PYRAZOLOPYRIMIDINE COMPOUND

Abstract

Disclosed is a novel compound having Syk and/or Abl inhibitory activities, which is useful for prevention/treatment of allergic diseases, autoimmune diseases, arthritides and cancers. Specifically disclosed is a pyrazolopyrimidine compound represented by the formula [I] or [III] below, a tautomer thereof, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a solvent of any of them.

Description

TECHNICAL FIELD

The present invention relates to a novel pyrazolopyrimidine compound having Syk (spleen tyrosine kinase) and/or Abl (abelson tyrosine kinase) inhibitory activity, and to a medicine comprising the compound as an active ingredient.

BACKGROUND ART

Immediate allergic reactions playing a central role in allergic diseases typified by allergic rhinitis, atopic dermatitis, bronchial asthma and the like are known to be initiated by interaction between an antigen such as pollen, mite or house dust and immunoglobulin E (IgE) specific to the antigen.

Mast cells have a high-affinity IgE receptor (FcεRI) on their cell surface, abundantly contains, in the cytoplasm, granules containing histamine and other biologically active substances, and play an important role as cells as initiators of allergic disease.

Entrance of an antigen crosslinks the antigen-specific IgE on FcεRI and activates mast cells. Then, degranulation of intracellular granules occurs and lipid mediators such as prostaglandins and leukotrienes which are arachidonic acid metabolites, chemical mediators such as serotonin, and various cytokines are produced. Thus, an allergic reaction is induced.

FcεRI is composed of α, β and γ subunits (three subunits). The α-chain is the molecule exposed on the cell surface and constitutes the IgE-binding site. The β-chain is a four-transmembrane molecule and has, in the intracellular domain, an ITAM (immunoreceptor tyrosine-based activation motif) to transduce cell activation signals. The γ-chain is a single transmembrane molecule, forms a dimer, has an ITAM in the intracellular domain as does the β-chain, and is a molecule essential for expression on the cell membrane and activation signal transduction.

Syk is a non-receptor protein tyrosine kinase important for signal transduction via T-cell receptors and is a molecule classified, together with ZAP-70, into a subfamily referred to as Syk family.

Although Syk is not constitutively associated with FcεRI, Syk strongly binds to FcεRI through its SH2 domain when the intracellular tyrosine residues of the γ-chain are phosphorylated by Lyn which is a kinase of the Src family, due to aggregation of FcεRI. It has been found that because of this binding, Syk is autophosphorylated and phosphorylated by Lyn, multimerized, and therefore activated.

The activation of Syk causes degranulation, release of lipid mediators, and production of cytokines, active oxygen and the like. As a result of a study on Syk knockout mice, it has been observed that degranulation is inhibited and production of cytokines is inhibited in mast cells in an IgE-dependent manner, and production of active oxygen is inhibited in neutrophils (NON-PATENT DOCUMENT 1). The above-described inhibitory effects by Syk-specific inhibitors (NON-PATENT DOCUMENT 2) and Syk antisense oligodeoxynucleotides (NON-PATENT DOCUMENT 3) have been reported for an ovalbumin-sensitized asthma model.

On the other hand, it has been reported that differentiation of bone marrow cells obtained from Syk knockout mice into osteoclasts is inhibited (NON-PATENT DOCUMENT 4). Syk has also been suggested to be involved in signal transduction of immunoglobulin G receptors (FcγR). It has been reported that expression of Syk in the synovial tissue is significantly higher in human rheumatoid arthritis patients than in healthy subjects and osteoarthritis patients (NON-PATENT DOCUMENT 5). Further, Syk inhibitors have paw edema and joint destruction inhibitory effects in a mouse anti-collagen antibody arthritis model (NON-PATENT DOCUMENT 6).

Accordingly, Syk inhibitors are assumed to be effective for treating or preventing diseases such as allergic disease, autoimmune disease and arthritis. Conventionally, some imidazopyrimidine compounds (PATENT DOCUMENT 1), naphthyridine compounds (PATENT DOCUMENT 2, NON-PATENT DOCUMENT 7), heterocyclic carboxamide compounds (PATENT DOCUMENT 3, NON-PATENT DOCUMENT 8), purine compounds (PATENT DOCUMENT 4), imidazopyrimidine compounds (PATENT DOCUMENT 5), triazole compounds (PATENT DOCUMENT 6), aminopyridine compounds (PATENT DOCUMENT 7) and aminopyridine compounds (PATENT DOCUMENT 8) have been reported as Syk inhibitors; however, it is not known that the compound of the present invention has a Syk inhibitory effect.

Abl is known to be activated by a growth factor such as PDGF (platelet-derived growth factor) or EGF (epidermal growth factor). Abl is activated by PDGF through activation of Src (sarcoma virus tyrosine kinase), and Src directly phosphorylates Y412 and Y245 necessary for activating Abl. It has become known that the PLCγ1 (phospholipase C gammal) pathway, activated by PDGF stimulation as in Src, is also stimulated through activation of Abl. Activation of Abl is shown to be important for PDGF-induced cell growth, PDGF-derived cell membrane ruffling and PLCγ1-induced cell migration.

These growth factor receptors upstream of Abl, namely Src and PLCγ1, are often outside the physiological activity control in solid cancers such as breast cancer, and their activation is related with an increase in the tumor invasion ability and a decrease in the efficacy of tumor treatment. Since Abl is involved in cytoskeletal reorganization and cell invasion, Abl may increase growth and invasion ability of cancer cells in solid cancer having constitutively activated growth factor receptors and activated Src (NON-PATENT DOCUMENT 9).

Recently, it has been shown that si-RNA of c-abl (cellular oncogene-abl) and ST-1571 having an Abl inhibitory effect can inhibit invasion of breast cancer cells, and cell transformation by Src needs Abl (NON-PATENT DOCUMENT 10). It has also been shown that Src/Abl inhibitory substances inhibited an increase in the cancer cell volume in tumor-bearing model mice (NON-PATENT DOCUMENT 11). Thus, Abl is assumed to be an important target for development of drugs for cancer involving activation of Src such as breast cancer.

PATENT DOCUMENT 1: WO 01/83485

PATENT DOCUMENT 2: WO 03/57695

PATENT DOCUMENT 3: WO 00/75113

PATENT DOCUMENT 4: WO 01/09134

PATENT DOCUMENT 5: JP-A-2004-203748

PATENT DOCUMENT 6: WO 06/047256

PATENT DOCUMENT 7: WO 06/093247

PATENT DOCUMENT 8: WO 03/063794

NON-PATENT DOCUMENT 1: Oncogene 1996 Dec. 19; 13 (12), p. 2595-2605.

NON-PATENT DOCUMENT 2: J. Pharmacol. Exp. Ther. 2003 September; 306 (3), p. 1174-1181.

NON-PATENT DOCUMENT 3: J. Immunol. 2002 Jul. 15; 169 (2), p. 1028-1036.

NON-PATENT DOCUMENT 4: Proc. Natl. Acad. Sci. USA. 2004 Apr. 20; 101 (16), p. 6158-6163.

NON-PATENT DOCUMENT 5: J. Pharmacol. Exp. Ther. 2006 May; 317 (2), p. 571-578.

NON-PATENT DOCUMENT 6: J. Pharmacol. Exp. Ther. 2006 Aug. 31; [Epub ahead of print]

NON-PATENT DOCUMENT 7: Bioorganic & Medicinal Chemistry Letters (2003), 13 (8), p. 1415

NON-PATENT DOCUMENT 8: Bioorganic & Medicinal Chemistry 13 (2005), p. 4936

NON-PATENT DOCUMENT 9: Oncogene 2007 Nov. 15; 26 (52), p. 7313-7323.

NON-PATENT DOCUMENT 10: Cancer Res. 2006 Jun. 1; 66 (11), p. 5648-5655.

NON-PATENT DOCUMENT 11: Cancer Res. 2007 Feb. 15; 67 (4), p. 1580-1588.

WO 05/085249 and WO 05/028480 disclose substituted pyrazolopyrimidine compounds, but do not describe or suggest Syk and Abl inhibitory effects of these compounds. WO 07/070872 describes a group of compounds having Syk inhibitory activity; however, the document describes only one substituted pyrazolopyrimidine compound among them and does not describe that the compound has Syk inhibitory activity.

DISCLOSURE OF THE INVENTION

Problem to be Solved by the Invention

An object of the present invention is to provide a compound having Syk and/or Abl inhibitory effects and useful as a pharmaceutical agent.

Means for Solving the Problems

As a result of extensive studies to find a compound having Syk and/or Abl inhibitory effects, the present inventors have found that the object can be achieved by a pyrazolopyrimidine compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof. This finding has led to the completion of the present invention.

The present invention will be described below.

(1) A pyrazolopyrimidine compound represented by the formula [I]:

• wherein
• R¹ represents a C_1-6 alkyl group, a C_3-8 cycloalkyl group, a C_2-9 heterocyclyl group, a C_1-9 heteroaryl group or a phenyl group (wherein the C_1-6 alkyl group, the C_3-8 cycloalkyl group, the C_2-9 heterocyclyl group, the C_1-9 heteroaryl group and the phenyl group are unsubstituted or substituted with 1 to 4 substituents selected from the following Substituent Group A¹);
• Substituent Group A¹ represents a group consisting of a halogen atom, a hydroxy group, an amino group, a cyano group, a carboxy group, a C_1-6 alkyl group, a trifluoromethyl group, a C_3-8 cycloalkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), a sulfanyl group, a C_1-6 alkylsulfanyl group, a C_1-6 alkoxycarbonyl group, a C_3-8 cycloalkoxy group, a (C_1-6 alkyl)amino group, a di(C_1-6alkyl)amino group, a C_1-6 alkoxycarbonylamino group, a hydroxyaminocarbonyl group, a ureido group, a carbamoyl group, a C_2-9 heterocyclyl group (wherein the C_2-9 heterocyclyl group is unsubstituted or substituted with a C_1-8 alkyl group or an oxo group), a C_1-9 heteroaryl group, a (C_1-6 acyl)amino group and an oxo group;
• R² represents a C_1-6 alkyl group;
• n represents an integer of 0, 1 or 2;
• Y represents —O— or —NR³— (wherein R³ represents a hydrogen atom or a C_1-6 alkyl group);
• Ar represents a C_1-9 heteroaryl group (wherein the C_1-9 heteroaryl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a sulfanyl group, a hydroxy group, a C_1-6 alkoxy group, a morpholinyl group, a trifluoromethyl group and an oxo group) or a phenyl group (wherein the phenyl group is unsubstituted or substituted with the same or different 1 to 3 R^as); and
• R^a represents a hydroxy group, a cyano group, a carboxy group, a sulfanyl group, a C_1-6 alkoxycarbonyl group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a carboxy group or —CONR⁴R⁵ (wherein R⁴ and R⁵ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), a C_3-8 cycloalkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a carboxy group or —CONR⁶R⁷ (wherein R⁶ and R⁷ are the same or different and each represent a hydrogen atom, a C_1-6 alkyl group, a C_3-8 cycloalkyl group, a C_1-6 alkoxy group, a C_2-9 heterocyclyl group or a C_1-9 heteroaryl group)), a C_1-9 heteroaryl group, a C_3-8 cycloalkoxy group, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a phenoxy group, a phenyl group (wherein the phenyl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a carboxy group, a C_1-6 alkoxycarbonyl group and —SO₂NR¹⁴R¹⁵ (wherein R¹⁴ and R¹⁵ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), —NR⁸R⁹, —CONR⁸R⁹, —NR⁸SO₂R⁹ or —SO₂NR⁸R⁹ (wherein R⁸ and R⁹ are the same or different and each represent a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkoxycarbonyl group, a toluyl group, a naphthyl group, a C_1-9 heteroaryl group or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a carboxy group and a C_1-6 alkoxy group),
• or when R⁸ and R⁹ are substituents on the adjacent nitrogen atom, they, together with the adjacent nitrogen atom, represent the formula [II]:

• wherein Q represents —O—, —NR¹⁰—, —CHR¹¹—, —CO— (wherein the —CO— is unprotected or protected with ethylene ketal), —S—, —SO— or —SO₂—;

L¹ and L² are the same or different and each represent a linear C_1-3 alkylene group (wherein the linear C_1-3 alkylene group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a C_1-6 alkyl group and an oxo group);

• R¹⁰ represents a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkyl group, a C_1-6 alkylsulfonyl group, a trifluoromethylsulfonyl group, a phenylcarbonyl group or a phenylsulfonyl group (wherein the phenylcarbonyl group and the phenylsulfonyl group are unsubstituted or substituted with 1 to 2 substituents selected from Substituent Group B);
• Substituent Group B represents a group consisting of a halogen atom, a C_1-6 alkyl group and a C_1-6 alkoxy group; and
• R¹¹ represents a hydrogen atom, a hydroxy group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a C_1-6 alkoxy group or a hydroxy group), a C_1-6 alkoxy group, a carboxy group, an amino group, a (C_1-6 alkyl)amino group, a di(C_1-6 alkyl)amino group, a (C_1-6 acyl)amino group, a phenylcarbonyl group, —CONR¹²R¹³ (wherein R¹² and R¹³ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group, or they, together with the adjacent nitrogen atom, represent a C_2-9 heterocyclyl group) or a (C_1-6 alkylsulfonyl)amino group);
• a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(2) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to (1) above, wherein R¹ is a C_1-6 alkyl group, a C_3-8 cycloalkyl group or a C_2-9 heterocyclyl group (wherein the C_1-8 alkyl group, the C_3-8 cycloalkyl group and the C_2-9 heterocyclyl group are unsubstituted or substituted with 1 to 4 substituents selected from the following Substituent Group A);

• Substituent Group A represents a group consisting of a halogen atom, a hydroxy group, an amino group, a cyano group, a carboxy group, a C_1-6 alkyl group, a C_3-8 cycloalkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), a C_1-6 alkylsulfanyl group, a C_1-6 alkoxycarbonyl group, a C_3-8 cycloalkoxy group, a (C_1-6 alkyl)amino group, a di(C_1-6 alkyl)amino group, a C_1-6 alkoxycarbonylamino group, a hydroxyaminocarbonyl group, a ureido group, a carbamoyl group, a C_2-9 heterocyclyl group (wherein the C_2-9 heterocyclyl group is unsubstituted or substituted with a C_1-6 alkyl group or an oxo group) and a C_1-9 heteroaryl group;
• R² is a linear C_1-6 alkyl group;
• Ar is a C_1-9 heteroaryl group (wherein the C_1-9 heteroaryl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a sulfanyl group, a hydroxy group, a C_1-6 alkoxy group, a morpholinyl group and a trifluoromethyl group) or a phenyl group (wherein the phenyl group is unsubstituted or substituted with the same or different 1 to 3 R^as); and
• R^a is a hydroxy group, a cyano group, a carboxy group, a sulfanyl group, a C_1-6 alkoxycarbonyl group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a carboxy group or —CONR⁴R⁵ (wherein R⁴ and R⁵ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), a C_3-8 cycloalkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a carboxy group or —CONR⁶R⁷ (wherein R⁶ and R⁷ are the same or different and each represent a hydrogen atom, a C_1-6 alkyl group, a C_3-8 cycloalkyl group, a C_1-6 alkoxy group, a C_2-9 heterocyclyl group or a C_1-9 heteroaryl group)), a C_1-9 heteroaryl group, a C_3-8 cycloalkoxy group, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a phenoxy group, —NR⁸R⁹, —CONR⁸R⁹, —NR⁸SO₂R⁹ or —SO₂NR⁸R⁹ (wherein R⁸ and R⁹ are the same or different and each represent a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkoxycarbonyl group, a toluyl group, a C_1-9 heteroaryl group or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a carboxy group and a C_1-6 alkoxy group), or when R⁸ and R⁹ are substituents on the adjacent nitrogen atom, they, together with the adjacent nitrogen atom, represent the formula [II]:

• wherein Q represents —O—, —NR¹⁰—, —CHR¹¹—, —CO— (wherein the —CO— is unprotected or protected with ethylene ketal), —S—, —SO— or —SO₂—;

L¹ and L² are the same or different and each represent a linear C_1-3 alkylene group (wherein the linear C_1-3 alkylene group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a C_1-6 alkyl group and an oxo group);

• R¹⁰ represents a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkyl group, a C_1-6 alkylsulfonyl group, a trifluoromethylsulfonyl group, a phenylcarbonyl group or a phenylsulfonyl group (wherein the phenylcarbonyl group and the phenylsulfonyl group are unsubstituted or substituted with 1 to 2 substituents selected from Substituent Group B);
• Substituent Group B represents a group consisting of a halogen atom, a C_1-6 alkyl group and a C_1-6 alkoxy group; and
• R¹¹ represents a hydrogen atom, a hydroxy group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a C_1-6 alkoxy group or a hydroxy group), a C_1-6 alkoxy group, a carboxy group, an amino group, a (C_1-6 alkyl)amino group, a di(C_1-6 alkyl)amino group, a (C_1-6 acyl)amino group, a phenylcarbonyl group, —CONR¹²R¹³ (wherein R¹² and R¹³ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group, or they, together with the adjacent nitrogen atom, represent a C_2-9 heterocyclyl group) or a (C_1-6 alkylsulfonyl)amino group).

(3) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to (2) above, wherein Ar is a phenyl group (wherein the phenyl group is unsubstituted or substituted with the same or different 1 to 3 R^as).

(4) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to (2) above, wherein Ar is a phenyl group (wherein the phenyl group is substituted at the 3-, 4- or 5-position with the same or different 1 to 3 R^as).

(5) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (2) to (4) above, wherein Y is NH.

(6) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (2) to (5) above, wherein R¹ is a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with an amino group, a (C_1-6 alkyl)amino group or a di(C_1-6 alkyl)amino group).

(7) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (2) to (5) above, wherein R¹ is a C_3-8 cycloalkyl group (wherein the C_3-8 cycloalkyl group is unsubstituted or substituted with an amino group).

(8) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to (1) above, wherein R¹ is a C_1-9 heteroaryl group or a phenyl group (wherein the C_1-9 heteroaryl group and the phenyl group are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a C_1-6 alkyl group, a trifluoromethyl group, a C_1-6 alkoxy group, a sulfanyl group, a carbamoyl group, a (C_1-6 acyl)amino group and an oxo group); and Y is NH.

(9) A pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, represented by the formula [III]:

• wherein
• R¹′ represents a C_1-6 alkyl group or a C_3-8 cycloalkyl group (wherein the C_1-6 alkyl group and the C_3-8 cycloalkyl group are unsubstituted or substituted with 1 to 4 substituents selected from the following Substituent Group A′),
• Substituent Group A′ represents a group consisting of a halogen atom, a hydroxy group, an amino group, a cyano group, a carboxy group, a C_1-6 alkyl group, a trifluoromethyl group, a C_3-8 cycloalkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), a sulfanyl group, a C_1-6 alkylsulfanyl group, a C_1-6 alkoxycarbonyl group, a C_3-8 cycloalkoxy group, a (C_1-6 alkyl)amino group, a di(C_1-6 alkyl)amino group, a C_1-6 alkoxycarbonylamino group, a hydroxyaminocarbonyl group, a ureido group, a carbamoyl group, a C_2-9 heterocyclyl group (wherein the C_2-9 heterocyclyl group is unsubstituted or substituted with a C_1-6 alkyl group or an oxo group), a C_1-9 heteroaryl group, a (C_1-6 acyl)amino group and an oxo group;
• Y′ represents —O— or —NR¹⁶— (wherein R¹⁶ represents a hydrogen atom or a C_1-6 alkyl group);
• Ar′ represents a C_1-9 heteroaryl group (wherein the C_1-9 heteroaryl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a sulfanyl group, a hydroxy group, a C_1-6 alkoxy group, a morpholinyl group, a trifluoromethyl group and an oxo group) or a phenyl group (wherein the phenyl group is unsubstituted or substituted with the same or different 1 to 3 R^bs); and
• R^b represents a hydroxy group, a cyano group, a carboxy group, a sulfanyl group, a C_1-6 alkoxycarbonyl group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a carboxy group or —CONR¹⁷R¹⁸ (wherein R¹⁷ and R¹⁸ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), a C_3-8 cycloalkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a carboxy group or —CONR¹⁹R²⁰ (wherein R¹⁹ and R²⁰ are the same or different and each represent a hydrogen atom, a C_1-6 alkyl group, a C_3-8 cycloalkyl group, a C_1-6 alkoxy group, a C_2-9 heterocyclyl group or a C_1-9 heteroaryl group)), a C_1-9 heteroaryl group, a C_3-8 cycloalkoxy group, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a phenoxy group, a phenyl group (wherein the phenyl group is unsubstituted or substituted with a substituent selected from a carboxy group, a C_1-6 alkoxycarbonyl group and —SO₂NR²¹R²² (wherein R²¹ and R²² are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), —NR²³R²⁴, —CONR²³R²⁴, —NR²³SO₂R²⁴ or —SO₂NR²³R²⁴ (wherein R²³ and R²⁴ are the same or different and each represent a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkoxycarbonyl group, a toluyl group, a naphthyl group, a C_1-9 heteroaryl group or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a carboxy group and a C_1-6 alkoxy group), or when R²³ and R²⁴ are substituents on the adjacent nitrogen atom, they, together with the adjacent nitrogen atom, represent the formula [IV]:

wherein Q′ represents —O—, —NR²⁵—, —CHR²⁶—, —CO— (wherein the —CO— is unprotected or protected with ethylene ketal), —S—, —SO— or —SO₂—;

L¹′ and L²′ are the same or different and each represent a linear C_1-3 alkylene group (wherein the linear C_1-3 alkylene group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a C_1-6 alkyl group and an oxo group);

• R²⁵ represents a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkyl group, a C_1-6 alkylsulfonyl group, a trifluoromethylsulfonyl group, a phenylcarbonyl group or a phenylsulfonyl group (wherein the phenylcarbonyl group and the phenylsulfonyl group are unsubstituted or substituted with 1 to 2 substituents selected from Substituent Group B′);
• Substituent Group B′ represents a group consisting of a halogen atom, a C_1-6 alkyl group and a C_1-6 alkoxy group; and
• R²⁶ represents a hydrogen atom, a hydroxy group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a C_1-6 alkoxy group or a hydroxy group), a C_1-6 alkoxy group, a carboxy group, an amino group, a (C_1-6 alkyl)amino group, a di(C_1-6 alkyl)amino group, a (C_1-6 acyl)amino group, a phenylcarbonyl group, —CONR²⁷R²⁸ (wherein R²⁷ and R²⁸ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group, or they, together with the adjacent nitrogen atom, represent a C_2-9 heterocyclyl group) or a (C_1-6 alkylsulfonyl)amino group).

