# Patent

## Title
Heterocyclic compound

## Abstract

Provided is a novel compound which is an agent for treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, and based on a PI3Kδ selective inhibitory action and/or an IL-2 production inhibitory action and/or a B cell proliferation inhibitory action (including an activation inhibitory action). The provided compound has a PI3Kδ selective inhibitory action, an IL-2 production inhibitory action, and/or a B cell proliferation inhibitory action, including an activation inhibitory action.

## Background
TECHNICAL FIELD
The present invention relates to a heterocyclic compound which is useful as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for preventing and/or treating phosphatidylinositol-3-kinase δ (PI3Kδ)-related diseases.
BACKGROUND ART
Phosphatidylinositol-3-kinase (PI3K) is a lipid signaling kinase, which is present universally throughout species, ranging from plants or yeasts to mammals including humans. PI3K is an enzyme for phosphorylating the hydroxyl group at the 3-position of phosphatidylinositol, phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-diphosphate, which are cell membrane phospholipids, and from each of these substrates, phosphatidylinositol-3-phosphate, phosphatidylinositol-3,4-diphosphate, and phosphatidylinositol-3,4,5-triphosphate (PIP3) are produced. These phosphorylated phosphatidylinositols thus produced act as an intracellular second messenger. Particularly, PIP3 causes migration of various molecules having pleckstrin homology (PH) domains to a position near the cell membrane to induce activation of the molecules, and thus it is considered to be the most important phosphorylated phosphatidylinositol (“The Journal of Biological Chemistry”, 1999, Vol. 274, p. 8347-8350).
PI3K is divided into three classes, Classes I, II, and III, according to various characteristics, and from the viewpoints that the only enzyme producing PIP3 in vivo is Class I PI3K, the Class I PI3K is considered to be the most important class (“Biochimica et Biophysica Acta”, 2008, Vol. 1784, p. 159-185). The Class I PI3K is subdivided into IA and IB. The Class IA PI3K consists of heterodimers including a combination of a 110-kDa catalytic subunit (p110α, β, or δ) and a 50- to 85-kDa regulatory subunit (p85α, p85β, p55α, p55γ, or p50α), and the Class IB PI3K is a heterodimer of a 110-kDa catalytic subunit (p110γ) and a 101-kDa regulatory subunit (p101) (“Nature Immunology”, 2003, No. 4, p. 313-319). Hereinafter, the respective names of PI3K are referred to as PI3Kα, β, δ, and γ, corresponding to catalytic subunits included therein.
PI3Kα and β are widely present in a biological body and deficiency of PI3Kα and β in mice has been reported to be fetally lethal in both cases (“The Journal of Biological Chemistry”, 1999, Vol. 274, p. 10963-10968; and “Mammalian Genome”, 2002, Vol. 13, p. 169-172). As a result of studies using subtype selective compounds, it has been reported that PI3Kα plays an important role in insulin signaling and a PI3Kα inhibitor causes insulin resistance (“Cell”, 2006, Vol. 125, p. 733-747). Further, it has been reported that PI3Kβ is involved in platelet aggregation and a PI3Kβ inhibitor has an antithrombotic effect (“Nature Medicine”, 2005, Vol. 11, p. 507-514). On the other hand, mice deficient in PI3Kβ or γ are all born normally, and no problems concerning growth, life span, reproduction, or the like have been found (“Science”, 2000, Vol. 287, p. 1040-1046; and “Molecular and Cellular Biology”, 2002, Vol. 22, p. 8580-8591). In particular, expression of PI3Kδ is significantly limited to hemocytes and lymphoid tissues, and mice deficient in PI3Kδ have been found to have significant damage in activation of lymphocytes. A close relationship between the activation of lymphocytes and immunity/inflammation is well known, and compounds selectively inhibiting PI3Kδ have a potential to be immunity/inflammatory inhibitors having both a potent inhibitory action on the activation of lymphocytes and safety.
Interleukin-2 (IL-2) is a kind of cytokine which is mainly produced from activated T cells. IL-2 induces proliferation and activation of lymphocytes via an IL-2 receptor which is a receptor for IL-2. IL-2 is a very important molecule in signaling the activation of an immune system, and its production inhibitors (for example, Tacrolimus and Cyclosporin A) have been used clinically as immunosuppressing agents. In addition, anti-IL-2 receptor monoclonal antibodies such as Basiliximab and Daclizumab have been used clinically as immunosuppressing agent.
B cells are one of the main subsets of lymphocytes, along with T cells, and are cells which is a main actor of humoral immunity. It is known that humoral immunity plays an extremely important role in preventing infection from pathogens or the like, but in autoimmune diseases such as rheumatoid arthritis and the like, abnormal activation of humoral immunity occurs, which is deeply involved in the pathogenesis. In fact, an anti-CD20 antibody, Rituximab, has been used clinically as a drug for treating rheumatoid arthritis.
As the compound having a PI3K inhibitory action, for example, the compounds of the formula (A-1) (Patent Document 1), the formula (A-2) (Patent Document 2), the formula (A-3) (Patent Document 3), the formula (B-1) (Patent Document 4), the formula (B-2) (Patent Document 5), the formula (B-3) (Patent Document 6), the formula (C) (Patent Document 7), the formula (D-1) (Patent Document 8), the formula (D-2) (Patent Document 9), the formula (E-1) (Patent Document 10), the formula (E-2) (Patent Document 11), the formula (E-3) (Patent Document 12), the formula (F) (Patent Document 13), the formula (G) (Patent Document 14), the formula (H) (Patent Document 15 and Non-Patent Document 1), the formula (J) (Patent Document 16), and the formula (K) (Patent Document 17) described below have been reported. However, the compound of the formula (I) of the present application as described later is different in the structure of the group R1 of the formula (I) from the compounds of the formulae (A-1) to (E-3), (H), and (K). It is different in structure from the compounds of the formulae (F) and (G), in that it has a benzimidazolyl-1-yl group. As the group R2 of the formula (J), a heteroaryl group has been disclosed, but there is no specific disclosure of the benzimidazolyl-1-yl group, and there is no disclosure of the compound of the formula (I) of the present invention in Patent Document 16. Further, there is no description of a PI3Kδ selective inhibitory action in any documents.













(wherein R2 in the formulae (A-1) to (E-3) represents a difluoromethyl group or the like. R1 and R2 in the formula (F) are combined with each other to form an unsubstituted or substituted morpholino group, together with N to which they are bonded, X represents a bond or the like, and R3 represents an unsubstituted or substituted indolyl group. R2 in the formula (G) represents a substituted indol-4-yl group at the position 5 or 6. R3 in the formula (H) represents a difluoromethyl group or the like, and R6 represents a morpholino group which may be substituted, or the like. In the formula (J), Y1 and Y2 represent N, CH, or the like, X represents NR4CR6R7 or the like, R1 represents a heterocyclic group or the like, and R2 represents a heteroaryl group or the like. In the formula (K), X, Y, and Z represent N or CH, provided that at least two of X, Y, and Z represent N, R1 represents heteroaryl or the like, R2 represents a heterocycle or the like, Q represents a bond, azetidinylen-4-amino, or the like, T represents —C(O)—, —C(═S)—, or —S(O)2—, and R5 represents halogen or —O—S(O)2—R7. For the other symbols, reference may be made to the publication.)
It has been reported that the compounds of the formula (L-1) (Patent Document 18), the formula (L-2) (Patent Document 19), the formula (L-3) (Patent Document 20), the formula (L-4) (Patent Document 21), and the formula (L-5) (Patent Document 22) described below have an anti-tumor activity. Further, in Non-Patent Document 2, it has been suggested that a secondary amine compound of the formula (M) has an Lck inhibitory action and an IL-2 production inhibitory action, and is applied for autoimmune diseases and rejection reaction in organ transplantation. However, the compound of the formula (I) of the present invention essentially has a difluoromethyl group, which is different in the structure from the compounds of the formulae (L-1), (L-2), and (M). It is also different in the structure of the group of R1 of the formula (I) from the compounds of the formulae (L-3) and (L-5). In addition, it is different in the structure of the substituent on a benzimidazole ring from the compound of the formulae (L-4). Further, there is no description of a PI3Kδ selective inhibitory action in any literature.







(in the formula (L-1), both of X and Y represent N, or one of X and Y represents N and the other represents CR7, and R6 represents H or C1-6 alkyl; in the formula (L-2), both of X and Y represent N, or one of X and Y represents N and the other represents CR3, and R1 represents a morpholino group or the like; in the formula (L-3), X represents N or CH, R1 represents CHnF3-n (n is 1 or 2), and R2 represents morpholino which may be substituted, or the like; in the formula (L-4), X represents N or CH, and R1 represents halogen or a hydroxyl group; in the formula (L-5), X represents N or CH, R1 represents a morpholino group which may be substituted with 1 to 4 C1-6 alkyl groups, and Y represents C1-6 alkyl; and in the formula (M), R1 represents a morpholino group or the like. For the other symbols, reference may be made to the publication.)
Furthermore, a quinazolin-4-one derivative (Patent Documents 23 to 25) has been reported as a PI3Kδ selective inhibitor, and its usability in inflammation, immune diseases, or hematologic tumors (leukemia and the like) is indicated. As other PI3Kδ selective inhibitors, a thiazolylurea derivative (Patent Document 26) has been reported together with its usability in inflammation, immune diseases, or the like.
Furthermore, the invention relating to a triazine or pyrimidine derivative having a PI3Kδ selective inhibitory action, which is an invention in the prior art by the present inventors, has been disclosed after the priority date of the present application (Patent Document 27). The compound of the present invention is different in the structure of the group R1 in the formula (I) from the compound disclosed in the prior application.
RELATED ART
Patent Documents
[Patent Document 1] Pamphlet of International Publication WO 2008/032027
[Patent Document 2] Pamphlet of International Publication WO 2008/032077
[Patent Document 3] Pamphlet of International Publication WO 2008/032086
[Patent Document 4] Pamphlet of International Publication WO 2008/032028
[Patent Document 5] Pamphlet of International Publication WO 2008/032036
[Patent Document 6] Pamphlet of International Publication WO 2008/032041
[Patent Document 7] Pamphlet of International Publication WO 2008/032033
[Patent Document 8] Pamphlet of International Publication WO 2008/032060
[Patent Document 9] Pamphlet of International Publication WO 2008/032064
[Patent Document 10] Pamphlet of International Publication WO 2008/032072
[Patent Document 11] Pamphlet of International Publication WO 2008/032089
[Patent Document 12] Pamphlet of International Publication WO 2008/032091
[Patent Document 13] Pamphlet of International Publication WO 2007/042810
[Patent Document 14] Pamphlet of International Publication WO 2008/125839
[Patent Document 15] Specification of European Patent Application Publication No. 1864665
[Patent Document 16] Pamphlet of International Publication WO 2009/007751
[Patent Document 17] Pamphlet of International Publication WO 2009/120094
[Patent Document 18] Specification of European Patent Application Publication No. 1020462
[Patent Document 19] International Publication WO 00/43385
[Patent Document 20] Pamphlet of European Patent Application Publication No. 1389617
[Patent Document 21] Pamphlet of European Patent Application Publication No. 1557415
[Patent Document 22] Pamphlet of European Patent Application Publication No. 1741714
[Patent Document 23] Pamphlet of International Publication WO 01/81346
[Patent Document 24] Pamphlet of International Publication WO 03/035075
[Patent Document 25] Pamphlet of International Publication WO 2005/113556
[Patent Document 26] Pamphlet of International Publication WO 2008/000421
[Patent Document 27] Pamphlet of International Publication WO 2010/092962
Non-Patent Documents
[Non-Patent Document 1] Journal of the National Cancer Institute, 2006, Vol. 98, p. 545-556
[Non-Patent Document 2] Bioorganic & Medicinal Chemistry Letters, 2006, Vol. 16, p. 5973-5977
DISCLOSURE OF INVENTION
Problems to be Solved by the Invention
A pharmaceutical composition, for example, a pharmaceutical composition having a PI3Kδ inhibitory action, in particular, a pharmaceutical composition for preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumors, and a heterocyclic compound which is useful as an active ingredient of the pharmaceutical composition, are provided.
Means for Solving the Problems
The present inventors have extensively studied a PI3Kδ selective inhibitory action and/or an IL-2 production inhibitory action and/or a B cell proliferation inhibitory action (including an activation inhibitory action), and as a result, they have found that a novel triazine or pyrimidine derivative has an excellent PI3Kδ selective inhibitory action and/or IL-2 production inhibitory action and/or B cell proliferation inhibitory action (including an activation inhibitory action), and can be an agent for preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, thereby completing the present invention.
That is, the present invention relates to a compound of the formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound or a salt thereof and an excipient.




(wherein
A1, A2, and A3 are the same as or different from each other and are CH or N, provided that at least two of A1 to A3 are N,
B's are the same as or different from each other and are CR3 or N, provided that at least three of four B's are CR3,
R1 is —NH-lower alkylene-C(O)—OH or -L1-L2-Y,
R2's are the same as or different from each other and are halogen, —OH, —O-lower alkyl, —CN, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of halogen, —OH, —O-lower alkyl, and —CN,
n is an integer of 0 to 8,
R3's are the same as or different from each other and are H, —O-lower alkyl, cyano, —N(R4)2, —C(O)—OH, —C(O)—O-lower alkyl, —C(O)—N(R4)2, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —N(R4)2, —C(O)—OH, —C(O)—O-lower alkyl, —C(O)—N(R4)2, and halogen,
R4's are the same as or different from each other and are H, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, cycloalkyl, and phenyl,
L1 is -lower alkynylene-, —NR5—, —NR5—S(O)2—, —NR5—C(O)—, —O—, —S—, or —S(O)m—,
m's are the same as or different from each other and are 1 or 2,
L2 is a bond, -ALK-X2—, -ALK-NR6—C(O)—, -ALK-NR6—C(O)—O-ALK-, -ALK-S(O)m—X1—, or -ALK-C(O)—X2—,
ALK's are the same as or different from each other and are lower alkylene which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, cycloalkyl, and phenyl,
X1 is a bond, —NR6—, or —NR6-ALK-,
X2's are the same as or different from each other and are a bond, —NR6—, —NR6-ALK-, —O—, —S—, —NR6-ALK-O—, —NR6-ALK-C(O)—NR6—, or —NR6-ALK-C(O)—,
R5's are the same as or different from each other and are —R4, lower alkenyl, or cycloalkyl,
R6's are the same as or different from each other and are H, cycloalkyl, phenyl, a non-aromatic heterocycle which may be substituted with lower alkyl, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, —N(R4)2, cycloalkyl, phenyl, and a non-aromatic heterocycle,
Y is lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —N(lower alkyl)2 and —C(O)—N(lower alkyl)2, cycloalkyl which may be substituted with one or more substituents selected from a Group D1, aryl which may be substituted with one or more substituents selected from the Group D1, an aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, or a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1,
the Group D1 consists of:
(1) halogen,
(2) —O—R8,
(3) —S—R8,
(4) —CN,
(5) —NO2,
(6) —NR4R7, in which R7 is —R8, —C(O)—R8, —C(O)—C(O)—N(R8)2, —C(O)—O—R8, and —S(O)2—R8,
(7) —C(O)—R8,
(8) —S(O)2—R8 and —S(O)2—N(R8)2,
(9) —C(O)—O—R8,
(10) —C(O)—N(R8)2,
(11) —C(O)—C(O)—N(R8)2,
(12) —O—C(O)—R8, —O—C(O)—NH—C(═NH)—NH2, and —O—C(O)—N(R8)2,
(13) -L3-cycloalkyl, -L3-aryl, -L3-aromatic heterocycle, and -L3-non-aromatic heterocycle, in which the cycloalkyl, aryl, aromatic heterocycle, and non-aromatic heterocycle may be each substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with one or more substituents selected from the group consisting of —O—R6, —CN, halogen, —N(R6)2, —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)2, —N(R6)—C(O)—O—R6, —S(O)2-lower alkyl, cycloalkyl, phenyl, and a non-aromatic heterocycle; oxo; cycloalkyl, aryl, aromatic heterocycle, and a non-aromatic heterocycle, each of which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen; and the substituents of (1) to (12),
(14) oxo, and
(15) lower alkyl, —O-lower alkyl, and lower alkenyl, each of which may be substituted with one or more substituents selected from the substituents described in (1) to (14),
L3's are the same as or different from each other and are -a bond, —O—, —S—, —NR5—, —NR5—S(O)2—, —NR5—C(O)—, —C(O)—NR5—, —S(O)m—, -ALK-, —O-ALK-, -ALK-O—, —O-ALK-O—, —S-ALK-, -ALK-S—, -ALK-S(O)m—, —S(O)m-ALK-, —NR5-ALK-, -ALK-NR5—, —C(O)—NR5-ALK-, —C(O)—NR5-ALK-C(O)—, —C(O)—NR5-ALK-O-ALK-, —NR5—C(O)-ALK-, —NR5—C(O)-ALK-C(O)—, —NR5—C(O)-ALK-O-ALK-, -ALK-C(O)—NR5—, -ALK-NR5—C(O)—, —C(O)—O—, -ALK-C(O)—O—, —C(O)—O-ALK-, —C(O)-ALK-, -ALK-C(O)—, —NR5—C(O)-ALK-NR5—, or —C(O)—,
R8's are the same as or different from each other and are H; cycloalkyl, phenyl, pyridyl, or a non-aromatic heterocycle, each of which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen; —R9 or -ALK-L4-R9, in which R9 is lower alkyl which may be substituted with one or more substituents selected from the group consisting of —O—R6, —S—R6, —CN, —N(R6)2, —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)2, —N(R6)—C(O)—O—R6, -cycloalkyl, phenyl, and a non-aromatic heterocycle, and
L4 is —C(O)—, —C(O)—NR5—, —NR5—, —NR5—S(O)2—, —NR5—C(O)—, —NR5—C(O)—O—, —O—, —S—, or —S(O)m—,
provided that in a case where R1 has the following formula (II), all of B's are CH, W is NH or O, B1 is a bond or lower alkylene, and B2 is a bond or lower alkylene,




R10 is —C(O)-(lower alkylene substituted with —NH—C(O)—O-lower alkyl)-S-lower alkyl, —C(O)-non-aromatic heterocycle, —C(O)-lower alkylene-NH-lower alkylene-(cycloalkyl which may be substituted with —OH), —C(O)-lower alkylene-NH-(cycloalkyl which may be substituted with a group selected from the group consisting of lower alkyl and —OH), —C(O)-lower alkylene-NH-non-aromatic heterocycle, —C(O)-lower alkylene-NH-(lower alkyl substituted with —OH), or —C(O)-(cycloalkyl substituted with one or more substituents selected from the group consisting of —NH2, —N(lower alkyl)2, and —NH—C(O)—O-lower alkyl), or
R4 and R10 form a 4- to 8-membered monocyclic heterocyclic group containing 1 to 4 hetero atoms selected from O, S, and N, together with N to which they are bonded, and are further substituted with at least one substituent selected from a Group D2,
in which the Group D2 consists of:
(a) —O-(lower alkyl substituted with one or more substituents selected from the group consisting of —O—R6, —S—R6, —CN, —N(R6)2, —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)2, —N(R6)—C(O)—O—R6, cycloalkyl, and a non-aromatic heterocycle), —O-(cycloalkyl, phenyl, pyridyl, or a non-aromatic heterocycle, each of which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen), and —O-ALK-L4—R9,
(b) —SR8,
(c) —NO2,
(d) —NR11R7, in which R7 is —R8, —C(O)—R8, —C(O)—C(O)—N(R8)2, —C(O)—O—R8, and —S(O)2—R8, and R11 is lower alkyl substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, cycloalkyl, and phenyl,
(e) —C(O)—R8,
(f) —S(O)2—R8 and —S(O)2—N(R8)2,
(g) —C(O)—O-(lower alkyl substituted with one or more substituents selected from the group consisting of —O—R6, —S—R6, —CN, —N(R6)2, —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)2, —N(R6)—C(O)—O—R6, cycloalkyl, phenyl, and a non-aromatic heterocycle), —C(O)—O-(cycloalkyl, phenyl, pyridyl, or a non-aromatic heterocycle, each of which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen), and —C(O)O-ALK-L4-R9,
(h) —C(O)—N(R8)2,
(i) —C(O)—C(O)—N(R8)2,
(j) —O—C(O)-(lower alkyl substituted with one or more substituents selected from the group consisting of —O—R6, —S—R6, —CN, —N(R6)2, —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)2, —N(R6)—C(O)—O—R6, cycloalkyl, phenyl, and a non-aromatic heterocycle), —O—C(O)-(cycloalkyl, phenyl, pyridyl, or a non-aromatic heterocycle, each of which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen), —O—C(O)-ALK-L4-R9, —O—C(O)—NH—C(═NH)—NH2, and —O—C(O)—N(R8)2,
(k) lower alkyl substituted with one or more substituents selected from the group consisting of —CN, —N(R6)2, —C(O)—R6, —C(O)—O—R6, —C(O)—N(R6)2, —N(R6)—C(O)—O—R6, —S(O)2-lower alkyl, cycloalkyl, and phenyl,
(l) cycloalkyl which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen,
(m) aryl which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen,
(n) an aromatic heterocycle substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen, and
(o) a non-aromatic heterocycle substituted with one or more substituents selected from the group consisting of lower alkyl, —OH, —O-lower alkyl, —CN, and halogen.)
Unless specified otherwise, in the case where the symbols of the chemical formulae in the present specification are also used in other chemical formulae, the same symbols denote the same meanings.
Furthermore, the present invention relates to a pharmaceutical composition for preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, which comprises the compound of the formula (I) or a salt thereof as an active ingredient. Further, the pharmaceutical composition includes an agent for preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, which comprises the compound of the formula (I) or a salt thereof. In a certain embodiment, the present invention relates to an agent for preventing and/or treating rejection reactions in kidney, liver, and heart transplantations, in another embodiment, an agent for preventing and/or treating chronic rejection and acute rejection, and in still another embodiment, an agent for preventing and/or treating antibody-related rejection.
Furthermore, the present invention relates to use of the compound of the formula (I) or a salt thereof in the manufacture of a pharmaceutical composition for preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, and use of the compound of the formula (I) or a salt thereof in preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, the compound of the formula (I) or a salt thereof for preventing and/or treating rejection reactions in various organ transplantations, allergy diseases, auto immune diseases, and hematologic tumor, and a method for preventing or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor, including administering to a subject an effective amount of the compound of the formula (I) or a salt thereof. Here, the “subject” is a human or any of other animals in need of prevention or treatment thereof, and in a certain embodiment, a human in need of prevention or treatment thereof.
Furthermore, the present invention relates to a PI3Kδ selective inhibitor and/or an IL-2 production inhibitor and/or a B cell proliferation inhibitor, each of which contains the compound of the formula (I) or a salt thereof.
Effects of the Invention
The compound of the formula (I) has a PI3Kδ selective inhibitory action and/or an IL-2 production inhibitory action and/or a B cell proliferation inhibitory action (including an activation inhibitory action), and can therefore be used as an agent for preventing or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and hematologic tumor.


