group.

[0176] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₅ is Y-Z, wherein Z is of the formula:
wherein

• [0177] g is 0, 1 or 2; and
• [0178] R₃₂ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted arylalkyl group.

[0179] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₅ is Y-Z, wherein Z is of the formula:
wherein

• [0180] T is C(O), O, S, SO, SO₂, CH₂, CHOR₁₇ or NR₁₇, wherein R₁₇ is hydrogen, substituted or unsubstituted alkyl, aryl, arylalkyl, —C(NH)NH₂, —C(O)R₁₈, or —C(O)OR₁₈, wherein R₁₈ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted arylalkyl;
• [0181] g is 0 or 1; and
• [0182] R₃₂ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted arylalkyl group.

[0183] A more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₅ is Y-Z, wherein Z is of the formula:
wherein

• [0184] R₃₂ is hydrogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted aminocarbonyl, alkylcarbonyl , substituted or unsubstituted thioalkoxy or substituted or unsubstituted arylalkyl; and
• [0185] R₃₃ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkoxyalkyl, substituted or unsubstituted aminocarbonyl, perhaloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkylcarbonyl or substituted or unsubstituted arylalkyl.

[0186] A preferred compound of Formula (I) is where R₃ is H; R₂ is of the formula:
wherein

• [0187] m is 0 or 1;
• [0188] R₃₄, R₃₅, R₃₆, R₃₇, R₃₈, R₃₉, R₄₀ and R₄₁ are each, independently, methyl or hydrogen; or at least one pair of substituents R₃₄ and R₃₅; R₃₆ and R₃₇; R₃₈ and R₃₉; or R₄₀ and R₄₁ together are an oxygen atom; and
• [0189] R₄₂ is H, substituted or unsubstituted azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and Z is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl group; or
• [0190] R₄₂ is of the formula:
  wherein
• [0191] u is 0 or 1;
• [0192] R₄₃, R₄₄, R₄₅, R₄₆, R₄₇, R₄₈, R₄₉ and R₅₀ are each, independently, methyl or hydrogen;
• [0193] or at least one pair of substituents R₄₃ and R₄₄; R₄, and R₄₆; R₄₇ and R₄₈; or R₄₉ and R₅₀ together are an oxygen atom; and
• [0194] R₅₁ is H, substituted or unsubstituted azabicycloalkyl or V-L, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.

[0195] A preferred compound of Formula (I) is where R₃ is H; R₂ is of the formula:
wherein

• [0196] h, i, j, k and l are independently 0 or 1;
• [0197] R₅₂, R₅₃, R₅₄, R₅₅, R₅₆, R₅₇, R₅₈, R₅₉, R_g and R_h are each, independently, methyl or hydrogen; or at least one pair of substituents R₅₂ and R₅₃; R₅₄ and R₅₅; R₅₆ and R₅₇; or R₅₈ and R₅₉ together are an oxygen atom; and
• [0198] R₆₀ is H, substituted or unsubstituted azabicycloalkyl or Y-Z, wherein Y is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and Z is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl; or
• [0199] R₆₀ is of the formula:
  wherein
• [0200] v is 0 or 1;
• [0201] R₆₁, R₆₂, R₆₃, R₆₄, R₆₅, R₆₆, R₆₇ and R₆₈ are each, independently, lower alkyl or hydrogen; or at least one pair of substituents R₆₁ and R₆₂; R₆₃ and R₆₄; R₆₅ and R₆₆; and R₆₇ and R₆₈ together are an oxygen atom; and
• [0202] R₆₉ is H, substituted or unsubstituted azabicycloalkyl or V-l, wherein V is selected from the group consisting of —C(O)—, —(CH₂)_p—, —S(O)₂—, —C(O)O—, —SO₂NH—, —CONH—, (CH₂)_qO—, —(CH₂)_qNH—, and —(CH₂)_qS(O)_r—; wherein p is an integer from 0 to 6, q is an integer from 0 to 6, and r is 0, 1 or 2; and L is substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocycloalkyl.

[0207] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:
where Z¹⁰⁰ is a substituted or unsubstituted benzoxazolyl or a substituted or unsubstituted benzthiazolyl.

[0208] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:
where there is only one R_a and it is H or F.

[0210] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:

[0223] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds Z is hydrogen, methyl, ethyl, hydroxymethyl, methoxyethyl, N-methyl-piperidinyl, (t-butoxycarbonyl)(hydroxy)-piperidinyl, hydroxypiperidinyl, (hydroxymethyl)piperdinyl, (hydroxy)(methyl)-piperidinyl, morpholino, (methoxyethyl)piperizinyl, methylpiperizinyl, 4-piperidinylpiperidinyl, imidazolyl, methylimidazolyl, N-methylamino, N,N-dimethylamino, N-isopropylamino, N,N-diethylamino, 2,3-dihydroxypropylamino, 2-hydroxyethylamino, 3-hydroxypropylamino, methoxyethylamino, ethoxycarbonylmethylamino, phenylmethylamino, N-methyl-N-methoxyamino,
furanylmethylamino, piperidinylethylamino, N-(2-N,N-dimethylaminoethyl)-N-methylamino, 2-N,N-dimethylaminoethylamino, N-methyl-N-(N-methylpiperidin-4-yl)amino, 2-morpholino-ethylamino, 3-morpholino-propylamino, 3-imidazolylpropylamino, or 3-(2-oxopyrrolidinyl)propylamino.

[0224] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds m is 2; R₅ is Y-Z; Y is —C(O)—; and Z is:
where n is 0, 1, 2 or 3.

[0234] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:
where Z¹⁰⁰ is selected from the group consisting of benzo[b]thiophene, furanyl and thiophene.

[0236] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:

• [0237] A is selected from the group consisting of —N(R)—C(O)—N(R)—, —(CH₂)_n—N(R)C(O)N(R)—, —N(R)— and —N(R)—SO₂—; R is hydrogen or alkyl;
• [0238] Z¹⁰⁰ is:
  pyridinyl, thiazolyl, furanyl, benzofuranyl or oxazolyl;

[0241] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄ is methyl; G is:
where n is 0 to 3; Z¹⁰⁰ is an optionally substituted group selected from the group consisting of indolyl, indenyl, methylindenyl, methylindolyl, dimethylaminophenyl, phenyl, cyclohexyl and benzofuranyl.