(10) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to (9) above, wherein R¹′ is a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with an amino group, a cyano group, a (C_1-6 alkyl)amino group or a di(C_1-6 alkyl)amino group).

(11) The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to (9) above, wherein R¹′ is a C_3-8 cycloalkyl group (wherein the C_3-8 cycloalkyl group is unsubstituted or substituted with a hydroxy group or an amino group).

(12) A Syk inhibitor comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (1) to (11) above.

(13) A therapeutic agent or prophylactic agent for allergic disease, autoimmune disease or arthritis, comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (1) to (11) above.

(14) An Abl inhibitor comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (1) to (11) above.

(15) A therapeutic agent or prophylactic agent for cancer, comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of (1) to (11) above.

Advantageous Effects of Invention

The compound of the present invention has Syk and/or Abl inhibitory effects and is assumed to be effective for treating or preventing diseases such as allergic disease, autoimmune disease and arthritis, or cancer.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention will be described in more detail below.

First, the phrases used herein will be described.

In the present invention, “n” refers to normal, “i” refers to iso, “s” refers to secondary, “t” refers to tertiary, “c” refers to cyclo, “o” refers to ortho, “m” refers to meta, and “p” refers to para.

The “C_1-6 alkyl group” refers to a linear alkyl group having 1 to 8 carbon atoms or a branched alkyl group having 3 to 8 carbon atoms. Examples of the group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-heptyl group, an n-octyl group, an i-propyl group, an i-butyl group, a t-butyl group, an s-butyl group, an i-pentyl group, a neopentyl group and a t-pentyl group.

The “C_3-8 cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms. Examples of the group include a c-propyl group, a c-butyl group, a c-pentyl group, a c-hexyl group, a c-heptyl group and a c-octyl group.

The “C_1-6 alkoxy group” refers to a linear alkoxy group having 1 to 6 carbon atoms or a branched alkoxy group having 3 to 6 carbon atoms. Examples of the group include a methoxy group, an ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy group, an i-butoxy group, an s-butoxy group, a t-butoxy group, an n-pentyloxy group, an i-pentyloxy group and an n-hexyloxy group.

The “C_1-6 alkylsulfanyl group” refers to an alkylsulfanyl group having 1 to 6 carbon atoms and may include a linear alkylsulfanyl group, a branched alkylsulfanyl group and a C_3-6 cycloalkylsulfanyl group. Examples of the group include a methylsulfanyl group, an ethylsulfanyl group, an n-propylsulfanyl group, an i-propylsulfanyl group, an n-butylsulfanyl group, an i-butylsulfanyl group, a t-butylsulfanyl group, an n-pentylsulfanyl group, an i-pentylsulfanyl group, a c-pentylsulfanyl group, an n-hexylsulfanyl group and a c-hexylsulfanyl group.

The “C_1-6 alkoxycarbonyl group” refers to a C_1-6 alkoxycarbonyl group having 1 to 6 carbon atoms and may include a linear alkoxycarbonyl group, a branched alkoxycarbonyl group and a C_3-6 cycloalkoxycarbonyl group. Examples of the group include a methoxycarbonyl group, an ethoxycarbonyl group, an i-propoxycarbonyl group and a c-pentyloxycarbonyl group.

The “C_3-8 cycloalkoxy group” refers to a cyclic alkoxy group having 3 to 8 carbon atoms. Examples of the group include a c-propoxy group, a c-butoxy group, a c-pentyloxy group, a c-hexyloxy group, a c-heptyloxy group and a c-octyloxy group.

The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The “(C_1-6 alkyl)amino group” refers to an amino group having one C_1-6 alkyl group as a substituent and may include a linear alkylamino group, a branched alkylamino group and a (C_3-6 cycloalkyl)amino group. Examples of the group include a methylamino group, an ethylamino group, an n-propylamino group, an i-propylamino group, a c-propylamino group, an n-butylamino group, an i-butylamino group, an s-butylamino group, a t-butylamino group and a c-butylamino group.

The “di(C_1-6 alkyl)amino group” refers to an amino group having the same or different two C_1-6 alkyl groups as substituents and may include a linear dialkylamino group, a branched dialkylamino group and a di(C_3-6 cycloalkyl)amino group. Examples of the group include a dimethylamino group, a diethylamino group, a di-n-propylamino group, a di-i-propylamino group, a di-i-butylamino group, a di-s-butylamino group, a di-t-butylamino group, a (methyl, ethyl)amino group and a (methyl, n-propyl)amino group.

The “C_1-6 alkoxycarbonylamino group” refers to an amino group having a C_1-6 alkoxycarbonyl group and may include a linear alkoxycarbonylamino group, a branched alkoxycarbonylamino group and a C_3-6 cycloalkoxycarbonylamino group. Examples of the group include a methoxycarbonylamino group, an ethoxycarbonylamino group, an n-propoxycarbonylamino group, an i-propoxycarbonylamino group and a c-propoxycarbonylamino group.

The “C_2-9 heterocyclyl group” refers to a saturated monocyclic or fused bicyclic aliphatic heterocyclic group composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 2 to 9 carbon atoms. Examples of the group include a tetrahydrofuranyl group, a pyrrolidinyl group, an imidazolinyl group, a pyrazolinyl group, a piperidyl group, a piperazinyl group and a morpholinyl group.

The “C_1-9 heteroaryl group” refers to a monocyclic aromatic heterocyclic group, a polycyclic aromatic heterocyclic group or a polycyclic heterocyclic group containing an aromatic ring in the structure, which is composed of one or more atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and 1 to 9 carbon atoms. Examples of the monocyclic aromatic heterocyclic group include an imidazolyl group, a pyrazolyl group, a thiazolyl group, an oxazolyl group, a furyl group, a thienyl group, a pyrrolyl group, a pyridyl group, a pyrimidinyl group and a pyrazinyl group. Examples of the polycyclic aromatic heterocyclic group include an indolyl group, a quinolyl group, a benzoimidazolyl group, a benzothiazolyl group, an indazolyl group and a benzotriazolyl group. Examples of the polycyclic heterocyclic group containing an aromatic ring in the structure include a benzoxazinyl group and a pyridooxazinyl group.

The “linear C_1-6 alkyl group” refers to a linear alkyl group having 1 to 6 carbon atoms. Examples of the group include a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group and an n-hexyl group.

The “C_1-6 alkyl group” refers to a linear alkyl group having 1 to 6 carbon atoms or a branched alkyl group having 3 to 6 carbon atoms. Examples of the group include a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, an n-pentyl group and an n-hexyl group.

The “C_1-6 acyl group” refers to an acyl group having 1 to 6 carbon atoms and may include a linear acyl group, a branched acyl group and a cyclic acyl group. Examples of the group include a formyl group, an acetyl group, a propionyl group, an n-butyryl group, an i-butyryl group, a c-butyryl group, an n-valeryl group, an i-valeryl group and a pivaloyl group.

Examples of the “C_1-3 alkylene group” include a methylene group, an ethylene group and a trimethylene group.

The “C_1-6 alkylsulfonyl group” refers to an alkylsulfonyl group having 1 to 6 carbon atoms and may include a linear alkylsulfonyl group, a branched alkylsulfonyl group and a C_3-6 cycloalkylsulfonyl group. Examples of the group include a methylsulfonyl group, an ethylsulfonyl group, a propyl-l-sulfonyl group, a 2-methylpropyl-1-sulfonyl group, a butyl-l-sulfonyl group, a hexyl-1-sulfonyl group and a 3-methylbutyl-1-sulfonyl group.

The “(C_1-6 acyl)amino group” refers to an amino group having a C_1-6 acyl group as a substituent. Examples of the group include a formylamino group, an acetylamino group, a propionylamino group, an i-butyrylamino group, a c-butyrylamino group, an n-valerylamino group, an i-valerylamino group and a pivaloylamino group.

The “(C_1-6 alkylsulfonyl)amino group” refers to an amino group having a C_1-6 alkylsulfonyl group as a substituent. Examples of the group include a methylsulfonylamino group, an ethylsulfonylamino group, a propyl-1-sulfonylamino group, a 2-methylpropyl-1-sulfonylamino group, a butyl-1-sulfonylamino group, a hexyl-1-sulfonylamino group and a 3-methylbutyl-1-sulfonylamino group.

Preferred embodiments of the compound of the present invention are as follows.

Specifically, preferable R¹ is a C_1-6 alkyl group, a C_3-8 cycloalkyl group, a C_1-9 heteroaryl group or a phenyl group (wherein the C_1-6 alkyl group, the C_3-8 cycloalkyl group, the C_1-9 heteroaryl group and the phenyl group are unsubstituted or substituted with 1 to 3 substituents selected from Substituent Group A¹).

A preferable substituent among Substituent Group A¹ is a halogen atom, a hydroxy group, an amino group, a hydroxyaminocarbonyl group, a (C_1-6 alkyl)amino group, a di(C_1-6 alkyl)amino group or a carbamoyl group.

Preferable R² is a methyl group, an ethyl group or an isopropyl group.

Preferable n is 0, 1 or 2.

Preferable Y is —NR³—.

Preferable R³ is a hydrogen atom.

Preferable Ar is a C_1-9 heteroaryl group (wherein the C_1-9 heteroaryl group is unsubstituted or substituted with a sulfanyl group or a hydroxy group) or a phenyl group (wherein the phenyl group is substituted with the same or different 1 to 3 R^as).

More preferable Ar is a phenyl group (wherein the phenyl group is substituted at the 3-, 4- or 5-position with the same or different 1 to 3 R^as).

Preferable R^a is a C_1-6 alkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a carboxy group or —CONR⁶R⁷ (wherein R⁶ and R⁷ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), a halogen atom, —NR⁸R⁹, —CONR⁹R⁹ or —SO₂NR⁹R⁹ (wherein R⁸ and R⁹ are the same or different and each represent a hydrogen atom, an acyl group, a C_1-9 heteroaryl group or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a hydroxy group), or they, together with the adjacent nitrogen atom, represent the formula [II]:

• wherein Q represents —O—, —NR¹⁰—, —CHR¹¹—, —CO— (wherein the —CO— is unprotected or protected with ethylene ketal), —S—, —SO— or —SO₂—,
• L¹ and L² are the same or different and are each a linear C_1-3 alkylene group (wherein the linear C_1-3 alkylene group is unsubstituted or substituted with a C_1-6 alkyl group or an oxo group),

R¹⁰ is a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkyl group, a C_1-6 alkylsulfonyl group or a phenylcarbonyl group, and

• R¹¹ represents a hydroxy group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is substituted with a C_1-6 alkoxy group or a hydroxy group), a C_1-6 alkoxy group, a carboxy group or —CONR¹²R¹³ (wherein R¹² and R¹³ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group, or they, together with the adjacent nitrogen atom, represent a C_2-9 heterocyclyl group)).

Preferable R¹′ is a C_1-6 alkyl group or a C_3-8 cycloalkyl group (wherein the C_1-6 alkyl group and the C_3-8 cycloalkyl group are unsubstituted or substituted with 1 to 3 substituents selected from Substituent Group A′).

A preferable substituent among Substituent Group A′ is a hydroxy group, an amino group, a cyano group, a (C_1-6 alkyl)amino group or a di(_C1-6 alkyl)amino group.

Preferable Y′ is —NR¹⁶—.

Preferable R¹⁶ is a hydrogen atom.

Preferable Ar′ is a C_1-9 heteroaryl group (wherein the C_1-9 heteroaryl group is unsubstituted or substituted with a sulfanyl group or a hydroxy group) or a phenyl group (wherein the phenyl group is substituted with the same or different 1 to 3 R^bs).

More preferable Ar is a phenyl group (wherein the phenyl group is substituted at the 3-, 4- or 5-position with the same or different 1 to 3 R^bs).

Preferable R^b is a C_1-6 alkyl group, a C_1-6 alkoxy group (wherein the C_1-6 alkoxy group is unsubstituted or substituted with a carboxy group or —CONR¹⁷R¹⁸ (wherein R⁶ and R⁷ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group)), a halogen atom, —NR²³R²⁴, —CONR²³R²⁴ or —SO₂NR²³R²⁴ (wherein R²³ and R²⁴ are the same or different and each represent a hydrogen atom, an acyl group, a C_1-9 heteroaryl group or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with a hydroxy group),

• or R²³ and R²⁴, together with the adjacent nitrogen atom, represent the formula [IV]:

• wherein Q′ represents —O—, —NR²⁵—, —CHR²⁶—, —CO— (wherein the —CO— is unprotected or protected with ethylene ketal), —S—, —SO— or —SO₂—,
• L¹′ and L²′ are the same or different and are each a linear C_1-3 alkylene group (wherein the linear C_1-3 alkylene group is unsubstituted or substituted with a

C_1-6 alkyl group or an oxo group),

• R²⁵ is a hydrogen atom, a C_1-6 acyl group, a C_1-6 alkyl group, a C_1-6 alkylsulfonyl group or a phenylcarbonyl group, and
• R²⁶ represents a hydroxy group, a C_1-6 alkyl group (wherein the C_1-6 alkyl group is substituted with a C_1-6 alkoxy group or a hydroxy group), a C_1-6 alkoxy group, a carboxy group or —CONR²⁷R²⁸ (wherein R²⁷ and R²⁸ are the same or different and each represent a hydrogen atom or a C_1-6 alkyl group, or they, together with the adjacent nitrogen atom, represent a C_2-9 heterocyclyl group)).

Tautomers, stereoisomers such as geometric isomers, optical isomers, and prodrugs of the compound of the present invention may exist, and the present invention also encompasses them.

The present invention also encompasses various hydrates, solvates and crystalline polymorphs of the inventive compound and a salt thereof.

The prodrug is a derivative of the compound of the present invention having a chemically or metabolically decomposable group and is a compound converted to a pharmacologically active compound forming the present invention by solvolysis or in vivo under physiological conditions. Methods for selecting and preparing a suitable prodrug derivative are described in DESIGN OF PRODRUGS (Elsevier, Amsterdam 1985), for example. Examples of the prodrug of the compound of the present invention having a hydroxy group include an acyloxy derivative prepared by reacting the compound with a suitable acyl halide or a suitable acid anhydride. Examples of the acyloxy particularly preferable as a prodrug include —OCOC₂H₅, —OCO(t-Bu), —OCOC₁₅H₃₁, —OCO(m-CO₂Na-Ph), —OCOCH₂CH₂CO₂Na, —OCOCH(NH₂)CH₃ and —OCOCH₂N(CH₃)₂. Examples of the prodrug of the compound forming the present invention which has an amino group include an amide derivative prepared by reacting the compound having an amino group with a suitable acid halide or a suitable mixed acid anhydride. Examples of the amide particularly preferable as a prodrug include —NHCOCH(NH₂)CH₃. Examples of the prodrug of the compound forming the present invention which has a carboxyl group include a carboxylic acid ester synthesized by reaction with an aliphatic alcohol; and a carboxylic acid ester obtained by reaction with a free alcoholic hydroxyl group of 1,2- or 1,3-diglyceride. Examples of the carboxylic acid ester particularly preferable as a prodrug include a methyl ester and an ethyl ester.

The pharmaceutically acceptable salt is a salt with an alkali metal, an alkali earth metal, ammonium, an alkylammonium or the like, or a salt with an inorganic acid or organic acid. Examples of the salt include sodium salts, potassium salts, calcium salts, ammonium salts, aluminum salts, triethylammonium salts, acetates, propionates, butyrates, formates, trifluoroacetates, maleates, tartrates, citrates, stearates, succinates, ethylsuccinates, lactobionates, gluconates, glucoheptonates, benzoates, methanesulfonates, ethanesulfonates, 2-hydroxyethanesulfonates, benzenesulfonates, p-toluenesulfonates, lauryl sulfates, malates, aspartates, glutamates, adipates, salts with cysteine, salts with N-acetylcysteine, hydrochlorides, hydrobromides, phosphates, sulfates, hydroiodides, nicotinates, oxalates, picrates, thiocyanates, undecanoates, salts with acrylic acid polymers, and salts with carboxyvinyl polymers.

The compound of the present invention can be synthesized by the method shown below, for example.

(1) A compound represented by the following formula (a):

• wherein R² is a C_1-6 alkyl group and A represents a cyano group, a carboxy group, a C_1-6 alkoxycarbonyl group or a carbamoyl group, is reacted with a compound represented by the formula R′NHNH₂, wherein R′ represents a hydrogen atom or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with an Ar group), in a solvent or without a solvent to obtain a compound represented by the following formula (b):

• wherein A, R² and R′ are as defined above.

(2) The compound represented by the formula (b), wherein A, R² and R′ are as defined above, is appropriately subjected to hydrolysis of A and is then reacted with urea in a solvent or without a solvent to obtain a compound represented by the following formula (c):

• wherein R² and R′ are as defined above.

(3) The compound represented by the formula (c) is halogenated in a solvent or without a solvent in the presence or absence of a base.

Thus, a compound represented by the above formula (d) is obtained, wherein R² and R′ are as defined above and Xs are the same or different and each represent a halogen atom.

(4) The compound represented by the formula (d) is reacted with R¹—YH in a solvent or without a solvent in the presence or absence of a base, an acid or chlorotrimethylsilane, or an additive.

Thus, a compound represented by the above formula (e) is obtained, wherein R¹, R², R′, X and Y are as defined above.

(5) The compound represented by the formula (e) is oxidized with an oxidizing agent in a solvent or without a solvent to obtain a compound represented by the following formula (f):

• wherein n represents an integer of 1 or 2 and R¹, R², R′, X and Y are as defined above.

(6) The compound represented by the formula (e) or (f) is aminated with Ar-NH₂ in a solvent or without a solvent in the presence or absence of a base, an acid or chlorotrimethylsilane, or an additive to obtain the compound of the present invention which is represented by the following formula (g):

• wherein n represents an integer of 0, 1 or 2 and R¹, R², R′, X, Y and Ar are as defined above.

The compound of the present invention can also be synthesized by the method shown below, for example.

(7) Pyrimidine-2,4,6(1H,3H,5H)-trione is halogenated in DMF in the presence or absence of a base to obtain a compound represented by the following formula (h):

• wherein X is as defined above.

(8) The compound represented by the formula (h) is reacted with a compound represented by the formula R′NHNH₂, wherein R′ represents a hydrogen atom or a C_1-6 alkyl group (wherein the C_1-6 alkyl group is unsubstituted or substituted with an Ar group), in a solvent or without a solvent, or the compound is reacted with hydrazine, and then a protecting group is introduced as necessary, to obtain a compound represented by the following formula (i):

• wherein X and R′ are as defined above.

(9) The compound represented by the formula (i) is reacted with R¹′—Y′H in a solvent or without a solvent in the presence or absence of a base, an acid or chlorotrimethylsilane, or an additive to obtain a compound represented by the formula (j):

• wherein R¹′, R′, Y′ and X are as defined above.

(10) The compound represented by the formula (j) is aminated with Ar′—NH₂ in a solvent or without a solvent in the presence or absence of a base, an acid or chlorotrimethylsilane, or an additive to obtain the compound of the present invention which is represented by the following formula (k):

• wherein R¹′, R′, Y′ and Ar′ are as defined above.

The protecting group on R¹, Ar, R¹′ or Ar′, and R′ can be appropriately deprotected in each step.

The order of reaction steps such as substituent introduction can be changed as necessary when it is inappropriate to carry out the steps in the synthesis method shown above.

Examples of the base, when used in the above reaction, include alkali metal salts such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, sodium hydride, sodium amide, t-butylpotassium, lithium hydroxide, lithium hydride, t-butoxypotassium and t-butoxysodium; amines such as triethylamine, diisopropylamine, dimethylaniline, diethylaniline, pyrrolidine and piperidine; sodium acetate and potassium acetate.

Examples of the acid used include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and polyphosphoric acid; and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, trifluoroacetic acid, formic acid and acetic acid.

Examples of the additive include Pd₂(dba)₃, Pd(PPh₃)₄, BINAP, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, CuI, CuCl and copper powder.