EMBODIMENTS FOR CARRYING OUT THE INVENTION
Hereinbelow, the present invention will be described in detail.
The “lower alkyl” is linear or branched alkyl having 1 to 6 carbon atoms (which is hereinafter simply referred to as C1-6), and examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like. In another embodiment, the lower alkyl is C1-4 alkyl, in still another embodiment, methyl, ethyl, or tert-butyl, and in a further still other embodiment, methyl.
The “lower alkenyl” is linear or branched C2-6 alkenyl, and examples thereof include vinyl, propenyl, butenyl, pentenyl, 1-methylvinyl, 1-methyl-2-propenyl, 1,3-butadienyl, pentadienyl, and the like. In another embodiment, the lower alkenyl is C2-4 alkenyl, and in still another embodiment, propenyl.
The “lower alkylene” is a divalent group formed by the removal of any hydrogen atom of the “lower alkyl”. Accordingly, the “C1-6 alkylene” is linear or branched alkylene having 1 to 6 carbon atoms, and examples thereof include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, dimethylmethylene, ethylmethylene, methylethylene, dimethylethylene, ethylethylene, and the like. In another embodiment, the lower alkylene is methylene, ethylene, and in still another embodiment, methylene.
The “lower alkenylene” is linear or branched C2-6 alkenylene, and examples thereof include vinylene, ethylidene, propenylene, butenylene, pentenylene, hexenylene, 1,3-butadienylene, 1,3-pentadienylene, and the like. In another embodiment, the lower alkenylene is C2-4 alkenylene, and in still another embodiment, propenylene.
The “lower alkynylene” is linear or branched C2-6 alkynylene, and examples thereof include ethynylene, propynylene, butynylene, pentynylene, hexynylene, 1,3-butadiynylene, 1,3-pentadiynylene, and the like. In another embodiment, the lower alkynylene is C2-4 alkynylene, and in still another embodiment, propynylene.
The “halogen” is F, Cl, Br, or I, in another embodiment, F, and in still another embodiment, Cl.
The “cycloalkyl” is C3-10 saturated hydrocarbon ring group, which may have a bridge and may be combined with a non-aromatic heterocyclic group to form a spiro ring. Specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclooctyl, bicyclo[3.3.0]octane, hexahydro-1′H-spiro-1,3-dioxane-2,2′-pentalene, 1,4-dioxaspiro[4.5]decane, bicyclo[2.2.2]octyl, adamantyl, azaspiro[5.5]undecanyl, octahydrocyclopenta[c]pyrrole, indanyl, and the like. In another embodiment, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, octahydropentalene, bicyclo[2.2.2]octyl, or adamantyl, in still another embodiment, C3-8 cycloalkyl, in further still another embodiment, C3-6 cycloalkyl, in further still another embodiment, cyclohexyl, in further still another embodiment, octahydropentalene, and in further still another embodiment, adamantyl.
The “aryl” is C6-14 monocyclic to tricyclic aromatic hydrocarbon ring group, and examples thereof include phenyl, naphthyl, and the like. In another embodiment, the aryl is phenyl.
The “aromatic heterocycle” is an aromatic heterocycle having 5 to 6 ring members, containing at least one hetero atom selected from O, N, and S as a ring-constituting atom, and may be fused with a benzene ring or an aromatic heterocycle. Examples thereof include pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thienyl, furyl, indolyl, isoindolyl, benzoimidazolyl, indazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzoxazolyl, benzoisoxazolyl, benzofuranyl, benzothienyl, carbazolyl, dibenzo[b,d]furanyl, dibenzo[b,d]thienyl, thienopyridyl, thienopyrimidinyl, thienopyrazyl, 1,4-benzodioxin-2-yl, [1,2,4]triazolo[4,3-a]pyridyl, imidazo[1,2-a]pyridyl, and the like. In another embodiment, the aromatic heterocycle is imidazolyl, pyridyl, pyrazinyl, indolyl, indazolyl, benzoimidazolyl, or benzothiazolyl.
The “non-aromatic heterocycle” is a non-aromatic heterocycle having 4 to 8 ring members, containing at least one hetero atom selected from O, N, and S as a ring-constituting atom, which may have unsaturated bonds in a part of the ring and may be bridged. The non-aromatic heterocycle may be fused with a benzene ring or an aromatic heterocycle. Further, the sulfur atom that is a ring-constituting atom may be oxidized. Examples of the non-aromatic heterocycle include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, morpholinyl, thiomorpholinyl, quinuclidinyl, 1,1-dioxidethiomorpholinyl, tetrahydropyridinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, 4,5-dihydrothiazolyl, dioxolanyl, dioxanyl, tetrahydrothiopyranyl, tetrahydroisoquinolyl, oxazolidinyl, tropane, 3,9-diazaspiro[5.5]undecanyl, 2,8-diazaspiro[4.5]decanyl, octahydropyrrolo[1,2-a]pyrazyl, 5,6,7,8-tetrahydro-1,7-naphthalinyl, 3,4-dihydro-2H-1,4-benzoxazinyl, 1,3-benzodioxolyl, chromenyl, 1,4-benzothiazinyl, 4,5-dihydro-1,3-thiazolyl, and the like. In another embodiment, the non-aromatic heterocycle is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, or azepanyl, in still another embodiment, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or azepanyl, in further still another embodiment, piperidinyl, and in further still another embodiment, pyrrolidinyl.
The “cyclic amino” is a non-aromatic heterocyclic group having a nitrogen atom-containing group and has a bonding position on the nitrogen atom, among the above “non-aromatic heterocycles” and may form a spiro ring, and specific examples thereof include pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl, 1,3-oxazolidin-2-one, morpholin-4-yl, thiomorpholin-4-yl, 1,1-dioxidethiomorpholin-4-yl, 2-oxa-6-azaspiro[3.3]hept-6-yl, 1-oxa-3-azaspiro[4.5]decan-2-one, 2,5-diazabicyclo[2.2.1]heptane, 2-oxa-5-azaspiro[3.4]octane, 2-oxa-5-azabicyclo[2.2.1]heptane, and the like. In another embodiment, the cyclic amino is pyrrolidin-1-yl.
Furthermore, the monocyclic heterocyclic group in the expression “R10 and R4 form a 4- to 8-membered monocyclic heterocyclic group containing 1 to 4 hetero atoms selected from O, S, and N, together with N to which they are bonded” is a 4- to 8-membered monocyclic group containing 1 to 4 hetero atoms selected from O, S, and N in the “aromatic heterocycle” and the “cyclic amino” above.
In the present specification, the expression “which may be substituted” means non-substitution or substitution with 1 to 5 substituents. In a certain embodiment, it is unsubstitution or substitutions with 1 to 3 substituents, in another embodiment, unsubstitution or substitution with 1 substituent, and in still another embodiment, unsubstitution. Further, in a case of having a plurality of substituents, the substituents may be the same as or different from each other.
In a certain embodiment, the Group D1 consists of:
(1) halogen,
(2) —OH,
(3) —O-lower alkyl,
(4) —CN,
(5) —NO2,
(6) —NR4aR7, in which R4a is H or lower alkyl, R7 is lower alkyl which may be substituted with one or more substituents selected from the group consisting of halogen, —OH, —O-lower alkyl, and aryl, —C(O)-lower alkyl, —C(O)-lower alkylene-N(lower alkyl)2, lower alkenyl, —C(O)-lower alkylene-NH-(lower alkyl substituted with cycloalkyl), —C(O)-lower alkylene-NH-(cycloalkyl which may be substituted with lower alkyl), —C(O)O-lower alkyl or H,
(7) —C(O)-lower alkyl,
(8) —C(O)-lower alkylene-N(R4)2,
(9) —C(O)O-lower alkyl,
(10) —C(O)OH,
(11) —C(O)—N(R4)2,
(12) —O—C(O)—NH—C(═NH)—NH2,
(13) -L5-cycloalkyl, -L5-aromatic heterocycle, and -L5-non-aromatic heterocycle, in which the cycloalkyl, aryl, aromatic heterocycle, and non-aromatic heterocycle may be each substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, halogen, —O-lower alkyl, and a non-aromatic heterocycle, —OH, —O-lower alkyl, —NH2, halogen, —C(O)O-lower alkyl, —C(O)-lower alkyl, oxo, —NH—S(O)2-lower alkyl, —NH—S(O)2-cycloalkyl, —NH—C(O)-lower alkyl, —NR4—C(O)—O-(lower alkyl which may be substituted with —OH), —S(O)2-lower alkyl, —NH-(lower alkyl which may be substituted with —OH), cycloalkyl which may be substituted with —OH, and a non-aromatic heterocycle, in which L5's are the same as or different from each other and are a bond, —O—, -lower alkylene, —O-lower alkylene, —O-lower alkylene-O—, —C(O)—NH—, —NH—C(O)—, —C(O)-lower alkylene-, or —C(O)—;
in another embodiment, the cycloalkyl may be substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with one or more substituents selected from the group consisting of halogen, —OH, and —O-lower alkyl, halogen, —OH, —O-lower alkyl, —NH-lower alkylene-OH, —NH2, —NH—C(O)—O-lower alkyl, —NH-lower alkyl, and —C(O)—O-lower alkyl; the aryl may be substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, —O-lower alkyl, and —C(O)—O-lower alkyl; the aromatic heterocycle may be substituted with one or more substituents selected from the group consisting of lower alkyl and —NH2; and the non-aromatic heterocycle may be substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, halogen, —O-lower alkyl, and a non-aromatic heterocycle, —NH2, halogen, —C(O)—O-lower alkyl, —C(O)-lower alkyl, oxo, —NH—S(O)2-lower alkyl, —NH—S(O)2-cycloalkyl, —NH—C(O)-lower alkyl, —NR4—C(O)—O-(lower alkyl which may be substituted with —OH), —S(O)2-lower alkyl, —NH-(lower alkyl substituted with —OH), cycloalkyl which may be substituted with —OH, and a non-aromatic heterocycle,
(14) oxo, and
(15) lower alkyl, —O-lower alkyl, and lower alkenyl, each of which may be substituted with one or more substituents selected from the substituents described in (1) to (14) above.
In another embodiment, the Group D1 consists of:
(1) halogen,
(2) —OH,
(3) —O-lower alkyl,
(4) —NR4aR7, in which R4a represents H or lower alkyl, R7 represents lower alkyl which may be substituted with —OH, —C(O)-lower alkylene-N(lower alkyl)2, —C(O)-lower alkylene-NH-(lower alkyl substituted with cycloalkyl), —C(O)-(cycloalkyl substituted with —NH2—C(O)-lower alkylene-NH-tetrahydropyran, —C(O)-lower alkylene-N(lower alkyl)-(cycloalkyl which may be substituted with lower alkyl) or —C(O)-lower alkylene-NH-(cycloalkyl which may be substituted with lower alkyl),
(5) —C(O)-lower alkylene-N(R4)2,
(6) —C(O)O-lower alkyl,
(7) -L5-(aryl which may be substituted with one or more substituents selected from the group consisting of lower alkyl, halogen, and —O-lower alkyl),
(8) -L5-(non-aromatic heterocycle which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —NH—C(O)—O-lower alkyl, —NH—C(O)-lower alkyl, —C(O)—O-lower alkyl, —C(O)-lower alkyl, —S(O)2-lower alkyl, oxo, and —NH-lower alkyl),
(9) -L5-(cycloalkyl which may be substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with one or more groups selected from the group consisting of halogen and —OH, halogen, —OH, —O-lower alkyl, and —C(O)O-lower alkyl), and
(10) lower alkyl which may be each substituted with one or more substituents selected from the substituents described in (1) to (9) above.
In still another embodiment, the Group D1 consists of:
(1) —OH,
(2) —O-lower alkyl,
(3) —NR4aR7, in which R4a represents H or lower alkyl, R7 represents lower alkyl which may be substituted with —OH, —C(O)-(cycloalkyl substituted with —NH2), —C(O)-lower alkylene-NH-tetrahydropyran, —C(O)-lower alkylene-N(lower alkyl)-(cycloalkyl which may be substituted with lower alkyl), or —C(O)-lower alkylene-NH-(cycloalkyl which may be substituted with lower alkyl),
(4) -L5a-(non-aromatic heterocycle which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —NH—C(O)—O-lower alkyl, —NH—C(O)-lower alkyl, —C(O)—O-lower alkyl, —C(O)-lower alkyl, and oxo), in which L5a represents a bond, —C(O)-lower alkylene-, or —C(O)—, and
(5) -L5b-(cycloalkyl which may be substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with —OH, halogen, —OH, and —O-lower alkyl), in which L5b represents a bond or —C(O)—.
In further still another embodiment, the Group D1 consists of:
(1) -L5a-(non-aromatic heterocycle which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —NH—C(O)—O-lower alkyl, —C(O)O-lower alkyl, —C(O)-lower alkyl, and oxo), in which L5a represents a bond, —C(O)-lower alkylene-, or —C(O)—, and
(2) —C(O)-(cycloalkyl which may be substituted with one or more substituents selected from the group consisting of lower alkyl which may be substituted with —OH, —OH, and —O-lower alkyl).
Certain embodiments of the compound of the formula (I) of the present invention are shown below.
(1) In a certain embodiment of A1, A2 and A3, any one of A1, A2 and A3 is CH, in another embodiment, A1 and A3 are N and A2 is CH, and in still another embodiment, A2 and A3 are N and A1 is CH.
(2) In a certain embodiment of B, all of B's are CR3, in which R3 is H, lower alkyl which may be substituted with halogen, or —O-lower alkyl, in another embodiment, R3 is H or lower alkyl, in still another embodiment, R3 is lower alkyl, in further still another embodiment, R3 is H, in further still another embodiment, one of B's is N and the others are CH, and in further still another embodiment, all of B's are CH.
(3) In a certain embodiment of R1, R1 is -L1-L2-Y.
(4) In a certain embodiment of L1, L1 is —NR5—, —NR5—S(O)2—, —NR5—C(O)—, or —O—, in another embodiment, L1 is —NH—, —N(lower alkyl)-, or —O—, in still another embodiment, —NH—or —O—, in further still another embodiment, —NH—, and in further still another embodiment, —O—.
(5) In a certain embodiment, L2 is a bond, -ALK-, -ALK-S—, -ALK-S(O)m—X1—, or -ALK-C(O)—X2—, in which X1 is a bond or —NR6—, X2 is a bond, —NR6—, —NR6-ALK-, or —O—, ALK is lower alkylene, and R6 is H or lower alkyl, in another embodiment, L2 is a bond, lower alkylene, or -lower alkylene-C(O)NH—, in still another embodiment, a bond or lower alkylene, in further still another embodiment, a bond, in further still another embodiment, lower alkylene, and in further still another embodiment, methylene.
(6) In a certain embodiment, Y is cycloalkyl which may be substituted with one or more substituents selected from the Group D1, aryl which may be substituted with one or more substituents selected from the Group D1, an aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, or a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, in another embodiment, cycloalkyl which may be substituted with one or more substituents selected from the Group D1 or a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, in still another embodiment, cycloalkyl which may be substituted with one or more substituents selected from the Group D1, in further still another embodiment, a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, in further still another embodiment, cyclohexyl or cyclic amino, in further still another embodiment, cyclohexyl, in further still another embodiment, cyclic amino, in further still another embodiment, piperidinyl, pyrrolidinyl, or azetidinyl, and in further still another embodiment, pyrrolidinyl or azetidinyl.
(7) In a certain embodiment, n is an integer of 0 or 1 to 2, and in another embodiment, 0.
(8) In a certain embodiment, R2's are the same as or different from each other and are lower alkyl which may be substituted with halogen.
(9) The compound or a salt thereof, which is a combination of any two or more of the embodiments of (1) to (8) as described above.
The compound or a salt thereof, which is a combination of any two or more of the embodiments of (1) to (8) as described above, is also included in the present invention, as described in (9) above, and the specific examples thereof also include the following embodiments.
(10) The compound or a salt thereof, wherein R1 is —NH-lower alkylene-C(O)—OH or -L1-L2-Y, L1 is -lower alkynylene-, —NR5—, —NR5—S(O)2—, —NR5—C(O)—, —O—, —S—, or —S(O)m—, m is 1 or 2, L2 is a bond, -ALK-X2—, -ALK-NR6—C(O)—, -ALK-NR6—C(O)—O-ALK-, -ALK-S(O)m—X1—, or -ALK-C(O)—X2—, ALK's are the same as or different from each other and are lower alkylene which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, and cycloalkyl, X1 is a bond, —NR6—, or —NR6-ALK-, X2's are the same as or different from each other and are a bond, —NR6—, —NR6-ALK-, —O—, —S—, —NR6-ALK-O—, —NR6-ALK-C(O)—NR6—, or —NR6-ALK-C(O)—, R4's are the same as or different from each other and are H, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, and cycloalkyl, R5's are the same as or different from each other and are —R4, lower alkenyl, or cycloalkyl, R6's are the same as or different from each other and are H, cycloalkyl, a non-aromatic heterocycle which may be substituted with lower alkyl, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —CN, halogen, —N(R4)2, cycloalkyl, and a non-aromatic heterocycle, Y is lower alkyl which may be substituted with one or more substituents selected from the group consisting of —OH, —O-lower alkyl, —N(lower alkyl)2 and —C(O)—N(lower alkyl)2, cycloalkyl which may be substituted with one or more substituents selected from the Group D1, or a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, provided that L2 is -ALK-X2a—, -ALK-NR6—C(O)—, -ALK-NR6—C(O)—O-ALK-, -ALK-S(O)m—X1—, or -ALK-C(O)—X2—, in which in a case where X2a is —NR6—, —NR6-ALK-, —O—, —S—, —NR6-ALK-O—, —NR6-ALK-C(O)—NR6—, or —NR6-ALK-C(O)—, Y is aryl which may be substituted with one or more substituents selected from the Group D1 or an aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1.
(11) The compound or a salt thereof as described in (10), wherein R1 is -L1-L2-Y, L1 is —NR5—, —NR5—S(O)2—, —NR5—C(O)—, or —O—, in which R5 is H or lower alkyl, L2 is a bond, -ALK-, -ALK-S—, -ALK-S(O)m—X1—, or -ALK-C(O)—X2—, in which X1 is a bond or —NR6—, X2 is a bond, —NR6—, —NR6-ALK-, or —O—, ALK is lower alkylene, R6 is H or lower alkyl, and Y is cycloalkyl which may be substituted with one or more substituents selected from the Group D1, or a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1.
(12) The compound or a salt thereof as described in (11), wherein -L1-L2- is —NH— or —O—.
(13) The compound or a salt thereof as described in (12), wherein B's are all CH and n is 0.
(14) The compound or a salt thereof as described in (13), wherein A1 and A3 are N and A2 is CH.
(15) The compound or a salt thereof as described in (13), wherein A2 and A3 are N and A1 is CH.
Examples of the specific compounds included in the compound of the formula (I) or a salt thereof include the following compounds:

    methyl {(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate,
    methyl {(3R)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate,
    ethyl {(3R)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate,
    [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl][(2R)-tetrahydrofuran-2-yl]methanone,
    [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl](tetrahydro-2H-pyran-4-yl)methanone,
    methyl {(3S)-1-[trans-4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate,
    methyl {(3R)-1-[trans-4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate,
    methyl {(3R)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate,
    1-[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]-2-(tetrahydrofuran-2-yl)ethanone,
    1-[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]-2-(tetrahydro-2H-pyran-4-yl)ethanone,
    1-[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl]-2-(tetrahydrofuran-2-yl)ethanone,
    methyl 4-{[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]carbonyl}piperidine-1-carboxylate,
    [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)pyrrolidin-1-yl](tetrahydrofuran-3-yl)methanone,
    4-{[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)pyrrolidin-1-yl]carbonyl}-1-methylpyrrolidin-2-one,
    2-(1-acetylpiperidin-4-yl)-1-[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]ethanone,
    [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl](tetrahydrofuran-3-yl)methanone,
    4-{[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]carbonyl}-1-methylpyrrolidin-2-one,
    1-[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]-2-(piperidin-1-yl)ethanone,
    (5S)-5-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl]carbonyl}pyrrolidin-2-one,
    (5S)-5-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl]carbonyl}pyrrolidin-2-one,
    2-(1-acetylpiperidin-4-yl)-1-[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl]ethanone,
    [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl](tetrahydrofuran-3-yl)methanone,
    4-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl]carbonyl}-1-methylpyrrolidin-2-one,
    [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl][cis-4-(hydroxymethyl)cyclohexyl]methanone, and
    [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl][trans-4-(hydroxymethyl)cyclohexyl]methanone, and salts thereof.


The compound of the formula (I) may exist in the form of tautomers or geometrical isomers depending on the kind of substituents. In the present specification, the compound of the formula (I) shall be described in only one form of isomer, yet the present invention includes other isomers, isolated forms of the isomers, or a mixture thereof.
In addition, the compound of the formula (I) may have asymmetric carbon atoms or axial asymmetry in some cases, and correspondingly, it may exist in the form of optical isomers based thereon. The present invention includes both an isolated form of the optical isomers of the compound of the formula (I) or a mixture thereof.
Moreover, the present invention also includes a pharmaceutically acceptable prodrug of the compound represented by the formula (I). The pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like through solvolysis or under physiological conditions. Examples of the group forming the prodrug include the groups described in Prog. Med., 5, 2157-2161 (1985) and “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), Vol. 7, Molecular Design, 163-198.
Furthermore, the salt of the compound of the formula (I) may form an acid addition salt or a salt with a base depending on the kind of substituents, and such salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, and salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, or organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids such as acetylleucine, and amino acid derivatives, as well as ammonium salts.
In addition, the present invention also includes various hydrates or solvates, and polymorphic crystalline substances of the compound of the formula (I) and pharmaceutically acceptable salts thereof. In addition, the present invention also includes compounds labeled with various radioactive or non-radioactive isotopes.
The “PI3Kδ selective inhibitor” means an inhibitor exhibiting a potent activity, in which the inhibitory activity of PI3Kδ is 10-times or more, in another embodiment, 30-times or more, and in still another embodiment, 100-times or more than the inhibitory activity of PI3Kα in terms of the IC50 value.
(Preparation Methods)
The compound of the formula (I) and a pharmaceutically acceptable salt thereof can be prepared by applying various known synthesis methods on the basis of characteristics derived from their skeletal structure or the type of their substituents. During the preparation, replacement of the relevant functional group with a suitable protective group (a group that can be easily converted into the relevant functional group) at the stage from starting material to an intermediate may be effective depending on the type of the functional group in the production technology in some cases. Examples of such the functional group include an amino group, a hydroxyl group, and a carboxyl group, and such the protective group for such a functional group may include, for example, the protective groups described in Greene and Wuts, “Protective Groups in Organic Synthesis (3rd edition, 1999)”, which may be selected and used as appropriate, depending on reaction conditions. In such a method, after introduction of the protective group and a subsequent reaction, the protective group may be removed, if necessary to obtain a desired compound.
In addition, the prodrug of the compound of the formula (I) can be prepared by introducing a specific group at the stage from a starting material to an intermediate, or by carrying out the reaction using the obtained compound of the formula (I), as in the case of the above-mentioned protective group. The reaction can be carried out using methods known to those skilled in the art, such as ordinary esterification, amidation, dehydration, and the like.
Hereinbelow, the representative preparation methods for the compound of the formula (I) will be described. Each of the production processes may also be carried out with reference to the References appended in the present description. Further, the preparation methods of the present invention are not limited to the examples as shown below.
(Production Process 1)




(wherein X represents a leaving group, R21 represents —NH-lower alkylene-C(O)—OH or -L1-L2-Y, and L1 represents —NR5—, —NR5—S(O)2—, —NR5—C(O)—, —O—, —S—, or —S(O)m—. The same shall apply hereinafter.)
The compound (I-1) of the present invention can be obtained by the ipso substitution reaction of the compound (1) with, for example, -L1-L2-Y.
Examples of the leaving group X include halogen, methylsulfinyl, methylsulfonyl groups, and the like.
The present reaction is carried out by using the compound (1) and, for example, a compound -L1-L2-Y in equivalent amounts, or either thereof in an excess amount, and stirring a mixture thereof in a solvent which is inert to the reaction, or in the absence of a solvent, in a range of from cooling to heating and refluxing, preferably at 0° C. to 100° C., usually for 0.1 hours to 5 days. Examples of the solvent used herein are not particularly limited, but include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, acetonitrile, and a mixture thereof. It is preferable in some cases for the smooth progress of the reaction to use organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like, or inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, and the like. It may be advantageous in some cases for the smooth progress of the reaction to carry out the reaction by heating the reaction mixture by microwave irradiation.
[Documents]
S. R. Sandler and W. Karo, “Organic Functional Group Preparations”, 2nd edition, Vol. 1, Academic Press Inc., 1991
“Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition) (Vol. 14)”, edited by The Chemical Society of Japan, Maruzen, 2005
(Production Process 2)




The compound of the formula (I-2) can be obtained by the reaction of a compound (2) and a compound (3). The reaction conditions are the same as in the Production Process 1.
(Production Process 3)




(wherein L12 represents -lower alkynylene.)
The compound (I-3) of the present invention can be obtained by a Sonogashira coupling reaction of a compound (4) and a terminal alkyne derivative.
Examples of the leaving group X include halogen, and the like.
The present reaction is carried out by using the compound (4) and the terminal alkyne derivative in equivalent amounts, or either thereof in an excess amount, and stirring a mixture thereof in a solvent which is inert to the reaction, under the temperature condition ranging from room temperature to heating and refluxing, usually for 0.1 hours to 5 days, in the presence of a base and a palladium catalyst. The present reaction is preferably carried out under inert gas atmosphere. Examples of the solvent used herein are not particularly limited, but include aromatic hydrocarbons such as benzene, toluene, xylene, and the like, ethers such as diethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and the like, halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like, alcohols such as methanol, ethanol, 2-propanol, butanol, and the like, N,N-dimethylformamide, dimethylsulfoxide, and a mixed solvent thereof. As the base, inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, and the like are preferable. As the palladium catalyst, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium, palladium-1,1′-bis(diphenylphosphino)ferrocene chloride, and the like are preferred. Further, it may be advantageous in some cases for the smooth progress of the reaction to heat the reaction mixture by microwave irradiation.
[Documents]
“Metal-Catalyzed Cross-Coupling Reactions”, edited by A. d. Meijere and F. Diederich, Vol. 1, VCH Publishers Inc., 1997
“Jikken Kagaku Koza (Courses in Experimental Chemistry) (5th Edition)”, edited by The Chemical Society of Japan, Vol. 13 (2005) (Maruzen)
Various substituents on R1 in the compound of the formula (I) can be easily converted into other functional groups by using the compound of the formula (I) as a starting material by means of the reactions described in Examples as described later, the reactions apparent to a person skilled in the art, or modified methods thereof. For example, the steps that can be usually employed by a person skilled in the art, such as O-alkylation, N-alkylation, oxidation, reduction, reductive alkylation, ring formation, hydrolysis, amidation, acylation, deprotection, epoxylation, and the like can be arbitrarily combined and performed.
(Preparation of Starting Compound)
In the preparation method above, the starting compound can be prepared by using any of, for example, the methods below, the methods described in Preparation Examples as described later, known methods, or modified methods thereof.
(Starting Material Synthesis 1)




The present production process is a method for preparing a compound (9), in which X is —S(O)m-methyl in (1) which is the starting compound in Production Process 1.
A compound (7) can be obtained by the reaction of a compound (5) with a compound (6).
The reaction condition is the same as in Production Process 1.
A compound (8) can be obtained by the reaction of the compound (7) with the compound (3).
The reaction condition is the same as in Production Process 1.
A compound (9) can be obtained by the oxidation reaction of the compound (8).
The present reaction can be carried out by using the compound (9) in an equivalent amount or an excess amount, in a range of from cooling to heating. As the solvent, solvents such as aromatic hydrocarbons and halogenated hydrocarbons may be used singly or in a mixture of two or more kinds thereof. Examples of the oxidant include m-chloroperbenzoic acid, peracetic acid, and a hydrogen peroxide solution.
(Starting Material Synthesis 2)




The present production process is a method for preparing a compound (13), in which X is —S(O)m-methyl and R1 is R21, in (2) which is the starting compound in Production Process 2.
A compound (11) can be obtained by the reaction of the compound (10) with the compound (6).
The reaction conditions are the same as in Production Process 1.
A compound (12) can be obtained by the ipso substitution reaction of the compound (11) with, for example, -L1-L2-Y.
The reaction conditions are the same as in Production Process 1.
A compound (13) can be obtained by the oxidation reaction of the compound (12).
The reaction conditions are the same as in the oxidation reaction described in Starting Material Synthesis 1.
Other starting compounds (1), (2), and (4) can be prepared by, for example, the methods described in the following documents: WO2002/088112, EP1389617, WO2008/032033, WO2008/032036, WO2008/032041, or WO2008/032060.
The compounds of the formula (I) can be isolated and purified as their free compounds, pharmaceutically acceptable salts, hydrates, solvates, or polymorphic crystalline substances thereof. The pharmaceutically acceptable salts of the compound of the formula (I) can be prepared by carrying out the treatment of a conventional salt forming reaction.
Isolation and purification are carried out by employing ordinary chemical operations such as extraction, fractional crystallization, various types of fractional chromatography, and the like.
Various isomers can be prepared by selecting an appropriate starting compound or separated by using the difference in the physicochemical properties between the isomers. For example, the optical isomers can be obtained by means of a general method for designing optical resolution of racemates (for example, fractional crystallization for inducing diastereomer salts with optically active bases or acids, chromatography using a chiral column or the like, and others), and further, the isomers can also be prepared from an appropriate optically active starting compound.
The pharmacological activity of the compound of the formula (I) was confirmed by the tests shown below.
1. PI3Kδ Enzyme Inhibitory Activity
For the experiment, a PI3-Kinase HTRF Assay kit (Millipore Corporation, Catalogue No. 33-016) and a human PI3Kδ enzyme (Millipore Corporation, Catalogue No. 14-604) were used. The measurement method was in accordance with the appended instructions. The overview thereof is as follows.
PI3Kδ (10 ng/well), phosphatidylinositol-4,5-bisphosphate (10 μM), ATP (30 μM), and the test compound were mixed in a 384-well plate (total 20 μL), and incubated at room temperature for 30 minutes. EDTA and biotinylated phosphatidylinositol-3,4,5-triphosphate were added thereto to stop the reaction. Thereafter, a Europium labeled anti-GST antibody, a GST bond GRP1 PH domain, and streptavidin-APC were added thereto, followed by incubation overnight. An HTRF ratio was measured using an HTRF plate reader. The IC50 value of the compound was calculated, taking the inhibition rate without addition of the enzyme as 100% and the inhibition rate without addition of the test compound and with addition of an enzyme as 0%, by means of a logistic method.
2. PI3Kα Enzyme Inhibitory Activity
Human PI3Kα (12 ng/well, Millipore Corporation, Catalogue No. 14-602), phosphatidylinositol (0.2 μg/well), and the test compound were mixed in a 384-well plate in a reaction buffer (50 mM Hepes, 10 mM NaCl, 10 mM MgCl2, 2 mM EGTA, 2 mM DTT, pH 7.3) (total 10 μl), and incubated at 37° C. for 3 hours. After the reaction, 10 μL of a Kinase-Glo Plus reagent (Promega, Catalogue No. V3772) was added thereto, and a luminescence was measured with a luminometer. The IC50 value of the compound was calculated, taking the inhibition rate without addition of the enzyme as 100% and the inhibition rate without addition of the test compound as 0%, by a logistic method.
The results of the IC50 values (nM) of several representative compounds are shown in Table 1. In the Table, Ex represents Example Compound No. as described later of the test compounds.









