8-SUBSTITUTED IMIDAZOPYRIMIDINONE DERIVATIVE HAVING AUTOTAXIN INHIBITORY ACTIVITY

TECHNICAL FIELD

The present invention imidazopyrimidinone derivative having autotaxin inhibitory activity, as well as a pharmaceutical comprising said imidazopyrimidinone derivatives as an active ingredient.

BACKGROUND ART

Lysophosphatidic acid (LPA) is a lipid mediator that exhibits a variety of effects, such as cell proliferation, intracellular calcium influx, cytoskeletal changes, cell migration, via signal transduction through G protein-coupled receptor expressed on cell surface (LPA1-6). It has been reported that the lipid is involved in abnormalities of living body, such as fibrosis, pain, cancer, inflammation, arteriosclerosis (Non-Patent Document 1).

LPA can be biosynthesized by several metabolic pathways, primarily via hydrolysis of lysophosphatidylcholine by autotaxin (ENPP2, ATX). ATX is a secreted protein of ENPP (Ectonucleotide pyrophosphatase and phosphodiesterase) family (ENPP1-7) and referred to as ENPP2. ATX is the only one of this family that has a lysophospholipase D activity and thus is involved in LPA production. It has been reported that inhibiting the enzyme activity of ATX to inhibit LPA production is effective in the treatment of fibrotic diseases (Non-Patent Document 1).

Fibrosis can occur in any organ, and the mechanism of its progression is common regardless of the trigger involved.

Animal tissues and organs maintain its structure with fibers such as collagen, and injured tissues and organs are restored to the original condition through the process of wound healing with collagen production. However, in case where the tissue receives immunological, chemical, mechanical, metabolic or other injuries repeatedly or experiences a greater degree of injury, excessive accumulation of fibrous connective tissue may occur. Accumulation of such connective tissue is irreversible, and fibers abnormally increased cause fibrosis that is associated with dysfunction of tissues and organs.

Pathological feature of chronic kidney disease includes renal glomerular fibrosis and tubulointerstitial fibrosis. Dropout and fibrosis of parenchymal cells prevail in the pathology of end-stage renal failure. In chronic kidney disease patients having tubulointerstitial fibrosis, the progress to renal failure is faster as compared to chronic kidney disease patients without such fibrosis.

For preventing and treating chronic kidney disease, treatments with an antihypertensive drug, such as angiotensin receptor antagonists and calcium antagonists, have been practiced, as well as advice on daily living and dietary. However, the effect from such conventional treatments is not enough to be satisfied, and there still exists an ongoing need for new drugs to make prevention and treatment more effective.

Patent Document 1 discloses imidazopyrimidinone derivatives that inhibit gonadotropin releasing hormone. However, it is not described or suggested that such compounds inhibit autotaxin or may be a therapeutic agent for chronic kidney disease.

Patent Documents 2 to 15 describe polycyclic compounds that inhibit autotaxin, but no description or suggestion is provided for the imidazopyrimidinone derivative of the invention. Patent Documents 16-23 describe monocyclic compounds that inhibit autotaxin, but no description or suggestion is provided for the imidazopyrimidinone derivatives of the invention.

PRIOR ART DOCUMENTS
Patent Documents

WO2003/51885

WO2012/127885

WO2012/5227

WO2011/116867

WO2011/5669

WO2010/60532

WO2012/100018

US Patent Application Publication No. 2012/100592

WO2012/24620

WO2011/53597

WO2010/115491

WO2010/112124

WO2009/46841

WO2009/46842

WO2010/63352

WO2012/138648

WO2011/41462

WO2011/41694

WO2011/17350

WO2010/112116

WO2010/68775

US Patent Application Publication No. 2010/16258

WO2009/46804

Non-Patent Documents

Nature, vol. 411, pp. 494-498 (2001)

SUMMARY OF INVENTION
Problem to be Solved by the Invention

The object of the present invention is to provide 8-substituted-imidazopyrimidinone derivatives having an excellent inhibitory activity on autotaxin.

Means for Solving the Problem

The present invention is based on the inventor's discovery of the 8-substituted imidazopyrimidinone derivatives having an excellent inhibitory activity on autotaxin.

The present invention relates to the following.