Examples of the oxidizing agent used include organic peracids such as m-chloroperbenzoic acid, magnesium monoperphthalate hexahydrate, peracetic acid and performic acid; inorganic and organic peroxides such as hydrogen peroxide, urea-hydrogen peroxide adduct/phthalic anhydride, t-butyl hydroperoxide and cumene hydroperoxide; sodium periodate, Oxone(R), N-bromosuccinimide, N-chlorosuccinimide, chloramine-T, t-butyl hypochlorite, iodobenzene diacetate and bromine-1,4-diazabicyclo[2,2,2]octane addition complex.

Examples of the protecting group include alkoxymethyl groups such as methoxymethyl and 2-methoxyethoxymethyl; aryloxymethyl groups such as benzyloxymethyl and p-methoxybenzyloxymethyl; acyl groups such as formyl, acetyl and trifluoroacetyl; arylcarbonyl groups such as benzoyl, benzoylformyl and benzoylpropionyl; alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl and t-butoxycarbonyl; alkylaminocarbonyl groups such as methylcarbamoyl, ethylcarbamoyl and n-propylcarbamoyl; trialkylsilyl groups such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, dimethylisopropylsilyl, di-t-butylmethylsilyl and t-butyldimethylsilyl; trialkylarylsilyl groups such as diphenylmethylsilyl, t-butyldiphenylsilyl and t-butyldimethoxyphenylsilyl; alkylsulfonyl groups such as methanesulfonyl and ethanesulfonyl; arylsulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, p-chlorobenzenesulfonyl and p-methoxybenzenesulfonyl; acetal groups such as methyleneacetal and isopropylideneketal; a t-butyl group, an allyl group, a benzyl group, a tetrahydropyranyl group and a tetrahydrofuranyl group.

The reaction solvent is not particularly limited insofar as it is stable under the reaction conditions and is inert and does not inhibit the reaction. Examples of the solvent include alcohols such as methanol, ethanol, i-propanol, n-butanol, t-butanol and ethylene glycol; ethers such as diethyl ether, 1,4-dioxane, tetrahydrofuran and 1,2-dimethoxyethane; hydrocarbons such as toluene, benzene and xylene; esters such as ethyl acetate and ethyl formate; ketones such as acetone, methyl ethyl ketone and methyl i-butyl ketone; halogenated carbon solvents such as chloroform and dichloromethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone; acetonitrile, dimethyl sulfoxide, water, and mixed solvents thereof.

The reaction can be carried out under normal pressure, under pressure or under microwave irradiation, for example, at a suitable temperature selected within a range from −78° C. to the boiling point of the solvent used for the reaction.

When the compound of the present invention is used as a medicine, a common excipient, bulking agent, pH adjuster or solubilizer is added to the compound of the present invention, and the mixture is formulated into tablets, granules, pills, capsules, a powder, a solution, a suspension or an injection by a common technique, for example. Thus, the compound of the present invention can be administered as an oral formulation, or an injection or an application.

The compound of the present invention can be administered to an adult patient at 1 to 2000 mg per day in one to several doses. The dose can be appropriately increased and reduced according to the type of the disease the age, body weight and symptom of the patient, for example.

Examples

Next, the present invention will be described in more detail by way of Examples and Test Example. The compounds of the present invention are not limited to the compounds described in the following Examples.

The instruments used for measurement of the respective analysis data are as follows.

• [¹H-NMR]
• 600 MHz: JEOL JNM-ECA600
• 500 MHz: JEOL JNM-ECP500
• 300 MHz: JEOL JNM-ECX300
• [MS]
• Waters, Shimadzu

The abbreviations in the Examples are shown below.

• DEAD: Diethyl azodicarboxylate
• THF: Tetrahydrofuran
• BINAP: 2,2′-Bis(diphenylphosphino)-1,1-binaphthyl
• dba: Bis(dibenzylideneacetone)
• TFA: Trifluoroacetic acid
• Boc: t-Butoxycarbonyl
• mCPBA: m-Chloroperbenzoic acid
• DMSO: Dimethyl sulfoxide
• ESI: Electrospray ionization

Reference Example 1

[Bis(methylsulfanyl)methylene]malononitrile (10 g) was added to a solution of hydrazine monohydrate (4.5 g) in ethanol (10 ml) under ice-cooling. After stirred at room temperature for 30 minutes and refluxed at 80° C. for one hour, water was added dropwise to the reaction solution under ice-cooling. The precipitated solid was separated by filtration and dried to obtain 5-amino-3-(methylsulfanyl)-1H-pyrazole-4-carbonitrile (colorless solid) (7.6 g, 85%).

• MS(ESI):155(M+H)⁺, 153(M−H)⁻
• ¹H NMR(600 MHz,DMSO-D6) δppm 2.44(s,3H),6.47(bs,2H), 12.00(bs,1H)

Reference Example 2

5-Amino-3-(methylsulfanyl)-1H-pyrazole-4-carbonitrile (7.6 g) was added to concentrated sulfuric acid (25 ml) under ice-cooling, and the mixture was stirred at room temperature for five hours. The reaction solution was added dropwise to ice water (50 ml), and subsequently aqueous ammonia was added to precipitate crystals (pH 8 to 9). The precipitated solid was separated by filtration and dried to obtain 5-amino-3-(methylsulfanyl)-1H-pyrazole-4-carboxamide (colorless solid) (7.6 g, 90%).

MS(ESI):173(M+H)⁺, 171(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 2.38(s,3H),6.00(bs,2H), 6.71(br,2H),11.84(br,1H)

Example 1

N⁴-Cyclopropyl-3-(methylsulfonyl)-N⁶-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 6)

(1) 5-Amino-3-(methylsulfanyl)-1H-pyrazole-4-carboxamide obtained in Reference Example 2 (3.0 g) and urea (5.3 g) were stirred at 170° C. for two hours. After cooling to room temperature, a 1 M sodium hydroxide solution was added and the solid was dissolved. Then, acetic acid was added to precipitate a solid. The precipitated solid was separated by filtration and dried to obtain 3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (colorless solid) (3.4 g, quant.).

MS(ESI):197(M−H)⁻

(2) N,N-dimethylaniline (2.0 ml) was added dropwise to a suspension of 3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione obtained in Example 1-(1) (2.0 g) and phosphorus oxychloride (10 ml) under ice-cooling, and then the mixture was stirred at 100° C. for two hours. The reaction solution was dissolved in chloroform and the insoluble matter was separated by filtration. The objective product was extracted with chloroform. Cyclopropylamine (0.88 ml) was added to a solution of 4,6-dichloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained by concentrating the extract in ethanol (3.0 ml) under ice-cooling. The mixture was stirred at room temperature for 30 minutes and then 1 M hydrochloric acid was added, followed by extraction with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was concentrated under reduced pressure. The residue was washed with a diethyl ether-methanol mixed solution and separated by filtration to obtain 6-chloro-N-cyclopropyl-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (pale yellow solid) (0.29 g, 11% (2 steps)).

MS(ESI):256(M+H)⁺,254(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 0.62-0.70(m,2H),0.73-0.81(m,2H),2.52(s,3H),2.86-3.03(m,1H),7.01(s,1H), 13.63(s,1H)

(3) A 35% hydrogen peroxide solution (3.0 ml) was added to a solution of 6-chloro-N-cyclopropyl-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 1-(2) (0.29 g) in acetic acid (3.0 ml) at room temperature. The mixture was stirred at 80° C. for 2.5 hours and then cooled to room temperature. Water was added and the precipitate was separated by filtration and dried to obtain 6-chloro-N-cyclopropyl-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (colorless solid) (0.23 g, 72%).

MS(ESI):288(M+H)⁺,286(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 0.51-0.62(m,2H),0.81-0.91(m,2H),2.96-3.05(m,1H),3.44(s,3H), 8.02(d,J=3.7 Hz,1H),14.81(bs,1H)

(4) A mixture of 6-chloro-N-cyclopropyl-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 1-(3) (0.23 g), 4-morpholinoaniline (0.19 g) and n-butanol (3.0 ml) was reacted at 130° C. for two hours. The reaction solution was concentrated, and then the resulting crude product was purified by silica gel chromatography, followed by recrystallization from chloroform-methanol to obtain Compound 6 (colorless solid) (313 mg, 90%).

MS(ESI):430(M+H)⁺,428(M−H)⁻

¹H NMR(300 MHz,DMSO-D6)δppm 0.62-0.67(m,2H),0.92-0.98(m,2H),3.03(bs,1H),3.44(s,3H),3.54-3.60(m,4H),4.07-4.13(m,4H),7.78-7.80(m,2H),7.90(s,1H),8.03-8.05(m,2H),9.99(s,1H),14.28(bs,1H)

Example 2

N⁴-Cyclopropyl-3-(methylsulfonyl)-N⁶-(4-morpholin-4- ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine phosphate (Compound 9)

(1) The compound 6 obtained in Example 1-(4) (29 g) was dissolved in a 10% phosphoric acid solution (570 ml). Water (570 ml) was added and the mixture was stirred at room temperature for 13 hours. The precipitate was separated by filtration and dried to obtain Compound 9 (yellow solid) (32 g, 91%).

¹H NMR(600 MHz,DMSO-D6)δppm 0.51-0.56(m,2H),0.82-0.88(m,2H),2.94-2.98(m,1H),2.98-3.02(m,4H),3.26-3.33(m,3H),3.37(s,3H),3.69-3.73(m,4H),6.82-6.90(m,2H), 7.53-7.58(m,1H),7.66-7.74(m,2H),9.14(s,1H),13.85(s,1H)

Example 3

N⁴-Cyclopropyl-N⁶-[4-(4-methylpiperazin-1-yl)phenyl]-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 131)

(1) Diethyl azodicarboxylate (40% solution in toluene, 19 g) was added dropwise to a mixture of 6-chloro-N-cyclopropyl-3-(methylsulfonyl)-1H- pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 1-(3) (8.4 g), 2,4-dimethoxybenzyl alcohol (7.4 g) and triphenyiphosphine (12 g) in tetrahydrofuran (0.40 1) under ice-cooling, and the mixture was reacted at room temperature for 15 hours. The reaction solution was concentrated, and then the resulting crude product was purified by silica gel chromatography (hexane/chloroform =1/4) to obtain 6-chloro-N-cyclopropyl-1-(2,4-dimethoxybenzyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (colorless solid) (3.2 g, 25%).

MS(ESI):438(M+H)⁺,436(M−H)⁻

(2) A suspension of 6-chloro-N-cyclopropyl-1-(2,4-dimethoxybenzyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 3-(1) (0.60 g), sodium t-butoxide (0.21 g), BINAP (0.13 g), Pd₂(dba)₃ (63 mg) and 4-(N-methylpiperazinyl)aniline (0.31 g) in dioxane (20 ml) was stirred at 100° C. for 15 hours. The reaction solution was concentrated, and then the resulting crude product was purified by silica gel chromatography (NH silica gel, hexane/ethyl acetate=7/3) to obtain N⁴-cyclopropyl-N⁶-[4-(4-methylpiperazin-1-yl)phenyl]-1-(2,4-dimethoxybenzyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (colorless solid) (369 mg).

(3) Trifluoroacetic acid (1.0 ml) and thioanisole (2.0 ml) were added to a solution of N⁴-cyclopropyl-N⁶-[4-(4-methylpiperazin-1-yl)phenyl]-1-(2,4-dimethoxybenzyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine obtained in Example 3-(2) (0.37 g) in chloroform (4.0 ml) under ice-cooling, and the mixture was stirred at 60° C. for two days. The reaction solution was concentrated, and the resulting crude product was purified by silica gel chromatography (NH silica gel, chloroform/methanol=99/1), followed by recrystallization from chloroform-methanol to obtain Compound 131 (colorless solid) (58 mg, 10%).

MS(ESI):443(M+H)⁺,441(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 0.45-0.59(m,2H),0.85(m,2H), 2.18(s,3H),2.31-2.45(m,4H),2.93-3.00(m,1H),2.99-3.11(m,4H),3.37(s,3H),6.78-6.92(m,2H),7.54(s,1H),7.60-7.81(m,2H),9.11(s,1H),13.85(bs,1H)

Example 4

N⁴-(cis-4-Aminocyclohexyl)-3-(methylsulfonyl)-N^6-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 117)

(1) t-Butyl (cis-4-aminocyclohexyl)carbamate (1.8 g) and diisopropylethylamine (1.5 ml) were added to a solution of 4,6-dichloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 1-(2) (1.0 g) in ethanol (43 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=1/1) to obtain t-butyl (cis-4-{[6-chloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}cyclohexyl)carbamate (colorless powder) (1.6 g, 89%).

MS(ESI):413(M+H)⁺,411(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 1.36(s,9H),1.41-1.54(m,2H), 1.55-1.71(m,4H),1.73-1.85(m,2H)2.56(s,3H),3.40-3.58(m,1H),4.08-4.32(m,1H),6.47(d,J=7.8 Hz,1H), 6.77(d,J=7.8 Hz,1H),13.70(s,1H)

(2) m-Chloroperbenzoic acid (2.5 g) was added to a solution of t-butyl (cis-4-{[6-chloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}cyclohexyl)carbamate obtained in Example 4-(1) (1.6 g) in chloroform (37 ml) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction solution was washed with a 1 M sodium hydroxide solution and brine, dehydrated over anhydrous magnesium sulfate, separated by filtration and concentrated. The resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=3/2) to obtain t-butyl (cis-4-{[6-chloro-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}cyclohexyl)carbamate (colorless powder) (0.78 g, 47%).

MS(ESI):445(M+H)⁺,443(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 1.35(s,9H),1.40-1.51(m,2H),1.58-1.72(m,4H),1.71-1.81(m,2H),3.31-3.41(m,1H),3.46(s,3H),4.10-4.19(m,1H), 6.93(d,J=7.3 Hz,1H),8.13(d,J=7.3 Hz,1H),14.76(s,1H)

(3) 4-Morpholinoaniline (81 mg) was added to a suspension of t-butyl (cis-4-{[6-chloro-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]amino}cyclohexyl)carbamate obtained in Example 4-(2) (0.16 g) in n-butanol (3.0 ml), and the mixture was stirred at 130° C. for four hours. The reaction solution was concentrated, and the resulting crude product was purified by silica gel chromatography (chloroform/methanol=99/1). Thereafter, a 4 M hydrochloric acid/ethyl acetate solution (2.0 ml) was added and the mixture was stirred at 80° C. for 30 minutes. The reaction solution was concentrated, and the resulting crude product was purified by silica gel chromatography (chloroform/methanol=99/1), followed by recrystallization to obtain Compound 117 (pale purple powder) (95 mg, 56%).

MS(ESI):487(M+H)⁺,485(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 1.29-1.45(m,2H),1.54-1.72(m,4H),1.72-1.95(m,2H),2.75-2.85(m,1H),2.91-3.05(m,4H),3.36(s,3H),3.65-3.75(m,4H),4.15-4.30(m,1H),6.76-6.91(m,2H),7.55-7.68(m,3H),8.91(s,1H)

Example 5

N⁴-Cyclopropyl-3-(methylsulfinyl)-N⁶-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 4)

(1) A 35% hydrogen peroxide solution (1.0 ml) was added to a solution of 6-chloro-N-cyclopropyl-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 1-(2) (0.10 g) in acetic acid (1.0 ml) at room temperature, and the mixture was stirred at room temperature for six hours. Then, water was added, and the precipitate was separated by filtration and dried to obtain 6-chloro-N-cyclopropyl-3-(methylsulfinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (pale yellow solid) (0.10 g, 94%).

MS(ESI):272(M+H)⁺,270(M−H)⁻

¹H NMR(300 MHz,DMSO-D6)δppm 0.50-0.65(m,2H),0.80-0.95(m,2H),2.96(s,3H),3.03(m,1H),8.92(d,J=4.1 Hz,1H),14.4 (bs, 1H)

(2) A mixture of 6-chloro-N-cyclopropyl-3-(methylsulfinyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 5-(1) (15 mg), 4-morpholinoaniline (10 mg) and n-butanol (0.5 ml) was reacted under microwave irradiation at 130° C. for two hours. The reaction solution was concentrated, and then the resulting crude product was washed with diethyl ether to obtain Compound 4 (gray solid) (9 mg, 40%).

MS(ESI):414(M+H)⁺,412(M−H)⁻

¹H NMR(500 MHz,DMSO-D6)δppm 0.49-0.58(m,2H),0.82-0.90(m,2H),2.90(s,3H),2.99(bs,1H),3.05-3.15(m,4H),3.72-3.78(m,4H),6.89(d,J=8.0 Hz,2H),7.74(d,J=8.6 Hz,2H), 8.33(s,1H),9.11(s,1H),13.49(s,1H)

Example 6

N⁴-Cyclopropyl-3-(methylsulfanyl)-N⁶-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 13)

(1) A mixture of 6-chloro-N-cyclopropyl-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 1-(2) (30 mg), 4-morpholinoaniline (27 mg) and n-butanol (1.0 ml) was reacted under microwave irradiation at 130° C. for two hours. The reaction solution was concentrated, and then the resulting crude product was washed with diethyl ether to obtain Compound 13 (colorless solid) (23 mg, 49%).

MS(ESI):398(M+H)⁺,396(M−H)⁻

¹H NMR(300 MHz,DMSO-D6)δppm 0.77-0.80(m,2H),0.92-0.95(m,2H),2.56(s,3H),2.96(bs,1H),3.05-3.25(m,4H),3.75-3.85(m,4H),7.10-7.20(m,2H),7.27(bs,1H),7.60-7.80(m,2H), 9.88(bs,1H),12.89(bs,1H)

Example 7

4-Ethoxy-3-(methylsulfanyl)-N-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Compound 20)

(1) 40% sodium hydride (0.34 g) and methyl aziridine-2-carboxylate (0.65 g) were added to a mixed solution of 4,6-dichloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 1-(2) (1.0 g) in THF (10 ml) and ethanol (10 ml), and the mixture was reacted at 70° C. for three hours. Water was added to the reaction solution, followed by extraction with ethyl acetate and washing with brine. The extract was dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was concentrated under reduced pressure. The residue was washed with a methanol-chloroform mixed solution and separated by filtration to obtain 6-chloro-4-ethoxy-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine (green powder) (0.4 g, 38%).

(2) A mixture of 6-chloro-4-ethoxy-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 7-(1) (50 mg), 4-morpholinoaniline (44 mg) and ethylene glycol (1.0 ml) was reacted under microwave irradiation at 130° C. for one hour. Water was added to the reaction solution, followed by extraction with ethyl acetate and washing with brine. The extract was dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was concentrated under reduced pressure. The residue was washed with a methanol-acetonitrile mixed solution and separated by filtration to obtain Compound 20 (colorless powder) (39 mg, 49%).

MS(ESI):387(M+H)⁺,385(M−H)⁻

¹H NMR(500 MHz,DMSO-D6)δppm 1.39(t,J=7.0 Hz,3H), 2.52(s,3H),3.04(t,J=4.9 Hz,4H),3.74(t,J=4.9 Hz,4H),4.51(q, J=7.0 Hz,2H),6.89(d,J=9.2 Hz,2H),7.63(d,J=8.9 Hz,2H),9.29 (s,1H),12.99(s,1H)

Example 8

N⁴-Cyclopropyl-N⁶-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 177)

(1) Cyclopropylamine (0.12 g) was added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine synthesized according to the method of JP-A-48-99194 (0.40 g) in ethanol (4.0 ml) at room temperature. The mixture was stirred at the same temperature overnight. The precipitated solid was separated by filtration and dried to obtain 6-chloro-N-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (yellow solid) (0.43 g, 97%).

MS(ESI):210(M+H)⁺,208(M−H)⁻

¹H NMR(300 MHz,DMSO-D6)δppm 0.55-0.73(m,2H),0.74-1.06(m,2H),2.97(bs,1H),8.18(bs,1H),8.51(bs,1H), 13.37(bs,1H)

(2) A mixture of 6-chloro-N-cyclopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine obtained in Example 8-(1) (50 mg), 4-morpholinoaniline (55 mg) and n-butanol (1.0 ml) was reacted under microwave irradiation at 130° C. for two hours. The reaction solution was concentrated, and then the resulting crude product was crystallized from diethyl ether to obtain Compound 177 (colorless solid) (13 mg, 15%).

MS(ESI):352(M+H)⁺,350(M−H)⁻

¹H NMR(300 MHz,DMSO-D6)δppm 0.58-0.64(m,2H),0.80-0.85(m,2H),2.95(bs,1H),3.02(t,J=2.7 Hz, 4H), 3.73(t,J=2.7 Hz, 4H),6.84(d,J=5.3 Hz, 2H),7.55-7.75(m,3H),7.90(bs,1H),8.44(bs,1H),12.53(bs,1H)

Example 9

N⁴-(cis-4-Aminocyclohexyl)-N⁶-(4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 216)

(1) t-Butyl (cis-4-aminocyclohexyl)carbamate (680 mg) and diisopropylethylamine (552 μL) were added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine synthesized according to the method of JP-A-48-99194 (300 mg) in ethanol (16 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction solution was concentrated, and the resulting crude product was purified by silica gel chromatography (hexane/ethyl acetate=7/3 to 3/7) to obtain t-butyl [cis-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)cyclohexyl]carbamate (yellow powder) (354 mg, 61%).