TABLE 1





Ex
PI3Kδ
PI3Kα

















1
29
2800


4
60
>3000


10
5.8 
>3000


13
36
980


16
69
>10000


18
50
7700


20
19
1800


25
69
6200


28
35
>3000


29
45
>3000


30
12
>3000


33
11
>3000


34
14
>3000


35
18
4200


36
17
6700


37
20
1900


38
23
2200


39
27
3900


40
20
>10000


43-1
8
13000


43-2
8.6
8000


44
14
5000


45
56
6800


67
47
990


69
22
10000


75
25
5400


77
18
5400


78 
8.5
2900


85
21
5500


87 
4.9 
>10000


99
16
>10000


100
5.7
>3000


120
27
6400


121
13
4900


123
4.5
>3000


132
12 
>10000


133
5.2
5900


134
4.7
6600


135 
3.0 
8000


136
4.0
>10000


137
5.2
>10000


158
11
6700


193
4.9
8200


194
5.8
3300


195
4.1
>10000


196 
4.8
>10000


215
13
>10000


216
13
>10000


224
3.3
7300


248
34
720


371
35
5000


389
11
>10000


423
24
>10000


441
48
1400


A4  
31
730


A290
7.4
3800


A293
19
3200


A298
28
3500


A299
25
4900


A300
26
6500


A449
20
1400


A451
35
2200


A463
27
3100


A464
10
2200


A466
15
2000


A475
25
1400


A562
14
2900


A564
19
3000


A567
11
1600









3. Rat In Vivo IL-2 Production Inhibition Test
For the experiment, male LEW/CrlCrlj rats (Charles River Laboratories, Japan, Inc.) (6-week old, body weight 130 to 180 g) were used. The test compound was suspended in a 0.5% methyl cellulose solution and orally administered at 5 mL/kg. IL-2 production was induced by tail vein injection of Concanavalin A (Funakoshi Corporation, Catalogue No. L-1000) at a dose of 15 mg/kg.
The test was carried out according to the protocol shown below. At 2 hours or 16 hours before administration of Concanavalin A, the test compound was orally administered to rats. At 3 hours after administration of Concanavalin A, blood was collected. The IL-2 concentration in blood was quantified using an ELISA kit (R&D Systems, Inc., Catalogue No. DY502E). An inhibition rate was calculated from the amount of IL-2 produced in a group administered with the test compound with respect to the amount of the IL-2 produced in a control group administered with a vehicle.
As a result, it was confirmed that when the test compounds (10 mg/kg) were administered, for example, 2 hours before the administration of Concanavalin A, the several representative compounds of Examples 10, 29, 33, 34, 37, 43-1, and A4 exhibited inhibitory activities of 77%, 51%, 75%, 72%, 81%, 73%, and 58%, respectively, and had excellent IL-2 production inhibitory activities.
4. Rat B Cell Proliferation Inhibition Test
Spleen cells (1.0×105 cells/well) prepared from male LEW/CrlCrlj rats (Charles River Laboratories, Japan, Inc.), mouse F(ab′)2 fragment anti-rat IgM (3 μg/well, SouthernBiotech Associates, Inc., Catalogue No. 3082-14) and the test compound dissolved in DMSO (final DMSO concentration 0.1%) were mixed in a 96-well plate using a 10% FCS-containing RPMI-1640 culture medium (total 200 μL). They were cultured in a CO2 incubator for 48 hours and [3H]thymidine (925 GBq/mmol, Moravek Biochemicals, Inc., Catalogue No. MT6038) was added thereto at 0.037 MBq/well at 4 hours before completion of culture. Cells were harvested in a GF/C glass filter using a cell harvester, and a radioactivity on the filter was measured using a liquid scintillation counter. The IC50 value of the compound was calculated, taking the dpm (disintegration per minute) without addition of IgM as an inhibition rate of 100% and the dpm without addition of the test compound as an inhibition rate of 0%, by a logistic method.
The results of several representative compounds are shown in Table 2.










TABLE 2







Ex
IC50(nM)



