[0259] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds R₄ is methyl and there is only one R_a and it is F. Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:

• [0260] Z¹⁰⁰ is an optionally substituted group selected from the group consisting of phenyl, isoxazolyl, tetrahydronaphthyl, furanyl, benzofuranyl, pyridyl and indolyl;
• [0261] where Z¹⁰⁰ is optionally substituted with one or more substituents each independently selected from the group consisting of F, CN, NO₂, —C(O)H, —CONH₂, —NHSO₂CF₃, optionally substituted alkyl, optionally substituted heteroaryl and —O-(optionally substituted alkyl);
• [0262] Z¹¹⁰ and Z¹¹¹ are each independently optionally substituted (C₀-C₃); and
• [0263] A is O, —N(R)—C(O)—(CH₂)_n—N(R)—, —C(O)—N(R)—, —N(R)—C(O)—O—, —N(R)—C(O)— or —N(R)—.

[0265] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:
where R is H or lower alkyl and n is for each occurrence is independently 1 to 6.

[0266] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:

[0268] Another more preferred compound of Formula (I) is where in any of the applicable foregoing preferred compounds G is:
where Z¹⁰⁰ is an optionally substituted group selected from the group consisting of benzoxazolyl, benzothiazolyl and benzimidazolyl.

DETAILED DESCRIPTION OF THE INVENTION

SYNTHESIS

[0311] The compounds of the invention can be prepared using the methods depicted in Schemes I-XI.

[0312] A preferred method of preparing the compounds of the invention involves preparing a 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl intermediate (IV) (see Scheme XII). The method involves reacting an acid chloride (II) with a (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (III) in the presence of an aprotic base. Typically, the acid chloride (II) and (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (III) are dissolved in an organic solvent in approximately equal molar amounts. About 1 eq. to about 2 eq. of an aprotic base is added to the solution. Preferably, the solution is cooled to about −10° C. to about 10° C. before addition of the base and the base is added dropwise to the solution. After addition of the base, the solution is allowed to stir at ambient temperatures until the reaction is complete (as determined by thin layer chromatorgraphy, HPLC or other standard analytical techniques). Typically, the reaction is complete after about 10 h to about 26 h.

[0313] The 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl intermediate (IV) can be used to prepare compounds of formula I by reacting it with a 3iodo-1H-pyrazolo[3,4-d]pyrimidine (V) in the presence of tetrakis(triphenylphosphine)palladium(0) and sodium carbonate (see Scheme XIII). The 3-iodo-1H-pyrazolo[3,4-d]pyrimidine (V) in a polar organic solvent, such as an ether, is treated with an aqueous mixture of 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl intermediate (IV), tetrakis(triphenylphosphine)palladium(O) and sodium carbonate. Typically, the 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl intermediate (IV) is present in the solution in about 1 eq. to about 1.5 eq., the tetrakis(triphenylphosphine)palladium(0) is present in about 0.01 eq. to about 0.1 eq, and the sodium carbonate is present in about 1.5 eq. to about 3 eq. with respect to the 3-iodo-1H-pyrazolo[3,4-d]pyrimidine (V). The solution is heated to about 50° C. to about 100° C. The reaction is monitored by thin layer chromatorgraphy, HPLC or other standard analytical techniques to determine when the reaction is complete. Typically, the reaction is complete after about 16 h to about 30 h.

[0314] Compounds of formula II can be prepared by reacting a carboxylic acid represented by formula VI with oxalyl chloride in the presence of an aprotic base:

[0316] In another preferred embodiment, in the methods of Schemes XII and XIII and in the method of preparing the acid chloride (II), Z¹⁰⁰ is indolyl which is optionally substituted with R₁; the (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline is represented by formula VII:
and the 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl intermediate is represented by formula VIII:
and the compounds of the invention prepared can be represented by formula IX:

[0317] In a more preferred embodiment, in the methods of Schemes XII and XIII and in the method of preparing the acid chloride (II), Z¹⁰⁰ is 1-methyl-indol-2-yl or 1-methyl-indol-3-yl; the (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline is represented by formula VII; and the 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl intermediate is represented by formula X:
and the compounds of the invention prepared can be represented by formula XI:

EXAMPLES

Example 1

1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 1)

3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-ol (Intermediate A)

3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B)

1-(1-benzyl-4-piperidinyl)-3-bromo-4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate C)

1-(1-benzyl-4-piperidinyl)-3-bromo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate D)

1-(1-benzyl-4-piperidinyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 2

3-(4-phenoxyphenyl)-1-(4-piperidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 3

1-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, Trimaleate salt (compound 3)

1-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate E)

1-[1-(1-methyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt

Example 4

1-[1-(1-isopropyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt (compound 4)

1-[1-(1-isopropyl-4-piperidyl)-4-piperidyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate F)

1-[1-(1-isopropyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt

Example 5

1-[1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt (compound 5)

1-[1-(1-tert-butoxycarbonyl-4-piperidinyl)-4-piperidinyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate G)

1-[1-(1-tert-butoxyarbonyl-4-piperidinyl)-4-piperidinyl-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt

Example 6

1-(trans-4-(4-methylpiperazino)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, dimaleate salt (compound 6)

1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Compound 9) (Intermediate I)

4-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-Cyclohexanone (Compound 10) (Intermediate J)

1-(trans -4-(4-methylpiperazino)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate K) and 1-(cis-4-(4-methylpiperazino)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate L)

1-(trans-4-(4-methylpiperazino)cyclohexyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, dimaleate salt

Example 7

1-[4-(4-methylpiperazino)cyclohexyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine trimaleate (compound 7)

Example 8

N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide dimaleate salt (compound 8)

1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate KA)

3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate LA)

1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)

1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate N)

tert-Butyl N-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (Intermediate P)

tert-Butyl N-{4-[4-amino-1-(1,4-dioxaspiro[4.5]dec-8-yl-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}carbamate (Intermediate Q)

4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (Intermediate R)

Cis- and trans-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediates S and T)

N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-4-fluoro-1-benzenesulfonamide di maleate salt

Example 9

(Intermediate I) 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (compound 9, intermediate I)

4-phenoxyphenylboronic acid (Intermediate V)

1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)

3-bromo-4-chloro-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate W)

3-bromo-1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (Intermediate X)

1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine

1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine. Second Route

Example 10

4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (compound 10, intermediate J)

Example 11

tert-butyl 4-4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl-1-piperazinecarboxylate (Compounds 11 and 12)

Example 12

Cis-3-(4-phenoxyphenyl)-1-(4-piperazinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine trimaleate (compound 13)

Example 13

Trans-3-(4-phenoxyphenyl)-1-(4-piperazinocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine trimaleate (compound 14)

Example 14

4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (compound 15)

1,4-dioxaspiro[4.5]decan-8-ol (Intermediate M)

1,4-dioxaspiro[4.5]dec-8-yl 4-methyl-1-benzenesulfonate (Intermediate Y)

1,1-Dicyano-2-hydroxy-2-(4-phenoxyphenyl)ethene (Intermediate Z)

1,1-Dicyano-2-methoxy-2-(4-phenoxyphenyl)ethene (Intermediate AA)