MS(ESI):389(M+Na)⁺,365(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 1.36(s,9H),1.48-1.77(m,8H),3.35-3.45(m,1H),3.93-4.04(m,1H),6.74(bs,1H), 8.16(bs,1H),8.29(d,J=6.9 Hz,1H),13.46(bs,1H)

(2) 4-Morpholinoaniline (221 mg) was added to a solution of t-butyl [cis-4-(6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)cyclohexyl]carbamate obtained in Example 9-(1) (350 mg) in n-butanol (5.0 mL), and the mixture was stirred at 130° C. for four hours. The reaction solution was concentrated and dissolved in methanol/chloroform (10 mL, methanol/chloroform=1/9). A 4.0 M hydrochloric acid/ethyl acetate solution (4.0 mL) was added and the mixture was stirred at room temperature for one hour. Methanol (25 mL) was added to the reaction solution, and the precipitate was dissolved. Then, NH silica gel was added and the solvent was evaporated. The residue was purified by silica gel chromatography (NH silica gel, methanol/chloroform=0 to 10%), followed by recrystallization (chloroform/hexane) to obtain Compound 216 (gray powder) (308 mg, 79%).

MS(ESI):409(M+H)⁺,407(M−H)⁻

¹H NMR(600 MHz,DMSO-D6)δppm 1.47-1.81(m,8H),2.88-2.99(m,5H),3.64-3.70(m,4H),4.02-4.13(m,1H),6.74-6.82(m,2H),7.47-7.55(m,1H),7.57-7.63(m,2H),7.91(s,1H), 8.62(bs,1H),12.57(bs,1H)

Example 10

4-Ethoxy-3-(methylsulfonyl)-N-(4-morpholin-4-ylphenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Compound 179)

(1) A 35% hydrogen peroxide solution (2.0 ml) was added to a solution of 6-chloro-4-ethoxy-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 7-(1) (0.27 g) in acetic acid (2.0 ml) at room temperature, and the mixture was stirred at the same temperature for two days. Then, water was added, and the precipitate was separated by filtration and dried to obtain 6-chloro-4-ethoxy-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine (colorless solid) (0.15 g, 49%).

MS(ESI):277(M+H)⁺,275(M−H)⁻

¹H NMR(300 MHz,DMSO-D6)δppm 1.42(t,J=7.2 Hz, 3H),2.50(s, 3H),4.62(q,J=7.2 Hz,2H),15.05(s,1H)

(2) A mixture of 6-chloro-4-ethoxy-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 10-(1) (50 mg), 4-morpholinoaniline (39 mg) and n-butanol (1.0 ml) was reacted under microwave irradiation at 130° C. for 45 minutes. A 1 M hydrochloric acid solution was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with brine and then dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography, followed by recrystallization from chloroform-methanol to obtain Compound 179 (colorless solid) (3.0 mg, 4%).

MS(ESI):419(M+H)⁺,417(M−H)⁻

Example 11

cis-4-(4-Aminocyclohexyloxy)-N-(4-morpholinophenyl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Compound 217)

(1) Dihydropyrane (724 μl) and a catalytic amount of p-toluenesulfonic acid monohydrate were added to a solution of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine synthesized according to the method of JP-A-48-99194 (1.00 g) in ethyl acetate (30 ml). The mixture was stirred at room temperature for 35 minutes and then stirred at 50° C. for 25 minutes. Silica gel was added to the reaction mixture, followed by concentration. Then, the residue was purified by silica gel chromatography (hexane/ethyl acetate=8/1) to obtain 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (872 mg, colorless powder) and 4,6-dichloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine (672 mg, yellow oil).

• 4,6-Dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine

¹H NMR(600 MHz,CDC13)δppm 1.63-1.68(m,1H),1.73-1.83(m,2H),1.93-1.98(m,1H),2.12-2.18(m,1H),2.52-2.60(m,1H),3.78-3.84(m,1H),4.10-4.15(m,1H), 6.01(dd,J=10.6,2.8 Hz,1H),8.20(s,1H)

4,6-Dichloro-2-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine

¹¹H NMR(600 MHz,CDC13)δppm 1.70-1.83(m,3H),1.92-2.05(m,2H),2.39-2.45(m,1H),3.78-3.85(m,1H),4.14-4.19(m,1H),5.71(dd,J=8.9,3.0 Hz,1H),8.45(s,1H)

(2) cis-t-Butyl-4-hydroxycyclohexyl carbamate (680 mg) and sodium hydride (151 mg, ˜60% in mineral oil) were added to a solution of 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 11-(1) (870 mg) in dimethoxyethane (16.0 mL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered and silica gel was added to the filtrate, followed by concentration. Then, the residue was purified by silica gel chromatography to obtain cis-t-butyl-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)cyclohexyl carbamate (843 mg, colorless powder).

MS(ESI):474(M+Na)⁺,450(M−H)⁻

¹HNMR(600 MHz,CDC13)δppm 1.45(s,9H),1.58-2.15(m,14H),2.50-2.59(m,1H),3.58-3.67(m,1H),3.77-3.83(m,1H),4.09-4.14(s,1H),4.52-4.59(m,1H),5.52-5.57(m,1H),5.93(dd,J=10.6,2.8 Hz,1H),8.04(s,1H)

(3) A solution of cis-t-butyl-4-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)cyclohexyl carbamate obtained in Example 11-(2) (100 mg) and 4-morpholinoaniline (47 mg) in n-butanol (2.0 mL) was stirred at 130° C. for five hours. The green precipitate was filtered, washed with ethyl acetate and then purified by silica gel chromatography (NH silica gel, methanol/chloroform=1 to 10%), followed by recrystallization (hexane/chloroform) to obtain Compound 217 (15 mg, pale gray powder).

MS(ESI):410(M+H)⁺

¹HNMR(600 MHz,DMSO-D6) δppm1.46-1.74(m,6H),1.98-2.04(m,2H),2.48-2.54(m,1H),2.77-2.83(m,1H),3.02-3.06(m,4H),3.72-3.76(m,4H),6.87-6.91(m,2H),7.62-7.66(m,2H),7.85(s,1H),9.22(s,1H)

Example 12

N-(4-(3-(Methylthio)-6-(4-morpholinophenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)acetamide (Compound 234)

(1) Triethylamine (0.5 mL) was added to a solution of 4,6-dichloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 1-(2) (300 mg) and N-(4-aminophenyl)acetamide (211 mg) in ethanol (3.0 mL), and the mixture was stirred at 70° C. for 15 hours. After cooling to room temperature, the precipitated crystals were collected by filtration, washed with ethanol and dried to obtain N-(4-(6-chloro-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)acetamide (pale yellow powder) (424 mg, 94%).

(2) A mixture of N-(4-(6-chloro-3-(methylthio)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)phenyl)acetamide obtained in Example 12-(1) (100 mg), 4-morpholinoaniline (56 mg) and n-butanol (3.0 mL) was reacted at 130° C. for two hours. The reaction solution was concentrated, and then the resulting crude product was purified by silica gel chromatography (NH silica gel, methanol/chloroform=0 to 10%), followed by recrystallization from hexane-chloroform-methanol to obtain Compound 234 (colorless solid) (11 mg, 7.8%).

¹HNMR (600 MHz,DMSO-D6) δppm 2.05(s,3H),2.58(s,3H),3.01-3.07(m,4H),3.72-3.77(m,4H),6.80-7.78(m,8H),8.10(s,1H), 9.02(s,1H),9.92(s,1H),13.05(brs,1H)

Example 13

3-(3-(Methylsulfonyl)-6-(4-morpholinophenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzonitrile hydrochloride (Compound 194)

(1) N,N-diethylaniline (1.5 ml) was added dropwise to a suspension of 3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione obtained in Example 1-(1) (0.78 g) and phosphorus oxychloride (7.8 mL) under ice-cooling, and then the mixture was stirred at 110° C. for 4.5 hours. The reaction solution was concentrated and then dissolved in chloroform, and the insoluble matter was separated by filtration. The objective product was extracted with chloroform. Triethylamine (1.4 mL) and 3-aminobenzonitrile (0.44 g) were added to a solution of 4,6-dichloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained by concentrating the extract in ethanol (11 mL) at room temperature. The mixture was stirred with heating under reflux for 13 hours. After cooling to room temperature, the precipitated solid was washed with ethanol and separated by filtration to obtain a crude product of 3-(6-chloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzonitrile (pale yellow solid) (0.26 g, 21% (2 steps)).

(2) A 35% hydrogen peroxide solution (2.0 mL) was added to a solution of the crude 3-(6-chloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amino)benzonitrile obtained in Example 13-(1) (0.16 g) in acetic acid (2.0 mL) at room temperature, and the mixture was stirred at 80° C. for 10.5 hours. After cooling to room temperature, water was added and the precipitate was separated by filtration and dried to obtain 3-(6-chloro-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzonitrile (colorless solid) (0.11 g, 61%).

MS(ESI):349(M+H)⁺,347(M−H)⁻

¹HNMR(300 MHz,DMSO-D6) δppm 3.58(s,3H),7.50-7.72(m,2H),7.90(bs,1H),8.31(s,1H),10.16(s,1H),15.18(bs, 1H)

(3) A mixture of 3-(6-chloro-3-(methylsulfonyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino)benzonitrile obtained in Example 13-(2) (0.10 g), 4-morpholinoaniline (0.053 g), trimethylsilyl chloride (0.040 g) and n-butanol (1.5 mL) was reacted under microwave irradiation at 130° C. for two hours. The reaction solution was concentrated, and then the resulting crude product was washed with methanol and then separated by filtration and dried to obtain Compound 194 (pale blue solid) (0.076 g, 54%).

MS(ESI):491(M+H)⁺,489(M−H)⁻

¹HNMR(300 MHz,DMSO-D6) δppm 3.10-3.40(m,4H),3.54(s,3H), 3.75-3.95(m,4H),7.05-7.95(m,6H),8.51(s,1H),9.71(bs,1H), 9.99(s,1H),14.28(s,1H)

Example 14

3-(Methylthio)-N6-(4-morpholinophenyl)-N4-(thiazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-4,6-diamine (Compound 235)

(1) Dihydropyrane (268 mg) and a catalytic amount of p-toluenesulfonic acid monohydrate were added to a solution of 4,6-dichloro-3-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimidine obtained in Example 1-(2) (500 mg) in ethyl acetate (30 mL), and the mixture was stirred at room temperature for three hours. The reaction mixture was concentrated, and then the residue was purified by silica gel chromatography (hexane/ethyl acetate=9/1 to 8/2) to obtain a mixture of 4,6-dichloro-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine and 4,6-dichloro-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine (colorless powder) (623 mg, 92%).

MS(ESI):319(M+H)⁺

(2) A suspension of the mixture of 4,6-dichloro-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine and 4,6-dichloro-3-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-2H-pyrazolo[3,4-d]pyrimidine obtained in Example 14-(1) (70 mg), 2-aminothiazole (26 mg), Pd₂(dba)₃ (10 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6 mg) and potassium phosphate (153 mg) in dioxane (2.0 mL) was stirred at 100° C. for 2.5 hours. After cooling to room temperature, water was added, followed by extraction with chloroform. The extract was dried over anhydrous magnesium sulfate. The drying agent was separated by filtration, and then the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1 to 1/1) to obtain a pale brown amorphous compound (46 mg). A solution of the resulting compound (31 mg) and 4-morpholinoaniline (16 mg) in n-butanol (1.0 mL) was stirred at 130° C. for two hours. Then, one drop of trimethylsilyl chloride was added and the mixture was stirred at 130° C. for 16 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography (NH silica gel, methanol/chloroform=0 to 2%), followed by recrystallization from ethanol-ether to obtain Compound 235 (brown powder) (5 mg, 7.8% (2 steps)).

MS(ESI):441(M+H)⁺,439(M−H)⁻

¹HNMR(600 MHz,CDCl₃) δppm 3.13-3.18(m,4H),3.86-3.91(m,4H),6.90-7.04(m,3H),7.44-7.55(m,3H), 9.25(bs,1H),10.17(bs,1H)

The compounds shown in Tables 1-1 to 1-33 were prepared by the same methods as in the above Examples 1 to 14 using the corresponding raw materials, respectively. An Example No. indicates any of the above Examples based on which a compound shown in Tables 1-1 to 1-33 was prepared. A slash in the Tables indicates that measurement was not carried out.

The abbreviations in the Tables are shown below.

• Free: Not forming a salt (free form)
• MsOH: Methanesulfonic acid
• BsOH: Benzenesulfonic acid

TABLE 1-1
Com-				ESI	ESI	Exam-
pound				MS	MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M - H)-	No.
1		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 1.65-1.70 (m, 2H), 2.05-2.18 (m, 2H), 2.32-2.40 (m, 2H), 2.56 (s, 3H), 3.73 (s, 3H), 3.79 (s, 3H), 4.68- 4.75 (m, 1H), 6.37 (bs, 1H), 6.87 (d, J = 8.6 Hz, 1H), 7.20-7.35 (m, 1H), 7.54 (s, 1H), 8.87 (bs, 1H), 12.84 (bs, 1H)	387	385	6
2		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.72-0.80 (m, 2H), 0.85-0.95 (m, 2H), 2.55 (s, 3H), 3.00 (bs, 1H), 3.74 (s, 3H), 3.76 (s, 3H), 6.91 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 7.41 (s, 1H), 9.48 (bs, 1H), 13.0 (bs, 1H)	373	371	6
3		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 0.53-0.58 (m, 2H), 0.82-0.87 (m, 2H), 2.91 (s, 3H), 3.03 (bs, 1H), 3.72 (s, 3H), 3.75 (s, 3H), 6.87 (d, J = 8.7 Hz, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.54 (d, J = 2.1 Hz, 1H), 8.46 (s, 1H), 9.12 (bs, 1H), 13.48 (bs, 1H)	389	387	5
4		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.49-0.58 (m, 2H), 0.82-0.90 (m, 2H), 2.90 (s, 3H), 2.99 (bs, 1H), 3.05-3.15 (m, 4H), 3.72-3.78 (m, 4H), 6.89 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 8.33 (s, 1H), 9.11 (s, 1H), 13.49 (s, 1H)	414	412	5
5		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.55-0.60 (m, 2H), 0.85-0.89 (m, 2H), 3.04 (bs, 1H), 3.38 (s, 3H), 3.72 (s, 3H), 3.75 (s, 3H), 6.87 (d, J = 8.61 Hz, 1H), 1.42 (d, J = 8.6 Hz, 1H), 7.52 (s, 1H), 7.57 (d, J = 3.4Hz, 1H), 9.05 (s, 1H), 13.82 (s, 1H)	405	403	1
6		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 0.62-0.67 (m, 2H), 0.92-0.98 (m, 2H), 3.03 (bs, 1H), 3.44 (s, 3H), 3.54-3.60 (m, 4H), 4.07-4.13 (m, 4H), 7.78-7.80 (m, 2H), 7.90 (s, 1H), 8.03- 8.05 (m, 2H), 9.99 (s, 1H), 14.28 (bs, 1H)	430	428	1
7		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.57-0.65 (m, 2H), 0.88-0.94 (m, 2H), 2.99-3.04 (m, 1H), 3.34-3.51 (m, 4H), 3.42 (s, 3H), 3.95-4.01 (m, 4H), 7.49-7.55 (m, 2H), 7.73 (bs, 1H), 7.95-7.98 (m, 2H), 9.65 (bs, 1H), 14.08 (bs, 1H)	430	428	2

TABLE 1-2
Com-				ESI	ESI
pound				MS	MS
No.	Compound	Salt	NMR	(M + H)+	(M - H)-
8		H2SO4	1H NMR (600 MHz, DMSO-D6) δ ppm 0.46-0.74 (m, 2H), 0.82-0.97 (m, 2H), 2.99-3.05 (m, 1H), 3.27-3.37 (m, 4H), 3.42 (s, 3H), 3.82-3.94 (m, 4H), 5.21 (s, 3H), 7.17-7.35 (m, 2H), 7.68 (bs, 1H), 7.82-8.00 (m, 2H), 9.48 (bs, 1H), 14.00 (bs, 1H)	—	—	2
9		H3PO4	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.59 (m, 2H), 0.85-0.91, (m, 2H), 2.97-3.01 (m, 1H), 3.01-3.05 m, 4H), 3.29-3.36 (m, 3H), 3.40 (s, 3H), 3.72-3.76 (m, 4H), 6.85-6.93 (m, 2H), 7.56-7.61 (m, 1H), 7.69-7.77 (m, 2H), 9.17 (s, 1H), 13.88 (s, 1H)	—	—	2
10		BsOH	1H NMR (600 MHz, DMSO-D6) δ ppm 0.51-0.69 (m, 2H), 0.82-0.99 (m, 2H), 2.94-3.10 (m, 1H), 3.18-3.37 m, 4H), 3.41 (s, 3H), 3.75-3.98 (m, 4H), 4.41 (m, 2H), 7.10-7.24 (m, 2H), 7.25-7.38 (m, 3H), 7.55-7.62 (m, 2H), 7.63-7.72 (m, 1H), 7.79-7.99 (m, 2H), 13.98 (s, 1H)	—	—	2
11		MsOH	1H NMR (600 MHz, DMSO-D6) δ ppm 0.57-0.68 (m, 2H), 0.87-0.96 (m, 2H), 2.36 (s, 3H), 2.93-3.06 (m, 1H), 3.35-3.50 (m, 4H), 3.42 (s, 3H), 3.69-4.10 (m, 4H), 7.33-7.54 (m, 2H), 7.68-7.76 (bs, 1H), 7.87-8.07 (m, 2H), 9.60 (bs, 1H), 14.05 (bs, 1H)	—	—	2
12		Free	1H NMR, (300 MHz, DMSO-D6) δ ppm 0.56-0.59 (m, 2H), 0.88-0.91 (m, 2H), 1.78 (s, 3H), 2.91 (bs, 1H), 3.03 (s, 3H), 3.38 (s, 3H), 7.18-7.22 (m, 2H), 7.63 (s, 1H), 7.93-7.96 (m,	416	414	1
13		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 0.77-0.80 (m, 2H), 0.92-0.95 (m, 2H), 2.56 (s, 3H), 2.96 (bs, 1H), 3.05-3.25 (m, 4H), 3.75-3.85 (m, 4H), 7.10-7.20 (m, 2H), 7.27 (bs, 1H), 7.60-7.80 (m, 2H), 9.88 (bs, 1H), 12.89 (bs, 1H)	398	396	6
14		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 0.57-0.61 (m, 2H), 0.89-0.92 (m, 2H), 3.03 (bs, 1H), 3.39 (s, 3H), 7.16 (bs, 2H), 7.67-7.76 (m, 2H), 8.05- 8.13 (m, 2H), 9.82 (bs, 1H), 14.12 (bs,1H)	424	422	1

TABLE 1-3
Com-				ESI	ESI	Exam-
pound				MS	MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M - H)-	No.
15		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.57-0.62 (m, 2H), 0.87-0.83 (m, 2H), 2.98-3.10 (m, 7H), 3.39 (s, 3H), 7.15-7.55 (brm, 2H), 7.64 (s, 1H), 7.85-8.15 (m, 2H), 9.40 (bs, 1H), 13.91 (s, 1H)	388	386	1
16		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3H), 3.20-3.40 (m, 4H), 3.39 (s, 3H), 3.75-3.95 (m, 4H), 7.10-7.35 (m, 2H), 7.46 (s, 1H), 7.70- 7.85 (m, 2H), 9.28 (bs, 1H), 13.87 (bs, 1H)	404	402	1
17		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 3.10-3.36 (m, 10H), 3.43 (s, 3H), 3.70-3.94 (m, 4H), 7.05-7.33 (m, 2H), 7.74 (d, J = 8.7 Hz, 2H), 9.19 (bs, 1H), 13.72 (bs, 1H)	418	416	1
18		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 1.39 (t, J = 7.0 Hz, 3H), 2.52 (s, 3H), 3.04 (t, J = 4.9 Hz, 4H), 3.74 (t, J = 4.9 Hz, 4H), 4.51 (q, J = 7.0 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 9.29 (s, 1H), 12.99 (s, 1H)	387	385	7
19		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 2.53 (s, 3H), 3.02 (t, J = 4.9 Hz, 4H), 3.31 (s, 3H), 3.56 (t, J = 5.5 Hz, 2H), 3.70 (t, J = 5.5 Hz, 2H), 3.73 (t, J = 4.9 Hz, 4H), 6.38 (s, 1H), 6.86 (d, J = 9.2 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 8.88 (s, 1H), 12.84 (s, 1H)	416	414	6
20		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 2.54 (s, 3H), 3.02 (t, J = 4.9 Hz, 4H), 3.58-3.64 (m, 4H), 3.73 (t, J = 4.9 Hz, 4H), 4.89 (bs, 1H), 6.40 (s, 1H), 6.86 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 8.87 (s, 1H), 12.84 (s, 1H)	402	400	6
21		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.59-0.61 (m, 2H), 0.90-0.98 (m, 2H), 3.05 (bs, 1H), 3.42 (s, 3H), 7.38-7.70 (m, 3H), 8.09 (s, 1H), 8.30- 8.42 (bs, 1H), 9.30-9.40 (bs, 1H), 12.28 (s, 1H), 13.94 (s, 1H)	385	383	1