10
2.9



36
6.8



37
1.52



38
2.9



40
9.0



43-1
2.1



43-2
3.1



85
2.6



87
3.5



99
2.5



121
2.0



132
1.5



134
3.4



135
2.5



136
1.7



137
4.6



158
10



193
4.1



195
3.0



196
3.6



215
6.7



216
5.7



224
1.5



248
1.4



389 
4.4



423
3.1



441 
1.8



A290
2.2



A293
2.6



A298
1.2



A299
2.5



A300
2.6



A449
0.4



A451
1.2



A463
1.4



A466
1.8



A475
1.1



A562
3.9



A564
2.2



A567
1.8










As shown in the tests above, it was confirmed that several representative compounds have excellent PI3Kδ selective inhibitory action, and/or IL-2 production inhibitory action, and/or B cell proliferation inhibitory action (including an activation inhibitory action). Accordingly, the compound of the formula (I) can be used as an agent for preventing or treating rejection reactions in various organ transplantations, allergy diseases, autoimmune diseases, and/or hematologic tumor.
Furthermore, since the compound of the formula (I) is a PI3Kδ inhibitor having a significantly potent PI3Kδ inhibitory action than a PI3Kα inhibitory action, it can be an excellent immunosuppressing agent which does not cause insulin resistance based on the PI3Kα inhibitory action.
The various types of organs include the kidney, liver, and heart. The rejection reaction in organ transplantation involves chronic rejection and acute rejection, and its mechanism is largely classified into antibody-related rejection and T cell-related rejection. The compound of the formula (I) or a salt thereof is useful particularly as an agent for preventing and/or treating antibody-related rejection.
A pharmaceutical composition containing one or two or more kinds of the compound of the formula (I) or a salt thereof as an active ingredient can be prepared using excipients that are usually used in the art, that is, excipients for pharmaceutical preparations, carriers for pharmaceutical preparations, and the like according to the methods usually used.
Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, or the like, or parenteral administration, such as use of injections such as intraarticular, intravenous, and intramuscular injections, suppositories, eye drops, eye ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like.
The solid composition for use in the oral administration is used in the form of tablets, powders, granules, or the like. In such a solid composition, one or more active ingredient(s) are mixed with at least one inactive excipient such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and/or magnesium aluminometasilicate. In an ordinary method, the composition may contain inactive additives, such as a lubricant such as magnesium stearate, a disintegrating agent such as sodium carboxymethyl starch, a stabilizer, or a solubilization assisting agent. If necessary, tablets or pills may be coated with sugar or a film of a gastric-soluble or enteric coating substance.
The liquid composition for oral administration contains pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also contains generally used inert diluents, for example, purified water and ethanol. In addition to the inert diluent, the liquid composition may also contain auxiliary agents such as a solubilization assisting agent, a moistening agent, and a suspending agent, sweeteners, flavors, aromatics, or antiseptics.
The injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. The aqueous solvent includes, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, Polysorbate 80 (Japanese Pharmacopeia), and the like. Such a composition may further contain a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizer, or a solubilizing assisting agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use.
The agent for external use includes ointments, plasters, creams, jellies, poultices, sprays, lotions, eye drops, and eye ointments. The agents contain generally used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, and emulsions. Examples of the ointment bases or the lotion bases include polyethylene glycol, propylene glycol, white vaseline, bleached beeswax, polyoxyethylene hydrogenated castor oil, glyceryl monostearate, stearyl alcohol, cetyl alcohol, lauromacrogol, and sorbitan sesquioleate.
As the transmucosal agents such as an inhaler and a transnasal agent, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a conventionally known method. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizer, a thickening agent, or the like may be appropriately added thereto. For their administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device or sprayer, such as a measured administration inhalation device. A dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, and carbon dioxide.
Typically, in oral administration, the daily dose is appropriately from about 0.001 to 100 mg/kg, preferably from 0.1 to 30 mg/kg, and more preferably 0.1 to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 separate portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 to 100 mg/kg per body weight, once a day or two or more times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration.
Although varying depending on administration routes, dosage forms, administration sites, or the types of excipients and additives, the pharmaceutical composition of the present invention contains 0.01 to 100% by weight, and in a certain embodiment, 0.01 to 50% by weight of one or more kinds of the compound of the formula (I) or a salt thereof, which is an active ingredient.
The compound of the formula (I) can be used in combination with various agents for treating or preventing the diseases, in which the compound of the formula (I) is considered effective. In such use in combination, drugs may be administered simultaneously or separately in succession or at desired time intervals. Formulations for simultaneous administration may be in either mixed or have separate forms.
EXAMPLES
Hereinbelow, the preparation methods for the compound of the formula (I) and the starting compounds thereof will be described in more detail with reference to Examples, but the present invention is not limited to the compounds described in the Examples below. Further, the production processes for the starting compounds will be each described in Preparation Examples. In addition, the preparation methods for the compound of the formula (I) are not limited to the preparation methods of the specific Examples shown below, but the compound of the formula (I) can be prepared by a combination of the preparation methods or a method that is apparent to a person skilled in the art.
Furthermore, the following abbreviations may be used in some cases in Preparation Examples, Examples, and Tables below.
PEx: Preparation Example No., Ex: Example No., Syn: Example No. prepared by the same method, PSyn: Preparation Example No. prepared by the same method, Str: Structural formula, DAT: Physicochemical data, ESI+: m/z values in mass spectroscopy (Ionization ESI, representing (M+H)+ unless otherwise specified), ESI−: m/z values (Ionization ESI, representing (M−H)− unless otherwise specified), NMR1: δ (ppm) in 1H NMR in DMSO-d6, NMR2: δ (ppm) in 1H NMR in CDCl3, s: singlet (spectrum), d: doublet (spectrum), t: triplet (spectrum), q: quartet (spectrum), br: broad line (spectrum) (e.g.: br-s), RT: retention time (min) in HPLC, [M] in Preparation Examples and Examples: [mol/L], SFC preparative: preparative supercritical fluid chromatography, DEA: diethylamine.
Furthermore, for example, a description of “26+44” in Syn of Example Tables indicates that preparation is performed by the same method as in Example 26, and subsequently the product is prepared by the same method as in Example 44 as a starting material. Further, in Preparation Example Tables, there is, for example, a description of Syn. 87 in the PSyn column of Preparation Example 148, indicating that Preparation Example 148 is prepared by the same method as in Example 87. In Example Tables, there is, for example, a description of PSyn. 8 in the Syn column of Example 295, indicating that Example 295 is prepared by the same method as in Preparation Example 8. HCl in the structural formula denotes hydrochloride and the numeral before HCl denotes a molar ratio. For example, 2HCl means dihydrochloride. Further, Me in the structural formula denotes a methyl group, Et denotes an ethyl group, Ph denotes a phenyl group, iBu denotes an isobutyl group, tBu denotes a tert-butyl group, and Boc denotes a tert-butoxycarbonyl group. The compound having “*” in the structure indicates that the compound is an optically active substance.
Preparation Example 1
To a solution of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (5 g) in N,N-dimethylformamide (50 mL) were added potassium carbonate (5.3 g) and 2-(difluoromethyl)-1H-benzimidazole (3.9 g), and the mixture was stirred at room temperature for 5 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (5.49 g) as a white powder.
Preparation Example 2
To a solution of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (2.2 g) in N,N-dimethylformamide (11 mL) were added potassium carbonate (1.4 g) and morpholine (0.88 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.1 g) as a white powder.
Preparation Example 3
To a solution of 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (3 g) in dichloromethane (60 mL) was added m-chloroperbenzoic acid (75% wet) (1.9 g) under ice-cooling, and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 2-(difluoromethyl)-1-[2-(methylsulfinyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.8 g) as a white amorphous substance.
Preparation Example 4
To a solution of 2-(difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.1 g) in dichloromethane (42 mL) was added m-chloroperbenzoic acid (75% wet) (2.7 g) under ice-cooling and the mixture was stirred at 0° C. for 15 minutes. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (chloroform:methanol) to obtain 2-(difluoromethyl)-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.27 g) as a pale yellow amorphous substance.
Preparation Example 5
To a mixture of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (1 g) and N,N-dimethylacetamide (10 mL) were added tert-butyl 4-(hydroxymethyl)piperidine-1-carbamate (1 g) and cesium carbonate (3 g), and the mixture was stirred at 120° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with hexane-ethyl acetate (1:1). The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (680 mg) as a white amorphous substance.
Preparation Example 6
N-(2-{[6-Chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-5-methylphenyl)acetamide (270 mg) was dissolved in a mixed solvent of ethanol (2.8 mL) and 1,4-dioxane (2.8 mL), and 6 M hydrochloric acid (9.6 mL) was added thereto, followed by heating and refluxing for 3 hours. After air-cooling to room temperature, the pH was adjusted to 6 to 7 using saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain N1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-4-methylbenzene-1,2-diamine (230 mg).
Preparation Example 7
A mixture of 2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-amine (500 mg), 2-bromo-1-methyl-3-nitrobenzene (1 g), tris(dibenzylideneacetone)dipalladium (0) (202 mg), (9,9-dimethyl-9H-xanthen-4,5-diyl)bis(diphenylphosphine) (192 mg), and cesium carbonate (1.0 g) in toluene was stirred in a microwave reactor at 140° C. for 1 hour. The reaction mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain N-(2-methyl-6-nitrophenyl)-2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-amine (756 mg) as a yellow powder.
Preparation Example 8
N-(2-Methyl-6-nitrophenyl)-2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-amine (750 mg) was dissolved in ethanol (22.5 mL), and iron chloride (III) hexahydrate (56 mg) and activated carbon (75 mg) were added thereto, followed by stirring at 80° C. Hydrazine monohydrate (0.3 mL) was added dropwise thereto, followed by heating and refluxing overnight. The reaction mixture was cooled to room temperature and filtered through celite. The mother liquid was concentrated and the residue was purified using silica gel column chromatography (hexane:ethyl acetate) to obtain 3-methyl-N2-[2-(methylsulfanyl)-6-(morpholin-4-yl)pyrimidin-4-yl]benzene-1,2-diamine (544 mg) as a pale yellow powder.
Preparation Example 9
To tert-butyl [(2S)-1-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate (760 mg) was added methyl iodide (3.5 mL), followed by stirring at room temperature overnight. Methyl iodide was evaporated under reduced pressure to obtain a desired compound [(3S)-3-[(tert-butoxycarbonyl)amino]-4-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-oxobutyl](dimethyl)sulfonium iodide (919 mg).
Preparation Example 10
4,6-Dichloro-2-(methylsulfanyl)pyrimidine (50 mg) and tert-butyl (2-amino-4-methylphenyl)carbamate (57 mg) were dissolved in dimethylacetamide (250 μL), and N,N-diisopropyl ethylamine (69 μL) was added thereto, followed by stirring at 100° C. for 7 hours. After the completion of the reaction, the mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain a desired compound tert-butyl (2-{[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-4-methylphenyl)carbamate (50 mg) as a white powder.
Preparation Example 11
tert-Butyl (2-{[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]amino}-4-methylphenyl)carbamate (8.5 g) was dissolved in 1,4-dioxane (85 mL), and a 4 M solution (56 mL) of hydrogen chloride in 1,4-dioxane was added thereto, followed by stirring at room temperature for 8 hours. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution and a 4 M aqueous sodium hydroxide solution were added thereto. The mixture was quenched, made free, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain N2-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-4-methylbenzene-1,2-diamine (6 g) as a yellow powder.
Preparation Example 12
N2-[6-Chloro-2-(methylsulfanyl)pyrimidin-4-yl]-4-methylbenzene-1,2-diamine (6 g) and difluoroacetic anhydride (7.4 g) were dissolved in acetonitrile (60 mL), followed by stirring at room temperature for 1 hour. After confirming that the starting material had been disappeared, a 4 M solution (53 mL) of hydrogen chloride in 1,4-dioxane was added thereto, followed by stirring at 100° C. for 10 hours. After the completion of the reaction, the mixture was cooled to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-6-methyl-1H-benzimidazole (2.9 g) as a pale yellow powder.
Preparation Example 13
(3a′R,5′s,6a′S)-5,5-Dimethylhexahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′-ol (1.0 g) and 1H-isoindole-1,3(2H)-dione (780 mg) and triphenylphosphine (1.39 g) were dissolved in tetrahydrofuran (17 mL), and a 2.2 M solution (2.41 mL) of ethyl azodicarbonate in tetrahydrofuran was added dropwise thereto at 0° C., followed by stirring at 0° C. for 1 hour and at room temperature for 4 hours. To the reaction solution was added silica gel, followed by concentrating and purifying using silica gel column chromatography (hexane:ethyl acetate) to obtain 2-[(3a′R,5′r,6a′S)-5,5-dimethylhexahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′-yl]-1H-isoindole-1,3(2H)-dione (1.1 g) as a white powder.
Preparation Example 14
To a mixture of ethyl-4-(4-cyanophenyl)-1-piperazine carboxylate (10 g), sodium borohydride (3.4 g), and tetrahydrofuran (50 mL) was added a mixture of iodine (9.8 g) and tetrahydrofuran (50 mL) under a nitrogen gas flow while ice-cooling, followed by stirring at the same temperature for 1 hour, and then further heating and refluxing for 3 hours. The reaction solution was ice-cooled and a 6 M hydrochloric acid solution was added thereto to adjust the pH to 1. The reaction solution was stirred at 70° C. for 30 minutes. After leaving to be cooled, sodium hydroxide was added thereto to adjust the pH to 10, followed by extraction with ethyl acetate. The extracts were washed with saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was made into powder using tetrahydrofuran, ethyl acetate, and diisopropyl ether, to obtain ethyl-4-[4-(aminomethyl)phenyl]-1-piperazine carboxylate (5.2 g).
Preparation Example 15
2-(Difluoromethyl)-1-[2-(methylsulfanyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.1 g) was dissolved in methylene chloride (42 mL), and m-chloroperbenzoic acid (75% wet) (2.7 g) was added thereto under ice-cooling, followed by stirring at 0° C. for 1 hour. Saturated aqueous sodium bicarbonate was added thereto, followed by extraction with methylene chloride. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (chloroform:methanol) to obtain 2-(difluoromethyl)-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (2.27 g) as a pale yellow amorphous substance.
Preparation Example 16
To a mixture of 2-[(3a′R,5′r,6a′S)-5,5-Dimethylhexahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′-yl]-1H-isoindole-1,3(2H)-dione (1.1 g), tetrahydrofuran (22 mL) and ethanol (22 mL) was added hydrazine monohydrate (0.75 mL), followed by heating and refluxing for 2 hours. The insoluble matter was removed by filtration through celite and concentrated under reduced pressure. To the residue was added chloroform, followed by drying over sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain (3a′R,5′r,6a′S)-5,5-dimethylhexahydro-1′H-spiro[1,3-dioxane-2,2′-pentalen]-5′-amine (0.74 g) as a white powder.
Preparation Example 17
Benzyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (230 mg) was dissolved in methanol (4.5 mL) and methylene chloride (1.5 mL), and ammonium acetate (1.47 g) was added thereto, followed by stirring at room temperature for 10 minutes. Subsequently, sodium triacetoxyborohydride (323 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction solution was added saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain benzyl 9-amino-3-azaspiro[5.5]undecane-3-carboxylate (255 mg).
Preparation Example 80
trans-4-(Dibenzylamino)cyclohexanol (200 mg), 2-(3-bromopropoxy)tetrahydro-2H-pyran (604 mg), powder potassium hydroxide (179 mg), and tetrabutylammonium bromide (44 mg) were suspended in xylene (2 mL), followed by stirring at room temperature for 2 hours. To the reaction mixture were added ethyl acetate and water, and the organic layer was extracted and washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=100:0-80:20) to obtain trans-N,N-dibenzyl-4-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]cyclohexanamine (174 mg).
Preparation Example 81
trans-N,N-Dibenzyl-4-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]cyclohexanamine (170 ml) was dissolved in methanol (1 mL), and a 4 M solution (972 μL) of hydrogen chloride in 1,4-dioxane was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was neutralized with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-{[trans-4-(dibenzylamino)cyclohexyl]oxy}propan-1-ol (110 mg).
Preparation Example 82
To 3-{[trans-4-(dibenzylamino)cyclohexyl]oxy}propan-1-ol (110 mg) were added tosyl chloride (60 mg) and pyridine (51 μL) under ice-cooling, followed by stirring at room temperature for 1 hour. To the reaction mixture were added N,N-dimethylformamide (1.1 mL), potassium carbonate (43 mg), and pyrrolidine (26 μL), followed by stirring at room temperature overnight. The reaction mixture were added ethyl acetate and water, and the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate-90:10-70:30) to obtain trans-N,N-dibenzyl-4-[3-(pyrrolidin-1-yl)propoxy]cyclohexanamine (70 mg).
Preparation Example 83
trans-N,N-Dibenzyl-4-[3-(pyrrolidin-1-yl)propoxy]cyclohexanamine (115 mg) was dissolved in ethanol (2.3 ml), and 20% palladium hydroxide/carbon 50% wet (20 mg) was added thereto, followed by catalytic reduction at room temperature for 4 hours at 3 atm under a hydrogen atmosphere. The catalyst was removed by filtration after nitrogen substitution, and then concentrated under reduced pressure to obtain trans-4-[3-(pyrrolidin-1-yl)propoxy]cyclohexanamine (48 mg).
Preparation Example 84
Triethyl phosphonoacetate (107 mg) was dissolved in tetrahydrofuran (1 mL), and 60% sodium hydride (19 mg) was added thereto, followed by stirring at room temperature for 30 minutes. A solution of tert-butyl (trans-4-formylcyclohexyl)carbamate (90 mg) in tetrahydrofuran (1 mL) was added dropwise thereto, followed by stirring at room temperature for 2 hours. Ethyl acetate and water were added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-50:50) to obtain ethyl (2E)-3-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}acrylate (100 mg).
Preparation Example 85
60% Sodium hydride (394 mg) was suspended in 1,2-dimethoxyethane (20 mL), and tert-butyl 4-hydroxybenzylcarbamate (1 g) and 15-crown-5-ether (1.09 g) were added thereto, followed by stirring at room temperature for 30 minutes. 4,6-Dichloro-2-(methylsulfonyl)pyrimidine was added thereto, followed by stirring at 80° C. overnight. The reaction solution was cooled to room temperature and then an aqueous ammonium chloride solution (50 mL) was added thereto, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified using silica gel column chromatography (hexane:ethyl acetate=95:5-85:15) to obtain tert-butyl{-4-[(4,6-dichloropyrimidin-2-yl)oxy]benzyl}carbamate (762 mg).
Preparation Example 86
A mixture of 4,6-dichloro-2-(methylsulfanyl)pyrimidine (700 mg), 2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (761 mg), potassium carbonate (744 mg), and N,N-dimethylformamide (7 mL) was stirred at room temperature overnight. To the mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-80:20) to obtain 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-4-ethoxy-1H-benzimidazole (464 mg) (Preparation Example 86-1) and 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole]. 1,1′-[2-(Methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] was suspended in ethyl acetate and warmed. After leaving to be cooled, the insoluble matter was collected by filtration to obtain 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-4-ethoxy-1H-benzimidazole] (275 mg) (Preparation Example 86-2).
Preparation Example 87
To a mixture of trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanamine (700 mg) and N,N-dimethylformamide (7.0 mL) were added N-(tert-butoxycarbonyl)-N-methyl-L-methionine (622 mg), 1H-benzotriazol-1-ol (319 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (452 mg), followed by stirring at room temperature overnight. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10-40:60) to obtain tert-butyl [(2S)-1-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-(methylsulfanyl)-1-oxobutan-2-yl]methylcarbamate (859 mg).
Preparation Example 88
To a mixture of methyl[(2S)-1-({trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}amino)-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamate (2.0 g), methylene chloride (20 mL) and methanol (20 mL) was added methyl iodide (15.5 mL), followed by stirring at room temperature overnight. The solvent was evaporated under reduced pressure, and to a mixture of the residue and dimethylformamide (10 mL) was added cesium carbonate (4.8 g), followed by stirring overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and then the solvent was evaporated under reduced pressure. To the residue was added ethanol, and the resulting solid was collected by filtration and dried under reduced pressure to obtain methyl[(3S)-1-{trans-4-[(tert-butoxycarbonyl)amino]cyclohexyl}-2-oxopyrrolidin-3-yl]carbamate (0.65 g).
Preparation Example 89
To a solution of 1,1′-[2-(methylsulfanyl)pyrimidine-4,6-diyl]bis[2-(difluoromethyl)-1H-benzimidazole] (2 g) in N,N-dimethylacetamide (10 mL) were added tert-butyl (3S)-3-(hydroxymethyl)pyrrolidine-1-carboxylate (965 mg) and cesium carbonate (2.1 g), followed by stirring at 60° C. for 5 hours. After the completion of the reaction, to the reaction solution was added ice water and the precipitated solid was collected by filtration. After drying, the resultant was dissolved in dichloromethane and purified by silica gel column chromatography (hexane:ethyl acetate=90:10-65:35) to obtain tert-butyl (3S)-3-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}oxy)methyl]pyrrolidine-1-carboxylate (2.01 g).
Preparation Example 90
A mixture of 1-[6-chloro-2-(methylsulfanyl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (350 mg), methyl[(3R)-1-(trans-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl]carbamate hydrochloride (344 mg), potassium carbonate (178 mg), N-ethyl-N-isopropylpropan-2-amine (1.1 mL), and N,N-dimethylacetamide (1.75 mL) was stirred at 60° C. overnight. To the reaction solution were added water and ethyl acetate. The insoluble matter was collected by filtration, followed by extraction with ethyl acetate. The solvent was evaporated under reduced pressure, and then the residue and the insoluble matter were combined. Ethyl acetate was added thereto, and the mixture was suspended, stirred, and then collected by filtration. The resultant was washed with water and dried to obtain methyl{(3R)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfanyl)pyrimidin-4-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (446 mg).
Preparation Example 183
60% Sodium hydride (110 mg) was suspended in N,N-dimethylformamide (20 mL), and tert-butyl[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexyl]carbamate (1 g) was added thereto at 0° C., followed by stirring at room temperature for 30 minutes. To the reaction mixture was added a 1-bromo-2-methylpropan (807 mg), followed by stirring at room temperature for 12 hours. After the completion of the reaction, to the reaction solution was added ice water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified using silica gel chromatography to obtain tert-butyl{trans-4-[{6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}(isobutyl)amino]cyclohexyl}carbamate (163 mg).
Preparation Example 185
A mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-(3,4-dimethoxy benzyl)-6-(morpholin-4-yl)pyrimidin-2-amine (5.3 g) and trifluoroacetic acid (0.82 mL) was stirred at 10 for 1 hour. The reaction mixture was neutralized by the addition of saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and washed with diisopropyl ether to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-amine (1.36 g).
Example 1
A mixture of 2-difluoromethyl-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (770 mg), tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (525 mg), potassium carbonate (390 mg), and N,N-dimethylacetamide (19 mL) was stirred in a microwave reactor at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (310 mg) as a pale yellow amorphous substance.
Example 22
A mixture of 2-(difluoromethyl)-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (100 mg), 1-benzyl-3-(methylamino)pyrrolidine (93 mg), potassium carbonate (50 mg), and N,N-dimethylacetamide (2.5 mL) was stirred in a microwave reactor at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=80:20-50:50). Desired fractions were combined and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane, and a 4 M solution (61 μL) of hydrogen chloride in 1,4-dioxane was added thereto. Further, diisopropyl ether (10 mL) was added thereto. The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain N-(1-benzylpyrrolidin-3-yl)-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-methyl-6-morpholin-4-ylpyrimidin-2-amine hydrochloride (28 mg) as a pale yellow powder.
Example 26
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (58 mg) and N,N-dimethylformamide (1.2 mL) were added phenylacetaldehyde (21 mg), sodium triacetoxyborohydride (75 mg), and acetic acid (0.29 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (chloroform:methanol=100:0-90:10) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-1-(2-phenylethyl)pyrrolidin-3-yl]pyrimidin-2-amine (30 mg) as a white powder.
Example 43
To a solution of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (400 mg) in 1,2-dichloroethane (8 mL) was added 4-fluorocyclohexanone (210 mg), and the mixture was stirred at room temperature for 10 minutes. Subsequently sodium triacetoxyborohydride (382 mg) was added thereto, followed by stirring at room temperature overnight. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=70:30-40:60) to obtain two types of compounds below, each as a white powder.
4-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-N-{[1-(trans-4-fluorocyclohexyl)piperidin-4-yl]methyl}-6-(morpholin-4-yl)pyrimidin-2-amine (109 mg)
The Rf value in amino silica gel TLC (hexane:ethyl acetate=50:50) of the present compound was 0.35.
4-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-N-{[1-(cis-4-fluorocyclohexyl)piperidin-4-yl]methyl}-6-(morpholin-4-yl)pyrimidin-2-amine (87 mg)
The Rf value in amino silica gel TLC (hexane:ethyl acetate=50:50) of the present compound was 0.28.
The 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{[1-(trans-4-fluorocyclohexyl)piperidin-4-yl]methyl}-6-(morpholin-4-yl)pyrimidin-2-amine (80 mg) obtained above was dissolved in a mixed solvent of methylene chloride (1.7 mL) and methanol (0.3 mL), and a 4 M solution (0.37 mL) of hydrogen chloride in 1,4-dioxane was added thereto. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{[1-(trans-4-fluorocyclohexyl)piperidin-4-yl]methyl}-6-(morpholin-4-yl)pyrimidin-2-amine dihydrochloride (Example 43-1, 87 mg) as a white powder.
In the similar manner, 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{[1-(cis-4-fluorocyclohexyl)piperidin-4-yl]methyl}-6-(morpholin-4-yl)pyrimidin-2-amine dihydrochloride (Example 43-2, 70 mg) was obtained as a white powder from the 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{[1-(cis-4-fluorocyclohexyl)piperidin-4-yl]methyl}-6-(morpholin-4-yl)pyrimidin-2-amine (62 mg) obtained above.
Example 44
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-N-[(1-phenylpiperidin-4-yl)methyl]pyrimidin-2-amine (38 mg), chloroform (0.75 mL), and methanol (0.35 mL) was added a 4 M solution (0.2 mL) of hydrogen chloride in 1,4-dioxane, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-N-[(1-phenylpiperidin-4-yl)methyl]pyrimidin-2-amine dihydrochloride (43 mg) as a white powder.
Example 45
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (75 mg) and N,N-dimethylformamide (1.5 mL) were added 2-(dimethylamino)ethyl bromide (26 mg) and potassium carbonate (85 mg), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100, and subsequently chloroform:methanol=100:0-80:20). Desired fractions are combined and concentrated under reduced pressure. The residue was dissolved in 1,4-dioxane (0.5 mL) and a 4 M solution (80 μL) of hydrogen chloride in 1,4-dioxane was added thereto. Diisopropyl ether (10 mL) was further added thereto. The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{(3S)-1-[2-(dimethylamino)ethyl]pyrrolidin-3-yl}-6-morpholin-4-ylpyrimidin-2-amine dihydrochloride (10 mg) as a white powder.
Example 52
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (100 mg) and ethanol (2 mL) were added 2-(fluoromethyl)oxirane (19 μL) and N,N-diisopropyl ethylamine (79 μL), and the mixture was stirred in a microwave reactor at 120° C. for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate:hexane) to obtain 1-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}-3-fluoropropan-2-ol (81 mg) as a white powder.
Example 53
To a mixture of tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (300 mg) and 1,4-dioxane (3 mL) was added a 4 M solution (1.5 mL) of hydrogen chloride in 1,4-dioxane, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added diisopropyl ether (10 mL). The resulting powder was collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (354 mg) as a pale yellow powder.
Example 54
To a mixture of tert-butyl 4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)piperidine-1-carboxylate (63 mg) and methanol (1.3 mL) were added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.15 mL), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralized by the addition of saturated aqueous sodium bicarbonate solution, and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (27 mg) as a pale yellow powder.
Example 66
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-piperidin-4-ylpyrimidin-2-amine (18 mg) and N,N-dimethylformamide (0.36 mL) were added N,N-dimethylglycine (4.8 mg), 1-hydroxybenzotriazole (6.2 mg), and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (8.8 mg), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (ethyl acetate, and subsequently chloroform:methanol=96:4). Desired fractions were combined and concentrated under reduced pressure. The residue was solidified by the addition of a small amount of diisopropyl ether to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-N-{1-[(dimethylamino)acetyl]piperidin-4-yl}-6-morpholin-4-ylpyrimidin-2-amine (9 mg) as a white powder.
Example 71
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)-1,3,5-triazin-2-amine (50 mg) and pyridine (2 mL) was added acetic anhydride (14 μL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added toluene, followed by concentrating under reduced pressure. The residue was dissolved in dichloromethane, and silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, and subsequently chloroform:methanol) to obtain N-[(1-acetylpiperidin-4-yl)methyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-amine (44 mg) as a white powder.
Example 74
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)pyrimidin-2-amine (50 mg) and 1,2-dimethoxyethane (1 mL) were added bromobenzene (24 μL), tris(dibenzylideneacetone)dipalladium (0) (6.5 mg), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (11 mg), and potassium phosphate (96 mg), and the mixture was stirred in a microwave reactor at 130° C. for 1 hour. The reaction mixture was filtered through celite, and to the filtrate was added silica gel, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-N-[(1-phenylpiperidin-4-yl)methyl]pyrimidin-2-amine (39 mg) as a white powder.
Example 80
A mixture of tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(methylsulfinyl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (240 mg), morpholine (0.3 mL), and N,N-dimethylacetamide (2 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-50:50) to obtain tert-butyl 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)methyl]piperidine-1-carbamate (246 mg) as a white powder.
Example 82
1-[4-Chloro-6-(morpholin-4-yl)pyrimidin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (100 mg) was dissolved in dimethylformamide (1 mL), and 3-methoxyprop-1-yne (45 μL), tetrakistriphenylphosphine palladium (0) (16 mg), copper (I) iodide (1.3 mg), and potassium carbonate (227 mg) were added thereto, followed by stirring in a microwave reactor at 80° C. for 1 hour. An aqueous ammonium chloride solution and chloroform were added thereto, and the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=60:40). A mixed solvent of diisopropyl ether and hexane was added thereto, and the resulting solid was collected by filtration and further washed with hexane to obtain 2-(difluoromethyl)-1-[4-(3-methoxyprop-1-yn-1-yl)-6-(morpholin-4-yl)pyrimidin-2-yl]-1H-benzimidazole (10 mg) as a yellow powder.
Example 83
Methyl trans-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]cyclohexane carboxylate (150 mg) was dissolved in a mixed solvent of methanol (750 μL) and tetrahydrofuran (750 μL), and a 1 M aqueous sodium hydroxide solution (899 mL) was added thereto, followed by stirring at room temperature for 2 hours. After the completion of the reaction, 1 M hydrochloric acid was added thereto under ice-cooling until the reaction solution became weakly acidic, followed by stirring at 0° C. for 1 hour. The resulting solid was collected by filtration and washed with hexane to obtain trans-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]cyclohexanecarboxylic acid (74 mg) as a white powder.
Example 84
[(3S)-3-[(tert-Butoxycarbonyl)amino]-4-{[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]amino}-4-oxobutyl](dimethyl)sulfonium iodide (919 mg) was dissolved in tetrahydrofuran (9.2 mL), and cooled to 0° C. under a nitrogen air flow, and a 1.6 M solution (0.7 mL) of hexamethyldisilazanelithium in tetrahydrofuran was added dropwise thereto, followed by stirring at 0° C. for 2 hours. A 1.6 M solution (0.7 mL) of hexamethyldisilazanelithium in tetrahydrofuran was further added dropwise thereto, followed by stirring at 0° C. for 1 hour. A saturated aqueous ammonium chloride solution was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=70:30-0:100) to obtain tert-butyl{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (154 mg).
Example 85
N-[(4-Aminobicyclo[2.2.2]oct-1-yl)methyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-amine (150 mg) was dissolved in ethanol (3 mL), and N,N-diisopropyl ethylamine (81 μL) and 2,2-dimethyloxirane (36 μL) were added thereto, followed by stirring at 120° C. for 1 hour and at 140° C. for 1 hour using a microwave reactor. The reaction solution was concentrated and the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=20:80, and subsequently chloroform:methanol=98:2) to obtain 1-({4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]bicyclo[2.2.2]oct-1-yl}amino)-2-methylpropan-2-ol (148 mg) as a white amorphous substance.
Example 86
1-({trans-4-[({4-[2-(Difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}amino)methyl]cyclohexyl}amino)-2-methylpropan-2-ol (100 mg) was dissolved in tetrahydrofuran (2 mL), and di-1H-imidazol-1-ylmethanone (131 mg) and triethylamine (50 μL) were added thereto, followed by stirring for 3 hours while heating and refluxing. After the completion of the reaction, water was added thereto, followed by extraction with ethyl acetate. The extracts were washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=60:40) to obtain 3-{trans-4-[({4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-2-yl}amino)methyl]cyclohexyl}-5,5-dimethyl-1,3-oxazolidin-2-one (100 mg) as a white powder.
Example 87
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), triethylamine (22 μL), and dichloromethane (750 μL) was added methylchlorocarbonate (12 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain methyl{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (55 mg) as a white powder.
Example 88
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), N-ethyl-N-isopropylpropan-2-amine (73 μL), and 1,2-dichloroethane (750 μL) was added methanesulfonyl chloride (17 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain N-{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}methanesulfonamide (82 mg) as a pale yellow powder.
Example 89
2-Bromo-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]acetamide (100 mg) was suspended in dimethylformamide (2 mL), and potassium carbonate (30 mg) and cyclobutylamine (60 μL) were added thereto, followed by stirring at room temperature overnight. To the reaction solution was added water, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel chromatography (hexane:ethyl acetate=40:60-10:90) to obtain N2-cyclobutyl-N-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]glycinamide (79 mg).
Example 91
N-[2-(Cyclopentylsulfanyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (60 mg) was dissolved in methylene chloride (1.2 mL), and m-chloroperbenzoic acid (75% wet) (32 mg) was added thereto at 0° C., followed by stirring for 10 minutes. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80, and subsequently chloroform:methanol=98:2-90:10) to obtain N-[2-(cyclopentyl sulfinyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (53 mg) as a white powder.
Example 92
2-(Difluoromethyl)-1-[6-(1,4-dioxaspiro[4.5]deca-8-ylmethoxy)-2-(methylsulfanyl)pyrimidin-4-yl]-1H-benzimidazole (1.3 g) was dissolved in dichloromethane (20 mL), and m-chloroperbenzoic acid (75% wet) (712 mg) was added thereto at 0° C., followed by stirring for 30 minutes. To the reaction solution was added a saturated aqueous sodium bicarbonate, followed by extraction with chloroform. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in dimethylformamide (10 mL), and morpholine (1.22 mL) was added thereto, followed by stirring at room temperature for 2 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5-80:20) to obtain 2-(difluoromethyl)-1-[6-(1,4-dioxaspiro[4.5]deca-8-ylmethoxy)-2-(morpholin-4-yl)pyrimidin-4-yl]-1H-benzimidazole (1.21 g) as a white powder.
Example 93
2-(Difluoro methyl)-1-[6-(1,4-dioxaspiro[4.5]deca-8-ylmethoxy)-2-(morpholin-4-yl)pyrimidin-4-yl]-1H-benzimidazole (1.2 g) was dissolved in a mixed solvent of tetrahydrofuran (12 mL) and water (12 mL), and 4-methylbenzene sulfonic acid monohydrate (2.27 g) was added thereto, followed by stirring at room temperature for 3 hours. To the reaction solution was added saturated aqueous sodium bicarbonate, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20-40:60) to obtain 4-[({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)methyl]cyclohexanone (941 mg) as a white powder.
Example 94
N-[2-(Cyclopentylsulfanyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (60 mg) was dissolved in methylene chloride (1.2 ml), and m-chloroperbenzoic acid (75% wet) (73 mg) was added thereto at 0° C., followed by stirring for 10 minutes. Water was added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to obtain N4-[2-(cyclopentylsulfonyl)ethyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (58 mg) as a white powder.
Example 237
To a solution of [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl](cis-4-hydroxycyclohexyl)methanone (60 mg) in methylene chloride (1.2 mL) was added a Dess-Martin reagent (53 mg) under ice-cooling, followed by stirring at room temperature overnight. To the reaction mixture were added ethyl acetate and a saturated aqueous sodium bicarbonate solution, the organic layer was extracted, washed with saturated brine, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10) to obtain 4-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)azetidin-1-yl]carbonyl}cyclohexanone (20 mg).
Example 238
4-(Morpholin-4-ylmethyl)benzenesulfonamide (35 mg) was dissolved in N,N-dimethylacetamide (1.25 mL), and 60% sodium hydride (4 mg) was added thereto, followed by stirring at room temperature for 30 minutes. To the reaction mixture was added 1-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-2-(difluoromethyl)-1H-benzimidazole (50 mg), followed by stirring at 120° C. for 1 hour. The mixture was cooled to room temperature, and then a saturated aqueous sodium chloride solution, ethyl acetate, and tetrahydrofuran were added thereto, followed by neutralization with a 10% aqueous potassium hydrogen sulfate solution, and then the organic layer was extracted. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80-0:100 and subsequently chloroform:methanol=100:0-80:20) to obtain N-{6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}-4-(morpholin-4-ylmethyl)benzenesulfonamide (13 mg).
Example 239
trans-4-({6-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexanecarboxylic acid (232 mg) was dissolved in tetrahydrofuran (2.3 mL), and isobutyl chloroformate (70 μL) and 4-methylmorpholine (60 μL) were added thereto at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 2 hours. Subsequently, 28% aqueous ammonia (300 μL) was added thereto at 0° C., followed by stirring for 2 hours. The solvent was evaporated under reduced pressure and purified by silica gel chromatography (hexane:ethyl acetate=40:60-0:100 and chloroform:methanol-100:0-95:5) to obtain trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexanecarboxamide (230 mg).
Example 240
To a solution of N-{4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}cyclohexane-1,3-diamine (70 mg) in dimethylacetamide (1.4 mL) were added triethylamine (56 μL) and bis(2-bromomethyl)ether (31 μL), followed by stirring at 120° C. for 2 hours using a microwave reactor. To the reaction solution was added water, followed by extraction with ethyl acetate. The extracts were washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was removed by filtration, and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=60:40-20:80) to obtain 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-N-[3-(morpholin-4-yl)cyclohexyl]pyrimidin-2-amine (42 mg).
Example 241
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl)-N-[(3S)-pyrrolidin-3-yl]pyrimidin-2-amine dihydrochloride (100 mg) and methylene chloride (1 mL) were added triethylamine (0.1 mL) and benzoyl chloride (28.5 μL) under a nitrogen air flow while ice-cooling, followed by stirring at the same temperature for 4 hours. To the reaction mixture was added water (30 mL), followed by extraction with ethyl acetate (100 mL). The organic layer was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=100:0-90:10). This was solidified with ethyl acetate and diisopropyl ether, then collected by filtration, and dried to obtain [(3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)pyrrolidin-1-yl](phenyl)methanone (66 mg) as a white powder.
Example 242
To a solution of trans-N-{4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}cyclohexane-1,4-diamine (150 mg) in ethanol (3 mL) was added 1H-1,2,3-benzotriazol-1-ylmethanol (59 mg), followed by stirring at room temperature for 5 hours. To this mixture was added sodium borohydride (25 mg), followed by further stirring at room temperature for 1 hour. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was separated and purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100 and chloroform:methanol=100:0-98:2) to obtain trans-N′-{4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}-N,N-dimethylcyclohexane-1,4-diamine (50 mg) (free compound of Example 242-2) and trans-N-{4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}-N′-methylcyclohexane-1,4-diamine (100 mg) (free compound of Example 242-1).
Example 243
To a solution of trans-N-{4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}cyclohexane-1,4-diamine (50 mg) in methylene chloride (1 mL) were added triethylamine (46 μL) and 4-chlorobutyryl chloride (16 mg), followed by stirring for 1 hour in a water bath. The reaction solution was concentrated under reduced pressure and to the residue were added tetrahydrofuran (5 mL) and 60% sodium hydride (13 mg), followed by stirring at 0° C. for 30 minutes and at room temperature for 1 hour. To the reaction solution was added water, followed by extraction with ethyl acetate, and the extracts were washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=50:50-0:100 and chloroform:methanol=100:0-90:10) to obtain 1-[trans-4-({4-[2-(difluoromethyl)-6-methyl-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]pyrrolidin-2-one (40 mg).
Example 244
To a mixture of tert-butyl N-{4-[2-(difluoromethyl)-1H-benzimidazo-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}-L-alaninate (80 mg) and methylene chloride (3 mL) were added a 4 M solution of hydrogen chloride in 1,4-dioxane (0.84 mL), followed by stirring for 4 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure and then dried to obtain N-{4-[2-(difluoromethyl)-1H-benzimidazo-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}-L-alanine hydrochloride (83 mg).
Example 245
To a solution of 2-(benzyloxy)ethyl {(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (84 mg) in methanol (1 mL) was added 10% palladium-carbon (50% wet) (84 mg), followed by stirring at room temperature overnight at 3 atm under a hydrogen atmosphere. The catalyst was removed and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=100:0-92:8) to obtain 2-hydroxyethyl {(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (30 mg).
Example 246
To a mixture of methyl 2-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}cyclopentane carboxylate (50 mg) and tetrahydrofuran (1 mL) were added a 1.06 M solution of methyllithium in diethyl ether (0.33 mL) at 0° C., followed by stirring at the same temperature for 4 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by amino silica gel column chromatography (hexane:ethyl acetate) to obtain 2-(2-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}cyclopentyl)propan-2-ol (11.1 mg).
Example 247
trans-4-({6-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanol (100 mg) was suspended in N,N-dimethylformamide (4 mL), and 1,1′-carbonyldiimidazole (73 mg) was added thereto, followed by stirring at 60° C. for 2 hours. Further, 1,1′-carbonyldiimidazole (182 mg) was added thereto, followed by stirring at 60° C. for 2 hours. To this mixture was added guanidine carbonate (405 mg) at room temperature, followed by stirring at room temperature overnight. Water was added thereto, followed by extraction with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (10% MeOH/chloroform: chloroform=10:90-90:10) to obtain trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexylcarbamimidylcarbamate (103 mg).
Example 248
A mixture of 2-(difluoromethyl)-1-[2-(methylsulfonyl)-6-(morpholin-4-yl)pyrimidin-4-yl]-1H-benzimidazole (200 mg) and methyl[(3S)-1-(trans-4-aminocyclohexyl)-2-oxopyrrolidin-3-yl]carbamate hydrochloride (214 mg), potassium carbonate (135 mg), N-ethyl-N-diisopropylpropan-2-amine (0.38 mL) and N,N-dimethylacetamide (3 mL) was stirred at 100° C. for 6 hours. After leaving to be cooled, to the reaction solution was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The desiccant was removed by filtration and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol-100:0-80:20) to obtain methyl{(3S)-1-[trans-4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (102 mg) as a white powder.
Example 249
N-(Azetidin-3-yl)-6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-amine (100 mg) was dissolved in N,N-dimethylformamide (1 ml), and 4-methoxycyclohexanecarboxylic acid (43 mg), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (142 mg), and N,N-diisopropyl ethylamine (213 μL) were added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was added water (100 ml), followed by extraction with ethyl acetate (100 ml). The extracts were washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and then the solvent was evaporated under reduced pressure. The residue was separated/purified by silica gel column chromatography (from hexane:ethyl acetate=50:50-0:100 to chloroform:methanol=100:0-80:20) to obtain [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl](cis-4-methoxycyclohexyl)methanone (26 mg) (Example 249-1) and [3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl](trans-4-methoxycyclohexyl)methanone (7.1 mg) (Example 249-2).
Example 422
To a mixture of methyl 2-{-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}cyclopentane carboxylate (50 mg) and tetrahydrofuran (1 mL) were added a 1.01 M solution of (240 μL) diisobutylaluminum in toluene at 0° C., followed by stirring at the same temperature for 6 hours. To the reaction mixture were added methanol and sodium sulfate decahydrate, followed by stirring at room temperature for 1 hour. The insoluble matter was removed by filtration and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to obtain desired (2-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}cyclopentyl)methanol (33 mg).
Example 432
Racemic N-{6-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}-1-(tetrahydro-2H-pyran-4-yl)azepan-4-amine (300 mg) was optically resolved using supercritical fluid chromatography to obtain optically active substance, N-{6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}-1-(tetrahydro-2H-pyran-4-yl)azepan-4-amines (135 mg (RT 6.76 min) and 137 mg (RT 8.03 min)) as white amorphous substances, respectively.
SFC fractionation: AD-H/4.6×250 mm/CO2 75%, MeOH (0.1% DEA) 25%/Flow 3 ml/min/Conc. 2 mg/mL/rt=6.76 min, 8.03 min
Example A1
To a solution of 1-methylpiperidin-4-amine (4.6 mg) in N,N-dimethylformamide (200 μL) were added a solution of N,N-diisopropyl ethylamine (8.7 μL) in N,N-dimethylformamide (50 μL) and a solution of 1-[4-chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (9.2 mg) in N,N-dimethylformamide (300 μL), followed by stirring at 80° C. overnight. To the reaction mixture were added a saturated aqueous sodium bicarbonate solution and chloroform at room temperature, followed by liquid-liquid phase separation, and the organic layer was concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain 4-[2-(difluoromethyl)-1H-benzimidazolyl]-N-(1-methylpiperidin-4-yl)-6-(morpholin-4-yl)-1,3,5-triazin-2-amine (11.1 mg).
Example B1
To a solution of 1-(4-hydroxyphenyl)ethanone (5.4 mg) in N,N-dimethylformamide (200 μL) were added potassium carbonate (6.9 mg) and a solution of 1-[4-chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (9.2 mg) in N,N-dimethylformamide (300 μL), followed by stirring at 80° C. overnight. To the reaction solution were added water and chloroform at room temperature, followed by liquid-liquid phase separation, and the organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC to obtain 1-[4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}oxy)phenyl]ethanone (1.4 mg).
The conditions for HPLC carried out to determine RT in Examples A1 and B1 are shown below.
Columns: Wakosil-II 5 C18AR (Wako Pure Chemical Industries, Ltd.) (particle diameter: 5 μM, internal diameter: 2.0 mm, length: 30 mm)
Mobile phase: A Solution 5 mM aqueous trifluoroacetic acid solution, B Solution methanol
Flow rate: 1.2 mL/min; detection wavelength: 254 nm; column temperature: 35.0° C.; injection amount: 5 μL












TABLE 3







Time (min)
A sol (%)
B sol (%)
Elution









0-4
95→0
5→100
Gradient



4-4.5
0
100
Isocratic










Example A245
To a solution of rel-(1R,3R)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclopentanamine (10.8 mg), glycolic acid (1.9 mg), and 1-hydroxybenzotriazole (3.4 mg) in N,N-dimethylformamide (1.0 mL) was added a PS-Carbodiimide (Biotage Inc.) (100 mg), followed by stirring at room temperature overnight. To the reaction solution were added a PS-Isocyanate (Biotage Inc.) (50 mg) and a MP-Carbonate (Biotage Inc.) (50 mg), followed by stirring for four hours, and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain rel-N-[(1R,3R)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclopentyl]-2-hydroxyacetamide (7.2 mg).
Example B59
To a 2-methoxyethanamine (1.9 mg) were added a solution of trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexanecarboxylic acid (11.8 mg) and N,N-diisopropylethylamine (10.5 μL) in N,N-dimethylformamide (400 μL), and were added a solution of N-[(dimethylamino)(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methylMethanaminium hexafluorophosphoric acid (11.4 mg) in N,N-dimethylformamide (100 μL), followed by stirring at room temperature overnight. To the reaction solution were added water and chloroform, followed by liquid separation, and the organic layer was concentrated under reduced pressure. The residue was subjected to preparative purification with HPLC to obtain trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)-N-(2-methoxyethyl)cyclohexanecarboxamide (5.9 mg).
The condition for HPLC carried out to determine RT in Examples A245 and B59 are shown below.
columns: ACQUITY UPLC HSS T3 (particle diameter: 1.8 μm, internal diameter: 2.1 mm, length: 50 mm)
Mobile phase: A Solution 0.1% aqueous formic acid solution, B Solution 0.1% formic acid-methanol solution
Flow rate: 0.70 mL/min; detection wavelength: 254 nm; column temperature: 40.0° C.; injection amount: 1 μL












TABLE 4







Time (min)
A sol (%)
B sol (%)
Elution









0-3
95→10
5→90
Gradient



3-4
10
90
Isocratic










The compounds of Preparation Examples and Examples shown in Tables below were prepared in the same manner as in Preparation Examples and Examples as described above.
The chemical structural formulae, the preparation methods, and the physicochemical data of the compounds of Preparation Examples are shown in Tables 5 to 40. Further, the chemical structural formulae of the compounds of Examples are shown in Tables 41 to 145, and the preparation methods and the physicochemical data of the compounds of Examples are shown in Tables 146 to 167.
Furthermore, the structures and the physicochemical data of the compounds of Examples A1 to A60 prepared in the same manner as the method of Example A1 are shown in Tables 169 to 180, and the structures and the physicochemical data of the compounds of Examples A61 to A693 prepared in the same manner as the method of Example A245 are shown in Tables 181 to 312, and the structures and the physicochemical data of the compounds of Examples B1 to B56 prepared in the same manner as the method of Example B1 are shown in Tables 313 to 324, and the structures and the physicochemical data of the compounds of Examples B57 to B151 prepared in the same manner as the method of Example B59 are shown in Tables 324 to 343.