3-Amino-4-Cyano-5-(4-phenoxyphenyl)pyrazole (Intermediate AB)

4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine

Example 15

4-Amino-1-Cyclopentyl-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidine (compound 16)

Example 16

3-(4-Phenoxyphenyl)-1-(tetrahydropyran-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (compound 17)

Example 17

Cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaletate (compound 18) and trans-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazoloL[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaleate (compound 19)

Phenyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone (Intermediate AL)

4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-Cyclohexanone (Intermediate AK)

Cis- and trans-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediates AC and AD)

Cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaletate

Trans-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methanone dimaleate

Example 18

Cis-3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine trimaleate (compound 20)

N-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (Intermediate AE)

Cis-3-(4-anilinophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine trimaleate

Example 19

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dimaleate (compound 21) and trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine maleate (compound 22)

5-Bromo-2-phenoxypyridine (Intermediate AF)

2-Phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Intermediate AG)

1-(1,4-Dioxaspiro[4.5]dec-8-yl)-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate AH)

4-[4-Amino-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (Intermediate AI)

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dimaleate and trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(6-phenoxy-3-pyridyl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine maleate

Example 20

Trans-benzyl-N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate dimaleate (compound 23)

Benzyl N-(4-bromo-2-methoxyphenyl)carbamate (Intermediate AM)

Benzyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-carbamate (Intemediate AN)

Trans-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo-[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate dimaleate

Example 21

Trans-N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}benzamide dimaleate (Compound 24)

3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate AP)

Trans-N-(4-4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl-2-methoxyphenyl)benzamide dimaleate

Example 22

N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}-N′-phenylsulfamide dimaleate (Compound 25)

Example 23

Cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate (Compound 27) Trans{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate (Compound 26)

Phenyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone O-methyloxime (Intermediate AR)

cis-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate

Trans-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-phenyl}(phenyl)methanone O-methyloxime dimaleate

Example 24

Trans-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl} (phenyl)methanone oxime dimaleate (Compound 28)

(4-Bromophenyl)(phenyl)methanone oxime (intermediate AS)

Phenyl[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone oxime (Intermediate AT)

Trans-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl}(phenyl)methanone oxime dimaleate

Example 25

Trans-1-{4-[4-amino-3-(4-(1-phenylammonio)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-cyclohexyl}-4-methylhexahydropyrazinediium tri[(Z)-3-carboxy-2-propenoate] (Compound 29)

Example 26

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 30)

5-Bromo-2-phenoxypyrimidine (intermediate AU)

2-Phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyrimidine (intermediate AV)

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. (intermediate AW)

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis maleate

Example 27

Trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo [3,4-d]pyrimidin-4-amine bis maleate (Compound 31)

Trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine. (intermediate AX)

Trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-(2-phenoxy-5-pyrimidinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine bis maleate (compound 31)

Example 28

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound 32)

2-Phenoxypyrimidine. (Intermediate AY)

2-(4-Iodophenoxy)pyrimidine (Intermediate AZ)

2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrimidine (intermediate BA)

1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate BB)

4-{4-amino-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}-cyclohexanone (intermediate BC)

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate BD)

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine tris maleate

Trans-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (intermediate BE)

Example 29

Example 30

Cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

a) (4-bromophenyl)(phenyl)methanamine

b) tert-Butyl N-[(4-bromophenyl)(phenyl)methyl]carbamate

c) tert-Butyl N-{phenyl-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}carbamate

d) cis-tert-butyl N-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]carbamate

e) cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

f) cis-N1-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]acetamide diacetate

Example 31

Cis-N1-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]benzamide diacetate

Example 32

Cis-N-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3yl}phenyl)(phenyl)methyl]methanesulfonamide

Example 33

Cis-N1-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]-1-benzenesulfonamide acetate

Example 34

Cis-N1-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]-3-hydroxybutanamide acetate

Example 35

Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide

a) 4-(4-bromophenoxy)benzonitrile

b) 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile

c) cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile

d) Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide

Example 36

Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzoic acid

Example 37

Cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H -pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]acetamide acetate

a) cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b) Cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]acetamide acetate

Example 38

Cis-N-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]methanesulfonamide acetate

Example 39

cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide diacetate

a) 3-(4-bromophenoxy)benzonitrile

b) 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile

c) cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile

d) cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide diacetate

Example 40

Cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzoic acid

Example 41

Cis-N1-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]acetamide acetate

a) cis-3-{4-[3-(aminomethyl)phenoxy]phenyl}-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b) Cis-N1-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]acetamide acetate

Example 42

Cis-N1-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]benzamide

Example 43

Cis-N-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]methanesulfonamide acetate

Example 44

Cis-benzyl N-{4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo-[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl}carbamate dimaleate

Example 45

Cis-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N′-benzylurea acetate

General Procedure for Reductive Alkylation of cis- or trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 46

Cis-3-[4-(benzylamino)-3-methoxyphenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 47

Cis-3-(3-methoxy-4-[4-(trifluoromethyl)benzyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 48

Cis-3-{4-[(1H-4-imidazolylmethyl)amino]-3-methoxyphenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 49

Trans-3-[4-(benzylamino)-3-methoxyphenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine dimaleate

Example 50

Trans-3-{4-[(2,6-dimethoxybenzyl)amino]-3-methoxyphenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 51

Trans-3-{4-[(2-chloro-6-fluorobenzyl)amino]-3-methoxyphenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Cis- and trans-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

a) tert-butyl N-(4-bromophenyl)carbamate

b) tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

c) cis-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate

Cis-3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Trans -3-(4-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

General Procedure for Reductive Alkylation of cis- or trans-3-(4-amino-phenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 52

Cis-3-[4-(benzylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 53

Cis-3-{4-[(2-methylbenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclo-hexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 54

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(4-[2-(trifluoromethyl)benzyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 55

Cis-3-{4-[(2-chlorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 56

Cis-3-{4-[(2-bromobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 57

Cis-3-{4-[(2-ethoxybenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 58

Cis-3-(4-[2-(difluoromethoxy)benzyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 59

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-(4-[2-(trifluoromethoxy)benzyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 60

Cis-2-[2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)methyl]phenoxy-1-ethanol diacetate

Example 61

Cis-2-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)methyl]benzonitrile diacetate

Example 62

Cis-3-{4-[(2,6-difluorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 63

Cis-3-4-[(2-chloro-6-fluorobenzyl)amino]phenyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 64

Cis-3-(4-[2-fluoro-6-(trifluoromethyl)benzyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 65

Cis-3-{4-[(2-fluoro-6-methoxybenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

a) 2-fluoro-6-methoxybenzaldehyde

b) cis-3-{4-[(2-fluoro-6-methoxybenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 66