[1] An autotaxin inhibitor comprising a compound of formula (I):

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wherein

R¹is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group;

R², R³and R⁴are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino,

—N═C(R^4a)(OR^4b) wherein R^4ais substituted or unsubstituted alkyl and R^4bis substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl or substituted or unsubstituted aromatic heterocyclylsulfonyl;

R⁵is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.

[1′] A autotaxin inhibitor comprising a compound of formula (I) wherein

R¹is substituted or unsubstituted alkyl, substituted unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group;

R², R³and R⁴are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl or substituted or unsubstituted aromatic heterocyclylsulfonyl;

R⁵is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group,

or a pharmaceutically acceptable salt thereof.

[2] A medicament comprising the autotaxin inhibitor according to [1] or [1′] for the prevention or treatment of a disease involving autotaxin.

[3] A compound of formula (I) or a pharmaceutically acceptable salt thereof:

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and

which conforms to one of provisions (i) to (v):

(i) R²is substituted or unsubstituted amino-(C1-C2)alkyl or substituted or unsubstituted bromomethyl,

(ii) R¹is phenyl substituted with a group other than halogen, haloalkyl or haloalkyloxy or unsubstituted phenyl, R²is methyl, and R⁴is hydrogen or methyl,

(iii) R¹is substituted phenyl, R²is hydrogen, R³is substituted phenyl, and R⁴is methyl,

(iv) R³is bromo or alkyloxycarbonyl, and R⁴is hydrogen, or

(v) R¹is alkyl substituted with alkyloxycarbonyl or unsubstituted alkyl, R²is alkyl substituted with substituted or unsubstituted nitrogen-containing aromatic heterocyclic group, and R³is substituted phenyl and R⁴is methyl;

(b) a compound wherein R¹is substituted or unsubstituted aromatic carbocyclic group or unsubstituted furyl, and R²is substituted or unsubstituted phenyl; and

aromatic carbocyclic group or unsubstituted furyl, and R²is substituted or unsubstituted phenyl; and

(c) the compounds of the formula:

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are excluded.

[3′]A compound of formula (I) or a pharmaceutically acceptable salt thereof:

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which conforms to one of provisions (i) to (iv):

(i) R²is substituted or unsubstituted amino-(C1-C2)alkyl or substituted or unsubstituted bromomethyl,

(ii) R¹is phenyl substituted with a group other than halogen, haloalkyl or haloalkyloxy or unsubstituted phenyl, R²is methyl, and R⁴is hydrogen or methyl,

(iii) R¹is substituted phenyl, R²is hydrogen, R³is substituted phenyl, and R⁴is methyl, or

(iv) R³is bromo or alkyloxycarbonyl, and R⁴is hydrogen;

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are excluded.

[4] The compound according to [3] or [3′] wherein R⁵is substituted or unsubstituted C4-C8 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.

[5] The compound according to [3] or [3′] wherein R⁵is substituted or unsubstituted C4-C8 alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, or a pharmaceutically acceptable salt thereof.

[6] The compound according to [3] or [3′] wherein R⁵is alkyl substituted with one or more substituents selected from the Substituent Group A consisting of halogen, cyano, hydroxy, formyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl and substituted or unsubstituted amino, or a pharmaceutically acceptable salt thereof.

[7] The compound according to [3] or [3′] wherein R⁵is a group of formula:

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wherein

X¹and X²are each independently N or CH,

Y is substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene,

R^9a, R^9band R^9care each independently hydrogen, halogen, cyano, hydroxy, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl or substituted or unsubstituted amino,

or a pharmaceutically acceptable salt thereof.

[8] The compound according to any one of [2] to [7] or [3′] wherein R²is hydrogen, halogen, formyl or substituted or unsubstituted alkyl, or a pharmaceutically acceptable salt thereof.

[9] The compound according to any one of [2] to [8] or [3′] wherein R³is hydrogen, halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted amino, or a pharmaceutically acceptable salt thereof.

[10] The compound according to any one of [2] to [9] or [3′] wherein R⁴is hydrogen, halogen, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino, or a pharmaceutically acceptable salt thereof.

[11] The compound according to any one of claims [2] to [9] or [3′] wherein R⁴is halogen, formyl, substituted methyl, substituted or unsubstituted C2-C8 alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino, or a pharmaceutically acceptable salt thereof.

[12]A pharmaceutical composition comprising the compound according to any one of [2] to [11] or [3′] or a pharmaceutically acceptable salt thereof as an active ingredient.