TABLE 5





PEx
PSyn
Str
DAT







1
1




ESI+: 327


 


2
2




ESI+: 378


 


3
3




ESI+: 394


 


4
4




ESI+: 410


 


5
5



 
ESI+: 506



















TABLE 6





PEx
PSyn
Str
DAT


















6
6




ESI+: 281


 


7
7




ESI+: 362


 


8
8




ESI+: 332


 


9
9




ESI+: 690(M+)


 


10
10




ESI+: 381



















TABLE 7





PEx
PSyn
Str
DAT







11
11




ESI+: 281


 


12
12




ESI+: 341


 


13
13




ESI+: 356


 


14
14




ESI+: 264


 


15
15




ESI+: 410



















TABLE 8





PEx
PSyn
Str
DAT


















16
16




ESI+: 226


 


17
17




ESI+: 303


 


18
2




ESI+: 392


 


19
2




ESI+: 392


 


20
2




ESI+: 406



















TABLE 9





PEx
PSyn
Str
DAT







21
2




ESI+: 410


 


22
2




ESI+: 408


 


23
3




ESI+: 522


 


24
3




ESI+: 408


 


25
3




ESI+: 408



















TABLE 10





PEx
PSyn
Str
DAT







26
3




ESI+: 424


 


27
3




ESI+: 426


 


28
3




ESI+: 422


 


29
1




ESI+: 459


 


30
1




ESI+: 459



















TABLE 11





PEx
PSyn
Str
DAT







31
1




ESI+: 378


 


32
3




ESI+: 394


 


33
1




ESI+: 580(M + Na)


 


34
1




ESI+: 477


 


35
1




ESI+: 505



















TABLE 12





PEx
PSyn
Str
DAT


















36
3




ESI+: 408


 


37
1




ESI+: 392


 


38
12




ESI+: 341


 


39
1




ESI+: 323


 


40
3




ESI+: 408



















TABLE 13





PEx
PSyn
Str
DAT


















41
1




ESI+: 392


 


42
3




ESI+: 422


 


43
1




ESI+: 406


 


44
10




ESI+: 281


 


45
12




ESI+: 341




















TABLE 14






PEx
PSyn
Str
DAT




















46
1




ESI+: 392


 



47
3




ESI+: 408


 



48
12




ESI+: 392


 



49
15




ESI+: 424


 



50
1




ESI+: 357



















TABLE 15





PEx
PSyn
Str
DAT


















51
1




ESI+: 408


 


52
3




ESI+: 424


 


53
1




ESI+: 406


 


54
3




ESI+: 422


 


55
10




ESI+: 401/403



















TABLE 16





PEx
PSyn
Str
DAT


















56
10




ESI+: 435


 


57
11




ESI+: 301


 


58
5




ESI+: 492


 


59
5




ESI+: 492


 


60
1




ESI+: 279


 


61
12




ESI+: 361/363



















TABLE 17





PEx
PSyn
Str
DAT


















62
11




ESI+: 335


 


63
12




ESI+: 395


 


64
1




ESI+: 412


 


65
1




ESI+: 446


 


66
3




ESI+: 428


 


67
Syn.53




ESI+: 179



















TABLE 18





PEx
PSyn
Str
DAT


















68
3




ESI+: 462


 


69
89




ESI+: 407


 


70
3




ESI+: 423


 


71
3




ESI+: 423


 


72
1




ESI+: 516



















TABLE 19





PEx
PSyn
Str
DAT


















73
3




ESI+: 423


 


74
89




ESI+: 407


 


75
89




ESI+: 407


 


76
3




ESI+: 407


 


77
5




ESI+: 391



















TABLE 20





PEx
PSyn
Str
DAT


















78
1




ESI+: 505


 


79
11




ESI+: 458 NMR1: 0.82- 1.03(4H, m), 1.35- 1.60(2H, m), 1.65- 1.82(4H, m), 2.36- 2.52(2H, m), 2.99- 3.03(2H, m), 3.56- 3.75(8H, m), 6.23- 6.37(1H, m), 7.09- 7.17(1H, m), 7.37- 7.73(3H, m), 7.75- 7.79(1H, m), 7.82- 7.88(1H, m)


 


80
80




ESI+: 438


 


81
81




ESI+: 354


 


82
82




ESI+: 407


 


83
83




ESI+: 227



















TABLE 21





PEx
PSyn
Str
DAT







84
84




ESI+: 320(M + Na)+ 


 


85
85




NMR1: 1.40(9H, s), 4.08- 4.19(2H, m), 7.09- 7.34(4H, m), 7.37- 7.47(1H, m)


 


86-1
86




ESI+: 371


 


86-2
86




ESI+: 547


 


87
87




ESI+: 690



















TABLE 22





PEx
PSyn
Str
DAT







88
88




ESI+: 356


 


89
89




ESI+: 492


 


90
90




ESI+: 546


 


91
 5




NMR2: 1.83- 1.95 (2H, m), 2.04- 2.14 (2H, m), 3.58- 3.67 (2H, m), 3.95- 4.03 (2H, m), 5.32- 5.40 (1H, m)


 


92
Syn. 422




ESI+: 256


 


93
80




ESI+: 424



















TABLE 23





PEx
PSyn
Str
DAT







94
 5




not found


 


95
89




ESI+: 506


 


96
89




ESI+: 449


 


97
89




ESI+: 550


 


98
89




ESI+: 407


 


99
89




ESI+: 506



















TABLE 24





PEx
PSyn
Str
DAT







100
89 




ESI+: 478


 


101
89 




ESI+: 407


 


102
9




ESI+: 690


 


103
9




ESI+: 704


 


104
3




ESI+: 564



















TABLE 25





PEx
PSyn
Str
DAT







105
3




ESI+: 550


 


106
3




ESI+: 423


 


107
3




ESI+: 566


 


108
4




ESI+: 454


 


109
4




ESI+: 537



















TABLE 26





PEx
PSyn
Str
DAT







110
4




ESI+: 529


 


111
4




ESI+: 440


 


112
4




ESI+: 577


 


113
4




ESI+: 538


 


114
4




ESI+: 510



















TABLE 27





PEx
PSyn
Str
DAT







115
 4




ESI+: 496


 


116
87




ESI+: 656


 


117
87




ESI+: 404


 


118
87




ESI+: 404


 


119
 1




ESI+: 382



















TABLE 28





PEx
PSyn
Str
DAT







120
1




ESI+: 367


 


121
1




NMRI: 3.66- 3.79 (8H, m), 7.19 (1H, s), 7.40- 7.69 (3H, m), 7.80- 7.85 (1H, d), 7.87- 7.92 (1H, d)


 


122
1




ESI+: 234


 


123
1




ESI+: 236


 


124
1




ESI+: 366



















TABLE 29





PEx
PSyn
Str
DAT







125
1




ESI+: 422


 


126
1




ESI+: 527(M + Na)+


 


127
1




ESI+: 548


 


128
1




ESI+: 534


 


129
1




ESI+: 469



















TABLE 30





PEx
PSyn
Str
DAT







130
1




not found


 


131
1




ESI+: 462


 


132
1




ESI+: 476


 


133
1




ESI+: 476


 


134
1




Not found



















TABLE 31





PEx
PSyn
Str
DAT







135
1




ESI+: 490


 


136
1




ESI+: 516


 


137
1




ESI+: 422


 


138
1




ESI+: 505


 


139
1




ESI+: 505



















TABLE 32





PEx
PSyn
Str
DAT







140
1




ESI+: 497


 


141
1




ESI+: 544


 


142
1




ESI+: 545


 


143
1




ESI+: 517


 


144
1




ESI+: 477



















TABLE 33





PEx
PSyn
Str
DAT







145
 1




ESI+: 491


 


146
 1




ESI+: 477


 


147
90




ESI+: 546


 


148
Syn. 87




ESI+: 706


 


149
82




ESI+: 393



















TABLE 34





PEx
PSyn
Str
DAT







150
83




ESI+: 213


 


151
83




ESI+: 258


 


152
83




ESI+: 244


 


153
Syn53




ESI+: 156


 


154
Syn53




ESI+: 256


 


155
81




ESI+: 340


 


156
Syn. 54




ESI+: 528


 


157
Syn. 54




ESI+: 528



















TABLE 35





PEx
PSyn
Str
DAT







158
Syn. 54




ESI+: 445


 


159
2




ESI+: 567[M + Na]


 


160
5




ESI+: 528[M + Na]


 


161
Syn. 53




ESI+: 256


 


162
90 




ESI+: 546



















TABLE 36





PEx
PSyn
Str
DAT







163
 5




ESI+: 463


 


164
88




ESI+: 356


 


165
 2




ESI+: 408


 


166
12




ESI+: 357


 


167
11




ESI+: 297



















TABLE 37





PEx
PSyn
Str
DAT







168
10




ESI+: 397


 


169
89




ESI+: 464


 


170
Syn. 54




ESI+: 516


 


171
87




ESI+: 616


 


172
Syn. 1




ESI+: 578



















TABLE 38





PEx
PSyn
Str
DAT







173
Syn. 54




ESI+: 416


 


174
Syn. 92




ESI+: 529/531


 


175
Syn. 92




ESI+: 515/517


 


176
 4




ESI+: 510


 


177
89




ESI+: 478



















TABLE 39





PEx
PSyn
Str
DAT







178
Syn. 54




ESI+: 459


 


179
Syn. 92




not found


 


180
Syn. 54




ESI+: 542


 


181
 Syn. 241




ESI+: 565/567


 


182
2




ESI+: 527 (M + Na)+



















TABLE 40





PEx
PSyn
Str
DAT







183
183




ESI+: 600


 


184
Syn. 92




ESI+: 544


 


185
185




ESI+: 347


 


186
Syn. 92




ESI+: 488


 


187
 89




ESI+: 449

















TABLE 41





Ex
Str







1






 


2






 


3






 


4





















TABLE 42





Ex
Str







5






 


6






 


7






 


8






 


9





















TABLE 43





Ex
Str







10






 


11






 


12






 


13





















TABLE 44





Ex
Str







14






 


15






 


16






 


17





















TABLE 45





Ex
Str







18






 


19






 


20






 


21






 


22





















TABLE 46





Ex
Str







23






 


24






 


25






 


26






 


27





















TABLE 47





Ex
Str







28






 


29






 


30






 


31





















TABLE 48





Ex
Str







32






 


33






 


34






 


35





















TABLE 49





Ex
Str







36






 


37






 


38






 


39





















TABLE 50





Ex
Str







40






 


41






 


42






 


43-1





















TABLE 51





Ex
Str







43-2






 


44






 


45






 


46





















TABLE 52





Ex
Str







47






 


48






 


49






 


50





















TABLE 53





Ex
Str







51






 


52






 


53






 


54






 


55






















TABLE 54






Ex
Str








56






 



57






 



58






 



59






 



60






















TABLE 55






Ex
Str








61






 



62






 



63






 



64






 



65





















TABLE 56





Ex
Str







66






 


67






 


68






 


69






 


70





















TABLE 57





Ex
Str







71






 


72






 


73






 


74





















TABLE 58





Ex
Str







75






 


76






 


77






 


78





















TABLE 59





Ex
Str







79






 


80






 


81






 


82





















TABLE 60





Ex
Str







83






 


84






 


85






 


86





















TABLE 61





Ex
Str







87






 


88






 


89






 


90






 


91





















TABLE 62





Ex
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93






 


94






 


95






 


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TABLE 63





Ex
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98






 


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100






 


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TABLE 64





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TABLE 65





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TABLE 66





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TABLE 67





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TABLE 68





Ex
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120






 


121






 


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TABLE 69





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124






 


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TABLE 70





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128






 


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TABLE 71





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TABLE 72





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137






 


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TABLE 73





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TABLE 74





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TABLE 75





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TABLE 76





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TABLE 77






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TABLE 78






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TABLE 79





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TABLE 80





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TABLE 81





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TABLE 82





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TABLE 83





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TABLE 84





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TABLE 85





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TABLE 86





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TABLE 87






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TABLE 88






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TABLE 89





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TABLE 90






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TABLE 91





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TABLE 92





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TABLE 93






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TABLE 94





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TABLE 95





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TABLE 96





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TABLE 97





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Ex
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464






 


465






 


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467























TABLE 145







Ex
Str









468







 



469







 



470























TABLE 146





Ex
Syn
DAT







1
1
ESI+: 516




NMR1:1.39(9H,s),1.81-1.94(H,m),2.02-2.16(1H,m),3.11-




3.87(12H,m),4.27-4.43(1H,m),6.33-6.46(1H,m),7.29-7.87




(6H,m)


2
1
ESI+: 458




NMR1:1.14-1.27(2H,m),1.46-1.58(1H,m),1.64-1.85(4H,m),




2.13(3H,s),2.71-2.80(2H,m),3.06-3.34(2H,m),3.40-3.76(8H,m),




5.64(1H,s),7.33-7.49(3H,m),7.79-7.86(1H,m)8.32-8.44(1H,m)


3
1
ESI+: 458




NMR1:0.79-1.84(7H,m),2.12(3H,s),2.67-2.71(2H,m),




3.01-3.18(2H,m),3.63-3.68(8H,m),6.21-6.38(1H,m),




7.13-7.19(1H,m),7.39-7.86(5H,m)


4
1
ESI+: 458




NMR1:1.12-1.30(2H,m),1.43-1.60(1H,m),1.63-1.72(2H,m),




1.75-1.86(2H,m),2.14(3H,s),2.71-2.80(2H,m),3.21-3.32




(2H,m),3.61-3.72(8H,m),6.14(1H,s),7.37-7.89(6H,m)


5
1
ESI+: 567[M+Na]




NMR1:0.98-1.13(2H,m),1.36-1.40(9H,m),1.63-1.83(3H,m),




2.57-2.80(2H,m),3.22-3.32(2H,m),3.62-3.84(8H,m),3.87-4.01




(2H,m),7.39-8.07(5H,m),8.40-8.58(1H,m)


6
1
ESI+: 538[M+Na]




NMR1:1.39(9H,s),1.60-2.16(2H,m),3.12-3.45(2H,m),3.59-3.76




(9H,m),3.98-4.08(1H,m),4.31-4.40(1H,m),6.02-6.09(1H,m),




6.34-6.45(1H,m),7.33-7.90(5H,m)


7
1
ESI+: 552[M+Na]




NMR1:1.39(9H,s),1.66-1.98(4H,m),3.57-3.74(10H,m),3.74-3.94




(3H,m),6.28-6.41(1H,m),6.99-7.13(1H,m),7.37-7.90(5H,m)


8
1
ESI+: 524[M+Na]




NMR1:1.37(9H,s),3.57-4.17(12H,m),4.48-4.57(1H,m),6.37-6.47




(1H,m),7.20-7.97(6H,m)


9
1
ESI+: 524[M+Na]




NMR1:1.37-1.41(9H,m),3.60-3.72(8H,m),3.74-3.84(2H,m),




4.13-4.26(2H,m),4.55-4.70(1H,m),6.11(1H,s),7.36-7.66(3H,m),




7.70-7.89(2H,m),8.10-8.22(1H,m)


10
1
ESI+: 528




NMR1:0.79(9H,m),1.95-2.10(2H,m),2.26-2.45(1H,m),2.78-2.91




(2H,m),3.03-3.42(4H,m),3.54-3.71(8H,m),3.79-3.92(2H,m),




6.26-6.37(1H,m),7.13-7.18(1H,m),7.39-7.86(5H,m)


11
1
ESI+: 544




NMR1:0.90-1.12(2H,m)1.32-1.45(9H,m),1.58-1.81(3H,m),




2.53-2.80(2H,m),3.06-3.26(2H,m),3.55-3.75(8H,m),3.83-4.00




(2H,m),6.23-6.40(1H,m),7.18(1H,br-s),7.36-7.89(5H,m)


















TABLE 147





Ex
Syn
DAT







12
1
ESI+: 558




NMR1:0.91-1.12(2H,m),1.23(3H,d,J=6.8Hz),1.38(9H,s),1.60-1.82(3H,m),




2.53-2.78(2H,m),3.06-3.29(3H,m),3.39-3.52(1H,m),3.57-3.66(1H,m),




3.68-3.77(1H,m),3.85-4.16(4H,m),4.41(1H,br-s),6.20-6.35(1H,m),




7.18(1H,br-s),7.40-7.90(5H,m)


13
1
ESI+: 558




NMR1:0.91-1.12(2H,m),1.23(3H,d,J=6.8Hz),1.38(9H,s),1.60-1.82(3H,m),




2.53-2.78(2H,m),3.06-3.29(3H,m),3.39-3.52(1H,m),3.57-3.66(1H,m),




3.68-3.77(1H,m),3.85-4.16(4H,m),4.41(1H,br-s),6.20-6.35(1H,m),




7.18(1H,br-s),7.40-7.900(5H,m)


14
1
ESI+: 572




NMR1:0.90(3H,t,J=7.5Hz),0.92-1.11(2H,m),1.38(9H,s),1.60-1.87(5H,m),




2.56-2.78(2H,m),3.06-4.44(11H,m),6.18-6.35(1H,m),7.34-7.89(5H,m)


15
1
ESI+: 574




NMR1:0.91-1.11(2H,m),1.20-1.31(1H,m),1.32-1.41(9H,m),1.57-1.81(3H,m),




2.59-2.80(2H,m),3.02-3.25(3H,m),3.37-3.62(3H,m),3.66-3.77(1H,m),




3.81-4.44(5H,m),4.84-4.92(1H,m),6.20-6.36(1H,m),7.15(1H,br-s),




7.35-7.89(5H,m)


16
1
ESI+: 576




NMR1:0.92-1.11(2H,m),1.20-1.30(1H,m),1.33-1.42(9H,m),1.54-1.80(3H,m),




2.54-2.81(2H,m),3.06-4.30(10H,m),4.55-4.83(2H,m),6.29-6.40(1H,m),




7.25(1H,br-s),7.36-7.90(5H,m)


17
1
ESI+: 548




NMR1:1.40(9H,s),1.56-1.82(2H,m),2.71-3.80(10H,m),3.91-4.31(3H,m),




4.66-5.00(1H,m),6.31-6.48(1H,m),7.00-7.94(6H,m)


18
1
ESI+: 544




NMR1:0.99-1.43(11H,m),1.54-1.80(3H,m),2.69-2.85(1H,m),3.02-4.00




(13H,m),6.25-6.42(1H,m),7.12-7.29(1H,m),7.35-7.89(5H,m)


19
1
ESI+: 544




NMR1:0.99-1.43(11H,m),1.54-1.80(3H,m),2.69-2.85(1H,m),3.02-4.00




(13H,m),6.25-6.42(1H,m),7.12-7.29(1H,m),7.35-7.89(5H,m)


20
1
ESI+: 558




NMR1:1.00-1.42(14H,m),1.54-1.80(3H,m),2.69-2.85(1H,m),3.02-4.00




(13H,m),6.25-6.42(1H,m),7.12-7.29(1H,m),7.35-7.89(5H,m)


21
1
ESI+: 558




NMR1:1.00-1.41(14H,m),1.54-1.82(3H,m),2.68-2.85(1H,m),3.00-4.17,




(11H,m),4.42(1H,br-s),6.19-6.36(1H,m),7.10-7.27(1H,m),7.35-7.89(5H,m)


22
22
ESI+: 520




NMR1:2.06-2.27(3H,m),2.79-3.85(14H,m),4.27-4.48(2H,m),5.46-5.70(1H,m),




7.35-7.89(11H,m)


















TABLE 148





Ex
Syn
DAT







23
22
ESI+: 506




NMR1:2.98-3.84(14H,m),4.36-4.63(3H,m),6.39-6.52(1H,m),7.21-7.88(11H,m)


24
22
ESI+: 506




NMR1:1.87-2.54(2H,m),2.96-3.85(12H,m),4.23-4.67(3H,m),6.32-6.53(1H,m),




7.28-7.88(11H,m)


25
22
ESI+: 548




NMR1:1.33-1.96(8H,m),2.76-3.85(12H,m),4.23-4.67(3H,m),6.32-6.53(1H,m),




7.28-7.88(11H,m)


26
26
ESI+: 520




NMR1:1.22-3.08(10H,m),3.57-3.71(8H,m),4.24-4.38(1H,m),6.30-6.42(1H,m),




7.11-7.88(11H,m)


27
26
ESI+: 502




NMR1:0.79-0.89(1H,m),1.21-1.38(2H,m),2.62-2.71(2H,m),2.78-2.86(1H,m),




3.45-3.61(4H,m),3.61-3.72(8H,m),4.32-4.45(1H,m),6.29-6.44(1H,m),




7.36-7.93(6H,m)


28
26
ESI+: 542




NMR1:0.96-3.38(21H,m),3.56-3.78(8H,m),4.18-4.45(1H,m),6.23-6.37(1H,m),




7.08-7.18(1H,m),7.36-7.89(5H,m)


29
26
ESI+: 556




NMR1:0.74-3.36(23H,m),3.55-3.75(8H,m),4.28-4.37(1H,m),6.24-6.37(1H,m),




7.09-7.17(1H,m),7.36-7.90(5H,m)


30
26
ESI+: 627




NMR1:1.01-3.74(35H,m),3.85-4.01(2H,m),6.24-6.37(1H,m),7.11-7.19(1H,m),




7.36-7.89(5H,m)


31
26+44
ESI+: 541




NMR1:1.44-3.76(31H,m),6.29-6.44(1H,m),7.28-7.89(6H,m)


32
26+44
ESI+: 567




NMR1:0.70-3.75(33H,m),6.29-6.44(1H,m),7.26-7.89(6H,m)


33
26+44
ESI+: 569




NMR1:1.35-4.70(31H,m),6.29-6.45(1H,m),7.28-7.89(6H,m)


34
26+44
ESI+: 605




NMR1:1.45-3.77(31H,m),6.30-6.44(1H,m),7.27-7.89(6H,m)


35
26+44
ESI+: 522




NMR1:1.49-2.11(5H,m),3.04-3.53(6H,m),3.59-3.75(8H,m),3.83-4.05(1H,m),




4.80-5.15(4H,m),6.29-6.44(1H,m),7.25-7.89(6H,m)


36
26+44
ESI+: 562




NMR1:1.37-2.23(13H,m),2.83-3.49(7H,m),3.57-3.78(8H,m),6.28-6.43(1H,m),




7.25-7.35(1H,m),7.37-7.89(5H,m)


















TABLE 149





Ex
Syn
DAT







37
26+44
ESI+: 542




NMR1:1.00-1.27(5H,m),1.30-1.74(7H,m),1.95-2.10(2H,m),2.30-2.42(1H,m),




2.80-2.91(2H,m),3.05-3.34(5H,m),3.39-3.52(1H,m),3.56-3.65(1H,m),3.67-3.97




(4H,m),4.00-4.14(1H,m),4.33-4.49(1H,m),6.18-6.32(1H,m),7.13(1H,br-s),




7.35-7.89(5H,m)


38
26+44
ESI+: 542




NMR1:1.24(3H,d,J=6.7Hz),1.43-2.08(9H,m),2.71-2.97(2H,m),3.06-3.39(7H,m),




3.40-3.82(5H,m),3.89-3.99(3H,m),4.34-4.49(1H,m),6.24-6.39(1H,m),7.24-7.89(6H,m)


39
26+44
ESI+: 542




NMR1:1.02-3.36(17H,m),3.42-3.54(2H,m),3.59-3.74(8H,m),3.77-3.89(3H,m),6.39




(1H,br-s),7.25-7.89(6H,m)


40
26+44
ESI+: 529




NMR:1.64-2.17(9H,m),2.90-3.03(2H,m),3.23-3.81(13H,m),3.93-4.01(2H,m),




4.31(2H,d,J=6.3Hz),6.43(1H,s),7.39-7.68(3H,m),7.74-7.79(1H,m),7.85-7.90(1H,m)


41
26+44
ESI+: 528




NMR1:1.43-2.08(9H,m),2.74-2.94(2H,m),3.07-3.38(5H,m),3.40-3.52(2H,m),




3.58-3.75(8H,m),3.88-4.01(2H,m),6.28-6.45(1H,m),7.24-7.90(6H,m)


42
26+44
ESI+: 528




NMR:1.06-4.30(28H,m),6.30-6.45(1H,m),7.29(1H,br-s),7.37-7.88(5H,m)


43-1
43
ESI+: 544




NMR1:1.19-2.25(13H,m),2.79-3.43(7H,m),3.58-3.75(8H,m),4.39-4.62(1H,m),




6.30-6.46(1H,m),7.25-7.90(6H,m)


43-2
43
ESI+: 544




NMR1:1.20-2.18(13H,m),2.82-3.46(7H,m),3.59-3.75(8H,m),4.72-4.91(1H,m),




6.26-6.47(1H,m),7.19-7.89(6H,m)


44
44
ESI+: 520




NMR1:1.68-2.10(5H,m),3.18-3.95(14H,m),6.29-6.45(1H,m),7.31-7.96(11H,m)


45
45
ESI+: 487




NMR1:1.96-2.57(4H,m),2.75-4.07(20H,m),4.45-4.65(1H,m),6.41-6.59(1H,m),




7.37-7.90(6H,m)


46
45
ESI+: 530




NMR1:1.07-1.30(5H,m),1.43-1.73(3H,m),2.03-2.18(2H,m),2.75-2.86(2H,m),




3.07-3.23(4H,m),3.58-3.74(8H,m),4.02-4.11(2H,m),6.23-6.38(1H,m),




7.09-7.18(1H,m),7.28-7.87(5H,m)


47
45+44
ESI+: 501




NMR1:1.36-2.01(5H,m),2.84-4.51(16H,m),6.27-6.45(1H,m),7.20-8.06(8H,m)


















TABLE 150





Ex
Syn
DAT







48
45+44
ESI+: 528




NMR1:1.42-2.03(5H,m),2.49-3.44(7H,m),3.56-4.60(12H,m),6.37(1H,br-s),7.23-7.88(6H,m)


49
45+44
ESI+: 515




NMR1:1.37-1.92(5H,m),2.55-2.95(4H,m),3.10-3.48(6H,m),3.60-3.75(8H,m),6.38(1H,br-s),




6.98-7.89(8H,m)


50
45+44
ESI+: 504




NMR1:1.36-1.93(5H,m),2.01-2.20(2H,m),2.76-2.94(2H,m),3.03-3.54(6H,m),3.60-3.74(8H,m),




4.42-4.63(2H,m),6.29-6.45(1H,m),7.24-7.90(6H,m)


51
45+44
ESI+: 518




NMR1:1.35-1.92(9H,m),2.74-3.53(8H,m),3.57-3.73(8H,m),4.36-4.57(2H,m),6.29-6.44(1H,m),)