Cis-3-4-[(2,6-dichlorobenzyl)amino]phenyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 67

Cis-3-{4-[(2,6-dimethoxybenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 68

Cis-3-{4-[(2-fluoro-4-methylbenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

a) 2-fluoro-4-methylbenzaldehyde

b) Cis-3-{4-[(2-fluoro-4-methylbenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 69

Cis-3-{4-[(1H-2-indolylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 70

Cis-3-(4-[(1-methyl-1H-2-indolyl)methyl]aminophenyl)-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 71

Trans-3-[4-(benzylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine tris-maleate

Example 72

Trans-3-{4-[(2-methylbenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 73

Trans-3-{4-[(2,6-dimethoxybenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 74

Trans-3-{4-[(2-chlorobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 75

Trans-3-{4-[(2-bromobenzyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 76

3-[4-(benzylamino)phenyl]-1-[1-(1-methylpiperid-4-yl)piperid-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 77

3-{4-[(2,6-dimethoxybenzyl)amino]phenyl}-1-[1-(1-methylpiperid-4-yl)piperid-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 78

3-{4-[(2-chloro-6-fluorobenzyl)amino]phenyl}-1-[1-(1-methylpiperid-4-yl)piperid-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 79

Cis-3-4-[benzyl(methyl)amino]phenyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

a) N-benzyl-N-methyl-N-phenylamine

b) N-benzyl-N-(4-bromophenyl)-N-methylamine

c) N-benzyl-N-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine

d) Cis-3-{4-[benzyl(methyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 80

Cis-3-{4-[benzyl(ethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

a) N-benzyl-N-(4-bromophenyl)-N-ethylamine

b) N-benzyl-N-ethyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine

c) Cis-3-{4-[benzyl(ethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 81

Cis-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-2-phenylacetamide diacetate

Example 82

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(phenethylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 83

Cis-N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-3-phenylpropanamide diacetate

Example 84

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(3-phenylpropyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Intermediate A

3-(Benzyloxy)phenylboronic acid

Intermediate B

4-(4-Amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenol

Intermediate C

tert-butyl N-(3-bromophenyl)carbamate

Intermediate D

tert-butyl N-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate

Intermediate E

cis-tert-butyl N-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)carbamate

Intermediate F

Cis-3-(3-aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Intermediate G

2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzonitrile

Example 85

1-Cyclopentyl-3-[4-(3-methoxyphenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 86

3-[4-(Benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 87

1-Cyclopentyl-3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 88

1-Cyclopentyl-3-4-[3-(trifluoromethyl)phenoxy]phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 89

1-Cyclopentyl-3-[4-(3-nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 90

1-Cyclopentyl-3-4-[4-(trifluoromethoxy)phenoxy]phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 91

1-Cyclopentyl-3-4-[4-(trifluoromethyl)phenoxy]phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 92

3-[3-(Benzyloxy)phenyl]-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Examples 93-99

Example 100

Cis-3-[3-(benzylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine triacetate salt

Example 101

Cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzonitrile

Example 102

Cis-2-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzamide triacetate salt

Example 103

Cis-3-4-[2-(aminomethyl)phenoxy]phenyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 104

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-4-[2-(2H-1,2,3,4-tetraazol-5-yl)phenoxy]phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate salt

Example 105

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-[4-(2-nitrophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate salt

Example 106

Cis-3-[4-(2-aminophenoxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 107

[2-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-phenoxyphenyl]methanol

a) (2-Bromo-5-phenoxyphenyl)methanol

b) 5-Phenoxy-1,3-dihydro-2,1-benzoxaborol-1-ol

c) [2-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-5-phenoxyphenyl]methanol

Example 108

Cis-1-(aminomethyl)-4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanol maleate

a) Cis-1-(1-oxaspiro[2.5]oct-6-yl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b) Cis-1-(aminomethyl)-4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanol maleate

Example 109

Cis-1-(2-aminoethyl)-4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanol maleate

a) Cis-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}methyl cyanide

b) Cis-1-(2-aminoethyl)-4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanol maleate

c) Cis-2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetamide

Example 110

1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

a) Tert-butyl 3-hydroxy-1-azetanecarboxylate

b) Tert-butyl 3-[(methylsulfonyl)oxy]-1-azetanecarboxylate

c) Tert-butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanecarboxylate

1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Alkylation of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 111

a) Alkyl Bromide: 2-bromo-1-ethanol 2-{3-[4-Amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-1-ethanol

Example 112

b) Alkyl Bromide: 2-bromoethyl methyl ether 1-[1-(2-Methoxyethyl)-3-azetanyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 113

c) Alkyl Bromide: 1-bromo-2-(2-methoxyethoxy)ethane 1-{1-[2-(2-Methoxyethoxy)ethyl]-3-azetanyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 114

1-[1-(1-methyl-4-piperidyl)-3-azetanyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 115

1-{1-[(1-methyl-1H-2-imidazolyl)methyl]-3-azetanyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 116

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-1-ethanone

Example 117

Cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol

a) 3-propylidenecyclobutyl methanesulfonate

b) 3-(4-phenoxyphenyl)-1-(3-propylidenecyclobutyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

c) 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanone

Cis 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol

Example 118

Trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol

a) Trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl 4-nitrobenzoate

Trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclobutanol)

Example 119

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutyl}-4-methylhexahydropyrazinediium dimaleate

Example 120

Trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

a) Cis 3-[(benzyloxy)methyl]cyclobutyl methanesulfonate

b) Trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Trans 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclobutylmethanol

Examples 121-137

General procedure for the synthesis of aryl alkyl cis-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs

Example 137

Maleate Salt of cis-3-{4-[(4-bromobenzyl)amino]-3-fluorophenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine tris maleate salt

[0966]

Ex	Structure	m/z (MH+)	HPLC Rt (min)
121		515.2	13.74
122		529.3	14.04
123		516.3	10.82
124		543.3	14.91
125		557.4	15.53
126		545.3	13.27
127		591.4	15.89
128		561.0	11.58
129		569.3	11.27
130		583.3	14.83
131		595.4	15.48
132		545.3	12.91
133		516.3	10.10
134		516.2	10.41
135		583.3	14.78
136		573.3	13.10
137		594.8	14.61

Examples 138-153

General procedure for the synthesis of sulfonamide variants of cis and trans-3-(4-Amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

[0968]

Ex	Structure	m/z (MH+)	HPLC Rt (min)
140		645.1	12.22
141		623.3	11.30
142		610.2	11.85
143		633.2	12.50
144		624.3	11.86
145		583.3	11.29
147		623.2	11.14
148		633.2	12.38
149		643.2	12.04
150		624.3	11.67
151		619.2	12.22
152		633.2	13.09
153		649.3	12.81