TABLE 1-4
Compound				ESI MS	ESI MS	Example
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
22		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.58-0.61(m, 2H), 0.87-0.91 (m, 2H), 3.03-3.05(bs, 1H), 3.41(s, 3H), 6.33(s, 1H), 7.26-7.29(m, 2H), 7.40(d, J = 7.3 Hz, 1H), 7.56(s, 1H), 8.14(bs, 1H), 9.13(s, 1H), 10.91 (bs, 1H), 13.85(bs, 1H)	384	382	1
23		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.59-0.62(m, 2H), 0.90-0.93 (m, 2H), 3.04(bs, 1H), 3.42(s, 3H), 7.45(d, J = 8.9 Hz, 1H), 7.62(s, 1H), 7.66(d, J = 8.9 Hz, 1H), 7.98(s, 1H), 8.43(bs, 1H), 9.37(s, 1H), 12.90 (bs, 1H), 13.94(bs, 1H)	385	383	1
24		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 0.50-0.70(m, 2H), 0.75-0.95 (m, 2H), 3.04(bs, 1H), 3.40(s, 3H), 7.67(s, 1H), 7.75-8.00(m, 2H), 8.92 (s, 1H), 9.16(s, 1H), 9.61(s, 1H), 13.94(s, 1H)	402	400	1
25		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.58-0.62(m, 2H), 0.89-0.93 (m, 2H), 3.04(bs, 1H), 3.43(s, 3H), 7.16(s, 1H), 7.72(s, 1H), 7.74-7.87 (m, 3H), 8.00(d, J = 8.9 Hz, 2H), 9.72(s, 1H), 14.10(s, 1H)	388	386	1
26		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 1.25-1.45(m, 2H), 1.25-1.70 (m, 4H), 1.70-1.80(m, 2H), 2.54(s, 3H), 3.02(t, J = 4.9 Hz, 4H), 3.73 (t, J = 4.94 Hz, 4H), 3.89(bs, 1H), 4.14(bs, 1H), 5.03(s, 1H), 6.33 (s, 1H), 6.85(d, J = 9.2 Hz, 2H), 7.63(d, J = 8.9 Hz, 2H), 8.86(s, 1H), 12.83(s, 1H)	456	454	6
27		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 1.54-2.10(m, 4H), 2.54(s, 3H), 3.02(t, J = 4.9 Hz, 4H), 3.50-4.20(m, 9H), 6.31(s, 1H), 6.86(d, J = 9.2 Hz, 2H), 7.63(d, J = 8.9 Hz, 2H), 8.89(s, 1H), 12.86(s, 1H)	442	440	6
28		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.29-0.33(m, 2H), 0.44-0.49 (m, 2H), 1.21(bs, 1H), 2.54(s, 3H), 3.02(t, J = 4.9 Hz, 4H), 3.41(t, J = 6.4 Hz, 2H), 3.73(t, J = 4.9 Hz, 4H), 6.42(s, 1H), 6.86(d, J = 9.2 Hz, 2H), 7.64(d, J = 8.9 Hz, 2H), 8.85(s, 1H), 12.82(s, 1H)	412	410	6

TABLE 1-5
Compound No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
29		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.58-0.62(m, 2H), 0.95-1.02(m, 2H), 3.06(bs, 1H), 3.43(s, 3H), 7.60-7.78(m, 3H), 8.55(s, 1H), 9.63(s, 1H), 14.03(s, 1H)	453	451	1
30		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.55-0.58(m, 2H), 0.95-1.00(m, 2H), 3.04(bs, 1H), 3.42(s, 3H), 7.03(d, J = 8.6 Hz, 1H), 7.41(d, J = 8.0 Hz, 1H), 7.67(d, J = 2.5 Hz, 1H), 8.13 bs, 1H), 9.46(s, 1H), 12.37(s, 1H), 12.48(s, 1H), 13.94(s, 1H)	417	415	1
31		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.54-0.58(m, 2H), 0.89-0.94(m, 2H), 3.01(bs, 1H), 3.41(s, 3H), 6.81(d, J = 8.3 Hz, 1H), 7.29(d, J = 8.3 Hz, 1H), 7.60(s, 1H), 7.72(bs, 1H), 9.24(s, 1H), 10.40(s, 1H), 10.56(s, 1H), 13.89(s, 1H)	401	399	1
32		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.50-0.65(m, 2H), 0.80-0.95(m, 2H), 2.99(bs, 1H), 3.38(s, 3H), 4.52(s, 2H), 6.78(d, J = 8.4 Hz, 1H), 7.32(d, J = 9.0 Hz, 1H), 7.59(s, 1H), 7.77(s, 1H), 9.22(s, 1H), 10.43(s, 1H), 13.86(s, 1H)	416	414	1
33		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 2.53(s, 3H), 3.02(t, J = 4.9 Hz, 4H), 3.54-3.70(m, 4H), 3.73(t, J = 4.9 Hz, 4H), 4.27(bs, 1H), 4.90(t, J = 4.9 Hz, 2H), 6.23(d, J = 8.3 Hz, 1H), 6.86(d, J = 8.9 Hz, 2H), 7.63(d, J = 8.9 Hz, 2H), 8.86(s, 1H), 12.85(s, 1H)	432	430	6
34		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 0.27-0.32(m, 2H), 0.49-0.54(m, 2H), 1.07-1.16(m, 1H), 3.02-3.08 (m, 4H), 3.38-3.45(m, 5H), 3.72-3.77(m, 4H), 6.90(d, J = 8.6 Hz, 2H), 7.55- 7.70(m, 3H), 9.11(s, 1H), 13.89(s, 1H)	444	442	1
35		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 1.02-1.06(m, 6H), 1.25(d, J = 6.4 Hz, 3H), 1.30-1.70(m, 6H), 2.53(s, 3H), 3.02(t, J = 4.9 Hz, 4H), 3.73(t, J = 4.9 Hz, 4H), 4.09(s, 1H), 4.34(bs, 1H), 5.86(d, J = 8.3 Hz, 1H), 6.86(d, J = 9.2 Hz, 2H), 7.63(d, J = 9.2 Hz, 2H), 8.86(s, 1H), 12.84(s, 1H)	486	484	6

TABLE 1-6
Compound No.	Compound	Salt	NMR	ESI MSI (M + H)+	ESI MS (M − H)−	Example No.
36		Free	1H NMR (500 MHz, DMSO-D6) δ ppm 1.02-1.08(m, 6H), 1.23(d, J = 6.4 Hz, 3H), 1.30-1.60(m, 6H), 3.03(t, J = 4.9 Hz, 4H), 3.41(s, 3H), 3.74(t, J = 4.9 Hz, 4H), 4.09(s, 1H), 4.30(bs, 1H), 6.88(d, J = 9.2 Hz, 2H), 7.41(d, J = 7.4 Hz, 1H), 7.63(d, J = 9.2 Hz, 2H), 9.06(s, 1H), 13.84(s, 1H)	518	516	1
37		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 0.45-0.60(m, 2H), 0.75-0.91(m, 2H), 2.65-2.85(m, 4H), 3.02(bs, 1H), 3.39(s, 3H), 3.52-3.72(m, 4H), 7.50(d, J = 8.4 Hz, 1H), 7.67(s, 1H), 8.08(s, 1H), 8.30(s, 1H), 9.55(s, 1H), 13.94(bs, 1H)	498	496	1
38		HCl	1H NMR (500 MHz, DMSO-D6) δ ppm 0.55-0.65(m, 2H), 0.85-0.91(m, 2H), 2.27(s, 3H), 2.80-2.87(m, 4H), 3.03(bs, 1H), 3.38(s, 3H), 3.72-3.78(m, 4H), 7.00(d, J = 8.6 Hz, 1H), 7.55-7.73(m, 3H), 9.05(s, 1H), 13.81(s, 1H)	444	442	1
39		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 3.04-3.05(m, 4H), 3.42(s, 3H), 3.74-3.76(m, 4H), 3.82-3.84(m, 1H), 3.92-3.93(m, 1H), 4.57-4.60(m, 1H), 4.73-4.76(m, 1H), 6.89(d, J = 9.0 Hz, 2H), 7.61(d, J = 9.0 Hz, 2H), 7.67-7.71(m, 1H), 9.15(bs, 1H)	436	434	1
40		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 2.73-2.74(m, 4H), 3.45(s, 3H), 3.73-3.76(m, 4H), 4.48-4.60(m. 2H), 6.90(d, J = 9.0 Hz, 2H), 7.60(d, J = 9.0 Hz, 2H), 7.74-7.79(m, 1H), 9.30(bs, 1H), 14.07(bs, 1H)	472	470	1
41		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.08-1.24(m, 4H), 3.02-3.05(m, 4H), 3.40-3.48(m, 5H), 3.52-3.58 (m, 2H), 3.72-3.76(m, 4H), 6.88(d, J = 9.3 Hz, 2H), 7.46-7.52(m, 1H), 7.64 (d, J = 9.0 Hz, 2H), 9.10(bs, 1H), 13.86(bs, 1H)	462	460	1
42		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 2.47-2.61(m, 6H), 3.00-3.03(m, 4H), 3.30(s, 3H), 3.60-3.63(m, 6H), 3.72-3.75(m, 4H), 6.64-6.67(m, 1H), 6.84-6.87(m, 2H), 7.62-7.65(m, 2H), 8.86(bs, 1H), 12.83(bs, 1H)	471	469	6

TABLE 1-7
Compound				ESI MS	ESI MS	Example
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
43		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.79-1.81(m, 2H), 2.32-2.40 (m, 6H), 3.00-3.04(m, 4H), 3.30(s, 3H), 3.57-3.61(m, 6H), 3.72-3.75 (m, 4H), 6.47(bs, 1H), 6.84-6.87 (m, 2H), 7.62-7.65(m, 2H), 8.82 (bs, 1H), 12.80(bs, 1H)	485	Not detected	6
44		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.75-1.80(m, 2H), 2.14(s, 3H), 2.35-2.39(m, 10H), 3.00-3.04(m, 4H), 3.32(s, 3H), 3.53-3.57(m, 2H), 3.72-3.75(m, 4H), 6.82-6.87(m, 2H), 7.63-7.66(m, 2H), 8.82(bs, 1h), 12.80 (bs, 1H)	498	496	6
45		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.66-1.70(m, 1H), 2.12-2.17 (m, 1H), 2.98-3.01(m, 4H), 3.03-3.08 (m, 1H), 3.16(s, 3H), 3.59-3.65 (m, 1H), 3.72-3.75(m, 6H), 4.55-4.56 (m, 1H), 6.82-6.85(m, 2H), 7.41-7.43 (m, 1H), 7.77-7.80(m, 2H), 8.16 (bs, 1H)	459	457	4
46		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.67-1.71(m, 1H), 2.15-2.17 (m, 1H), 2.98-3.00(m, 4H), 3.04-3.09 (m, 1H), 3.16(s, 3H), 3.60-3.65 (m, 1H), 3.72-3.73(m, 6H), 4.57-4.59(m, 1H), 6.82-6.85(m, 2H), 7.41-7.43(m, 1H), 7.77-7.80(m, 2H), 8.17 (bs, 1H)	459	457	4
47		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.72-1.98(m, 4H), 2.20(t, J = 8.3 Hz, 2H), 2.90-3.05(m, 4H), 3.20- 3.40(m, 4H), 3.42(s, 3H), 3.45-3.60 (m, 2H), 3.62-3.85(m, 4H), 6.89(d, J = 9.1 Hz, 2H), 7.49(m, 1H), 7.63 (d, J = 8.6 Hz, 2H), 9.11(s, 1H), 13.85(s, 1H)	515	513	1
48		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 2.90-3.12(m, 4H), 3.20-3.60 (m, 9H), 3.60-3.90(m, 6H), 4.55(m, 1H), 6.89(d, J = 9.1 Hz, 2H), 7.50-7.70(m, 3H), 9.11(s, 1H), 13.87(s, 1H)	478	476	1
49		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 2.02-2.17(m, 2H), 2.95-3.10 (m, 4H), 3.32(s, 3H), 3.45-3.56(m, 2H), 3.65-3.80(m ,4H), 3.95-4.10 (m, 2H), 6.54(m, 1H), 6.80-6.90 (m, 3H), 7.20(s, 1H), 7.50-7.70 (m, 3H), 8.77(s, 1H), 12.80(s, 1H)	466	464	6

TABLE 1-8
Compound				ESI MS	ES MS	Example
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
50		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.80-1.95(m, 2H), 2.06(s, 3H), 2.50(s, 3H), 2.90-3.15(m, 4H), 3.22-3.47(m, 2H), 3.53-3.65(m, 2H), 3.65-3.85(m, 4H), 6.53(s, 1H), 6.87 (d, J = 8.7 Hz, 2H), 7.64(d, J = 7.8 Hz, 2H), 8.85(s, 1H), 12.81(s, 1H)	446	444	6
51		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 1.07-1.24(m, 6H), 1.25-1.37 (m, 3h), 1.60-1.85(m, 4H), 2.60(s, 3H), 2.90-3.10(m, 6H), 3.20-3.40 (m, 4H), 3.75-3.95(m, 4H), 4.32-4.50 (m, 1H), 6.84(bs, 1H), 7.20-7.40 (m, 2H), 7.55-7.72(m, 2H), 10.12 (bs, 1H), 10.43(bs, 1H)	499	497	6
52		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 2.85-3.15(m, 6H), 3.32(s, 3H), 3.60-3.90(m, 6H), 6.53(s, 1H), 6.84 (d, J = 9.0 Hz, 2H), 7.30(d, J = 5.4 Hz, 2H), 7.61(d, J = 8.7 Hz, 2H), 8.49(d, J = 5.4 Hz, 2H), 8.86(s, 1H), 12.80 (s, 1H)	463	461	6
53		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 1.15-1.60(m, 12H), 1.70-2.15 (m, 4H), 2.57(s, 3H), 3.05-3.30(m, 4H), 3.70-3.95(m, 4H), 4.55-4.74 (m, 1H), 6.95-7.35(m, 2H), 7.40-7.75 (m, 2H), 8.33(bs, 1H), 9.30-9.60 (m, 2H)	497	495	6
54		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 1.60-2.10(m, 4H), 2.20-2.40 (m, 2H), 2.65-2.83(m, 2H), 2.87-3.13 (m, 5H), 3.15-3.45(m, 6H), 3.46-3.67 (m, 2h), 3.67-3.88(m, 4H), 6.63(s, 1H), 6.89(d, J = 8.7 Hz, 2H), 7.60 (d, J = 9.0 Hz, 2H), 8.84(s, 1H), 10.10-10.45(m, 1H), 12.82(s, 1H)	469	467	6
55		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 1.49(s, 9H), 2.95-3.15(m, 4H), 3.41(s, 3H), 3.60-3.80(m ,4H), 6.90 (d, J = 9.0 Hz, 2H), 7.54(s, 1H), 7.60 (d, J = 9.0 Hz, 2H), 9.00(s, 1H), 13.84 (s, 1H)	446	444	1
56		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 3.40-3.09(m, 6H), 3.64-3.85 (m, 9H), 6.95-7.00(m, 3H), 7.05-7.10 (m, 2H), 7.22(bs, 1H), 7.34-7.37 (m, 2H), 7.58-7.61(m, 3h), 10.90 (bs, 1H)	501	499	6

TABLE 1-9
Compound No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
57		HCl	1H NMR (300 MHz, DMSO-D6) δ ppm 1.77-1.84(m, 2H), 2.22-2.28(m, 2H), 3.03-3.13(m, 2H), 3.28-3.52 (m, 5H), 3.98-4.28(m, 9H), 7.43-7.54(m, 2H), 7.66-7.68(m, 1H), 7.82-7.87 (m, 2H), 8.92-8.97(m, 1H), 9.09-9.14(m, 1H), 9.52-9.54(m, 1H)	473	471	4
58		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.19(t, J = 7.2 Hz, 3H), 2.69-2.73(m, 2H), 3.02-3.05(m, 4H), 3.39(s, 3H), 3.72-3.82(m, 6H), 4.09(q, J = 7.2 Hz, 2H), 6.87-6.90(m, 2H), 7.61-7.64 (m, 3H), 9.14(bs, 1H)	490	488	1
59		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 2.61-2.66(m, 2H), 3.02-3.05(m, 4H), 3.38(s, 3H), 3.73-3.76(m, 6H), 6.87-6.90(m, 2H), 7.61-7.65(m, 3H), 9.14(bs, 1H)	462	460	1
60		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.79-1.88(m, 2H), 2.15-2.20(m, 2H), 3.02-3.05(m, 4H), 3.42(s, 3H), 3.49-3.56(m, 2H), 3.72-3.75(m, 4H), 6.77(bs, 1H), 6.87-6.90(m, 2H), 7.30(bs, 1H), 7.48(bs, 1H), 7.62-7.65(m, 2H), 9.10(bs, 1H)	475	473	1
61		Free	1H NMR (300 MHz, DMSO-D6) δ ppm 1.80-1.90(m, 2H), 2.06-2.11(m, 2H), 3.03-3.06(m, 4H), 3.42(s, 3H), 3.50-3.56(m, 2H), 3.73-3.76(m, 4H), 6.88-6.91(m, 2H), 7.49(bs, 1H), 7.62-7.65(m, 2H), 9.10(bs, 1H), 10.4(bs, 1H)	491	489	1
62		Free	1H NMR (600 MHz, CHLOROFORM-D) δ ppm 0.62-0.72(m, 2H), 0.83-0.94(m, 2H), 1.15(t, J = 7.1 Hz, 6H), 2.96- 3.04(m, 1H), 3.28(s, 3H), 3.33(q, J = 7.1 Hz, 4H), 6.68(bs, 2H), 6.97(bs, 1H), 7.45(bs, 2H), 7.63(bs, 1H)	416	414	1
63		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.59(m, 2H), 0.85-0.90(m, 2H), 1.47-1.54(m, 2H), 1.59-1.65 (m, 4H), 2.99(bs, 1H), 3.03(t, J = 5.5 Hz, 4H), 3.39(s, 3H), 6.84-6.88(m, 2H), 7.56(s, 1H), 7.65-7.71(m, 2H), 9.12(s, 1H), 13.86(bs, 1H)	428	426	1

TABLE 1-10
Compound
No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
64		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.60(m ,2H), 0.83-0.91(m, 2H), 1.85-1.94(m, 2H), 3.00(m, 1H), 3.39(s, 3H), 3.49-3.61(m, 6H), 3.71(t, J = 5.0 Hz, 2H), 6.63-6.74(m, 2H), 7.49-7.68(m, 3H), 8.99(s, 1H), 13.81(bs, 1H)	444	442	1
65		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.50-0.60(m, 2H), 0.84-0.94(m, 2H), 3.23-3.38(m, 1H), 3.32(s, 3H), 5.61-5.74(m, 1H), 6.72(m, 2H), 7.50-7.62(m, 2H), 8.21-8.27(m, 1H), 8.55-8.62(m, 1h), 10.13-10.27(m, 1H)	411	409	1
66		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.62(m, 2H), 0.85-0.91(m, 2H), 2.01(s, 3H), 2.98-3.04(m, 1H), 3.41(s, 3H), 7.44-7.49(m, 2H), 7.68(bs, 1H), 7.74-7.79(m, 2H), 9.41 (bs, 1h), 9.82(bs, 1H), 13.98(bs, 1H)	402	400	1
67		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.63(m, 2H), 0.80-0.92(m, 2H), 2.33(s, 3h), 2.94-3.01(m, 1H), 3.41(s, 3H), 6.91-7.03(m, 2H), 7.28-7.40(m, 2H), 7.57-7.65(m, 2H), 7.66-7.73(m, 3H), 9.45(bs, 1H), 9.93(bs, 1H)	514	512	1
68		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.50-0.63(m, 2H), 0.81-0.94(m, 2H), 1.87-2.01(m, 4H), 2.99(m, 1H), 3.14-3.25(m, 4H), 3.39(s, 3H), 6.41-6.59(m, 2H), 7.42-7.75(m, 3H), 8.98(s, 1H), 13.81(bs, 1H)	414	412	1
69		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.59(m, 2H), 0.83-0.91(m, 2H), 1.43-1.51(m, 4H), 1.66-1.78 (m, 4H), 3.00(m, 1H), 3.40(s, 3H), 3.42(t, J = 6.0 Hz, 4H), 6.54-6.66(m, 2H), 7.46-7.65(m, 3H), 8.96(s, 1H), 13.80(bs, 1H)	442	440	1
70		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.55-0.61(m, 2H), 0.86-0.91(m, 2H), 1.17-1.44(m, 5H), 1.66-1.83 (m, 5H), 2.39-2.46(m, 1H), 2.98-3.04(m, 1H), 3.41(s, 3H), 7.08-7.15(m, 2H), 7.63(bs, 1H), 7.75-7.80(m, 2H), 9.32-9.33(m, 1H), 13.95(bs, 1H)	427	425	1