7.23-7.34(1H,m),7.37-7.88(5H,m


52
52
ESI+: 520




NMR1:1.09-1.31(2H,m),1.46-1.72(2H,m),1.87-1.98(2H,m),2.20-2.34(2H,m),2.77-2.91(2H,m),




3.09-3.21(2H,m),3.60-3.73(8H,m),3.73-3.83(2H,m),4.17-4.47(2H,m),4.81-4.87(1H,m),6.26-6.37




(1H,m),7.12-7.20(1H,m),7.38-7.90(5H,m)


53
53
ESI+: 416




NMR1:1.93-2.02(1H,m),2.11-2.23(1H,m),3.07-3.92(12H,m),4.42-4.53(1H,m),6.46(1H,br-s),




7.39-7.87(7H,m),9.35(2H,br-s)


54
54
ESI+: 430




NMR1:1.27-1.38(2H,m),1.70-1.88(2H,m),2.86-2.98(2H,m),3.57-3.78(11H,m),




6.28-6.38(1H,m),6.94-7.06(1H,m),7.36-7.87(6H,m)


55
54
ESI+: 445




NMR1:0.97-1.13(2H,m),1.57-1.73(3H,m),2.31-2.48(2H,m),2.86-2.96(2H,m),3.16-3.32(2H,m),




3.62-3.86(8H,m),7.38-7.52(2H,m),7.63-8.08(3H,m),8.42-8.59(1H,m)


56
54
ESI+: 416




NMR1:1.57-1.65(1H,m),1.86-2.04(1H,m),2.59-2.78(2H,m),2.83-3.07(2H,m),3.58-3.72(8H,m),




4.17-4.27(1H,m),6.28-6.43(1H,m),7.00-7.18(1H,m),7.37-7.87(5H,m)


57
54
ESI+: 402




NMR1:3.44-3.60(4H,m),3.62-3.75(8H,m),4.56-4.69(1H,m),6.30-6.42(1H,m),6.83(1H,s),




7.37-7.93(5H,m),8.31(1H,s)


58
54
ESI+: 402




NMR1:3.41-3.49(2H,m),3.59-3.71(10H,m),4.70-4.81(1H,m),6.10(1H,s),7.36-7.65(3H,m),




7.69-7.88(2H,m),7.98-8.06(1H,m)


59
54
ESI+: 499




NMR1:1.52-1.66(4H,m),2.62-2.69(1H,m),2.85-2.94(1H,m),3.39-3.53(4H,m),




3.62-3.72(8H,m),4.52-4.63(2H,m),6.37-6.49(1H,m),7.37-7.97(6H,m)


















TABLE 151





Ex
Syn
DAT







60
54
ESI+: 444




NMR1:0.91-3.28(11H,m),3.55-3.76(8H,m),6.23-6.39(1H,m),




7.07-7.19(1H,m),7.36-7.89(5H,m)


61
54
ESI+: 458




NMR1:1.0.91-1.11(2H,m),1.23(3H,d,J=6.7Hz),1.54-1.70(3H,m),




2.31-2.44(2H,m),2.84-2.95(2H,m),3.03-3.52(5H,m),3.56-3.77(2H,m),




3.88-3.98(1H,m),4.00-4.16(1H,m),4.33-4.50(1H,m),6.18-6.32(1H,m),




7.05-7.19(1H,m),7.58-7.88(5H,m)


62
54
ESI+: 458




NMR1:0.91-1.11(2H,m),1.23(3H,d,J=6.7Hz),1.54-1.70(3H,m),2.31-2.45(2H,m),




2.84-2.97(2H,m),3.03-3.53(5H,m),3.57-3.77(2H,m),3.88-3.98(1H,m),




4.00-4.16(1H,m),4.33-4.50(1H,m),6.18-6.32(1H,m),7.05-7.19(1H,m),7.58-7.88(5H,m)


63
54
ESI+: 445




NMR1:1.09-1.23(2H,m),1.62-1.72(2H,m),1.78-1.91(1H,m),2.40-2.50(2H,m),




2.91-2.98(2H,m),3.64-3.79(8H,m)4.22(2H,d,J=6.4Hz),6.42(1H,s),7.39-7.50(2H,m),




7.54(1H,t,J=52.5Hz),7.74-7.89(2H,m)


64
54
ESI+: 444




NMR1:0.93-1.13(1H,m),1.19-1.37(2H,m),1.44-1.80(3H,m),2.07-2.45(2H,m),2.72-2.99




(2H,m),3.02-3.20(2H,m),3.56-3.74(8H,m),6.22-6.39(1H,m),7.13(1H,br-s),7.36-7.89(5H,m)


65
54
ESI+: 444




NMR1:0.93-1.13(1H,m),1.19-1.37(2H,m),1.44-1.80(3H,m),2.07-2.45(2H,m),




2.72-2.99(2H,m),3.02-3.20(2H,m),3.56-3.74(8H,m),6.22-6.39(1H,m),7.13(1H,br-s),




7.36-7.89(5H,m)


66
66
ESI+: 515




NMR1:1.22-1.51(2H,m),1.77-2.00(2H,m),2.17(6H,s),2.63-2.83(1H,m),2.96-3.18(3H,m),




3.56-3.75(8H,m),3.90-4.05(2H,m),4.18-4.31(1H,m),6.28-6.43(1H,m),7.04-7.17(1H,m),




7.37-7.89(5H,m)


67
66
ESI+: 530




NMR1:0.95-1.31(2H,m),1.67-1.91(3H,m),2.11-2.21(6H,m),2.86-3.15(3H,m),3.22-3.33




(2H,m),3.63-3.85(8H,m),3.99-4.09(1H,m),4.30-4.39(1H,m),7.39-7.53(2H,m),7.64-8.09




(3H,m),8.41-8.59(1H,m)


68
66
ESI+: 501




NMR1:1.80-2.25(10H,m),2.92-3.01(2H,m),3.45-3.75(10H,m),4.32-4.45(1H,m),6.33-6.47




(1H,m),7.31-7.88(6H,m)


69
66
ESI+: 487




NMR1:2.17(6H,s),2.83-2.96(2H,m),3.55-3.74(8H,m),3.79-3.85(1H,m),4.01-4.19(2H,m),




4.39-4.61(2H,m),6.37-6.48(1H,m),7.37-7.89(6H,m)


70
66
ESI+: 599


















TABLE 152





Ex
Syn
DAT







71
71
ESI+: 509[M+Na]




NMR1:0.96-1.21(4H,m),1.66-1.90(3H,m),1.95-1.99(3H,m),2.91-3.04




(1H,m),3.23-3.32(2H,m),3.63-3.87(8H,m),4.32-4.41(1H,m),7.39-7.54




(2H,m),7.63-8.09(3H,m),8.41-8.59(1H,m)


72
66+44
ESI+: 529




NMR1:0.92-1.28(2H,m),1.67-1.93(3H,m),2.59-2.86(7H,m),2.91-3.30




(3H,m),3.54-4.41(12H,m),6.26-6.44(1H,m),7.27(1H,br-s),7.37-7.90(5H,m)


73
66+44
ESI+: 543




NMR1:0.89-1.28(2H,m),1.64-1.91(3H,m),2.45-3.28(15H,m),3.76-3.97




(8H,m),4.31-4.41(1H,m),6.38(1H,br-s),7.25-7.99(6H,m)


74
74
ESI+: 520


75
74+44
ESI+: 538




NMR1:1.60-2.07(5H,m),3.17-3.95(14H,m),6.29-6.45(1H,m),




7.29-7.97(10H,m)


76
74+44
ESI+: 538




NMR1:1.41-1.72(2H,m),1.79-1.95(3H,m),2.95-3.35(4H,m),3.59-3.76(10H,m),




6.38(1H,br-s),6.80-7.91(10H,m)


77
74+44
ESI+: 538




NMR1:1.33-1.53(2H,m),1.68-1.88(3H,m),2.68-2.83(2H,m),3.18-3.32(2H,m),




3.34-3.44(2H,m),3.61-3.73(8H,m),6.36(1H,br-s),6.97-7.90(10H,m)


78
74+44
ESI+: 550




NMR1:1.74-2.08(5H,m),3.18-3.78(17H,m),6.36(1H,br-s),7.02-7.13(2H,m),




7.26-7.90(8H,m)


79
74+44
ESI+: 534




NMR1:1.67-2.08(5H,m),2.33(3H,s),3.16-3.77(14H,m),6.36(1H,br-s),7.25-7.89




(10H,m)


80
80
ESI+: 545




NMR1:1.11-1.26(2H,m),1.40(9H,s),1.70-1.79(2H,m),1.89-2.03(1H,m),2.64-2.85




(2H,m),3.63-3.80(8H,m),3.91-4.05(2H,m),4.27(2H,d,J=6.4Hz),6.43(1H,s),




7.38-7.50(2H,m),7.54(1H,t,J=52.5Hz),7.73-7.89(2H,m)


81
80
ESI+: 559




NMR1:1.10-1.27(5H,m),1.40(9H,s),1.70-1.79(2H,m),1.91-2.03(1H,m),2.68-2.84




(2H,m),3.17-3.29(1H,m),3.40-3.49(1H,m),3.55-3.62(1H,m),3.68-3.75(1H,m),




3.89-4.04(3H,m),4.19-4.33(3H,m),4.56-4.64(1H,m),6.43(1H,s),7.39-7.50(2H,m),




7.54(1H,t,J=52.5Hz),7.74-7.90(2H,m)


82
82
ESI+: 422[M+Na]


83
83
ESI+: 487


84
84
ESI+: 628


















TABLE 153





Ex
Syn
DAT

















85
52
ESI+: 556




NMR1:1.03(6H, s), 1.43(12H, brs), 2.28(2H, brs), 3.01-3.14(2H, m),




3.57-3.72(8H, m), 4.01(1H, brs), 6.21-6.37(1H, m), 6.76-7.02(1H, m),




7.34-7.96(5H, m)


86
86
ESI+: 584


87
87
ESI+: 586




NMR1:1.50-1.81(7H, m), 2.23(3H, br), 3.16-3.25(1H, m), 3.28-3.36




(1H, m), 3.54(3H, s), 3.70(4H, br), 3.74(4H, br), 3.81(1H, br), 4.08-4.18




(1H, m), 4.99-5.08(1H, m), 6.40(1H, m), 6.40(1H, s), 7.38-7.50(3H, m),




7.53(1H, t, J = 52.5 Hz), 7.75(1H, d, J = 7.8 Hz), 7.86(1H, d, J = 7.8 Hz)


88
88
ESI+: 606


89
89
ESI+: 556




NMR1:1.36-1.73(8H, m), 1.81-1.91(2H, m), 1.97-2.21(4H, m), 2.97(2H, s),




3.05-3.16(1H, m), 3.60-3.80(9H, m), 5.00-5.10(1H, m), 6.40(1H, s), 7.38-7.68




(4H, m), 7.72-7.78(1H, m), 7.83-7.89(1H, m)


90
54
ESI+: 472


91
91
ESI+: 514[M + Na]




NMR:1.44-1.67(5H, m), 1.76-2.03(3H, m), 2.76-2.87(1H, m), 2.95-3.09(1H, m),




3.12-3.23(1H, m), 3.62-3.94(10H, m), 7.39-7.52(2H, m), 7.70-8.28(3H, m),




8.43-8.58(1H, m)


92
92
ESI+: 502


93
93
ESI+: 458


94
94
ESI+: 530[M + Na]




NMR1:1.47-1.73(4H, m), 1.80-2.00(4H, m), 3.29-3.92(13H, m),




7.38-8.24(5H, m), 8.43-8.56(1H, m)


95
92
ESI+: 531


96
92
ESI+: 516




NMR1:1.39(9H, s), 2.15-2.34(4H, m), 3.61-3.72(8H, m), 3.99-4.13(1H, m),




4.38-4.50(1H, m), 6.09(1H, s), 7.25-7.94(7H, m)


97
92
ESI+: 544


98
92
ESI+: 531




NMR1:1.38(9H, s), 1.42-2.36(6H, m), 3.54-4.12(9H, m), 5.48(1H, m), 




6.97(1H, d, J = 8 Hz), 7.18-7.93(5H, m)


99
71
ESI+: 570




NMR1:1.51-1.79(7H, m), 1.84(3H, s), 2.17-2.34(3H, m), 3.17-3.26(1H, m), 3.27-




3.38(2H, m), 3.70(4H, br), 3.74(4H, br), 3.82(1H, br), 4.98-5.10(1H, m), 6.40(1H, s),




7.38-7.49(2H, m), 7.54(1H, t, J = 52.4 Hz), 7.74(1H, d, J = 7.8 Hz), 7.86(1H, d, J = 7.4 Hz),




8.15(1H, d, J = 8.2 Hz)


100
66 + 44
ESI+: 529




NMR1:1.20-1.90(8H, m), 2.72-2.85(6H, m), 3.58-4.38(12H, m), 6.26(1H, s),




7.39-7.69(4H, m), 7.72-7.78(1H, m), 7.84-7.89(1H, m), 8.54-8.63(1H, m)


101
66
ESI+: 676


















TABLE 154





Ex
Syn
DAT

















102
66
ESI+: 676


103
66
ESI+: 516


104
66
ESI+: 516


105
66
ESI+: 544


106
66
ESI+: 552


107
66
ESI+: 541


108
66
ESI+: 541


109
66
ESI+: 541


110
66
ESI+: 542


111
66
ESI+: 515


112
1
ESI+: 463




NMR1:1.23(4H, s), 3.57(8H, s), 6.21-8.09(12H, m)


113
66
ESI+: 529


114
66
ESI+: 529


115
66
ESI+: 556


116
66
ESI+: 583




NMR1:0.2-0.6(4H, m), 0.65-2(12H, m), 2.17(6H, s),




2.80(2H, s), 3.0-4.0(9H, m), 6.30(1H, brs), 7.0-8.0(5H, m)


117
66
ESI+: 585


118
66 + 44
ESI+: 529


119
66 + 44
ESI+: 501


120
45 + 44
ESI+: 554




NMR1:1.54(6H, brs), 1.82(6H, brs), 2.87-3.02(2H, m),




3.07-3.20(2H, m), 3.29-3.39(2H, m), 3.57-3.76(8H, m),




3.81-4.01(4H, m), 6.27-6.46(1H, m), 7.14(1H, brs),




7.35-7.92(5H, m)


121
44 + 44
ESI+: 570




NMR1:1.25(6H, brs), 1.44-2.97(15H, m), 3.13(3H, brs),




3.39-3.49(1H, m), 3.58-3.76(8H, m), 6.29-6.46(1H, m),




7.08-7.91(6H, m)


122
45 + 44
ESI+: 514


123
45 + 44
ESI+: 514


124
45 + 44
ESI+: 542


125
45
ESI+: 542




NMR1:0.75-2.16(10H, m), 2.22(3H, s), 2.43(4H, brs),




2.95-3.18(2H, m), 3.42-3.72(12H, m), 6.36(1H, brs),




7.02-7.39(4H, m), 7.61-7.71(1H, m)


126
45
ESI+: 570


127
45
ESI+: 574




NMR1:0.80-2.18(15H, m), 3.02(2H, s), 3.14




(2H, d, J = 5.2 Hz), 3.61-3.77(9H, m), 4.48(1H, t, J = 5.2 Hz), 




5.01-5.10(1H, m), 6.39(1H, s), 7.39-7.66(4H, m), 




7.70-7.77(1H, m), 7.84-7.88(1H, m)


















TABLE 155





Ex
Syn
DAT







128
45
ESI+: 600




NMR1:1.34-2.40(19H, m), 3.05(2H, s), 3.58-3.78(9H, m),




4.29(1H, d, J = 4.0 Hz), 5.0-5.15(1H, s), 7.39-7.66(4H, m),




7.72-7.76(1H, m), 7.84-7.88(1H, m)


129
45
ESI+: 600




NMR1:0.81-2.28(19H, m), 3.05(2H, s), 3.61-3.77(9H, m),




4.45(1H, d, J = 4.4 Hz), 5.05-5.15(1H, m), 6.39(1H, s), 7.39-




7.66(4H, m), 7.72-7.76(1H, m), 7.84-7.88(1H, m)


130
45
ESI+: 598




NMR1:0.17-0.68(4H, m), 0.76-2.13(22H, m), 3.01-3.60




(6H, m), 6.31(1H, brs), 6.73(1H, brs), 7.25-8.03(5H, m)


131
45 + 44
ESI+: 542


132
45 + 44
ESI+: 542


133
89
ESI+: 556




NMR1:0.05-1.11(2H, m), 0.36-0.44(2H, m), 0.80-0.90




(2H, m), 1.37-1.63(4H, m), 1.81-1.92(2H, m), 2.09-2.19




(2H, m), 2.27-2.37(2H, m), 3.06(2H, s), 3.60-3.78(9H, m),




5.00-5.10(1H, m), 6.40(1H, s), 7.38-7.68(4H, m),




7.72-7.78(1H, m), 7.83-7.88(1H, m)


134
89
ESI+: 570




NMR1:1.20-1.72(12H, m), 1.82-1.92(2H, m), 2.05-2.18




(3H, m), 2.89-2.98(1H, m), 3.03(2H, s), 3.60-3.80(9H, m),




5.01-5.11(1H, m), 6.40(1H, s), 7.38-7.68(4H, m), 7.72-7.77




(1H, m), 7.84-7.89(1H, m)


135
89
ESI+: 584




NMR1:0.79-2.35(20H, m), 3.06(2H, m), 3.60-3.77(9H, m),




5.01-5.11(1H, m), 6.40(1H, s), 7.39-7.68(4H, m), 




7.72-7.78(1H, m), 7.84-7.89(1H ,m)


136
89
ESI+: 586




NMR1:1.18-1.31(2H, m), 1.36-1.63(4H, m), 1.65-1.75




(2H, m), 1.81-1.91(2H, m), 2.08-2.18(2H, m), 3.08




(2H, s), 3.21-3.34(4H, m), 3.60-3.86(11H, m), 5.01-5.11




(1H, m), 6.40(1H, s), 7.38-7.68(4H, m), 




7.72-7.77(1H, m), 7.84-7.89(1H, m)


137
89
ESI+: 556




NMR1:0.26-0.31(2H, m), 0.46-0.52(2H, m), 1.15(3H, s),




1.37-1.62(4H, m), 1.80-1.90(2H, m), 2.07-2.18(2H, m), 




2.33-2.44(1H, m), 3.06-3.11(2H, m), 3.59-3.78(9H, m),




5.00-5.11(1H, m), 6.40(1H, s), 7.38-7.68(4H, m), 




7.72-7.78(1H, m), 7.83-7.89(1H, m)


138
89
ESI+: 572




NMR1:1.35-3.80(27H, m), 5.00-5.11(1H, m), 6.40(1H, s),




7.38-7.69(4H, m), 7.71-7.78(1H, m), 7.83-7.90(1H, m)


139
89
ESI+: 572




NMR1:1.35-3.80(27H, m), 5.00-5.11(1H, m), 6.40(1H, s),




7.37-7.69(4H, m), 7.71-7.78(1H, m), 7.82-7.89(1H, m)


















TABLE 156





Ex
Syn
DAT







140
89
ESI+: 596




NMR1:1.58-2.21(19H, m), 2.81-3.06(3H, m), 




3.59-3.80(9H, m), 5.00-5.12(1H, m), 6.40(1H, s), 




7.39-7.69(4H, m), 7.72-7.79(1H, m), 7.84-7.89(1H, m)


141
89
ESI+: 636




NMR1:1.37-1.65(16H, m), 1.80-1.90(2H, m), 1.94-2.04(4H, m),




2.08-2.18(2H, m), 3.03(2H, s), 3.59-3.79(9H, m), 




5.02-5.13(1H, m), 6.40(1H, s), 7.39-7.71(4H, m), 




7.72-7.78(1H, m), 7.83-7.89(1H, m)


142
89
ESI+: 652




NMR1:1.35-1.62(16H, m), 1.81-1.90(2H, m), 2.05-2.19(5H, m),




3.02(2H, s), 3.59-3.79(9H, m), 4.40(1H, s), 5.02-5.12(1H, m),




6.40(1H, s), 7.38-7.70(4H, m), 7.72-7.78(1H, m), 




7.83-7.89(1H, m)


143
89
ESI+: 614




NMR1:1.07(3H, s), 1.15-2.22(18H, m), 3.06(2H, s), 




3.59-3.80(9H, m), 3.93(1H, s), 5.01-5.12(1H, m), 6.40(1H, s), 




7.38-7.69(4H, m), 7.72-7.78(1H, m), 7.83-7.89(1H, m)


144
89
ESI+: 614




NMR1:1.11-2.46(21H, m), 3.10(2H, s), 3.65-3.87(9H, m), 




4.17(1H, s), 5.05-5.17(1H, m), 6.46(1H, s), 7.43-7.75(4H, m), 




7.77-7.84(1H, m), 7.88-7.95(1H, m)


145
52
ESI+: 558


146
1
ESI+: 572


147
1
ESI+: 572


148
1
ESI+: 558


149
1
ESI+: 530


150
1
ESI+: 474[M + Na]




NMR:3.63-3.93(8H, m), 7.41-8.76(10H, m)


151
1
ESI+: 530


152
1
ESI+: 584


153
1
ESI+: 574




NMR1:0.85-1.13(2H, m), 1.38(9H, s), 1.56-1.80(3H, m), 




2.57-2.76(2H, m), 3.06-3.24(2H, m), 3.51-3.75(8H, m), 




3.83-4.03(5H, m), 6.20-6.35(1H, m), 6.91(1H, d, J = 8.0 Hz), 




7.09-7.80(4H, m)


154
1
ESI+: 612


155
1
ESI+: 453




NMR1:2.45(3H, s), 3.37-3.75(8H, m), 4.53-4.61(2H, m), 




6.25-6.49(1H, m), 7.10-7.91(6H, m), 8.38-8.56(2H, m)


156
1
ESI+: 523


157
1
ESI+: 536


158
1
ESI+: 593




NMR1:1.19(3H, t, J = 8.0 Hz), 3.01-3.13(4H, m), 




3.44-3.54(4H, m), 3.56-3.94(8H, m), 4.06(2H, q, 




J = 8.0 Hz), 4.31-4.45(2H, m), 6.25-6.40(1H, m), 




6.92(2H, d, J = 12 Hz), 7.10-7.94(8H, m)


















TABLE 157





Ex
Syn
DAT







159
1
ESI+: 494




NMR1:1.41(3H, d, J = 8.0 Hz), 3.40-3.78(8H, m),




4.33-4.47(1H, m), 6.29-6.47(1H, m), 6.92-7.96




(11H, m), 9.84-10.17(1H, m)


160
1
ESI+: 511




NMR1:0.62-0.84(2H, m), 0.86-1.03(2H, m),




3.47-3.88(10H, m), 6.18-6.42(1H, m), 6.91-7.93




(10H, m)


161
1
ESI+: 508


162
1
ESI+: 522




NMR1:2.73-2.92(4H, m), 3.47-3.82(12H, m),




4.48-4.65(2H, m), 6.21-6.44(1H, m), 6.86-7.98




(10H, m)


163
1
ESI+: 430


164
1
ESI+: 446




NMR1:1.28-1.43(2H, m), 1.50-1.69(4H, m),




1.70-1.79(1H, m), 1.92-2.03(1H, m), 3.69




(4H, d, J = 4.7 Hz), 3.72(4H, d, J = 4.7 Hz), 3.90(1H, br), 




4.70(1H, d, J = 4.7 Hz), 5.15-5.22(1H,m), 6.39(1H,s), 




7.39-7.52(2H,m), 7.55(1H, t, J = 52.5 Hz), 




7.77(1H, d, J = 7.9 Hz), 7.87(1H, d, J = 7.9 Hz)


165
1
ESI+: 446




NMR1:1.20-1.43(4H, m), 1.67(2H, br), 1.90(1H, br),




2.12(1H, br), 3.53-3.64(1H, m), 3.69(4H, d, J = 4.2 Hz),




3.73(4H, d, J = 3.7 Hz), 4.86-4.95(1H, m), 4.94




(1H, d, J = 4.7 Hz), 6.39(1H, s), 7.40-7.50(2H, m),




7.55(1H, t, J = 52.5 Hz), 7.77(1H, d, J = 7.9 Hz),




7.87(1H, d, J = 7.9 Hz)


166
1
ESI+: 486




NMR1:0.94-1.31(14H, m), 1.72(1H, br), 1.82(1H, br),




3.64(4H, br), 3.68(4H, br), 4.19(1H, br), 6.32(1H, br),




6.96(1H, br), 7.33-7.88(5H, m)


167
1
ESI+: 446


168
1
ESI+: 482[M + Na]




NMR1:1.02-1.16(3H, m), 1.33-1.45(2H, m), 1.55-1.79




(6H, m), 3.64-4.09(10H, m), 7.37-8.10(5H, m),




8.39-8.63(1H, m)


169
1
ESI+: 482[M + Na]




NMR1:1.00-1.06(3H, m), 1.35-1.92(8H, m), 3.61-3.94




(9H, m), 4.26-4.33(1H, m), 7.38-8.09(5H, m),




8.40-8.63(1H, m)


170
1
ESI+: 498




NMR1:1.30-1.42(2H, m), 1.60-1.71(4H, m),




1.72-1.84(2H, m), 1.94-2.08(3H, m),




2.09-2.20(2H, m), 3.63-3.88(8H, m), 3.97-4.12




(1H, m), 4.40-4.50(1H, m), 7.38-7.52(2H, m),




7.62-8.20(3H, m), 8.41-8.66(1H, m)


171
1
ESI+: 454[M + Na]


172
1
ESI+: 430


173
1
ESI+: 476




NMR1:1.34-1.74(6H, m), 1.86-2.03(2H, m),




3.13-3.27(1H, m), 3.48-3.88(10H, m), 7.33-7.53




(2H, m), 7.62-8.18(3H, m), 8.40-8.58(1H, m)


174
1
ESI+: 540


















TABLE 158





Ex
Syn
DAT







175
1
ESI+: 444




NMR1:0.99-1.38(4H, m), 1.38-1.76(4H, m), 1.76-2.10(2H, m),




3.25-3.54(2H, m), 3.54-3.75(8H, m), 6.22-6.39(1H, m), 6.87-




7.02(1H, m), 7.35-7.91(5H, m)


176
1
ESI+: 444




NMR1:1.13-1.85(10H, m), 2.94-3.11(1H, m), 




3.51-3.76(8H, m), 3.76-3.90(1H, m), 6.24-6.44(1H, m),




6.44-6.73(1H, m), 7.35-7.91(5H, m)


177
1
ESI+: 503


178
1
ESI+: 498




NMR1:1.42-1.65(6H, m), 1.92-2.07(6H, m), 




2.16-2.24(2H, m), 3.64-3.83(8H, m), 4.55-4.60(1H, m), 




7.38-8.15(5H, m), 8.44-8.63(1H, m)


179
1
ESI+: 487


180
1
ESI+: 522[M + Na]


181
1 + 44
ESI+: 556


182
1
ESI+: 523


183
1
ESI+: 654[M + Na]