Example 154

cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(2,4-difluorophenyl)urea

Example 155

trans-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methoxyphenyl)urea monoacetate salt

Example 156

trans-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methylphenyl)urea monoacetate salt, was prepared in the same manner as detailed above

Example 157

cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N′-(3-methylphenyl)urea, was prepared using the same method as described for the trans isomer

Example 158

cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N-ethyl-N′-(3-methylphenyl)urea

a. cis-3-[4-(Ethylamino)-3-fluorophenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b. cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N-ethyl-N′-(3-methylphenyl)urea

Example 159

cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-N-benzyl-N′-(2,4-difluorophenyl)urea

Example 160

cis-N-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-N′-(3-methylphenyl)urea

Examples 161-164

Amide analogs of N-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea

a. tert-Butyl 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate

a. tert-Butyl 4-(4-amino-3-{3-fluoro-4-[(3-toluidinocarbonyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate

a. N-{4-[4-Amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea dihydrochloride salt

a. General synthesis of amide analogs of N-{4-[4-amino-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea

Example 161

N-[4-(4-amino-1-{1-[2-(dimethylamino)acetyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea

Example 162

N-[4-(4-Amino-1-{1-[3-(diethylamino)propanoyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea monoacetate salt was prepared as described in general procedure A

Example 163

N-[4-(4-Amino-1-{1-[2-(methylamino)acetyl]-4-piperidyl}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl]-N′-(3-methylphenyl)urea

Example 164

N-{4-[4-Amino-1-(1-{3-[(2-hydroxyethyl)amino]propanoyl}-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea monoacetate salt

a). 3-[(tert-Butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid

b). N-{4-[4-Amino-1-(1-{3-[(2-hydroxyethyl)amino]propanoyl}-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3-methylphenyl)urea monoacetate salt was carried out via the method described in d. ii). General procedure B

Example 165

Cis-3-{4-[(1-methyl-1H-benzo[d]imidazol-2-yl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

a) N2-(4-bromophenyl)-1-methyl-1H-benzo[d]imidazol-2-amine

b) N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-benzo[d]imidazol-2-amine

c) Cis-3-{4-[(1-methyl-1H-benzo[d]imidazol-2-yl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Examples 166-170

Amides derived from cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrazolo[3,4-d]pyrimidin-4-amine

[0991]

			Qty.
Compound Name	R	Ex	(mg)	MH+	Rt (mins)
N2-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]-1H- pyrazolo[3,4-d]pyrimidin-3-y}-2- methoxyphenyl)-1H-2- indolecarboxamide		166	34	580.5	1.98
N2-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]-1H- pyrazolo[3,4-d]pyrimidin-3-y}1-2- methoxyphenyl)-3-methyl-1H-2- indenecarboxamide		167	14	593.3	3.2
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}-2- methoxyphenyl)-(E)-3-phenyl-2- propenamide		168	17	567.3	2.85
N2-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}2- methoxyphenyl)-1-methyl-1H-2- indolecarboxamide		169	20	594.3	3.18
N3-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]-1H- pyrazolo[3,4-d]pyrimidin-3-yl}-2- methoxyphenyl)-1H-3- indolecarboxamide		170	6	580.4	2.74

Example 171

Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide

Example 172

Trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide trimaleate salt

Example 173

N-4-[4-Amino-1-(3-cyano-2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl-N′-(3-methylphenyl)urea

a). 2-(4-Amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-3-pyridyl cyanide

b) 2-[4-Amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-3-pyridyl cyanide

c). N-4-[4-amino-1-(3-cyano-2-pyridyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl-N′-(3-methylphenyl)urea

Examples 174-185

General route to N1-4-(4-amino-1-{4-[1-(1-methylpiperid-4-yl)piperidyl]}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenyl-1-arylsulfonamides

a) tert-Butyl 4-(4-amino-3-4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate

b) 3-(4-amino-3-fluorophenyl)-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

c) N1-4-(4-amino-1-{4-[1-(1-methylpiperid-4-yl)piperidyl]}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenylaniline

d) General procedure for the sulfonylation of N1-4-(4-amino-1-{4-[1-(1-methylpiperid-4-yl)piperidyl]}-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-2-fluorophenylaniline

[1001]

174		11.045	98.6	619.2
175		11.982	91.6	633.1
176		10.099	77.9	601.2
177		11.059	93.9	617.2
178		10.332	92.5	583.5
180		10.929	84.3	643.2
181		10.074	87.1	583.2
182		11.256	90.5	633.1
183		11.807	75.7	649.2
184		10.617	100	610.2
185		11.895	88.4	633.2

Examples 186-189

cis-3-{4-[amino(phenyl)methyl]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs

a. General synthetic route to sulfonamide and carboxamide derivatives

[1004]

		HPLC	Purity	m/z
Ex	Structure	Rt (min)	(%)	(MH+)
186		15.76	94.9	721.6
187		13.21	94.9	697.3
188		14.20	91.3	697.4
189		15.30	96.8	705.3
190		14.00	100	675.4
191		12.00	99	602.4
192		12.08	100	602.3
		13.68	100	695
		12.08	100	100

Example 195

1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(phenethylamino)(phenyl)methyl]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 196

N-{4-[4-amino-1-(4-oxocyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl}-N′-(3 methylphenyl)urea

Example 197

Ethyl 2-[4-amino-3-(4-[(2,3-dichlorophenyl)sulfonyl]amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate

a) Ethyl 2-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate

b) Ethyl 2-(4-amino-3-4-[(tert-butoxycarbonyl)amino]-3-fluorophenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)acetate

c) Ethyl 2-[4-amino-3-(4-[(2,3-dichlorophenyl)sulfonyl]amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]acetate

Example 198

N1-4-[4-Amino-1-(2-hydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-fluorophenyl-2,3-dichloro-1-benzenesulfonamide

Example 199

N1-(4-{4-Amino-1-[2-cyano-4-(4-methylpiperazino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-2,3-dichloro-1-benzenesulfonamide

Example 200

cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

a) 4-Bromo-2-methoxybenzonitrile

b) 4-Bromo-2-methoxybenzoic acid

c) 4-Bromo-2-methoxy-1-benzenecarbonyl chloride

d) N1-Phenyl-4-bromo-2-methoxybenzamide

e) 4-(Anilinocarbonyl)-3-methoxyphenylboronic acid

f) cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

Example 201

trans-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

Example 202

cis-N1-Benzyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

a) N1-Benzyl-4-bromo-2-methoxybenzamide

b) 4-[(Benzylamino)carbonyl]-3-methoxyphenylboronic acid

c) cis-N1-Benzyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

Example 203

cis-N1-Phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

a) N1-Phenethyl-4-bromo-2-methoxybenzamide

b) 4-[(Phenethylamino)carbonyl]-3-methoxyphenylboronic acid

c) cis-N1-Phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide

Example 204

cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide

a) N1-Phenyl-4-bromobenzamide

b) 4-(Anilinocarbonyl)phenylboronic acid

c) cis-N1-Phenyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide

Example 205

cis-N1-Phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide

a) N1-phenethyl-4-bromobenzamide

b) 4-[(Phenethylamino)carbonyl]phenylboronic acid

c) cis-N1-Phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide

Example 206

trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1H-2-indolecarboxamide, trimaleate salt

a) trans-tert-butyl N-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate

b) trans-3-(4-Amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

c) trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1H-2-indolecarboxamide

d) trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1H-2-indolecarboxamide, trimaleate salt