TABLE 1-11
Compound No.	Compound	Salt	NMR	ESI MS (M + H)+	ES MS (M − H)−	Example No.
71		Free	1H NMR (600 MHz, CHLOROFORM-D) δ ppm 0.63-.68(m, 2H), 0.86-0.92(m, 2H), 2.93-3.01(m ,1H), 3.30(s, 3H), 3.44-3.52(m, 4H), 3.79-3.90(m ,4H), 6.65-6.70(m, 1H), 7.01(bs, 1H), 7.71(bs, 1H), 7.93(bs, 1H), 8.48(bs, 1H)	431	429	1
72		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-.0.60(m, 2H), 0.83-0.91(m, 2H), 2.87(s, 3H), 3.00(m, 1H), 3.25(s, 3H), 3.40(s, 3H), 3.41-3.52(m, 4H), 6.61-6.71(m, 2H), 7.55(s, 1H), 7.57-7.72(m, 2H), 9.01(s, 1H), 13.47(bs, 1H)	432	430	1
73		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.60(m, 2H), 0.83-0.92(m, 2H), 1.44-1.54(m, 2H), 1.76-1.86 (m, 2H), 2.69-2.79(m, 2H), 2.98(m, 1H), 3.38-3.48(m, 2H), 3.39(s, 3H), 3.58(m, 1H), 4.65(d, J = 4.6 Hz, 1H), 6.87(d, J = 87 Hz, 2H), 7.57(s, 1H), 7.61-7.76(m, 2H), 9.12(s, 1H), 13.86(bs, 1H)	444	442	1
74		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.50-0.65(m, 2H), 0.83-0.94(m, 2H), 2.95-3.04(m ,1H), 3.15-3.35 (m, 9H), 3.40(s, 3H), 6.88-6.99(m, 2H), 7.60(bs, 1H) 7.72-7.82(m, 2H), 9.03(bs, 1H), 9.23(bs, 1H)	429	427	1
75		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.65(m, 2 H), 0.90-0.98(m, 2H), 2.87-2.95(m, 4H), 2.96-3.02 (m, 1H), 3.42(s, 3H), 3.69-3.78(m, 4H), 4.33(bs, 1H), 7.64-7.72(m, 2H), 8.25(bs, 1H), 9.50(bs, 1H), 14.01(bs, 1H).	464	462	1
76		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.60(m, 2H), 0.83-0.88(m, 2H), 1.28-1.37(m, 6H), 2.95-3.01 (m, 4H), 3.01-3.07(m, 1H), 3.40(s, 3H), 3.68-3.77(m ,4H), 4.00(q, J = 7.0 Hz, 2H), 4.09(q, J = 6.9 Hz, 2H), 6.60(s, 1H), 7.63(bs, 1H), 7.66(bs, 1H), 8.06(bs, 1H), 13.93(bs, 1H)	518	516	1
77		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.51-0.60(m, 2H), 0.82-0.93(m, 2H), 1.47-1.58(m, 2H), 1.89-2.00 (m, 2H), 2.43-2.56(m, 2H), 2.74-2.85(m, 2H), 2.98(m, 1H), 3.26(s, 3H), 3.35-3.47(m, 1H), 3.40(s, 3H), 6.83-6.93(m, 2H), 7.57(s, 1H), 7.62-7.76 (m, 2H), 9.13(s, 1H), 13.87(bs, 1H)	458	456	1

TABLE 1-12
Compound No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
78		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.60(m, 2H), 0.83-0.92(m, 2H), 1.22(m, 1H), 1.54(m, 1H), 1.73(m, 1H), 1.87(m, 1H), 2.41(dd, J = 11.0 and 9.2 Hz, 1H), 2.55(m, 1H), 2.98(m, 1H), 3.38(m, 1H), 3.40(s, 3H), 3.49(m, 1H), 3.59(m, 1H), 4.77 (d, J = 5.0 Hz, 1H), 6.80-6.90(m, 2H), 7.57(s, 1H), 7.62-7.75(m, 2H), 9.13 (s, 1H), 13.87(bs, 1H)	444	442	1
79		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.62(m, 2H), 0.83-0.92(m, 2H), 2.64-2.74(m, 4H), 2.97-3.04 (m, 1H), 3.35-3.44(m, 4H), 3.40(s, 3H), 6.83-6.91(m, 2H), 7.57-7.59(m, 1H), 7.68-7.76(m, 2H), 9.16(bs, 1H), 13.88(bs, 1H)	446	444	1
80		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.57-0.59(m, 2H), 0.84-0.93(m, 2H), 1.15(d, J = 6.4 Hz, 6H), 2.19 (dd, J = 11.5, 10.6 Hz, 2H), 2.98-3.03(m, 1H), 3.40(s, 3H), 3.46-3.51(m, 2H), 3.63-3.77(m, 2H), 6.83-6.92(m, 2H), 7.58-7.60(m, 1H), 7.67-7.77(m, 2H), 9.15(bs, 1H), 13.88(bs, 1 H)	458	456	1
81		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.72-1.84(m, 2H), 2.53(s, 3H), 2.98-3.05(m, 4H), 3.54-3.58(m, 2H), 3.60-3.64(m, 2H), 3.70-3.77(m, 4H), 4.69(t, J = 5.0 Hz, 1H), 6.61(m, 1H), 6.81-6.90(m, 2H), 7.62-7.68(m, 2H), 8.84(s, 1H), 12.80(bs, 1H)	416	414	1
82		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.65(m, 2H), 0.83-0.95(m, 2H), 2.06(s, 3H), 3.06-3.82(m, 10H), 3.41(s, 3H), 7.10-7.19(m, 2H), 7.64(bs, 1H) 7.79-7.89(m, 2H), 9.38 (bs, 1H), 13.97(bs, 1H)	471	469	1
83		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.59(m, 2H), 0.83-0.92(m, 2H), 1.27(m, 1H), 1.55(m, 1H), 1.77(m, 1H), 1.98(m, 1H), 2.55(m, 1H), 2.66(m, 1H), 2.99(m, 1H), 3.28- 3.36(m, 2H), 3.32(s, 3H), 3.40(s, 3H), 3.56(m, 1H), 6.84-6.92(m, 2H), 7.57(s, 1H), 7.64-7.75(m, 2H), 9.14(bs, 1H)	458	456	1
84		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.51-0.61(m, 2H), 0.82-0.92(m, 2H), 1.67-1.76(m, 4H), 2.99(m, 1H), 3.13-3.21(m, 4H), 3.40(s, 3H), 3.90(s, 4H), 6.84-6.95(m, 2H), 7.57 (s, 1H), 7.63-7.77(m, 2H), 9.14(s, 1H), 13.87(bs, 1H)	486	484	1

TABLE 1-13
Compound
No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
85		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.62(m, 2H), 0.92-1.00(m, 2H), 3.04-3.11(m, 1H), 3.10-3.18 (m, 4H), 3.42(s, 3H), 3.75-3.90(m, 4H), 4.99-5.02(m, 1H), 7.67-7.75(m, 2H), 8.13-8.19(m, 1H), 8.69(bs, 1H), 9.74(bs, 1H), 14.08(bs, 1H)	474	472	1
86		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.60(m, 2H), 0.84-0.91(m, 2H), 1.65(dq, J = 4.1, 12.4 Hz, 2H), 1.73-1.81(m, 2H), 2.20(tt, J = 4.1, 11.9 Hz, 1H), 2.58(dt, J = 2.3, 12.4 Hz, 2H), 2.99(m, 1H), 3.40(s, 3H), 3.56-3.64(m, 2H), 6.77(s, 1H), 6.83-6.92 (m, 2H), 7.27(s, 1H), 7.57(s, 1H), 7.70(m, 2H), 9.13(s, 1H), 13.87(bs, 1H)	471	469	1
87		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.60(m, 2H), 0.84-0.90(m, 2H), 3.03(m, 1H), 3.05-3.10(m, 4H), 3.41(s, 3H), 3.71-3.77(m, 4H), 6.55(dd, J = 8.3, 1.8 Hz, 1H), 7.11(t, J = 8.0 Hz, 1H), 7.44(m, 1H), 7.50(m, 1H), 7.62(m, 1H), 9.21(s, 1H), 13.95 (bs, 1H)	430	428	1
88		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.59(m, 2H), 0.85-0.91(m, 2H), 2.42(t, J = 6.0 Hz, 4H), 3.00 (m, 1H), 3.40(s, 3H), 3.51(t, J = 6.0 Hz, 4H), 6.94-7.02(m, 2H), 7.58(s, 1H), 7.68-7.80(m, 2H), 9.17(s, 1H), 13.88(bs, 1H)	442	440	1
89		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.556-0.65(m, 2H), 0.89-0.95(m, 2H), 2.02-2.10(m, 2H), 2.47(t, J = 8.0 Hz, 2H), 3.02(m, 1H), 3.42(s, 3H), 3.82(t, J = 7.1 Hz, 2H), 7.51-7.60 (m, 2H), 7.72(s, 1H), 7.84-7.91(m, 2H), 9.54(s, 1H), 14.05(bs, 1H)	428	426	1
90		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.66(m, 2H), 0.88-0.99(m, 2H), 3.00-3.08(m, 1H), 3.43(s, 3H), 3.46-3.58(m, 4H), 3.56-3.68(m, 4H), 7.32-7.44(m, 2H), 7.72-7.81 (bs, 1H), 7.95-8.05(m, 2H), 9.75-9.87(m, 1H), 14.14(bs, 1H)	458	456	1
91		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 2.97-3.09(m, 4H), 3.39(s, 3H), 3.56-3.68(m, 4H), 3.69-3.78(m, 4H), 4.83-4.88(m, 1H), 6.84-6.92(m, 2H), 7.59-7.65(m, 2H), 7.65-7.71 (m, 1H), 9.08(bs, 1H), 13.86(bs, 1H)	434	432	1

TABLE 1-14
Compound No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
92		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 2.59(s, 3H), 3.07-3.15(m, 2H), 3.27-3.53(m, 4H), 3.73-3.87(m, 2H), 3.87-4.13(m, 2H), 7.39-7.65(m, 2H) 7.67-7.92(m, 2H), 8.05-8.30(m, 4H), 10.03(bs, 1H)	401	399	6
93		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 2.84(t, J = 6.2 Hz, 2H), 3.05(t, J = 4.8 Hz, 4H), 3.41(s, 3H), 3.50-3.60 (m, 2H), 3.73-3.77(m, 4H), 6.85-6.94(m, 2H), 7.60-7.72(m, 3H), 9.04(s, 1H)	433	Not detected	4
94		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.37(s, 9H), 1.67-1.76(m, 2H), 2.52(s, 3H), 2.99-3.06(m, 6H), 3.52(q, J = 6.4 Hz, 2H), 3.71-3.75(m, 4H), 6.51-6.60(m, 1H), 6.83-6.88(m, 2H), 6.90(t, J = 5.7 Hz, 1H), 7.58-7.68(m, 2H), 8.82(s, 1H), 12.79(bs, 1H)	515	513	6
95		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.64-1.71(m, 2H), 2.51(s, 3H), 2.66(t, J = 6.4 Hz, 2H), 2.98-3.05(m, 4H), 3.56-3.64(m, 2H), 3.70-3.76(m, 4H), 6.80-6.89(m, 3H), 7.60-7.67(m, 2H), 8.81(bs, 1H)	415	413	6
96		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.35(s, 9H), 2.99-3.07(m, 4H), 3.17-3.24(m, 2H), 3.38(s, 3H), 3.56-3.64(m, 2H), 3.70-3.76(m, 4H), 6.86-6.91(m, 2H), 6.97(t, J = 5.7 Hz, 1H), 7.53(m, 1H), 7.58-7.66(m, 2H), 9.09(bs, 1H)	533	531	4
97		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.89-1.99(m, 2H), 2.83-2.92(m, 2H), 3.01-3.09(m, 4H), 3.44(s, 3H), 3.61-3.66(m, 2H), 3.71-3.78(m, 4H), 6.86-6.94(m, 2H), 7.52(m, 1H), 7.60-7.69(m, 2H), 7.92-8.13(m, 3H), 9.19(s, 1H), 13.95(bs, 1H)	447	445	4
98		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.36(s, 9H), 1.71-1.75(m, 2H), 3.01-3.07(m, 6H), 3.40(s, 3H), 3.49-3.57(m, 2 H), 3.71-3.76(m, 4H), 6.85-6.93(m, 3H), 7.46(m, 1H), 7.60-7.66(m, 2H), 9.07(bs, 1H)	547	545	4

TABLE 1-15
Compound				ESI MS	ESI MS	Example
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
99		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.29-1.44(m, 2H), 1.46-1.68 (m, 5H), 1.76(m, 1H), 2,99-3.08(m, 5H), 3.40(s, 3H), 3.71-3.77(m, 4H), 4.33(m, 1H), 6.84-6.90(m, 2H), 7.60- 7.66(m, 2H), 7.70(m, 1H), 8.99 (bs, 1H)	487	485	4
100		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.49-1.67(m, 4H), 1.68-1.79 (m, 2H), 1.99-2.11(m, 2H), 2.53(s, 3H), 2.97-3.06(m, 4H), 3.68-3.78 (m, 4H), 4.50(m, 1H), 5.97(d, J = 7.3 Hz, 1H), 6.81-6.90(m, 2H), 7.60-7.69(m, 2H), 8.87(s, 1H) 12.84(bs, 1H)	426	424	6
101		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.36(s, 9H), 1.41-1.51(m, 2H), 1.55-1.65(m, 2H), 2.52(s, 3H), 2.92-2.98(m, 2H), 2.99-3.05(m, 4H), 3.51(q, J = 6.7 Hz, 2H), 3.70-3.77(m, 4H), 6.41(m, 1H), 6.82(t, J = 5.5 Hz, 1H), 6.83-6.89(m, 2H), 7.60-7.67(m, 2H), 8.82(s, 1H), 12.78(bs, 1H)	529	527	6
102		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.59-1.78(m, 4H), 2.61(s, 3H), 2.68-2.92(m, 2H), 3.20-3.46(m, 4H), 3.54-3.72(m, 2H), 3.81-4.06(m, 4H), 7.22-7.53(m, 2H), 7.55-7.80(m, 2H), 7.94-8.21(m, 3H)	429	427	6
103		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.47-1.57(m, 2H), 1.59-1.68 (m, 2H), 1.68-1.78(m, 2H), 1.98-2.11 (m, 2H), 3.00-3.09(m, 4H), 3.42 (s, 3H), 3.70-3.78(m, 4H), 4.47 (m, 1H), 6.84-6.93(m, 2H), 7.57 (d, J = 6.9 Hz, 1H), 7.61-7.71(m, 2H), 9.08(s, 1H), 13.85(bs, 1H)	458	456	1
104		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.27(m, 1H), 1.34-1.46 (m, 4 H), 1.62(m, 1H), 1.68-1.78 (m, 2H), 1.94-2.06(m, 2H), 2.54 (s, 3H), 2.96-3.10(m, 4H), 3.71-3.77(m, 4H), 4.12 (m, 1H), 5.92(d, J = 7.8 Hz, 1H), 6.82-6.89(m, 2H), 7.61-7.67 (m, 2H), 8.87(s, 1H), 12.85(bs, 1H)	440	438	6
105		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.24-1.50(m, 5H), 1.55(m, 1H), 1.64-1.78(m, 2H), 1.88-2.06(m, 2H), 2.95-3.08(m, 4H), 3.41(s, 3H), 3.68-3.80(m, 4H), 4.05-4.27(m, 1H), 6.79-6.95(m, 2H), 7.54(d, J = 7.3 Hz, 1H), 7.58-7.71(m, 2H), 9.06(s, 1H), 13.83(bs, 1H)	472	470	1

TABLE 1-16
Compound
No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
106		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.25(d, J = 6.4 Hz, 6H), 2.99-3.06(m, 4H), 3.41(s, 3H), 3.69-3.77(m, 4H), 4.35(m, 1H), 6.80-6.94(m, 2H), 7.42(d, J = 6.9 Hz, 1H), 7.59-7.68(m, 2H), 9.07(s, 1H), 13.85(bs, 1H)	432	430	1
107		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.43-1.55(m, 2H), 1.57-1.71(m, 2H), 2.58-2.69(m, 2H), 2.94-3.07 (m, 4H), 3.36(s, 3H), 3.48-3.59(m, 2H), 3.67-3.78(m, 4H), 6.82-6.92(m, 2H), 7.45(m, 1H), 7.61-7.72(m, 2H), 8.89(s, 1H)	461	459	4
108		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.64-0.70(m, 2H), 0.80-0.88(m, 2H), 1.24(t, J = 7.3 Hz, 3H), 2.93- 3.00(m, 1H), 2.96(q, J = 7.3 Hz, 2H), 3.00-3.07(m, 4H), 3.69-3.77(m, 4H), 6.42(bs, 1H), 6.82-6.90(m, 2H), 7.68-7.80(m, 2H), 8.94(s, 1H), 12.92(s, 1H)	412	410	6
109		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.49-0.62(m, 2H), 0.79-0.93(m, 2H), 1.18(t, J = 7.3 Hz, 3H), 2.95- 3.10(m ,5H), 3.47(q, J = 7.3 Hz, 2H), 3.66-3.79(m, 4H), 6.83-6.92(m, 2H), 7.63(bs, 1H), 7.66-7.81(m, 2H), 9.16(s, 1H), 13.93(bs, 1H)	444	442	1
110		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.28-1.47(m, 2H), 1.53-1.74(m, 4H), 2.61(s, 3H), 2.69-2.89(m, 2H), 3.18-3.49(m, 4H), 3.50-3.67(m, 2H), 3.80-4.05, (m, 4H), 7.10-7.83 (m, 4H), 7.90-8.12(m, 3H)	443	441	6
111		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.06-1.29(m, 2H), 1.31-1.51(m, 2H), 1.69-1.89(m, 2H), 1.93-2.10 (m, 2H), 2.52(s, 3H), 2.54-2.67(m, 1H), 2.95-3.09(m, 4H), 3.66-3.80(m, 4H), 3.93-4.11(m, 1H), 5.83(d, J = 8.3 Hz, 1H), 6.78-6.90(m, 2H), 7.56-7.71 (m, 2H), 8.86(s, 1H)	455	453	6
112		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.29-1.49(m, 2H), 1.58-1.73(m, 4H), 1.78-1.97(m, 2H), 2.56(s, 3H), 2.76-2.93(m, 1H), 2.95-3.09(m, 4H), 3.67-3.84(m, 4H), 4.15-4.35(m, 1H), 6.06(d, J = 7.8 Hz, 1H), 6.86(d, J = 8.7 Hz, 2H), 7.54-7.77(m, 2H), 8.89 (s, 1H)	455	453	6

TABLE 1-17
Compound
No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
113		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.03-1.16(m, 2H), 1.55-1.68(m, 2H), 1.69-1.83(m, 1H), 2.41(m, 2H), 2.53(s, 3H), 2.87-2.98(m, 2H), 2.98-3.06(m, 4H), 3.42(t, J = 6.4 Hz, 2H), 3.69-3.78(m ,4H), 6.29-6.45(m, 1H), 6.80-6.90(m, 2H), 7.59-7.68(m, 2H), 8.84(s, 1H)	455	453	6
114		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.27(t, J = 7.3 Hz, 3H), 1.53-1.78(m, 4H), 2.70-2.91(m, 2H), 3.06(q, J = 7.3 Hz, 2H), 3.15-3.46(m, 4H), 3.53-3.70(m, 2H), 3.76-4.04(m, 4H), 7.07-7.81(m, 4H), 7.89-8.15(m, 3H)	443	Not detected	6
115		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.26(t, J = 7.3 Hz, 3H), 1.30-1.45(m, 2H), 1.58-1.75(m, 4h), 1.78- 1.91(m, 2H), 2.76-2.90(m, 1H), 2.98(q, J = 7.3 Hz, 2H), 2.98-3.09(m, 4H), 3.66-3.81(m, 4H), 4.17-4.36(m, 1H), 6.34(d, J = 7.8 Hz, 1H), 6.79-6.96(m, 2H), 7.55-7.73(m, 2H), 8.90(s, 1H)	469	467	6
116		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.64-1.74(m, 4H), 2.49(s, 3H), 2.61(s, 3H), 2.80-2.97(m, 2H), 3.19-3.47(m, 4H), 3.54-3.68(m, 2H), 3.79-4.03(m, 2H), 7.13-7.83(m, 2H), 8.84-9.07(m, 3H)	443	Not detected	6
117		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.33-1.49(m, 2H), 1.58-1.76(m, 4H), 1.76-1.99(m, 2H), 2.79-2.89 (m, 1H), 2.95-3.09(m, 4H), 3.40(s, 3H), 3.69-3.79(m, 4H), 4.19-4.34(m, 1H), 6.80-6.95(m, 2H), 7.59-7.72(m, 3H), 8.95(s, 1H)	487	485	4
118		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.14-1.42(m, 4H), 1.74-1.92(m, 2H), 1.99-2.17(m, 2H), 2.64-2.77 (m, 1H), 2.99-3.09(m, 4H), 3.37(s, 3H), 3.69-3.80(m, 4H), 3.88-4.15(m, 1H), 6.70-6.99(m, 2H), 7.40(d, J = 7.8 Hz, 1H), 7.61-7.73(m, 2H), 8.92(bs, 1H)	487	485	4
119		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 1.28(d, J = 6.4 Hz, 6H), 1.31-1.45(m, 2H), 1.59-1.76(m, 4H), 1.77- 1.91(m, 2H), 2.73-2.91(m, 1H), 2.95-3.08(m, 4H), 3.32-3.42(m, 1H), 3.65-3.78(m, 4H), 4.18-4.33(m, 1H), 6.55(d, J = 7.8 Hz, 1H), 6.80-6.96(m, 2H), 7.60-7.70(m, 2H), 8.90(s, 1H)	483	481	6