NMR1:1.01-1.82(12H, m), 3.31-3.45(4H, m), 




3.59-3.74(9H, m), 5.06(2H, s), 6.25-6.38(1H, m), 




6.89-7.04(1H, m), 7.27-7.88(10H, m)


184
1
ESI+: 501


185
1
ESI+: 572


186 
26
ESI+: 546


187
1
ESI+: 572


188 
22
ESI+: 495


189 
93
ESI+: 469


190 
83
ESI+: 473




NMR1:1.18-1.35(2H, m), 1.39-1.55(2H, m), 1.85-2.10(4H, m), 




2.16-2.27(1H, m), 3.60-3.87(9H, m), 6.09(1H, s), 




7.35-7.66(4H, m), 7.68-7.74(1H, m), 7.82-7.87(1H, m), 




12.08(1H, brs)


191
26
ESI+: 556


192 
26
ESI+: 558


193 
26
ESI+: 526




NMR1:0.98-1.13(2H, m), 1.19(6H, br), 




1.57(2H, d, J = 11.2 Hz), 1.72(6H, br), 2.13(2H, br), 




2.79(1H, br), 3.16(2H, br), 3.30(1H, br), 3.64(4H, br), 




3.68(4H, br), 6.31(1H, br), 7.15(1H, br), 7.37-7.47(2H, m), 




7.53(1H, br), 7.76(1H, d, J = 7.9 Hz), 7.85(1H, d, J = 7.7 Hz)


194 
26
ESI+: 556




NMR1:0.92-1.02(2H, m), 1.08(6H, d, J = 6.1 Hz), 1.12(2H, br),




1.50(1H, br), 1.66(2H, br), 1.68(2H, br), 2.05(2H, br), 




2.45(1H, br), 2.82(2H, br), 3.14(1H, s), 3.18(1H, s), 




3.28-3.38(2H, m), 3.63(4H, br), 3.68(4H, br), 6.31(1H, br), 




7.13(1H, br), 7.36-7.47(2H, m), 7.50-7.72(1H, m), 




7.77(1H, d, J = 7.6 Hz), 7.85(1H, d, J = 7.6 Hz)


195 
26
ESI+: 540


















TABLE 159





Ex
Syn
DAT







196
26
ESI+: 570




NMR1:1.41-1.65(6H, m), 1.72-2.00(6H, m), 2.07(3H, s),




2.10-2.19(2H, m), 2.76(2H, s), 2.87-2.97(1H, m), 3.60-




3.79(9H, m), 5.00-5.10(1H, m), 6.40(1H, s), 7.38-7.68




(4H, m), 7.72-7.78(1H, m), 7.83-7.89(1H, m)


197
26
ESI+: 500


198
26
ESI+: 584




NMR1:1.49-2.30(16H, m), 2.66-2.71(6H, m), 




3.64-3.84(9H, m), 4.98-5.11(1H, m), 6.40(1H, s), 




7.39-7.69(3H, m), 7.72-7.77(1H, m), 7.84-7.89(1H, m), 




8.19-8.29(1H, m), 10.75-1.88(1H, m)


199
26
ESI+: 598




NMR1:0.80-2.30(22H, m), 3.08-3.17(1H, m), 




3.56-3.79(9H, m), 5.01-5.11(1H, m), 6.40(1H, s), 




7.38-7.70(4H, m), 7.72-7.78(1H, m), 7.84-7.89(1H, m)


200
34
ESI+: 542


201
34
ESI+: 528


202 
26 + 44
ESI+: 596


203 
26 + 44
ESI+: 542


204 
26 + 44
ESI+: 514


205
53
ESI+: 472


206
53
ESI+: 458


207
53
ESI+: 430


208
53
ESI+: 474


209
53
ESI+: 498




NMR1:0.16-0.73(4H, m), 1.02-2.20(10H, m), 2.80-




3.99(11H, m), 6.33(1H, brs), 7.24-8.01(5H, m), 




8.21(2H, brs)


210
53
ESI+: 472


211
54
ESI+: 472


212
54
ESI+: 484


213
54
ESI+: 478


214
54
ESI+: 512


215
54
ESI+: 542




NMR1:1.38-2.42(14H, m), 3.55-3.78(9H, m), 




5.00-5.10(1H, m), 6.40(1H, s), 7.38-7.89(6H, m)


216
54
ESI+: 556




NMR1:1.35-2.18(16H, m), 3.54-3.78(9H, m), 




5.02-5.11(1H, m), 6.40(1H, s), 7.39-7.88(6H, m)


217
54
ESI+: 444


218
54
ESI+: 444


219
54
ESI+: 472


220
54
ESI+: 486


221
54
ESI+: 431


222
54
ESI+: 431


















TABLE 160





Ex
Syn
DAT







223
53
ESI+: 500


224
26
ESI+: 556




NMR1:1.07(6H, d, J = 6.2 Hz), 1.14(2H, br), 1.16(2H, br), 1.52(1H, br), 




1.70(2H, br), 1.72-1.79(2H, m), 1.86(2H, br), 2.28(1H, br), 3.02(2H, br),




3.13(1H, br), 3.20(1H, br), 3.63(4H, br), 3.68(4H, br), 3.73(2H, br), 




6.31(1H, br), 7.14(1H, t, J = 5.7 Hz), 7.36-7.48(2H, m), 7.49-7.73(1H, m), 




7.76(1H, d, J = 7.7 Hz), 7.85(1H, d, J = 7.7 Hz)


225
92
ESI+: 544


226
92
ESI+: 555


227
66
ESI+: 642


228
66
ESI+: 656


229
1
ESI+: 586


230
1
ESI+: 572


231
1
ESI+: 516


232
1
ESI+: 516


233
54
ESI+: 416


234
54
ESI+: 416


235
54
ESI+: 458


236
1
ESI+: 558


237
237
ESI+: 527


238
239
ESI+: 586


239
239
ESI+: 472


240
240
ESI+: 514


241
241
ESI+: 520


242-1
242 + 44
ESI+: 472


242-2
242 + 44
ESI+: 486


243
243
ESI+: 526


244
244
ESI+: 419


245
245
ESI+: 616


246
246
ESI+: 531


247
247
ESI+: 531


248
248
ESI+: 585




NMR:1.27-2.31(10H, m), 3.06-3.38(2H, m), 3.53(3H, s), 3.56-3.92(10H, m),




4.06-4.20(1H, m), 6.22-6.43(1H, m), 6.88-7.13(1H, m), 7.34-7.96(6H, m)


249-1
249
ESI+: 542




NMR:1.33-1.88(8H, m), 2.21-2.30(1H, m), 3.20(3H, s), 3.60-3.71(8H, m),




3.75-3.81(1H, m), 4.01-4.06(1H, m), 4.15-4.19(1H, m), 4.48-4.50(1H, m),




4.59-4.71(1H, m), 6.12(1H, s), 7.37-7.64(3H, m), 7.12-7.74(1H, m), 7.73




(1H, d, J = 8 Hz), 7.86(1H, d, J = 7.6 Hz), 8.12-8.20(1H, m)


















TABLE 161





Ex
Syn
DAT







249-2
249
ESI+: 542




NMR1:1.07-2.21(8H, m), 3.22(3H, s),




3.62-3.71(8H, m), 3.75-3.81(1H, m),




4.02-4.06(1H, m), 4.15-4.19(1H, m),




4.49-4.53(1H, m), 4.59-4.70(1H, m),




6.12(1H, s), 7.33-7.64(5H, m), 7.73




(1H, d, J = 8.0 Hz), 7.86(1H, d, J = 7.5 Hz),




8.13-8.19(1H, m)


250
1
ESI+: 438


251
1
ESI+: 439


252
1
ESI+: 439


253
1
ESI+: 439


254
1
ESI+: 452


255
1
ESI+: 498


256
1
ESI+: 432


257
1
ESI+: 424


258
1
ESI+: 454


259
1
ESI+: 426


260
1
ESI+: 425


261
1
ESI+: 433


262
1
ESI+: 504[M + Na]


263
1
ESI+: 504[M + Na]


264
1
ESI+: 468[M + Na]


265
1
ESI+: 496


266
1
ESI+: 445


267
1
ESI+: 445


268
1
ESI+: 445


269
1
ESI+: 497


270
1
ESI+: 508


271
1
ESI+: 497


272
1
ESI+: 459


273
1
ESI+: 481[M + Na]


274
1
ESI+: 429


275
1
ESI+: 530[M + Na]


276
1
ESI+: 497


277
1
ESI+: 547[M + Na]


278
1
ESI+: 553[M + Na]


279
1
ESI+: 567[M + Na]


280 
94 
ESI+: 454


281
1
ESI+: 440


282
1
ESI+: 442


283
1
ESI+: 463


284
1
ESI+: 464


285
1
ESI+: 464


286
1
ESI+: 481




















TABLE 162







Ex
Syn
DAT









287
1
ESI+: 496



288
1
ESI−: 479



289
74
ESI+: 520



290
1
ESI+: 478



291
1
ESI+: 520



292
26 + 44
ESI+: 520



293
74
ESI+: 570



294
92
ESI+: 504[M + Na]



295
PSyn.8
ESI+: 452



296
240 + 44
ESI+: 522



297
22
ESI+: 556



298
22
ESI+: 542



299
22
ESI+: 542



300
74
ESI+: 522



301
74
ESI+: 480



302
1
ESI+: 520



303
1
ESI+: 544



304
54
ESI+: 444



305
1
ESI+: 573



306
1
ESI+: 587



307
66 + 44
ESI+: 529



308
PSyn.81
ESI+: 489



309
PSyn.81
ESI+: 503



310
1
ESI+: 497



311
74
ESI+: 453



312
74
ESI+: 454



313
74
ESI+: 453



314
74
ESI+: 521



315
74
ESI+: 520



316
1
ESI+: 575[M + Na]



317
54
ESI+: 453



318
240 + 44
ESI+: 523



319
1
ESI+: 485



320
54
ESI+: 458



321
54
ESI+: 458



322
26
ESI+: 542



323
26
ESI+: 542



324
26
ESI+: 528



325
1
ESI+: 532



326
66
ESI+: 529



327
1
ESI+: 520





















TABLE 163







Ex
Syn
DAT









328
1
ESI+: 520



329
66
ESI+: 501



330
PSyn.148 
ESI+: 488



331
66
ESI+: 534



332
66
ESI+: 534



7 333
66
ESI+: 534



334
74
ESI+: 506



335
74
ESI+: 538



336
74
ESI+: 538



337
74
ESI+: 550



338
74
ESI+: 566



339
74
ESI+: 524



340
92
ESI+: 515



341
84
ESI+: 628



342
26
ESI+: 500



343
66
ESI+: 550



344
66
ESI+: 554



345
66
ESI+: 538



346
66
ESI+: 538



347
66
ESI+: 538



348
74
ESI+: 580



349
74
ESI+: 566



350
66
ESI+: 569



351
66
ESI+: 521



352
66
ESI+: 521



353
66
ESI+: 521



354
53
ESI+: 430



355
26
ESI+: 520



356
26
ESI+: 520



357
66
ESI+: 552



358
89 + 44
ESI+: 584



359
92
ESI+: 556



360
92
ESI+: 555



361
93
ESI+: 469



362
26 + 44
ESI+: 540



363
92
ESI+: 488



364
26
ESI+: 514



365
26
ESI+: 528



366
241
ESI+: 534



367
22
ESI+: 437



368
84
ESI+: 664[M + Na]



















TABLE 164





Ex
Syn
DAT







369 
1
ESI+: 536


370
92
ESI+: 585




NMR1:1.33(3H, br), 1.52-1.81(5H, m), 2.10(2H, br), 2.24




(1H, br), 3.15-3.25(1H, m), 3.54(3H, s), 3.67(8H, br), 3.75




(1H, br), 4.06-4.18(1H, m), 6.10(1H, s), 7.35-7.50(5H, m),




7.51(1H, t, J = 52 Hz), 7.71(1H, d, J = 7.9 Hz), 




7.85(1H, d, J = 7.9 Hz)


371
92
ESI+: 585




NMR1:1.20-1.33(3H, m), 1.50-1.83(5H, m), 2.01-2.18(2H, m),




2.17-2.31(1H, m), 3.13-3.25(1H, m), 3.54(3H, s), 3.59-3.91




(10H, m), 4.05-4.19(1H, m), 6.10(1H, s), 7.34-7.54(5H, m),




7.72(1H, d, J = 8.2 Hz), 7.85(1H, d, J = 7.7 Hz)


372 
1
ESI+: 588


373 
1
ESI+: 446


374 
53
ESI+: 488


375 
26
ESI+: 572


376
1
ESI+: 536


377 
1
ESI+: 544


378 
54
ESI+: 444


379 
92
ESI+: 544


380 
54
ESI+: 444


381 
26
ESI+: 528


382 
66
ESI+: 529


383 
26
ESI+: 528


384 
26
ESI+: 562


385 
43
ESI+: 556


386 
43
ESI+: 556


387 
88
ESI+: 632


388 
85
ESI+: 600


389
87
ESI+: 586




NMR1:1.52-1.82(7H, m), 2.23(3H, br), 3.17-3.24(1H, m),




3.28-3.36(1H, m), 3.54(3H, s), 3.70(4H, br), 3.75(4H, br),




3.81(1H, br), 4.13(1H, q, J = 9.3 Hz), 5.00-5.08(1H, m), 




6.40(1H, s), 7.38-7.50(3H, m), 7.53(1H, t, J = 52.2 Hz),




7.75(1H, d, J = 7.7 Hz), 7.86(1H, d, J = 7.7 Hz)


390
1
ESI+: 550


391
1
ESI+: 536


392
26
ESI+: 555


393
26
ESI+: 556


394
26
ESI+: 570


395
26
ESI+: 500


396
26
ESI+: 628


397
1
ESI+: 475


















TABLE 165





Ex
Syn
DAT







398
1
ESI+: 522


399
66
ESI+: 537


400
43
ESI+: 558


401
43
ESI+: 558


402
26
ESI+: 546


403
26
ESI+: 576


404
89
ESI+: 544


405
89
ESI+: 544


406
54
ESI+: 444


407
26 + 44
ESI+: 569


408
26
ESI+: 528


409
1
ESI+: 558


410
1
ESI+: 584


411
54
ESI+: 484


412
52
ESI+: 556


413
89
ESI+: 570


414
89
ESI+: 584


415
1
ESI+: 545


416
54
ESI+: 445


417
26
ESI+: 529


418 
240 + 44
ESI+: 538


419
89 + 44
ESI+: 574


420
240
ESI+: 538


421
26
ESI+: 570


422
422
ESI+: 542


423
87
ESI+: 600




NMR1:1.16(3H, t, J = 7.1 Hz), 1.50-1.83(7H, m),




2.23(3H, br), 3.15-3.25(1H, m), 3.27-3.36(1H, m),




3.70(4H, d, J = 4.7 Hz), 3.74(4H, d, J = 4.6 Hz), 




3.77-3.86(1H, m), 3.99(2H, q, J = 7.1 Hz), 4.12




(1H, q, J = 9.1 Hz), 4.98-5.09(1H, m), 6.40(1H, s),




7.34-7.50(3H, m), 7.53(1H, t, J = 52.5 Hz), 7.75




(1H, d, J = 7.6 Hz), 7.86(1H, d, J = 7.6 Hz)


424
87
ESI+: 600


425
83
ESI+: 474


426
92
ESI+: 531


427
1
ESI+: 503


428
1
ESI+: 517


429
54
ESI+: 417


430
54
ESI+: 431


431
54
ESI+: 403


432-1
432
ESI+: 528


432-2
432
ESI+: 528


433
54
ESI+: 417


















TABLE 166





Ex
Syn
DAT







434 
92
ESI+: 446


435 
92
ESI+: 516


436 
54
ESI+: 416


437 
92
ESI+: 530


438
54
ESI+: 430


439 
92
ESI+: 516


440 
54
ESI+: 416


441
248
ESI+: 585




NMR1:1.27-2.29(10H, m), 3.07-3.21(2H, m), 3.53(3H, s),




3.57-3.83(10H, m), 4.06-4.18(1H, m), 6.22-6.41(1H, m),




6.87-7.08(1H, m), 7.31-7.92(6H, m)


442 
66
ESI+: 529


443 
66
ESI+: 529


444 
66
ESI+: 528


445 
66
ESI+: 528


446 
66
ESI+: 542


447 
66
ESI+: 542


448 
52
ESI+: 560


449 
54
ESI+: 488


450
1
ESI+: 588


451
249
ESI+: 543




NMR1:1.34-1.45(4H, m), 1.53-1.65(2H, m), 1.78-1.88




(2H, m), 2.25-2.35(1H, m), 3.19(3H, s), 3.66-3.76(8H, m),




3.86-3.91(1H, m), 4.19-4.34(2H, m), 4.60-4.66(1H, m),




5.44-5.50(1H, m), 6.52(1H, s), 7.41-7.67(4H, m),




7.77-7.79(1H, m), 7.86-7.88(1H, m)


452
249
ESI+: 543




NMR1:1.03-1.40(4H, m), 1.67-1.75(2H, m),




1.96-2.25(3H, m), 3.00-3.12(1H, m), 3.22(3H, s),




3.66-3.76(8H, m), 3.85-3.92(1H, m), 4.18-4.33(2H, m),




4.60-4.67(1H, m), 5.43-5.51(1H, m), 6.52(1H, s), 7.42-




7.67(3H, m), 7.78(1H, d, J = 7.4 Hz), 7.87(1H, d, J = 7.4 Hz)


453
66
ESI+: 556




NMR1:1.38-1.66(10H, m), 1.81-2.02(1H, m), 2.05-2.30(1H, m),




3.31-3.40(2H, m), 3.40-3.52(1H, m), 3.56-3.63 (2H, m),




3.84-3.94(1H, m), 3.66(4H, br), 3.70(4H, br), 4.37




(1H, d, t, J = 1.4, 5.2 Hz), 4.43-4.60(1H, m), 6.14(1H, br),




7.36-7.50(2H, m), 7.52(1H, t, J = 52.7 Hz),




7.73(1H, d, J = 7.6 Hz), 7.75-7.88(1H, m), 




7.86(1H, d, J = 7.8 Hz)


454 
66
ESI+: 556




NMR1:0.85-1.01(2H, m), 1.33(4H, br), 1.67-1.80(4H, m),




1.82-2.03(1H, m), 2.09-2.40(1H, m), 3.17-3.23 (2H, m),




3.34-3.50(1H, m), 3.57-3.63(2H, m), 3.66(4H, br), 3.70




(4H, br), 3.91(1H, br), 4.36(1H, t, J = 5.3 Hz), 4.44-4.60




(1H, br), 6.14(1H, d, J = 4.8 Hz), 7.37-7.49(2H, m),




7.52(1H, t, J = 52.7 Hz), 7.72(1H, d, J = 8.3 Hz), 7.75-7.88




(1H, br), 7.85(1H, d, J = 7.9 Hz)




















TABLE 167







Ex
Syn
DAT









455
66
ESI+: 544



456
1
ESI+: 458



457
66 + 44
ESI+: 543



458
71
ESI+: 500



459
54
ESI+: 458



460
92
ESI+: 558



461
66
ESI+: 543



462
66
ESI+: 557



463
71
ESI+: 514



464
1
ESI+: 589



465
53
ESI+: 489



466
85
ESI+: 586



467
66
ESI+: 574



468
422 
ESI+: 542



469
1
ESI+: 562



470
54
ESI+: 462




















TABLE 168





Ex
Str
ESI+
RT







A1




445
2.19


 


A2




473
2.81


 


A3




521
2.56


 


A4




459
2.28


 


A5




475
2.19



















TABLE 169





Ex
Str
ESI+
RT







A6




459
2.33


 


A7




521
2.61


 


A8




392
2.58


 


A9




406
2.67


 


A10 




406
2.87



















TABLE 170





Ex
Str
ESI+
RT


















A11




419
2.1


 


A12




433
2.59


 


A13




422
2.37


 


A14




479
2.06


 


A15




446
3.03



















TABLE 171





Ex
Str
ESI+
RT







A16




537
2.46


 


A17




459
2.16


 


A18




473
2.95


 


A19




475
2.09


 


A20




509
2.89



















TABLE 172





Ex
Str
ESI+
RT


















A21




525
3.18


 


A22




442
2.8


 


A23




478
3.41


 


A24




468
3.39


 


A25




481
2.51



















TABLE 173





Ex
Str
ESI+
RT







A26




496
3.24


 


A27




509
3.01


 


A28




521
2.51


 


A29




530
3.74



















TABLE 174





Ex
Str
ESI+
RT







A30




521
2.51


 


A31




420
2.92


 


A32




420
3.17


 


A33




436
2.58



















TABLE 175





Ex
Str
ESI+
RT







A34




482
3.31


 


A35




473
2.29


 


A36




482
3.6


 


A37




482
3.59



















TABLE 176





Ex
Str
ESI+
RT







A38




482
3.68


 


A39




535
2.76


 


A40




544
3.95


 


A41




440
2.94



















TABLE 177





Ex
Str
ESI+
RT


















A42




440
3.01


 


A43




440
3.16


 


A44




454
3.3


 


A45




454
3.36


 


A46




467
2.54



















TABLE 178





Ex
Str
ESI+
RT







A47




425
2.29


 


A48




455
3.24


 


A49




455
3.15


 


A50




477
3.37


 


A51




507
2.54



















TABLE 179





Ex
Str
ESI+
RT







A52




489
3.63


 


A53




521
2.57


 


A54




521
3.16


 


A55




571
3.46


 


A56




543
3.31



















TABLE 180





Ex
Str
ESI+
RT







A57




438
3.55


 


A58




439
2.25


 


A59




468
3.53


 


A60




496
3.47



















TABLE 181





Ex
Str
ESI+
RT


















A61




536
2.9


 


A62




446
2.42


 


A63




474
2.67


 


A64




476
2.3


 


A65




490
2.41



















TABLE 182





Ex
Str
ESI+
RT







A66




504
2.51


 


A67




506
2.18


 


A68




490
2.52


 


A69




504
2.64


 


A70




518
2.74



















TABLE 183





Ex
Str
ESI+
RT







A71




534
2.62


 


A72




503
1.87


 


A73




517
1.88


 


A74




517
2.35


 


A75




547
2.36



















TABLE 184





Ex
Str
ESI+
RT







A76




511
2.53


 


A77




514
2.94


 


A78




528
3.06


 


A79




544
2.79


 


A80




601
2.07



















TABLE 185





Ex
Str
ESI+
RT







A81




571
2.31


 


A82




593
2.73


 


A83




542
2.69


 


A84




529
1.88



















TABLE 186





Ex
Str
ESI+
RT







A85




559
1.84


 


A86




587
1.88


 


A87




573
2.02


 


A88




587
2.05


 


A89




586
1.41



















TABLE 187





Ex
Str
ESI+
RT







A90




600
1.41


 


A91




583
2.58


 


A92




601
2.46


 


A93




587
2.69



















TABLE 188





Ex
Str
ESI+
RT







A94




530
2.78


 


A95




530
2.52


 


A96




543
1.93


 


A97




543
1.93


 


A98




543
1.91



















TABLE 189





Ex
Str
ESI+
RT







A99




543
1.91


 


A100




573
1.93


 


A101




575
1.92


 


A102




559
2.35


 


A103




588
2.91



















TABLE 190





Ex
Str
ESI+
RT







A104




552
2.66


 


A105




566
2.69


 


A106




566
2.88


 


A107




579
2.21


 


A108




552
2.86



















TABLE 191





Ex
Str
ESI+
RT







A109




552
2.79


 


A110




552
2.78


 


A111




582
2.65


 


A112




565
2.62


 


A113




556
2.89



















TABLE 192





Ex
Str
ESI+
RT







A114




635
2.25


 


A115




523
2.39


 


A116




523
2.16


 


A117




523
2.02


 


A118




528
2.31



















TABLE 193





Ex
Str
ESI+
RT







A119




580
2.74


 


A120




553
1.93


 


A121




567
1.96


 


A122




581
2.34


 


A123




580
1.66



















TABLE 194





Ex
Str
ESI+
RT







A124




594
1.62


 


A125




622
1.69


 


A126




536
2.88


 


A127




596
2.72


 


A128




566
2.75



















TABLE 195





Ex
Str
ESI+
RT


















A129




537
1.99


 


A130




542
2.5


 


A131




550
2.95


 


A132




594
3.01



















TABLE 196





Ex
Str
ESI+
RT







A133




607
2.37


 


A134




582
2.73


 


A135




554
1.88


 


A136




607
2.72


 


A137




486
2.72



















TABLE 197





Ex
Str
ESI+
RT







A138




488
2.38


 


A139




501
1.77


 


A140




502
2.41


 


A141




502
2.34


 


A142




516
2.56



















TABLE 198





Ex
Str
ESI+
RT







A143




518
2.26


 


A144




559
1.85


 


A145




529
1.83


 


A146




529
2.25


 


A147




573
2.28



















TABLE 199





Ex
Str
ESI+
RT







A148




571
1.83


 


A149




578
2.71


 


A150




585
1.87


 


A151




472
2.55


 


A152




522
2.62



















TABLE 200





Ex
Str
ESI+
RT







A153




516
2.61


 


A154




515
1.76


 


A155




515
1.8 


 


A156




501
2.13


 


A157




515
2.19



















TABLE 201





Ex
Str
ESI+
RT


















A158




555
2.42


 


A159




545
2.45


 


A160




565
2.3


 


A161




594
2.45


 


A162




536
2.21



















TABLE 202





Ex
Str
ESI+
RT


















A163




488
2.3


 


A164




488
2.29


 


A165




502
2.49


 


A166




556
2.84


 


A167




502
2.44



















TABLE 203





Ex
Str
ESI+
RT







A168




502
2.44


 


A169




502
2.33


 


A170




516
2.54


 


A171




516
2.46


 


A172




516
2.41



















TABLE 204





Ex
Str
ESI+
RT


















A173




518
2.29


 


A174




518
2.3


 


A175




516
2.64


 


A176




516
2.66


 


A177




516
2.57



















TABLE 205





Ex
Str
ESI+
RT


















A178




530
2.76


 


A179




530
2.72


 


A180




530
2.66


 


A181




530
2.6


 


A182




530
2.54



















TABLE 206





Ex
Str
ESI+
RT







A183




530
2.48


 


A184




544
2.78


 


A185




545
1.81


 


A186




544
2.58


 


A187




545
1.74



















TABLE 207





Ex
Str
ESI+
RT







A188




573
1.85


 


A189




575
1.76


 


A190




515
1.77


 


A191




515
1.76


 


A192




529
1.87



















TABLE 208





Ex
Str
ESI+
RT







A193




557
1.85


 


A194




543
1.95


 


A195




543
1.85


 


A196




545
1.81


 


A197




557
1.91



















TABLE 209





Ex
Str
ESI+
RT







A198




558
1.82


 


A199




543
2.37


 


A200




543
2.35


 


A201




529
2.26


 


A202




572
1.83



















TABLE 210





Ex
Str
ESI+
RT







A203




593
2.08


 