Example 207

trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide, trimaleate salt

a) trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide

b) trans-N2-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide, trimaleate salt

Example 208

trans-N1-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethyl)benzamide, trimaleate salt

a) trans-N1-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethyl)benzamide

b) trans-N1-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethyl)benzamide, trimaleate salt

Example 209

trans-N1-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide, trimaleate salt

a) trans-N1-(4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide

b) trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide, trimaleate salt

Example 210

N1-{4-[4-Amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-3-phenylpropanamide

a) tert-Butyl 4-hydroxy-1-piperidinecarboxylate

b) tert-Butyl-4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate

c) 3-Iodo-1-(4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

d) 3-Iodo-1-[1-(1-methylpiperidin-4-yl)]-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

e) tert-Butyl N-{4-[4-amino-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate

f) N1-{4-[4-Amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-3-phenylpropanamide

Example 211

N1-{4-[4-Amino-1-[1-(1-methylpiperidin-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethoxy)benzamide

Example 212

N1-{4-[4-Amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide, trimaleate salt

a) N1-{4-[4-Amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide

b) N1-{4-[4-Amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-4-(trifluoromethyl)benzamide, Triimaleate Salt

Example 213

1-[1-(1H-2-Imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

a) tert-Butyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyrrolidinecarboxylate

b) 3-(4-Phenoxyphenyl)-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine

c) 1-[1-(1H-2-Imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 214

1-[1-(1-Methyl-4-piperidyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt

a) 1-[1-(1-Methyl-4-piperidyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b) 1-[1-(1-Methyl-4-piperidyl)tetrahydro-1H-3-pyrrolyl]-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, trimaleate salt

Example 215

N1-(4-{4-Amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide

a) 1-[1-(1H-2-Imidazolylmethyl)-4-piperidyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b) tert-Butyl N-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate

c) 3-(4-Amino-3-methoxyphenyl)-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

e) N1-(4-{4-Amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide

Examples 216-221

Amides derived from cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrazolo[3,4-d]pyrimidin-4-amine

[1062] To the appropriate carboxylic acid (0.46 mmol) in dichloromethane (1.4 mL) was added oxalyl chloride (0.4 mL, 4.6 mmol) and DMF (1 drop). The vials were septum capped and a small bore needle inserted in each cap to relieve pressure. The vials were shaken overnight on a J-Kem shaker. 50% of the solution was separated and the excess oxalyl chloride and dichloromethane was then removed on a 12-port Supelco manifold under vacuum with nitrogen bleed. The crude acid chloride (0.23 mmol) was added to cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.11 mmol) in dry pyridine (0.6 mL) and stirred at room temperature overnight. The resulting solutions were submitted directly to purification by preparative HPLC (Hypersil BSD C18, 5 um, 100×21 mm, 0%-100% acetonitrile/0.05M ammonium acetate over 10 min, 25.0 mL/min). The resulting products were further purified by partioning between dichloromethane (4 ml) and 1.0 N sodium hydroxide (2 ml) and passing through an Empore™ high performance extraction disk cartridge (C18-SD octadecyl) to give the corresponding products. The compounds are detailed overleaf with corresponding LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.) data.

[1063]

Compound Name	R	Ex	Qty. (mg)	MH+	Rt (mins)
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4-d]pyrimidin-3- yl}-2-methoxyphenyl)-3-(2- methoxyphenyl)propanamide		216	29	599.4	2.72
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4-d]pyrimidin- 3-yl}-2-methoxyphenyl)-3-(4- methoxyphenyl)propanamide		217	31	599.4	2.58
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4-d]pyrimidin- 3-yl}-2-methoxyphenyl)-3-(3- methoxyphenyl)propanamide		218	30	599.4	2.61
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4-d]pyrimidin- 3-yl}-2-methoxyphenyl)-3-(4- methylphenyl)propanamide		219	33	583.4	2.70
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexy]- 1H-pyrazolo[3,4-d]pyrimidin- 3-yl}-2-methoxyphenyl)-3-(4- fluorophenyl)propanamide		220	27	587.3	2.72
N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4-d]pyrimidin- 3-yl}-2-methoxyphenyl)-3- (3,4-diflurorphenyl)propanamide		221	34	605.3	2.80

Example 221

cis-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 222

cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile

cis-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol

2-fluoro-6-[(2-methoxyethyl)amino]benzonitrile

cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile

Example 223

cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(4-methylphenyl)sulfanyl]benzonitrile tris-maleate

2-fluoro-6-[(4-methylphenyl)sulfanyl]benzonitrile

Example 224

cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile bis-maleate

cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-(2-pyridylsulfanyl)benzonitrile bis-maleate

Example 225

trans-3-[4-(benzyloxy)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 226

trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tris-maleate

trans-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenol

trans-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)-6-[(3-methoxypropyl)amino]benzonitrile tris-maleate

Example 227

trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide tris-maleate

4-bromo-2-methoxyaniline

N1-(4-bromo-2-methoxyphenyl)-3-phenylpropanamide

3-methoxy-4-[(3-phenylpropanoyl)amino]phenylboronic acid

trans-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide tris-maleate

Example 228

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide

N1-(4-bromo-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide

N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N1-methyl-3-phenylpropanamide

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-N1-methyl-3-phenylpropanamide

Example 229

N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide tris-maleate

tert-butyl N-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl-2-methoxyphenyl)carbamate

3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(trifluoromethoxy)benzamide tris-maleate

Example 230

4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino(4-methylpiperazino)methanone bis-maleate

Example 231

N1-(4-{4-amino-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-4-(dimethylamino)benzamide tris-maleate

Examples 232-237

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-(trifluoromethyl)benzamide

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl }-2-methoxyphenyl)-2-(trifluoromethoxy)benzamide

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-(trifluoromethoxy)benzamide

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-fluoro-4-(trifluoromethyl)benzamide

cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-(trifluoromethyl)benzamide