TABLE 1-18
Compound
No.	Compound	Salt	NMR	ESI MS (M + H)+	ESI MS (M − H)−	Example No.
120		Free	1H NMR (600 MHz, CHLOROFORM-D) δ ppm 1.74-1.85(m, 2H), 1.98-2.06(m, 2H), 2.38-2.56(m, 2H), 3.15-3.20 (m, 4H), 3.30(s, 3H), 3.86-3.89(m ,4H), 4.57-4.63(m, 1H), 6.91(bs, 1H), 7.06-7.10(m, 1H), 7.13-7.15(m, 1H), 7.80(d, J = 7.3 Hz, 1H), 7.90(d, J = 8.7 Hz, 1H)	512	510	3
121		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.23(t, J = 7.1 Hz, 3H), 2.61(s, 3H), 3.28-3.43(m, 4H), 3.58-3.70(m, 2H), 3.86-3.98(m, 4H), 7.35-7.41(m, 2H), 7.62-7.72(m, 2H), 10.41(s, 1H)	386	385	6
122		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.26(t, J = 7.1 Hz, 3H), 3.45(s, 3H), 3.48-3.52(m, 4H), 3.57-3.65(m, 2H), 4.03-4.08(m, 4H), 5.65-5.72(m, 1H), 7.62-7.69(m, 2H), 7.90-7.96(m, 2H), 9.68(bs, 1H), 14.13(bs, 1H)	418	416	1
123		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.67-1.79(m, 2H), 2.18-2.26(m, 2H), 2.32-2.39(m, 2H), 2.61(s, 3H), 3.35(bs, 4H), 3.47-4.19(m, 4H), 4.63-4.72(m, 1H), 7.39(bs, 2H), 7.71(bs, 1H)	412	411	6
124		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 1.73-1.85(m, 2H), 1.92-2.01(m, 2H), 2.41-2.48(m, 2H), 3.46(s, 3H), 3.49(bs, 4H), 3.73-4.38(m, 4H), 4.61-4.69(m, 1H), 7.64(bs, 1H), 7.84-7.94(m, 4H), 9.63(s, 1H), 14.12(bs, 1H)	444	442	1
125		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.62(m, 2H), 0.83-0.93(m, 2H), 1.59-1.74(m, 2H), 1.85-1.95 (m, 2H), 2.31-2.41(m, 1H), 2.63-2.75(t, J = 11.0 Hz, 2H), 2.91-3.10(m, 1H), 3.40(s, 3H), 3.47-3.58(m, 2H), 6.77-6.95(m, 2H), 7.58(s, 1H), 7.64- 7.78(m, 2H), 9.16(s, 1H), 12.22(s, 1H), 13.89(s, 1H)	472	470	1
126		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.58(m, 2H), 0.85-0.90(m, 2H), 1.19-1.28(m, 2H), 1.42-1.50 (m, 1H), 1.70-1.76(m, 2H), 2.52-2.58(m, 2H), 2.99(bs, 1H), 3.27-3.30(m, 2H), 3.40(s, 3H), 3.56-3.61(m, 2H), 4.48(t, J = 5.3 Hz, 1H), 6.85-6.89(m, 2H), 7.57(s, 1H), 7.65-7.71(m, 2H), 9.14(s, 1H), 13.88(bs, 1H)	458	456	1

TABLE 1-19
						Ex-
Com-				ESI	ESI	am-
pound				MS	MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
127		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.58 (m, 2H), 0.85-0.90 (m, 2H), 1.23-1.33 (m, 2H), 1.60-1.69 (m, 1H), 1.69-1.75 (m, 2H), 2.53-2.59 (m, 2H), 2.99 (bs, 1H), 3.21 (d, J = 6.4 Hz, 2H), 3.24 (s, 3H), 3.40 (s, 3H), 3.55-3.61 (m, 2H), 6.84-6.89 (m, 2H), 7.57 (s, 1H), 7.66-7.71 (m, 2H), 9.13 (s, 1H), 13.88 (bs, 1H)	472	470	1
128		Free	1H NMR (600MHz, DMSO-D6) δ ppm 0.50-0.60 (m, 2H), 0.83-0.92 (m, 2H), 1.59-1.76 (m, 4H), 2.59-2.77 (m, 3H), 2.82 (s, 3H), 2.96-3.02 (m, 1H), 3.04 (s, 3H), 3.39 (s, 3H), 3.56-3.66 (m, 2H), 6.83-6.92 (m, 2H), 7.56 (s, 1H), 7.64-7.75 (m, 2H), 9.11 (s, 1H), 13.88 (bs, 1H)	499	497	1
129		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.51-0.59 (m, 2H), 0.82-0.90 (m, 2H), 2.88 (s, 3H), 2.94-3.03 (m, 1H), 3.39 (s, 3H), 3.31-3.37 (m, 2H), 3.47-3.60 (m, 2H), 4.61 (t, J = 5.5 Hz, 1H), 6.58-6.69 (m, 2H), 7.46-7.70 (m, 3H), 8.99 (s, 1H), 13.82 (bs, 1H)	418	416	1
130		Free	1H NMR (600MHz, DMSO-D6) δ ppm 0.50-0.62 (m, 2H), 0.82-0.91 (m, 2H), 0.97-1.09 (m, 1H), 1.50-1.61 (m, 1H), 1.65-1.77 (m, 3H), 2.28-2.36 (m, 1H), 2.52-2.60 (m, 1H), 2.94-3.04 (m, 1H), 3.25-3.38 (m, 2H), 3.40 (s, 3H), 3.44-3.50 (m, 1H), 3.54-3.61 (m, 1H), 4.52 (t, J = 5.27 Hz, 1H), 6.81-6.90 (m, 2H), 7.53-7.61 (m, 1H), 7.64-7.76 (m, 2H), 9.14 (bs, 1H), 13.87 (bs, 1H)	458	456	1
131		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.48-0.62 (m, 2H), 0.88 (m, 2H), 2.21 (s, 3H), 2.34-2.48 (m, 4H), 2.96-3.03 (m, 1H), 3.02-3.14 (m, 4H), 3.40 (s, 3H), 6.81-6.95 (m, 2H), 7.57 (s, 1H), 7.63-7.84 (m, 2H), 9.14 (s, 1H), 13.88 (bs, 1H)	443	441	1
132		Free	1H NMR (600MHz, DMSO-D6) δ ppm 0.52-0.61 (m, 2H), 0.82-0.94 (m, 2H), 1.40-1.51 (m, 1H), 1.51-1.62 (m, 1H), 1.66-1.76 (m, 1H), 1.78-1.89 (m, 1H) 2.39-2.47 (m, 1H), 2.53-2.61 (m, 1H), 2.62-2.71 (m, 1H), 2.92-3.06 (m, 1H), 3.40 (s, 3H), 3.45-3.54 (m, 1H), 3.55-3.63 (m, 1H), 6.79-6.86 (m, 1H), 6.86-6.92 (m, 2H), 7.29-7.40 (m, 1H), 7.51-7.61 (m, 1H), 7.63-7.76 (m, 2H), 9.14 (bs, 1H), 13.87 (bs, 1H)	471	469	1
133		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.61 (m, 2H), 0.81-0.92 (m, 2H), 2.94-3.24 (m, 5H), 3.40 (s, 3H), 3.41-3.57 (m, 2H), 3.68-3.87 (m, 2H), 6.87-6.96 (m, 2H), 7.39-7.51 (m, 5H), 7.54-7.63 (m, 1H), 7.69-7.79 (m, 2H), 9.19 (bs,1H), 13.88 (bs, 1H)	Not detected	531	1

TABLE 1-20
						Ex-
Com-						am-
pound				ESI MS	ESI MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
134		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.62 (m, 2H), 0.85-0.93 (m, 2H), 2.94-3.04 (m, 1H), 3.09-3.17 (m, 4H), 3.40 (s, 3H), 3.63-3.73 (m, 4H), 6.92-7.02 (m, 2H), 7.55-7.63 (m, 1H), 7.71-7.82 (m, 2H), 9.22 (bs, 1H), 13.90 (bs, 1H)	478	476	1
135		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.43-0.68 (m, 2H), 0.81-0.95 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H), 2.36 (q, J = 7.1 Hz, 2H), 2.44-2.55 (m, 4H), 2.94-3.03 (m, 1H), 3.03-3.10 (m, 4H), 3.40 (s, 3H), 6.82-6.93 (m, 2H), 7.58 (bs, 1H), 7.64-7.78 (m, 2H), 9.14 (s, 1H), 13.88 (bs, 1H)	457	455	3
136		HCl	1H NMR (600 MHz, DMSO-D6) δ ppm 0.55-0.70 (m, 2H), 0.87-0.98 (m, 2H), 2.76 (d, J = 4.1 Hz, 3H), 2.97-3.08 (m, 1H), 3.43 (s, 3H), 7.72 (d, J = 3.7 Hz, 1H), 7.74-7.82 (m, 2H), 7.92-8.07 (m, 2H), 8.20-8.29 (m, 1H), 9.72 (s, 1H), 14.10 (bs, 1H)	402	400	1
137		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.65 (m, 2H), 0.85-0.97 (m, 2H), 2.97 (s, 6H), 3.00-3.07 (m, 1H), 3.42 (s, 3H), 7.33-7.40 (m, 2H), 7.69 (d, J = 3.2 Hz, 1H), 7.95-8.01 (m, 2H), 9.63 (s, 1H), 14.05 (bs, 1H)	416	414	1
138		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.45-0.71 (m, 2H), 0.83-0.95 (m, 2H), 1.02 (d, J = 6.4 Hz, 6H), 2.55-2.65 (m, 4H), 2.64-2.80 (m, 1H), 2.93-3.14 (m, 5H), 3.42 (s, 3H), 6.80-6.95 (m, 2H), 7.59 (bs, 1H), 7.65-7.82 (m, 2H), 9.15 (s, 1H), 13.89 (bs, 1H)	471	469	3
139		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.49-0.61 (m, 2H), 0.83-0.94 (m, 2H), 1.64-1.77 (m, 2H), 1.83-1.91 (m, 2H), 2.73-2.87 (m, 2H), 2.96-3.05 (m, 1H), 3.40 (s, 3H), 3.52-3.62 (m, 1H), 3.62-3.72 (m, 2H), 6.86-6.96 (m, 2H), 7.49-7.61 (m, 3H), 7.62-7.70 (m, 1H), 7.68-7.77 (m, 2H), 7.98-8.05 (m, 2H), 9.14 (bs, 1H), 13.88 (bs, 1H)	532	530	1
140		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.59 (m, 2H), 0.85-0.91 (m, 2H), 1.63-1.75 (m, 4H), 1.74-1.80 (m, 2H), 1.85-1.91 (m, 2H), 2.50-2.59 (m, 1H), 2.58-2.72 (m, 2H), 2.92-3.07 (m, 1H), 3.23-3.31 (m, 2H), 3.40 (s, 3H), 3.46-3.53 (m, 2H), 3.57-3.68 (m, 2H), 6.86-6.92 (m, 2H), 7.54-7.62 (m, 1H), 7.65-7.74 (m, 2H), 9.15 (bs, 1H), 13.88 (bs, 1H)	525	Not detected	1

TABLE 1-21
						Ex-
Com-						am-
pound				ESI MS	ESI MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
141		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.60 (m, 2H), 0.82-0.93 (m, 2H), 1.63-1.75 (m, 4H), 2.62-2.70 (m, 2H), 2.69-2.77 (m, 1H), 2.95-3.04 (m, 1H), 3.40 (s, 3H) 3.41-3.49 (m, 2H), 3.50-3.65 (m, 8H), 6.84-6.91 (m, 2H), 7.52-7.60 (m, 1H), 7.64-7.77 (m, 2H), 9.13 (bs, 1H), 13.87 (bs, 1H)	471	539	1
142		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.62-0.70 (m, 2H), 0.78-0.86 (m, 2H), 1.41-1.51 (m, 1H), 1.52-1.62 (m, 1H), 1.67-1.76 (m, 1H), 1.79-1.87 (m, 1H), 2.38-2.47 (m, 1H), 2.50 (s, 3H), 2.52-2.60 (m, 1H), 2.61-2.69 (m, 1H), 2.91-2.99 (m, 1H), 3.45-3.53 (m, 1H), 3.53-3.60 (m, 1H), 6.28-6.36 (m, 1H), 6.79-6.90 (m, 3H), 7.35 (bs, 1H), 7.67-7.77 (m, 2H), 8.89 (bs, 1H), 12.82 (bs, 1H)	439	437	6
143		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.59 (m, 2H), 0.82-0.91 (m, 2H), 1.38-1.49 (m, 1H), 1.61-1.75 (m, 2H), 1.76-1.85 (m, 1H), 2.52-2.61 (m, 1H), 2.65-2.72 (m, 1H), 2.83-2.91 (m, 1H), 2.96-3.04 (m, 1H), 3.35-3.44 (m, 2H), 3.40 (s, 3H), 3.45-3.65 (m, 8H), 6.84-6.91 (m, 2H), 7.54-7.62 (m, 1H), 7.65-7.75 (m, 2H), 9.16 (bs, 1H)	541	539	1
144		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.59 (m, 2H), 0.82-0.91 (m, 2H), 1.39-1.49 (m, 1H), 1.59-1.75 (m, 2H), 1.77-1.85 (m, 1H), 2.53-2.60 (m, 1H), 2.62-2.69 (m, 1H), 2.82 (s, 3H), 2.83-2.91 (m, 1H), 2.95-3.03 (m, 1H), 3.04 (s, 3H), 3.40 (s, 3H), 3.52-3.62 (m, 2H), 6.84-6.91 (m, 2H), 7.54-7.61 (m, 1H), 7.65-7.75 (m, 2H), 9.15 (bs, 1H) 13.88 (bs, 1H)	499	467	1
145		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.51-0.60 (m, 2H), 0.80-0.92 (m, 2H), 2.93-3.05 (m, 5H), 3.07-3.18 (m, 4H), 3.39 (s, 3H), 6.80-6.89 (m, 2H), 7.53-7.63 (m, 1H), 7.63-7.82 (m, 7H), 9.18 (bs, 1H), 13.89 (bs, 1H)	569	567	1
146		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.59 (m, 2H), 0.85-0.92 (m, 2H), 2.93 (s, 3H), 2.96-3.03 (m, 1H), 3.13-3.19 (m, 4H), 3.21-3.27 (m, 4H), 3.40 (s, 3H), 6.90-6.95 (m, 2H), 7.56-7.62 (m, 1H), 7.71-7.79 (m, 2H), 9.20 (bs, 1H) 13.90 (bs, 1H)	507	505	1
147		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.59 (m, 2H), 0.85-0.91 (m, 2H), 2.96-3.03 (m, 1H), 3.40 (s, 3H), 3.72 (s, 3H,) 6.84-6.89 (m, 2H), 7.56-7.62 (m, 1H), 7.73-7.81 (m, 2H), 9.21 (bs, 1H), 13.90 (bs, 1H)	375	373	1

TABLE 1-22
						Ex-
Com-						am-
pound				ESI MS	ESI MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
148		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.59 (m, 2H), 0.85-0.91 (m, 2H), 2.98-3.04 (m, 1H), 3.41 (s, 3H), 6.93-6.98 (m, 2H), 6.97-7.02 (m, 2H), 7.04-7.09 (m, 1H), 7.33-7.38 (m, 2H), 7.61-7.66 (m, 1H), 7.89-7.95 (m, 2H), 9.46 (bs, 1H), 13.97 (bs, 1H)	437	435	1
149		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.63 (m, 2H), 0.88-0.95 (m, 2H), 2.03 (s, 3H), 3.00-3.09 (m, 1H), 3.43 (s, 3H), 3.44-3.54 (m, 8H), 7.34-7.41 (m, 2H), 7.67-7.72 (m, 1H), 7.98-8.04 (m, 2H), 9.67 (bs, 1H)	499	497	1
150		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.61 (m, 2H), 0.87-0.94 (m, 2H), 2.66 (d, J = 4.59 Hz, 3H), 3.02-3.09 (m, 1H), 3.43 (s, 2H), 4.43 (s, 2H), 6.50-6.55 (m, 1H), 7.16-7.21 (m, 1H), 7.47-7.54 (m, 1H), 7.62-7.72 (m, 2H), 7.96-8.05 (m, 1H), 9.45 (bs, 1H), 14.05 (bs, 1H)	432	430	1
151		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.57-0.66 (m, 2H), 0.91-0.99 (m, 2H), 2.80-2.90 (m, 4H), 3.01-3.10 (m, 1H), 3.45 (s, 3H), 3.61-3.68 (m, 4H,) 7.61-7.70 (m, 2H), 7.75-7.82 (m, 1H), 8.18-8.26 (m, 2H), 10.01 (bs, 1H), 14.14 (bs, 1H)	494	492	3
152		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.58-0.63 (m, 2H), 0.90-0.96 (m, 2H), 2.39 (d, J = 5.0 Hz, 3H), 3.01-3.07 (m, 1H), 3.43 (s, 3H), 7.18-7.23 (m, 1H), 7.65-7.70 (m, 2H), 7.72-7.77 (m, 1H), 8.10-8.16 (m, 2H), 9.89 (bs, 1H), 14.12 (bs, 1H)	438	436	1
153		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.60 (m, 2H), 0.88-0.93 (m, 2H), 3.01-3.06 (m, 1H), 3.41 (s, 3H), 4.76 (s, 2H), 6.51-6.55 (m, 1H), 7.12-7. 15 (m, 1H), 7.18 (t, J = 8.3 Hz, 1H), 7.45-7.49 (m, 1H), 7.64-7.67 (m, 1H), 7.74-7.77 (m, 1H), 7.79-7.83 (m, 1H), 8.04-8.09 (m, 1H), 8.33-8.35 (m, 1H), 9.44 (bs, 1H), 10.44 (bs, 1H), 14.04 (bs, 1H)	495	493	1
154		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.52-0.63 (m, 2H), 0.78-1.00 (m, 2H), 2.90-3.08 (m, 1H), 3.40 (s, 3H), 3.72 (s, 6H), 6.07-6.16 (m, 1H), 7.16-7.29 (m, 2H), 7.64 (s, 1H), 9.29 (s, 1H), 14.00 (s, 1H)	405	403	1

TABLE 1-23
						Ex-
Com-						am-
pound				ESI MS	ESI MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
155		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.56-0.60 (m, 2H), 0.88-0.93 (m, 2H), 2.98-3.04 (m, 1H), 3.42 (s, 3H), 7.43-7.47 (m, 2H), 7.68 (d, J = 3.2 Hz, 1H), 7.89-7.93 (m, 2H), 9.57 (s, 1H), 14.04 (bs, 1H)	423	421	1
156		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.58-0.63 (m, 2H), 0.93-0.98 (m, 2H), 2.97-3.03 (m, 1H), 3.42 (s, 3H), 7.08-7.12 (m, 1H), 7.22 (t, J = 8.0 Hz, 1H), 7.68-7.75 (m, 2H), 8.48 (s, 1H), 9.62 (s, 1H), 14.06 (bs, 1H)	423	421	1
157		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.65 (m, 2H), 0.84-0.96 (m, 2H), 2.19 (s, 3H), 2.25-2.36 (m, 4H), 2.96-3.10 (m, 1H), 3.38-3.61 (m, 4H), 3.42 (s, 3H), 7.28-7.41 (m, 2H), 7.69 (d, J = 3.7 Hz, 1H), 7.94-8.06 (m, 2H), 9.64 (s, 1H), 14.04 (bs, 1H)	471	469	3
158		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.54-0.64 (m, 2H), 0.84-0.96 (m, 2H), 2.35 (t, J = 8.0 Hz, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.77 (t, J = 8.0 Hz, 2H), 3.00-3.10 (m, 1H), 3.42 (s, 3H), 6.78 (d, J = 7.8 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.68-7.73 (m, 1H), 7.73-7.82 (m, 2H), 9.33 (s, 1H), 13.96 (bs, 1H)	430	428	1
159		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.53-0.66 (m, 2H), 0.87-0.93 (m, 2H), 2.57 (d, J = 4.6 Hz, 3H), 2.99-3.09 (m, 1H), 3.35 (s, 2H), 3.41 (s, 3H), 6.83 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.64 (d, J = 3.2 Hz, 1H), 7.72-7.82 (m, 2H), 7.83-7.94 (m, 1H), 9.36 (s, 1H), 13.95 (bs, 1H)	416	414	1
160		Free	1H NMR (600 MHz, DMSO-D6) d ppm 0.55-0.65 (m, 2H), 0.88-0.95 (m, 2H), 2.99-3.07 (m, 1H), 3.30-3.57 (m, 1H), 3.42 (s, 3H), 6.84-6.97 (m, 1H), 7.09-7.17 (m, 1H), 7.66-7.72 (m, 1H), 7.72-7.76 (m, 1H), 7.76-7.81 (m, 2H), 8.02-8.11 (m, 3H), 9.86 (bs, 1H) 14.10 (bs, 1H)	501	499	1
161		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.55-0.61 (m, 2H), 0.88-0.95 (m, 2H), 2.99-3.06 (m, 1H), 3.42 (s, 3H), 4.63 (s, 2H), 6.48 (dd, J = 8.1, 2.1 Hz, 1H), 7.16 (t, J = 8.1 Hz, 1H), 7.47 (dd, J = 8.1, 1.8 Hz, 1H), 7.62-7.73 (m, 2H), 9.42 (s, 1H), 12.91-13.02 (m, 1H), 14.04 (s, 1H)	419	417	1