A204




534
2.84


 


A205




564
2.83


 


A206




568
2.95


 


A207




564
2.71



















TABLE 211





Ex 
Str
ESI+
RT







A208




564
2.71


 


A209




569
1.89


 


A210




555
1.84


 


A211




585
1.81


 


A212




584
1.56



















TABLE 212





Ex
Str
ESI+
RT







A213




571
1.81


 


A214




600
1.86


 


A215




626
1.49


 


A216




626
1.48


 


A217




562
3.02



















TABLE 213





Ex
Str
ESI+
RT


















A218




562
3


 


A219




562
2.98


 


A220




578
2.83


 


A221




612
2.86


 


A222




563
2.02



















TABLE 214





Ex
Str
ESI+
RT







A223




603
2.87


 


A224




603
2.34


 


A225




583
2.08


 


A226




583
1.91


 


A227




585
2.08



















TABLE 215





Ex
Str
ESI+
RT







A228




585
1.98


 


A229




598
1.46


 


A230




599
1.92


 


A231




617
3.14


 


A232




576
3.08



















TABLE 216





Ex
Str
ESI+
RT







A233




576
3.09


 


A234




592
2.79


 


A235




578
2.97


 


A236




577
2.09


 


A237




598
1.94



















TABLE 217





Ex
Str
ESI+
RT


















A238




590
3.17


 


A239




607
2.03


 


A240




619
2.24


 


A241




607
2.2


 


A242




634
2.23



















TABLE 218





Ex
Str
ESI+
RT


















A243




655
2.46


 


A244




621
2.19


 


A245




489
2.66


 


A246




503
2.66


 


A247




503
2.8



















TABLE 219





Ex
Str
ESI+
RT







A248




517
2.78


 


A249




546
2.69


 


A250




530
2.72


 


A251




558
2.75


 


A252




529
2.88



















TABLE 220





Ex
Str
ESI+
RT







A253




529
2.88


 


A254




543
2.88


 


A255




543
2.81


 


A256




557
2.79


 


A257




571
2.97



















TABLE 221





Ex
Str
ESI+
RT


















A258




570
2.7


 


A259




584
2.74


 


A260




600
2.88


 


A261




543
2.87


 


A262




557
2.86



















TABLE 222





Ex
Str
ESI+
RT


















A263




565
3.02


 


A264




566
3


 


A265




475
2.46


 


A266




489
2.57


 


A267




503
2.65



















TABLE 223





Ex
Str
ESI+
RT


















A268




532
2.54


 


A269




516
2.49


 


A270




544
2.6


 


A271




515
2.68


 


A272




515
2.69



















TABLE 224





Ex
Str
ESI+
RT


















A273




529
2.72


 


A274




529
2.64


 


A275




543
2.7


 


A276




557
2.88


 


A277




556
2.5



















TABLE 225





Ex
Str
ESI+
RT







A278




570
2.55


 


A279




586
2.72


 


A280




529
2.74


 


A281




543
2.72


 


A282




551
2.9 



















TABLE 226





Ex
Str
ESI+
RT







A283




552
2.83


 


A284




474
2.4 


 


A285




488
2.51


 


A286




502
2.59


 


A287




531
2.49



















TABLE 227





Ex
Str
ESI+
RT







A288




515
2.43


 


A289




543
2.56


 


A290




514
2.62


 


A291




514
2.62


 


A292




528
2.66



















TABLE 228





Ex
Str
ESI+
RT







A293




528
2.59


 


A294




542
2.65


 


A295




556
2.83


 


A296




555
2.46


 


A297




569
2.5 



















TABLE 229





Ex
Str
ESI+
RT







A298




585
2.68


 


A299




528
2.68


 


A300




542
2.66


 


A301




550
2.83


 


A302




551
2.76



















TABLE 230





Ex
Str
ESI+
RT







A303




489
2.57


 


A304




503
2.68


 


A305




517
2.76


 


A306




546
2.64


 


A307




530
2.57



















TABLE 231





Ex
Str
ESI+
RT







A308




558
2.7 


 


A309




529
2.78


 


A310




529
2.78


 


A311




543
2.82


 


A312




543
2.75



















TABLE 232





Ex
Str
ESI+
RT







A313




557
2.8 


 


A314




571
2.97


 


A315




570
2.61


 


A316




584
2.65


 


A317




600
2.82



















TABLE 233





Ex
Str
ESI+
RT







A318




543
2.84


 


A319




557
2.83


 


A320




565
2.97


 


A321




566
2.9 


 


A322




488
2.44



















TABLE 234





Ex
Str
ESI+
RT







A323




502
2.54


 


A324




516
2.62


 


A325




545
2.52


 


A326




529
2.45


 


A327




557
2.58



















TABLE 235





Ex
Str
ESI+
RT







A328




528
2.65


 


A329




528
2.65


 


A330




542
2.69


 


A331




542
2.62


 


A332




556
2.66



















TABLE 236





Ex
Str
ESI+
RT







A333




570
2.85


 


A334




569
2.48


 


A335




583
2.53


 


A336




599
2.7 


 


A337




542
2.71



















TABLE 237





Ex
Str
ESI+
RT







A338




556
2.69


 


A339




564
2.83


 


A340




565
2.76


 


A341




474
2.42


 


A342




488
2.6 



















TABLE 238





Ex
Str
ESI+
RT







A343




502
2.58


 


A344




531
2.47


 


A345




515
2.49


 


A346




543
2.53


 


A347




514
2.68



















TABLE 239





Ex
Str
ESI+
RT







A348




514
2.68


 


A349




528
2.69


 


A350




528
2.61


 


A351




542
2.61


 


A352




556
2.82



















TABLE 240





Ex
Str
ESI+
RT







A353




555
2.49


 


A354




569
2.53


 


A355




585
2.71


 


A356




528
2.68


 


A357




542
2.66



















TABLE 241





Ex
Str
ESI+
RT


















A358




550
2.87


 


A359




551
2.84


 


A360




461
2.4


 


A361




475
2.58


 


A362




489
2.61



















TABLE 242





Ex
Str
ESI+
RT


















A363




518
2.49


 


A364




502
2.49


 


A365




530
2.56


 


A366




501
2.7


 


A367




501
2.7



















TABLE 243





Ex
Str
ESI+
RT







A368




515
2.69


 


A369




515
2.61


 


A370




529
2.66


 


A371




543
2.86


 


A372




542
2.46



















TABLE 244





Ex
Str
ESI+
RT


















A373




556
2.51


 


A374




572
2.7


 


A375




515
2.7


 


A376




529
2.69


 


A377




537
2.92



















TABLE 245





Ex
Str
ESI+
RT







A378




538
2.85


 


A379




460
2.32


 


A380




474
2.49


 


A381




488
2.54


 


A382




517
2.43



















TABLE 246





Ex
Str
ESI+
RT


















A383




501
2.41


 


A384




529
2.5


 


A385




500
2.61


 


A386




500
2.61


 


A387




514
2.62



















TABLE 247





Ex
Str
ESI+
RT


















A388




514
2.53


 


A389




528
2.6


 


A390




542
2.8


 


A391




541
2.39


 


A392




555
2.44



















TABLE 248





Ex
Str
ESI+
RT







A393




571
2.63


 


A394




514
2.64


 


A395




528
2.62


 


A396




536
2.83


 


A397




537
2.77



















TABLE 249





Ex
Str
ESI+
RT







A398




475
2.45


 


A399




489
2.61


 


A400




503
2.64


 


A401




532
2.53



















TABLE 250





Ex
Str
ESI+
RT


















A402




516
2.5


 


A403




544
2.59


 


A404




515
2.71


 


A405




515
2.71



















TABLE 251





Ex
Str
ESI+
RT







A406




529
2.71


 


A407




529
2.64


 


A408




543
2.69


 


A409




557
2.88



















TABLE 252





Ex
Str
ESI+
RT







A410




556
2.49


 


A411




570
2.54


 


A412




586
2.72


 


A413




529
2.73



















TABLE 253





Ex
Str
ESI+
RT


















A414




543
2.71


 


A415




551
2.92


 


A416




552
2.86


 


A417




488
2.5



















TABLE 254





Ex
Str
ESI+
RT







A418




502
2.54


 


A419




531
2.44


 


A420




528
2.61


 


A421




528
2.53



















TABLE 255





Ex
Str
ESI+
RT







A422




556
2.78


 


A423




555
2.41


 


A424




569
2.44


 


A425




585
2.62



















TABLE 256





Ex
Str
ESI+
RT


















A426




542
2.6


 


A427




550
2.8


 


A428




551
2.75


 


A429




542
2.65



















TABLE 257





Ex
Str
ESI+
RT


















A430




542
2.65


 


A431




557
3


 


A432




598
2.79


 


A433




529
2.79


 


A434




570
2.74



















TABLE 258





Ex
Str
ESI+
RT







A435




556
2.69


 


A436




543
2.82


 


A437




600
2.75


 


A438




556
2.71


 


A439




587
3.1 



















TABLE 259





Ex
Str
ESI+
RT







A440




536
3.03


 


A441




536
2.84


 


A442




550
2.67


 


A443




570
2.23


 


A444




584
2.26



















TABLE 260





Ex
Str
ESI+
RT







A445




528
2.44


 


A446




528
2.43


 


A447




543
2.9 


 


A448




584
2.63


 


A449




515
2.62



















TABLE 261





Ex
Str
ESI+
RT


















A450




556
2.52


 


A451




542
2.48


 


A452




586
2.6


 


A453




542
2.5


 


A454




573
2.85



















TABLE 262





Ex
Str
ESI+
RT







A455




522
2.75


 


A456




522
2.56


 


A457




536
2.46


 


A458




556
2.05


 


A459




570
2.11



















TABLE 263





Ex
Str
ESI+
RT







A460




527
2.39


A461




527
2.39


 


A462




542
2.85


 


A463




583
2.57


 


A464




514
2.56



















TABLE 264





Ex
Str
ESI+
RT







A465




555
2.47


 


A466




541
2.43


 


A467




585
2.56


 


A468




541
2.45


 


A469




572
2.8 



















TABLE 265





Ex
Str
ESI+
RT


















A470




521
2.67


 


A471




521
2.49


 


A472




535
2.41


 


A473




555
2


 


A474




569
2.05



















TABLE 266





Ex
Str
ESI+
RT







A475




541
1.97


 


A476




543
1.94


 


A477




555
2.52


 


A478




557
1.94


 


A479




571
1.98



















TABLE 267





Ex
Str
ESI+
RT







A480




500
2.58


 


A481




556
2.72


 


A482




528
2.76


 


A483




542
2.54


 


A484




542
2.54



















TABLE 268





Ex
Str
ESI+
RT







A485




557
2.99


 


A486




598
2.73


 


A487




529
2.73


 


A488




570
2.62


 


A489




556
2.58



















TABLE 269





Ex
Str
ESI+
RT


















A490




600
2.7


 


A491




556
2.6


 


A492




587
2.93


 


A493




536
2.83


 


A494




536
2.65



















TABLE 270





Ex
Str
ESI+
RT


















A495




570
2.14


 


A496




584
2.2


 


A497




541
2.42


 


A498




541
2.42


 


A499




556
2.87



















TABLE 271





Ex
Str
ESI+
RT


















A500




597
2.6


 


A501




528
2.6


 


A502




569
2.5


 


A503




555
2.46


 


A504




599
2.58



















TABLE 272





Ex
Str
ESI+
RT


















A505




555
2.48


 


A506




586
2.82


 


A507




535
2.67


 


A508




535
2.5


 


A509




549
2.42



















TABLE 273





Ex
Str
ESI+
RT







A510




569
2.04


 


A511




583
2.08


 


A512




555
2.02


 


A513




557
1.98


 


A514




569
2.55



















TABLE 274





Ex
Str
ESI+
RT







A515




571
1.99


 


A516




585
2.02


 


A517




618
2.12


 


A518




514
2.62


 


A519




570
2.74



















TABLE 275





Ex
Str
ESI+
RT







A520




542
2.79


 


A521




549
2.17


 


A522




527
2.42


 


A523




527
2.42


 


A524




542
2.83



















TABLE 276





Ex
Str
ESI+
RT







A525




583
2.58


 


A526




514
2.59


 


A527




555
2.52


 


A528




541
2.47


 


A529




528
2.62



















TABLE 277





Ex
Str
ESI+
RT







A530




585
2.53


 


A531




541
2.49


 


A532




572
2.94


 


A533




521
2.85


 


A534




521
2.62



















TABLE 278





Ex
Str
ESI+
RT







A535




535
2.43


 


A536




555
2.01


 


A537




569
2.06


 


A538




514
2.39


 


A539




514
2.39



















TABLE 279





Ex
Str
ESI+
RT







A540




529
2.88


 


A541




570
2.59


 


A542




501
2.59


 


A543




542
2.48


 


A544




528
2.44



















TABLE 280





Ex
Str
ESI+
RT







A545




572
2.56


 


A546




528
2.46


 


A547




559
2.88


 


A548




508
2.88


 


A549




508
2.58



















TABLE 281





Ex
Str
ESI+
RT







A550




522
2.48


 


A551




542
1.99


 


A552




556
2.04


 


A553




528
1.96


 


A554




530
1.98



















TABLE 282





Ex
Str
ESI+
RT







A555




542
2.52


 


A556




544
1.93


 


A557




558
1.97


 


A558




487
2.59


 


A559




543
2.75



















TABLE 283





Ex
Str
ESI+
RT







A560




515
2.77


 


A561




513
2.33


 


A562




513
2.33


 


A563




528
2.81


 


A564




569
2.52



















TABLE 284





Ex
Str
ESI+
RT


















A565




500
2.51


 


A566




541
2.41


 


A567




527
2.37


 


A568




571
2.5


 


A569




527
2.4



















TABLE 285





Ex
Str
ESI+
RT


















A570




558
2.8


 


A571




507
2.75


 


A572




507
2.49


 


A573




521
2.39


 


A574




541
1.96



















TABLE 286





Ex
Str
ESI+
RT


















A575




555
1.99


 


A576




527
1.94


 


A577




529
1.93


 


A578




541
2.45


 


A579




543
1.9



















TABLE 287





Ex
Str
ESI+
RT


















A580




557
1.93


 


A581




590
2.04


 


A582




486
2.49


 


A583




514
2.68


 


A584




521
2.09



















TABLE 288





Ex
Str
ESI+
RT


















A585




528
2.43


 


A586




528
2.43


 


A587




543
2.89


 


A588




584
2.61



















TABLE 289





Ex
Str
ESI+
RT


















A589




515
2.61


 


A590




556
2.51


 


A591




542
2.47


 


A592




542
2.49



















TABLE 290





Ex
Str
ESI+
RT


















A593




573
2.87


 


A594




522
2.87


 


A595




522
2.6


 


A596




536
2.5



















TABLE 291





Ex
Str
ESI+
RT


















A597




556
2.04


 


A598




570
2.07


 


A599




517
2.73


 


A600




543
2.85



















TABLE 292





Ex
Str
ESI+
RT


















A601




531
2.88


 


A602




545
2.93


 


A603




575
2.96


 


A604




561
2.8



















TABLE 293





Ex
Str
ESI+
RT







 










A605




558
2.8


 


A606




555
3.21


 


A607




571
2.87


 


A608




557
2.92



















TABLE 294





Ex
Str
ESI+
RT


















A609




587
2.83


 


A610




598
2.84


 


A611




628
3.07


 


A612




632
3.14


 


A613




640
2.48



















TABLE 295





Ex
Str
ESI+
RT


















A614




584
2.78


 


A615




557
2.96


 


A616




557
2.97


 


A617




571
3.08


 


A618




571
2.98



















TABLE 296





Ex
Str
ESI+
RT


















A619




571
2.94


 


A620




585
3.01


 


A621




601
2.81


 


A622




600
2.3


 


A623




586
2.31



















TABLE 297





Ex
Str
ESI+
RT


















A624




614
2.33


 


A625




600
2.79


 


A626




585
3


 


A627




600
2.31



















TABLE 298





Ex
Str
ESI+
RT


















A628




616
2.32


 


A629




593
3.12


 


A630




593
3.09


 


A631




593
3.08


 


A632




579
2.87



















TABLE 299





Ex
Str
ESI+
RT







A633




564
2.8 


 


A634




564
2.64


 


A635




564
2.5 


 


A636




569
2.75



















TABLE 300





Ex
Str
ESI+
RT







A637




648
3.03


 


A638




607
3.14


 


A639




578
2.62


 


A640




578
2.59



















TABLE 301





Ex
Str
ESI+
RT







A641




578
2.47


 


A642




621
3.2 


 


A643




501
2.94


 


A644




545
2.99



















TABLE 302





Ex
Str
ESI+
RT


















A645




589
3.07


 


A646




572
2.81


 


A647




599
3.19


 


A648




571
3



















TABLE 303





Ex
Str
ESI+
RT







A649




642
3.12


 


A650




585
3.22


 


A651




585
3.03


 


A652




598
2.37



















TABLE 304





Ex
Str
ESI+
RT







A653




614
2.81


 


A654




607
3.2 


 


A655




578
2.63


 


A656




592
2.58


 


A657




541
3.18



















TABLE 305





Ex
Str
ESI+
RT







A658




543
2.91


 


A659




543
2.8 


 


A660




543
2.8 


 


A661




557
2.89



















TABLE 306





Ex
Str
ESI+
RT







A662




557
2.84


 


A663




571
3.07


 


A664




571
3.04


 


A665




571
3.13



















TABLE 307





Ex
Str
ESI+
RT







A666




571
3.13


 


A667




571
2.9 


 


A668




585
3.12


 


A669




573
2.79



















TABLE 308





Ex
Str
ESI+
RT







A670




598
2.81


 


A671




628
2.99


 


A672




584
2.74


 


A673




586
2.27


 


A674




627
2.33



















TABLE 309





Ex
Str
ESI+
RT







A675




572
2.69


 


A676




570
2.76


 


A677




584
2.79


 


A678




600
2.95



















TABLE 310





Ex
Str
ESI+
RT







A679




624
2.87


 


A680




582
2.3 


 


A681




619
3.28


 


A682




590
2.97


 


A683




626
2.32



















TABLE 311





Ex
Str
ESI+
RT







A684




604
2.66


 


A685




640
2.35


 


A686




626
2.35


 


A687




634
2.44


 


A688




655
2.33



















TABLE 312





Ex
Str
ESI+
RT







A689




636
3.11


 


A690




580
3.09


 


A691




593
3.32


 


A692




607
3.24


 


A693




621
3.27



















TABLE 313





Ex
Str
ESI+
RT







B1




467
3.1 


 


B2




425
3.32


 


B3




443
3.32


 


B4




443
3.37


 


B5




443
3.35



















TABLE 314





Ex
Str
ESI+
RT







B6 




467
3.09


 


B7 




483
3.14


 


B8 




483
3.28


 


B9 




483
3.31


 


B10




450
2.96



















TABLE 315





Ex
Str
ESI+
RT







B11




468
3.27


 


B12




496
2.86


 


B13




471
3.36


 


B14




471
3.51


 


B15




483
3.37



















TABLE 316





Ex
Str
ESI+
RT







B16




455
3.34


 


B17




499
2.95


 


B18




497
3.24


 


B19




511
3.37


 


B20




469
3.28



















TABLE 317





Ex
Str
ESI+
RT







B21




493
2.97


 


B22




496
3.24


 


B23




525
3.12


 


B24




526
3.17


 


B25




476
2.73



















TABLE 318





Ex
Str
ESI+
RT


















B26




476
2.98


 


B27




476
2.46


 


B28




575
2.88


 


B29




552
2.62


 


B30




508
3



















TABLE 319





Ex
Str
ESI+
RT







B31




510
3.25


 


B32




551
3.02


 


B33




510
3.23


 


B34




531
3.84


 


B35




559
3.82



















TABLE 320





Ex
Str
ESI+
RT







B36




490
3.43


 


B37




490
3.62


 


B38




491
2.35


 


B39




493
2.88


 


B40




493
2.95



















TABLE 321





Ex
Str
ESI+
RT


















B41




507
3.36


 


B42




492
3


 


B43




552
3.58


 


B44




542
3.51


 


B45




541
2.54



















TABLE 322





Ex
Str
ESI+
RT







B46




505
3.31


 


B47




523
2.73


 


B48




578
3.52


 


B49




536
3.57


 


B50




517
3.59



















TABLE 323





Ex
Str
ESI+
RT







B51




517
3.78


 


B52




522
3.06


 


B53




579
2.76


 


B54




529
3.56


 


B55




529
3.54



















TABLE 324





Ex
Str
ESI+
RT







B56




563
3.54


 


B57




517
2.73


 


B58




543
2.85


 


B59




531
2.88


 


B60




545
2.93



















TABLE 325





Ex
Str
ESI+
RT


















B61




575
2.96


 


B62




561
2.8


 


B63




558
2.8


 


B64




555
3.21


 


B65




571
2.87



















TABLE 326





Ex
Str
ESI+
RT







B66




557
2.92


 


B67




587
2.83


 


B68




598
2.84


 


B69




628
3.07


 


B70




632
3.14



















TABLE 327





Ex
Str
ESI+
RT







B71




640
2.48 


 


B72 




584
2.78


 


B73




557
2.96


 


B74




557
2.97


 


B75




571
3.08



















TABLE 328





Ex
Str
ESI+
RT


















B76




571
2.98


 


B77




571
2.94


 


B78




585
3.01


 


B79




601
2.81


 


B80




600
2.3



















TABLE 329





Ex
Str
ESI+
RT


















B81




586
2.31


 


B82




614
2.33


 


B83




600
2.79


 


B84




585
3


 


B85




600
2.31



















TABLE 330





Ex
Str
ESI+
RT







B86




616
2.32


 


B87




593
3.12


 


B88




593
3.09


 


B89




593
3.08


 


B90




579
2.87



















TABLE 331





Ex
Str
ESI+
RT







B91




564
2.8 


 


B92




564
2.64


 


B93




564
2.5 


 


B94




569
2.75


 


B95




648
3.03



















TABLE 332





Ex
Str
ESI+
RT







B96




607
3.14


 


B97




578
2.62


 


B98




578
2.59


 


B99




578
2.47


 


B100




621
3.2 



















TABLE 333





Ex
Str
ESI+
RT







B101




501
2.94


 


B102




545
2.99


 


B103




589
3.07


 


B104




572
2.81


 


B105




599
3.19



















TABLE 334





Ex
Str
ESI+
RT


















B106




571
3


 


B107




642
3.12


 


B108




585
3.22


 


B109




585
3.03


 


B110




598
2.37



















TABLE 335





Ex
Str
ESI+
RT







B111




614
2.81


 


B112




607
3.2 


 


B113




578
2.63


 


B114




592
2.58


 


B115




541
3.18



















TABLE 336





Ex
Str
ESI+
RT







B116




543
2.91


 


B117




543
2.8 


 


B118




543
2.8 


 


B119




557
2.89


 


B120




557
2.84



















TABLE 337





Ex
Str
ESI+
RT







B121




571
3.07


 


B122




571
3.04


 


B123




571
3.13


 


B124




571
3.13


 


B125




571
2.9 



















TABLE 338





Ex
Str
ESI+
RT







B126




585
3.12


 


B127




573
2.79


 


B128




598
2.81


 


B129




628
2.99


 


B130




584
2.74



















TABLE 339





Ex
Str
ESI+
RT







B131




586
2.27


 


B132




627
2.33


 


B133




572
2.69


 


B134




570
2.76


 


B135




584
2.79



















TABLE 340





Ex
Str
ESI+
RT







B136




600
2.95


 


B137




624
2.87


 


B138




582
2.3 


 


B139




619
3.28


 


B140




590
2.97



















TABLE 341





Ex
Str
ESI+
RT







B141




626
2.32


 


B142




604
2.66


 


B143




640
2.35


 


B144




626
2.35


 


B145




634
2.44



















TABLE 342





Ex
Str
ESI+
RT







B146




655
2.33


 


B147




636
3.11


 


B148




580
3.09


 


B149




593
3.32


 


B150




607
3.24



















TABLE 343





Ex
Str
ESI+
RT







B151




621
3.27









INDUSTRIAL APPLICABILITY
The compound, which is the active ingredient of the drug of the present invention, has a PI3Kδ selective inhibitory action and/or an IL-2 production inhibitory action and/or a B cell proliferation inhibitory action (including an activation inhibitory action), as well as a good pharmacological action based thereon. Thus, the pharmaceutical composition of the present invention can be used as an agent for preventing or treating rejection reactions in various organ transplantations, allergy diseases (asthma, atopic dermatitis, and the like), autoimmune diseases (rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, systemic lupus erythematosus, and the like), and hematologic tumor (leukemia and the like).

## Claims

1. A compound of the formula (I) or a salt thereof:



wherein
A2 and A3 are N and A1 is CH, or A1 and A3 are N and A2 is CH,
B's are CH and n is 0,
R1 is -L1-L2-Y, wherein -L1-L2-is —NH— or —O—,
R2 is halogen, —OH, —O-lower alkyl, —CN, or lower alkyl which may be substituted with one or more substituents selected from the group consisting of halogen, —OH, —O— lower alkyl, and —CN,
Y is a non-aromatic heterocycle which may be substituted with one or more substituents selected from the Group D1, and
the Group D1 consists of:
-L5a-non-aromatic heterocycle which may be substituted with one or more substituents selected from the group consisting of lower alkyl, —C(O)O-lower alkyl, —C(O)-lower alkyl, and oxo, wherein L5a represents a bond or —C(O)—.

2. The compound or a salt thereof according to claim 1, wherein A2 and A3 are N and A1 is CH.

3. The compound or a salt thereof according to claim 1, wherein the compound is
[(3 S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl][(2R)-tetrahydrofuran-2-yl]methanone,
[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl](tetrahydro-2H-pyran-4-yl)methanone,
methyl 4-{[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]carbonyl}piperidine-1-carboxylate,
[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)pyrrolidin-1-yl](tetrahydrofuran-3-yl)methanone,
4-{[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl }oxy)pyrrolidin-1-yl]carbonyl }-1-methylpyrrolidin-2-one,
[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl](tetrahydrofuran-3-yl)methanone,
4-{[(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl]carbonyl }-1-methylpyrrolidin-2-one,
4-{[3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)azetidin-1-yl]carbonyl}-1-methylpyrrolidin-2-one.

4. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and a pharmaceutically acceptable excipient.

5. A method for treating systemic lupus erythematosus, comprising administering to a subject in need thereof an effective amount of the compound or a salt thereof according to claim 3.

6. The compound or a salt thereof according to claim 2, wherein -L1-L2- is —NH—.

7. The compound or a salt thereof according to claim 6, wherein Y is a non-aromatic heterocycle which is substituted with —C(O)-non-aromatic heterocycle.

8. The compound or a salt thereof according to claim 3, wherein the compound is [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl][(2R)-tetrahydrofuran-2-yl]methanone.

9. The compound or a salt thereof according to claim 3, wherein the compound is [(3S)-3-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)pyrrolidin-1-yl](tetrahydro-2H-pyran-4-yl)methanone.