[1091] Amides derived from cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrazolo[3,4-d]pyrimidin-4-amine The commercially available acid chlorides (0.23 mmol) in dichloromethane (100 μL) were added to cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrazolo[3,4-d]pyrimidin-4-amine (0.050 g, 0.115 mmol) in pyridine (800 μL). The reaction mixtures were stirred over night. The reaction mixtures were quenched with 1 N sodium hydroxide solution. Solvent was removed on a Supelco-manifold under vacuum and nitrogen purge. The remaining solids were submitted for preparative HPLC (Hypersil C18, 100×21 mm column, 5 μm, 15-100% Acetonitrile gradient over 8 min, total run time—10 min, buffer—50 mM Ammonium Acetate, 25 m/min). Dichloromethane and 1 N sodium hydroxide solution were added to the solids. The layers were partitioned using an Empore extraction cartridge to give corresponding products. HPLC Perkin Elmer Pecosphere C18, 3 μM, 33×4.6, 3.5 ml/min 100-100% 50 mM ammonium acetate to acetonitrile in 4.5 minutes, C₃₆H₄₄N₆O₃ (581.2), 95%. LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min)

[1092]

Compound Name	R	Ex	Qty. (mg)	MH+	Rt (mins)
cis-N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4- d]pyrimidin-3-yl}-2- methoxyphenyl)-2- (trifluoromethyl)benzamide		232	44 (63%)	609.1	2.957
cis-N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4- d]pyrimidin-3-yl}-2- methoxyphenyl)-2- (trifluoromethoxy)benzamide		233	10 (14%)	625.5	3.464
cis-N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo]3,4- d]pyrimidin-3-yl}-2- methoxyphenyl)-3- (trifluoromethoxy)benzamide		234	40 (56%)	625.1	3.405
cis-N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4- d]pyrimidin-3-yl}-2- methoxyphenyl)-2-fluoro-4- (trifluoromethyl)benzamide		235	47 (65%)	627.5	3.405
cis-N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4- d]pyrimidin-3-yl}-2- methoxyphenyl)-3- (trifluoromethyl)benzamide		236	41 (59%)	609.3	3.223
cis-N1-(4-{4-amino-1-[4-(4- methylpiperazino)cyclohexyl]- 1H-pyrazolo[3,4- d]pyrimidin-3-yl}-2- methoxyphenyl)-3-fluoro-4- (trifluoromethyl)benzamide		237	48 (67%)	627.4	3.613

Example 238

Cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyanilino)-2-phenyl-1-ethanol

Intermediates

cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

trans-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 239

Cis-3-{4-[(2-furylmethyl)amino]-3-methoxyphenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 240

Cis-5-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyanilino)methyl]-2-furylmethanol acetate

Example 241

Trans-3-{4-[(2-furylmethyl)amino]-3-methoxyphenyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine dimaleate

Trans-3-{4-[(2-furylmethyl)amino]-3-methoxyphenyl-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine dimaleate

Example 242

Trans-3-(3-methoxy-4-[(5-methyl-2-furyl)methyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine dimaleate

Example 243

Cis-2-[2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)methyl]phenoxyacetic acid diacetate

Example 244

Cis-3-{4-[(2-furylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 245

Cis-3-(4-[(5-methyl-2-furyl)methyl]aminophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 246

Cis-3-{4-[(3-furylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 247

Cis-3-{4-[(benzo[b]furan-2-ylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 248

Trans-3-{4-[(2-furylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 249

3-(4-[(5-methyl-2-furyl)methyl]aminophenyl)-1-[1-(1-methylpiperid-4-yl)piperid-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate

Example 250

Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(1-phenylethyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

a) N-(4-bromophenyl)-N-(1-phenylethyl)amine

b) N-(1-phenylethyl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine

c) Cis-1-[4-(4-methylpiperazino)cyclohexyl]-3-{4-[(1-phenylethyl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 251 and Example 252

Cis-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Trans-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

a) N-(4-bromophenyl)-N-(2,3-dihydrobenzo[b]furan-3-yl)amine

b) N-(2,3-dihydrobenzo[b]furan-3-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine

c) Cis-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Trans-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine diacetate

Example 253

Cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1-phenyl-1-ethanone diacetate

Example 254

Cis-2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-1-phenyl-1-ethanol diacetate

Example 255

Cis-N-[(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl]-N′-benzylurea acetate

Example 256

Cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]benzamide acetate

Example 257

Cis-N1-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]-1-benzenesulfonamide acetate

Example 258

Cis-N-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]-N′-benzylurea acetate

Example 259

Cis-N1-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]benzamide diacetate

a) cis-3-{4-[3-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

b) Cis-N1-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]benzamide diacetate

Example 260

Cis-N1-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]-1-benzenesulfonamide acetate

Example 261

Cis-N-[3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]-N′-benzylurea acetate

Example 262 and Example 263

Cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-phenyl-1,3-oxazolan-2-one acetate

Trans-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-phenyl-1,3-oxazolan-2-one

a) 2-(4-bromoanilino)-1-phenyl-1-ethanone

b) 2-(4-bromoanilino)-1-phenyl-1-ethanol

c) 3-(4-bromophenyl)-5-phenyl-1,3-oxazolan-2-one

d) 5-phenyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazolan-2-one

e) Cis-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-phenyl-1,3-oxazolan-2-one acetate

f) Trans-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-phenyl-1,3-oxazolan-2-one

Example 264

Trans-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-benzyl-1,3-oxazolan-2-one diacetate

a) 1-(4-bromoanilino)-3-phenyl-2-propanol

b) 5-benzyl-3-(4-bromophenyl)-1,3-oxazolan-2-one

c) 5-benzyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-oxazolan-2-one

d) Trans-3-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5-benzyl-1,3-oxazolan-2-one diacetate

Example 265

Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-2-methyl-2-phenylpropanamide diacetate

Example 266 and Example 267

Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-4-oxo-2-phenylbutanoic acid acetate

Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-4-oxo-3-phenylbutanoic acid acetate

a) 1-(4-bromophenyl)-3-phenyl-2,5-pyrrolidinedione

b) 3-phenyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,5-pyrrolidinedione

c) Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-4-oxo-2-phenylbutanoic acid acetate and

Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-4-oxo-2-phenylbutanoic acid acetate

Cis-4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}anilino)-4-oxo-3-phenylbutanoic acid acetate

Example 268

Cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl cyanide

a) 2-phenyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]acetonitrile

b) Cis-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)(phenyl)methyl cyanide

Example 269

Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl)-1,3-benzoxazol-2-amine diacetate

a) N-(1,3-benzoxazol-2-yl)-N-(4-bromophenyl)amine

b) N-(1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine

c) Cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-1,3-benzoxazol-2-amine diacetate