TABLE 1-24
						Ex-
Com-						am-
pound				ESI MS	ESI MS	ple
No.	Compound	Salt	NMR	(M + H)+	(M − H)−	No.
162		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.55-0.63 (m, 2H), 0.88-0.95 (m, 2H), 2.85 (s, 3H), 3.00 (s, 3H), 3.01-3.06 (m, 1H), 3.42 (s, 3H), 4.74 (s, 2H), 6.50 (dd, J = 8.1, 2.1 Hz, 1H), 7.15 (t, J = 8.1 Hz, 1H), 7,42-7.49 (m, 1H), 7.62-7.68 (m, 2H), 9.38 (s, 1H), 14.02-14.09 (m, 1H)	446	444	1
163		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.58-0.62 (m, 2H), 0.92-0.97 (m, 2H), 2.59 (s, 6H), 3.03-3.08 (m, 1H), 3.44 (s, 3H), 7.63-7.68 (m, 2H), 7.76 (d, J = 3.7 Hz, 1H), 8.17-8.22 (m, 2H), 9.97 (s, 1H), 14.15 (bs, 1H)	452	450	1
164		Free	1H NMR (600 MHz, DMSO-D6) δ ppm 0.55-0.60 (m, 2H), 0.87-0.92 (m, 2H), 3.01-3.06 (m, 1H) 3.41 (s, 3H), 6.35-6.39 (m, 1H), 7.03 (t, J = 8.0 Hz, 1H), 7.30-7.34 (m, 1H), 7.41 (s, 1H), 7.62 (d, J = 3.2 Hz, 1H), 9.18 (s, 1H), 9.27 (s, 1H), 13.96 (bs, 1 H)	361	359	1

TABLE 1-25
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
165		Free	343	341	8
166		Free	341	339	8
167		Free	340	338	8
168		Free	366	364	8
169		Free	352	350	8
170		Free	324	322	8
171		Free	360	358	8
172		Free	325	Not detected	8
173		Free	353	351	8

TABLE 1-26
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
174		Free	325	323	8
175		Free	339	Not detected	8
176		Free	408	406	8
177		Free	352	350	8
178		Free	430	Not detected	6
179		Free	419	417	10
180		Free	498	496	1
181		HCl	444	442	1
182		HCl	381	379	1

TABLE 1-27
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
183		HCl	363	361	1
184		HCl	375	373	1
185		Free	429	427	1
186		HCl	448	446	1
187		HCl	466	464	1
188		Free	509	507	13
189		Free	509	507	13
190		HCl	435	433	1
191		Free	534	532	12

TABLE 1-28
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
192		HCl	474	472	12
193		HCl	539	537	12
194		HCl	491	489	13
195		Free	445	443	1
196		Free	509	507	13
197		HCl	470	468	6
198		Free	463	461	6
199		Free	463	461	6
200		Free	452	450	6

TABLE 1-29
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
201		HCl	506	504	13
202		Free	474	472	12
203		HCl	491	489	12
204		HCl	473	471	12
205		Free	475	473	12
206		Free	474	472	12
207		Free	473	471	12
208		Free	490	488	12
209		Free	506	504	12

TABLE 1-30
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
210		HCl	542	540	12
211		Free	461	459	1
212		HCl	489	487	12
213		HCl	473	471	12
214		Free	494	492	1
215		Free	355	353	9
216		Free	409	407	9
217		Free	410	Not detected	11
218		Free	410	408	8

TABLE 1-31
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
219		Free	555	553	4
220		Free	529	527	4
221		Free	Not detected	526	1
222		Free	528	526	1
223		Free	422	420	1
224		Free	422	Not detected	1
225		Free	479	477	1
226		Free	479	477	1
227		HCl	465	463	1

TABLE 1-32
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
228		HCl	465	463	1
229		Free	389	387	1
230		Free	418	416	1
231		Free	460	458	1
232		Free	450	448	12
233		Free	381	379	12
234		Free	491	489	12
235		Free	441	439	14
236		Free	468	466	12

TABLE 1-33
Compound			ESI MS	ESI MS	Example
No.	Compound	Salt	(M + H)+	(M − H)−	No.
237		Free	464	462	12
238		Free	468	466	14
239		Free	484	482	14
240		Free	486	484	1
241		Free	550	548	1

Test Example

The effect of the compound of the present invention was confirmed by the following pharmacological test. The abbreviations in the Test Example are shown below.

• ATP: Adenosine triphosphate
• Tris: Tris(hydroxymethyl)aminomethane-hydrochloride buffer solution
• DTT: Dithiothreitol
• CHAPS: 3-[(3-Cholamidopropyl)dimethylammonio]propanesulfonate
• BSA: Bovine serum albumin
• PBS: Phosphate buffer solution
• MOPS: 3-Morpholinopropanesulfonic acid
• EDTA: Ethylenediaminetetraacetic acid
• Brij-35: Polyoxyethylene (23) lauryl ether

1. Syk Inhibition Test

10 ng/10 μl/well of a Syk (Wako Pure Chemical Industries) solution, 15 μl of a poly(L-glu-L-tyr) substrate peptide solution (Sigma, final concentration 5 μM), 20 μl of an ATP mixture (ATP: Oriental Yeast, final concentration 5 μM, [γ-33P]ATP: GE Healthcare Biosciences, 0.1 μCi/well) and 5 μl of a test substance solution were added to a 96-well Corning reaction plate, followed by incubation at room temperature for 30 minutes. An assay buffer containing 50 mM Tris pH 7.5, 10 mM MgCl₂, 0.1 mM Na₃VO₄, 1 mM DTT, 0.01% CHAPS and 100 μg/ml BSA was used. The test substance solution was made by dissolving the test substance in DMSO at each concentration. The final concentration of DMSO was 1%. The reaction was terminated by adding 100 μl of a 120 mM phosphoric acid solution as a reaction terminator. Then, the total reaction solution was transferred to MultiScreen (Millipore) and washed with 200 μl of 100 mM phosphoric acid four times.

After drying, 20 μl of MicroScint-O (PerkinElmer) was added and the radioactivity was measured by TopCount (PerkinElmer). The ratio of the radioactivity when the test substance was added to the radioactivity when the test substance was not added was determined. The IC₅₀ value was calculated from the inhibition rate at each concentration and used as an index of inhibitory activity.

The compounds of Compound Nos. 6 and 112 had Syk inhibitory activity with IC₅₀ values of 0.16 μM and 0.020 μM, respectively, and the other compounds of Compound Nos. 74, 102, 107, 114, 115, 128, 130, 131, 134, 135, 138, 143 and 146 each had inhibitory activity with an IC₅₀ value of 0.2 μM or less.

2. Degranulation Test Using Human Mast Cell Line LAD Cells

Human mast cell line LAD cells were sensitized with human IgE (Cosmo Bio; final concentration 1 μg/ml) overnight. The cells were harvested, and then washed with PBS (Invitrogen) and washed again with Tyrode's buffer solution (Sigma) containing 0.1% BSA (Sigma). The cells were seeded into a 96-well plate at 10⁵ cells/well and then the compound (0.1% final concentration DMSO solution) was added, followed by incubation at 37° C. for 15 minutes. Rabbit anti-human IgE (Dako Japan; final concentration 10 μg/ml) or control Ig (Dako Japan; final concentration 10 μg/ml) was added, followed by incubation at 37° C. for 30 minutes. The supernatant was recovered and p-nitrophenyl-2-acetamido-2-deoxy-β-D-glucopyranoside (Sigma; final concentration 4 mM), a substrate of β-hexosaminidase which is an index of degranulation, was added, followed by incubation at 37° C. for 45 minutes. Glycine (Wako; final concentration 0.2 M, pH 10.4) was added and the reaction was terminated. Then, the absorbance at 405 nm was measured.

The inhibition rate (%) was calculated as (anti-IgE antibody degranulation rate—compound-added group degranulation rate)/(anti-IgE antibody degranulation rate—control antibody degranulation rate)×100. The IC₅₀ value was calculated from the inhibition rate at each concentration and used as an index of inhibitory activity.

The compounds of Compound Nos. 7 and 112 had inhibitory activity with IC₅₀ values of 0.024 μM and 0.019 μM, respectively, and the other compounds of Compound Nos. 4, 13, 74, 88, 102, 107, 128, 130, 131, 134, 135, 138 and 143 each had inhibitory activity with an IC₅₀ value of 0.1 !μM or less.

3. Rat Passive Cutaneous Anaphylaxis (PCA) Test

The back of seven-week-old male Wistar rats was clipped under light anesthesia with ether, and the rats were sensitized by intradermal administration of 100 μl of 25 ng/ml anti-dinitrophenyl-IgE (DNP-IgE) (Sigma) to the back. 24 hours after the sensitization, 1 ml of a 0.5% Evans blue solution containing 1 mg of DNP-BSA was intravenously administered. Further, 30 minutes after the administration, the rats were sacrificed and the back skin was collected. The test compound, or only a vehicle as a control, was orally administered four hours prior to the antigen challenge. The length and breadth of the skin blue spot were calipered, and the area of the blue spot was calculated as length×breadth.

The PCA inhibition rate by the test substance was calculated by the following formula. In the formula,

• C represents: a blue spot area by PCA reaction when only the vehicle was administered, and
• X represents: a blue spot area by PCA reaction when the test compound was administered.

Inhibition rate (%)=(C−X)×100/C

The compound of Compound No. 6 excellently inhibited PCA reaction.

4. Mouse Collagen-Induced Arthritis (CIA) Test

Seven-week-old male DBA/1 mice were sensitized by intradermal administration of bovine type II collagen/complete Freund's adjuvant emulsion (150 μg/0.1 ml/mouse) to the tail head. 21 days after the primary sensitization, the mice were similarly boosted by intradermal administration of bovine type II collagen/complete Freund's adjuvant emulsion (100 μg/0.1 ml/mouse) to the tail head. After the booster, the degree of arthritis was scored by observation for each extremity twice a week on the following scale.

• 0: No arthritis
• 1: Edema in one finger joint
• 2: Edema in two or more finger joints or instep
• 3: Edema in tarsus or ankle
• 4: Severe edema or joint deformation

Oral administration of the test compound, or only a vehicle as a control, was started 30 minutes prior to the booster, and administration was carried out for 42 consecutive days thereafter. For each day passed, the total score for the extremities was provided as an arthritis score for one individual (0 to 16), and the arthritis onset inhibitory effect was evaluated as an average value for eight cases using the vehicle-administered group as a control group.

The compound of Compound No. 7 excellently inhibited the onset of arthritis in the CIA model.

5. Abl Inhibition Test

5 ng/5 μl/well of an Abl (Wako Pure Chemical Industries) solution, 30 μl of an Abltide substrate peptide solution (Wako Pure Chemical Industries; final concentration 5 μM) and 5 μl of a test substance solution were added to a 96-well plate (Corning), followed by incubation at room temperature for 15 minutes. Then, 10 μl of an ATP mixture (ATP: Oriental Yeast, final concentration 6 μM, [γ-33P]ATP: GE Healthcare Biosciences, 0.06 μCi/well, MgAcetate: Cosmo Bio, final concentration 10 mM) was added, followed by incubation at room temperature for 40 minutes. The Abl solution was prepared using a kinase buffer (20 mM MOPS pH 7.0, 1 mM EDTA, 0.1% β-mercaptoethanol, 0.01% Brij-35, 5% glycerol, 1 mg/ml BSA). The substrate peptide solution and the ATP mixture were prepared using 8 mM MOPS pH 7.0 and 0.2 mM

EDTA. The test substance solution was made by dissolving the test substance in DMSO at each concentration. The final concentration of DMSO was 1%. The reaction was terminated by adding 100 μl of a 100 mM phosphoric acid solution as a reaction terminator. Then, the total reaction solution was transferred to a 96-well MultiScreen plate (Millipore) and washed with 200 μl of 100 mM phosphoric acid three times. After drying, 20 μl of MicroScint-O (PerkinElmer) was added and the radioactivity was measured by TopCount (PerkinElmer). After subtracting the radioactivity in the well to which the Abltide substrate peptide was not added from each radioactivity, the ratio of the radioactivity when the test substance was added to the radioactivity when the test substance was not added was determined. The IC₅₀ value was calculated from the inhibition rate at each concentration and used as an index of inhibitory activity.

The compounds of Compound Nos. 55, 74, 78, 112, 115, 117, 119, 126, 130, 131, 132, 134, 143, 146, 152, 200, 216 and 217 each had inhibitory activity with an IC₅₀ value of 10 nM or less. The compounds of

Compound Nos. 6, 21, 38, 60, 102, 103, 107, 108, 110, 114, 116, 128, 150, 188, 192, 206, 208, 227 and 240 each had inhibitory activity with an IC₅₀ value of 50 nM or less.

From the test results of 1 to 4 above, it was confirmed that the compound of the present invention has a Syk inhibitory effect and a degranulation inhibitory effect and inhibits anaphylaxis and arthritis. Therefore, the compound is assumed to be useful as a prophylactic or therapeutic agent for diseases involving Syk such as allergic disease, autoimmune disease and arthritis.

From the test results of 5 above, it was confirmed that the compound of the present invention has an Abl inhibitory effect. Therefore, the compound is assumed to be useful as a prophylactic or therapeutic agent for diseases involving Abl such as cancer.

Formulation Examples are shown below.

Formulation Example 1

Granules containing the following ingredients are prepared.

Ingredients	Compound represented by formula [I]	10 mg
	Lactose	700 mg
	Corn starch	274 mg
	HPC-L	16 mg
		1000 mg

The compound represented by the formula [I] and lactose are allowed to pass through a 60-mesh sieve. Corn starch is allowed to pass through a 120-mesh sieve. They are mixed in a V-shape mixer. A low-viscosity hydroxypropylcellulose (HPC-L) solution is added to the mixed powder. The mixture is kneaded, granulated (extrusion granulation, pore size 0.5 to 1 mm) and then dried. The resulting dry granules are sieved through a vibrating sieve (12/60 mesh) to obtain granules.

Formulation Example 2

Encapsulation powder containing the following ingredients is prepared.

Ingredients	Compound represented by formula [I]	10 mg
	Lactose	79 mg
	Corn starch	10 mg
	Magnesium stearate	1 mg
		100 mg

The compound represented by the formula [I] and lactose are allowed to pass through a 60-mesh sieve. Corn starch is allowed to pass through a 120-mesh sieve. These ingredients and magnesium stearate are mixed in a V-shape mixer. A No. 5 hard gelatin capsule is filled with 100 mg of the 10% powder.

Formulation Example 3

Encapsulation granules containing the following ingredients are prepared.

Ingredients	Compound represented by formula [I]	15 mg
	Lactose	90 mg
	Corn starch	42 mg
	HPC-L	3 mg
		150 mg

The compound represented by the formula [I] and lactose are allowed to pass through a 60-mesh sieve. Corn starch is allowed to pass through a 120-mesh sieve. They are mixed in a V-shape mixer. A low-viscosity hydroxypropylcellulose (HPC-L) solution is added to the mixed powder. The mixture is kneaded, granulated and then dried. The resulting dry granules are sieved and size-regulated through a vibrating sieve (12/60 mesh) and a No. 4 hard gelatin capsule is filled with 150 mg of the resulting granules.

Formulation Example 4

A tablet containing the following ingredients is prepared.

Ingredients	Compound represented by formula [I]	10 mg
	Lactose	90 mg
	Microcrystalline cellulose	30 mg
	Magnesium stearate	5 mg
	CMC-Na	15 mg
		150 mg

The compound represented by the formula [I], lactose, microcrystalline cellulose and CMC—Na (sodium carboxymethylcellulose) are allowed to pass through a 60-mesh sieve and mixed. Magnesium stearate is added to the mixed powder to obtain a mixed powder for formulation. The mixed powder is directly compressed to obtain 150 mg of a tablet.

Formulation Example 5

An intravenous formulation is prepared as follows.

	Compound represented by formula [I]	100	mg
	Saturated fatty acid glyceride	1000	ml

Typically, the solution having the above ingredients is intravenously administered to a patient at a rate of 1 ml per minute.

INDUSTRIAL APPLICABILITY

The compound of the present invention has Syk and/or Abl inhibitory activity and can be used as a prophylactic or therapeutic agent for Syk- and/or Abl-related diseases, specifically, a prophylactic or therapeutic agent for diseases such as allergic disease, autoimmune disease and arthritis, or cancer.

Claims

1. A pyrazolopyrimidine compound represented by the formula [I]:

2. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to claim 1, wherein R1 is a C1-6 alkyl group, a C3-8 cycloalkyl group or a C2-9 heterocyclyl group (wherein the C1-6 alkyl group, the C3-8 cycloalkyl group and the C2-9 heterocyclyl group are unsubstituted or substituted with 1 to 4 substituents selected from the following Substituent Group A); Substituent Group A representsa group consisting of a halogen atom, a hydroxy group, an amino group, a cyano group, a carboxy group, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group (wherein the C1-6 alkoxy group is unsubstituted or substituted with a hydroxy group), a C1-6 alkylsulfanyl group, a C1-6 alkoxycarbonyl group, a C3-8 cycloalkoxy group, a (C1-6 alkyl)amino group, a di(C1-6 alkyl)amino group, a C1-6 alkoxycarbonylamino group, a hydroxyaminocarbonyl group, a ureido group, a carbamoyl group, a C2-9 heterocyclyl group (wherein the C2-9 heterocyclyl group is unsubstituted or substituted with a C1-6 alkyl group or an oxo group) and a C1-9 heteroaryl group;R2 is a linear C1-6 alkyl group;Ar is a C1-9 heteroaryl group (wherein the C1-9 heteroaryl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a sulfanyl group, a hydroxy group, a C1-6 alkoxy group, a morpholinyl group and a trifluoromethyl group) or a phenyl group (wherein the phenyl group is unsubstituted or substituted with the same or different 1 to 3 Ras); andRa is a hydroxy group, a cyano group, a carboxy group, a sulfanyl group, a C1-6 alkoxycarbonyl group, a C1-6 alkyl group (wherein the C1-6 alkyl group is unsubstituted or substituted with a carboxy group or —CONR4R5 (wherein R4 and R5 are the same or different and each represent a hydrogen atom or a C1-6 alkyl group)), a C3-8 cycloalkyl group, a C1-6 alkoxy group (wherein the C1-6 alkoxy group is unsubstituted or substituted with a carboxy group or —CONR6R7 (wherein R6 and R7 are the same or different and each represent a hydrogen atom, a C1-6 alkyl group, a C3-8 cycloalkyl group, a C1-6 alkoxy group, a C2-9 heterocyclyl group or a C1-9 heteroaryl group)), a C 1-9 heteroaryl group, a C3-8 cycloalkoxy group, a halogen atom, a trifluoromethyl group, a trifluoromethoxy group, a phenoxy group, —NR8R9, —CONR8R9, —NR8SO2R9 or —SO2NR8R9 (wherein R8 and R9 are the same or different and each represent a hydrogen atom, a C1-6 acyl group, a C1-6 alkoxycarbonyl group, a toluyl group, a C1-9 heteroaryl group or a C1-6 alkyl group (wherein the C1-6 alkyl group is unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a hydroxy group, a carboxy group and a C1-6 alkoxy group),or when R8 and R9 are substituents on the adjacent nitrogen atom, they, together with the adjacent nitrogen atom, represent the formula [II]:

3. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 2, wherein Ar is a phenyl group (wherein the phenyl group is unsubstituted or substituted with the same or different 1 to 3 Ras).

4. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 2, wherein Ar is a phenyl group (wherein the phenyl group is substituted at the 3-, 4- or 5-position with the same or different 1 to 3 Ras).

5. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 2 to 4, wherein Y is NH.

6. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 2 to 4, wherein R1 is a C1-8 alkyl group (wherein the C1-8 alkyl group is unsubstituted or substituted with an amino group, a (C1-6 alkyl)amino group or a di(C1-6 alkyl)amino group).

7. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to any one of claims 2 to 4, wherein R1 is a C3-8 cycloalkyl group (wherein the C3-8 cycloalkyl group is unsubstituted or substituted with an amino group).

8. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1, wherein R1 is a C1-9 heteroaryl group or a phenyl group (wherein the C1-9 heteroaryl group and the phenyl group are unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, a cyano group, a C1-6 alkyl group, a trifluoromethyl group, a C1-6 alkoxy group, a sulfanyl group, a carbamoyl group, a (C1-6 acyl)amino group and an oxo group), and Y is NH.

9. A pyrazolopyrimidine compound represented by the formula [III]:

10. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 9, wherein R1 is a C1-8 alkyl group (wherein the C1-6 alkyl group is unsubstituted or substituted with an amino group, a cyano group, a (C1-6 alkyl)amino group or a di(C1-6 alkyl)amino group).

11. The pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 9, wherein R1′ is a C3-8 cycloalkyl group (wherein the C3-8 cycloalkyl group is unsubstituted or substituted with a hydroxy group or an amino group).

12. A Syk inhibitor comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1 or 2.

13. A therapeutic agent or prophylactic agent for allergic disease, autoimmune disease or arthritis, comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1 or 2.

14. An Abl inhibitor comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1 or 2.

15. A therapeutic agent or prophylactic agent for cancer, comprising, as an active ingredient, the pyrazolopyrimidine compound, a tautomer or a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof according to claim 1 or 2.