Intermediate A

2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]benzaldehyde

Example 270

2-[4-(4-Amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenoxy]acetamide

Example 271

Methyl 5-[4-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenoxy]-2-furoate

Example 272

5-[4-(4-Amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenoxy]-2-furoic acid

Example 273

1-Cyclopentyl-3-[4-(3-thienyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 274

Cis-3-{3-[(benzo[b]furan-2-ylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine monoacetate salt

Example 275

Cis-3-{3-[di(2-furylmethyl)amino]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 276

Cis-N-[2-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]trifluoromethanesulfonamide diacetate salt

Example 277

Cis-2-(3-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzaldehyde

Example 278

Cis-3-{3-[2-(1H-2-imidazolyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 279

Cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-2-anilinoacetamide

Example 280

(2S)-3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}propane-1,2-diol

Example 281

(2R)-3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}propane-1,2-diol

Example 282

Tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate

a) Tert-butyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate

Tert-butyl 4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-hydroxy-1-piperidinecarboxylate

Example 283

4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-4-piperidinol

Example 284

4-(3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanylmethyl)-1-methyl-4-piperidinol

Example 285

N-methyl-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

a) Chloroacetamide: N-methyl-2-chloroacetamide

Example 286

N,N-dimethyl-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

b) Chloroacetamide: N,N-dimethyl-2-chloroacetamide

Example 287

N-isopropyl-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

c) Chloroacetamide: N-isopropyl-2-chloroacetamide

Example 288

N-(3-hydroxypropyl)-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

d) Chloroacetamide: N-(3-hydroxypropyl)-2-chloroacetamide

Example 289

Ethyl 2-[(2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetyl)amino]acetate (4037150)

e) Chloroacetamide: ethyl 2-[(2-chloroacetyl)amino]acetate

Example 290

N-benzyl-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

f) Chloroacetamide: N-benzyl-2-chloroacetamide

Example 291

N,N-methoxymethyl-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

g) Chloroacetamide: N,N-methoxymethyl-2-chloroacetamide

Example 292

2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-1-morpholino-1-ethanone

h) Chloroacetamide: 2-chloro-1-morpholino-1-ethanone

Example 293

N-(3-methyl-5-isoxazolyl)-2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}acetamide

i) Chloroacetamide: N-(3-methyl-5-isoxazolyl)-2-chloroacetamide

Example 294

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(1H-4-imidazolyl)-1-ethanone

Example 295

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(1H-4-imidazolyl)-1-propanone

Example 296

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(2-hydroxyethyl)amino]-1-ethanone

a) Amine: 2-amino-1-ethanol

Example 297

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(2-methoxyethyl)amino]-1-ethanone

b) Amine: 2-methoxy-1-ethanamine

Example 298

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]1-azetanyl}-2-[(3-hydroxypropyl)amino]-1-ethanone

c) Amine: 3-amino-1-propanol

Example 299

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(2,3-dihydroxypropyl)amino]-1-ethanone

d) Amine: 3-amino-1,2-propanediol

Example 300

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(tetrahydro-2-furanylmethyl)amino]-1-ethanone

e) Amine: tetrahydro-2-furanylmethanamine

Example 301

f) Amine: 2-piperidino-1-ethanamine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(2-piperidinoethyl)amino]-1-ethanone

Example 302

g) Amine: N,N,N-trimethyl-1,2-ethanediamine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[[2-(dimethylamino)ethyl](methyl)amino]-1-ethanone

Example 303

h) Amine: N,N-dimethyl-1,2-ethanediamine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-{[2-(dimethylamino)ethyl]amino}-1-ethanone acetate

Example 304

i) Amine: N-methyl-N-(1-methyl-4-piperidyl)amine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[methyl(1-methyl-4-piperidyl)amino]-1-ethanone

Example 305

j) Amine: 2-morpholino-1-ethanamine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(2-morpholinoethyl)amino]-1-ethanone

Example 306

k) Amine: 3-morpholino-1-propanamine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[(3-morpholinopropyl)amino]-1-ethanone

Example 307

l) Amine: 3-(1H-1-imidazolyl)-1-propanamine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-{[3-(1H-1-imidazolyl)propyl]amino}-1-ethanone

Example 308

m) Amine: 1-(3-aminopropyl)-2-pyrrolidinone

1-{3-[(2-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-oxoethyl)amino]propyl}-2-pyrrolidinone

Example 309

n) Amine: 4-piperidinol

1-{3-[4-amino-3-(4-phenoxyphenyl)-H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(4-hydroxypiperidino)-1-ethanone

Example 310

o) Amine: 4-piperidylmethanol

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[4-(hydroxymethyl)piperidino]-1-ethanone

Example 311

p) Amine: 1-(2-methoxyethyl)piperazine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[4-(2-methoxyethyl)piperidino]-1-ethanone

Example 312

q) Amine: Morpholine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-morpholino-1-ethanone

Example 313

r) Amine: 1-methylpiperazine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(4-methylpiperazino)-1-ethanone

Example 314

s) Amine: 4-piperidinopiperidine

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-[4-(piperid-1-yl)piperidino]-1-ethanone

Example 315

t) Amine: 1H-imidazole

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(1H-1-imidazolyl)-1-ethanone

Example 316

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(methylamino)-1-ethanone acetate

Example 317

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-2-(dimethylamino)-1-ethanone acetate

Example 318

1-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-(diethylamino)-1-propanone

Example 319

1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(methylamino)-1-ethanone acetate

Example 320

1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(dimethylamino)-1-ethanone

Example 321

1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-3-(diethylamino)-1-propanone acetate

Example 322

a) Amine: morpholine

1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-morpholino-1-ethanone acetate

Example 323

b) Amine: 1-methylpiperazine

1-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidino}-2-(4-methylpiperazino)-1-ethanone acetate

Example 324 and Example 325

Cis and trans 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetic acid

a) Cis and trans tert-butyl 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetate

Cis tert-butyl 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetate

Trans tert-butyl 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetate

Cis 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetic acid

Trans 2-{4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-hydroxycyclohexyl}acetic acid

Example 326

Trans 1-{3-[(benzyloxy)methyl]cyclobutyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

Example 327

[3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-(hydroxymethyl)cyclobutyl]methanol

a) Diethyl 3-[(methylsulfonyl)oxy]-1,1-cyclobutanedicarboxylate

b) Diethyl 3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1,1-cyclobutanedicarboxylate

c) [3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-(hydroxymethyl)cyclobutyl]methanol

Examples 328-334

General procedure for the synthesis of aryl alkyl cis-3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine analogs

[1455]

329		505.3	12.05
330		538.4	9.27
331		453.2	11.16
332		519.1	12.95
333		535.3	10.57
334		555.3	14.08

Example 335

N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-fluorophenyl)-5-chloro-2-thiophenesulfonamide maleate salt

Example 336