[13] The pharmaceutical composition according to [12] that has autotaxin inhibitory effect.

[14] The pharmaceutical composition according to [12] or [13] for the prevention or treatment of a disease involving autotaxin.

[15] Use of a compound according to any one of [2] to [11] or [3′] or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of a disease involving autotaxin.

[16]A method for the prevention or treatment of a disease involving autotaxin comprising administering a compound according to any one of [2] to [11] or [3′] or a pharmaceutically acceptable salt thereof.

[17] The compound according to any one of [2] to [11] or [3′] or a pharmaceutically acceptable salt thereof for the prevention or treatment of a disease involving autotaxin.

[18] The pharmaceutical composition according to [12] which is a chronic kidney disease therapeutic agent.

[19]A method for the prevention or treatment of a disease involving autotaxin comprising administering a compound of formula (I):

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Effect of the Invention

The compound of the invention exhibits excellent autotaxin inhibitory activity. Also, the compound of the invention prevents fibrosis based on the autotaxin inhibitory activity.

DESCRIPTION OF EMBODIMENTS

The definitions of the terms as used herein are as follows. Unless specified otherwise, these terms are used alone or in combination with another term in the meaning as defined.

The term “halogen” includes fluorine, chlorine, bromine and iodine. Fluorine and chlorine are particularly preferable.

Specific examples of “halogen” for R²include bromine.

Specific examples of “halogen” for R³include fluorine.

Specific examples of “halogen” for R⁴includes chlorine.

The term “alkyl” means a straight or branched hydrocarbon group having 1 to 10 carbon atoms, and includes alkyl of 1 to 6 carbon atoms, alkyl of 1 to 4 carbon atoms, and alkyl of 1 to 3 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, and n-decyl.

Specific examples of “alkyl” for R¹include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In particular, n-propyl is preferred.

Specific examples of “alkyl” for R²include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In particular, methyl is preferred.

Specific examples of “alkyl” for R³include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In particular, methyl, ethyl, n-propyl, and n-butyl are preferred.

Specific examples of “alkyl” for R⁴include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In particular, methyl and n-propyl are preferred.

Specific examples of “alkyl” for R^4ainclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In particular, methyl is preferred.

Specific examples of “alkyl” for R^4binclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. In particular, methyl, ethyl, and n-propyl are preferred.

Specific examples of “alkyl” for R⁵include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and isohexyl. In particular, methyl, ethyl, n-propyl, n-butyl, n-pentyl, methylbutyl, n-hexyl, isohexyl, and ethylpentyl are preferred.

The alkyl moiety of “alkyloxy”, “alkyloxycarbonyl”, “alkylcarbonyl”, “alkylsulfinyl”, “alkylsulfonyl” and “alkylthio” has the same meaning as defined above for “alkyl”.

Specific examples of the alkyl moiety of “alkyloxy” for R⁴include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. In particular, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, tert-butyloxy, n-octyloxy, isobutylmethylhexyloxy, and n-nonyloxy are preferred.

The term “haloalkyl” and “haloalkyloxy” mean respectively alkyl and alkyloxy substituted with 1 to 5, preferably 1 to 3, “halogen” at a substitutable position.

Specific examples of “haloalkyl” for R⁵include monohaloalkyl, dihaloalkyl, and trihaloalkyl. In particular, trifluorobutyl, fluoro-n-butyl, and fluoro-n-hexyl are preferred.

The term “alkenyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more double bonds at any position, and includes alkenyl of 2 to 6 carbon atoms, alkenyl of 3 to 4 carbon atoms. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, and decenyl.

Specific examples of “alkenyl” for R¹include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, and isohexenyl. In particular, propenyl is preferred.

Specific examples of “alkenyl” for R⁵include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, and isohexenyl. In particular, butenyl and pentenyl are preferred.

The alkenyl moiety of “alkenyloxy”, “alkenyloxycarbonyl”, “alkenylcarbonyl”, “alkenylsulfinyl”, “alkenylsulfonyl” and “alkenylthio” has the same meaning as defined above for “alkenyl”.

The term “alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms and one or more triple bonds at any position, and includes alkynyl of 2 to 6 carbon atoms, alkynyl of 2 to 4 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. Also, the alkynyl may further have a double bond, as well as one or more triple bonds at any position.

Specific examples of “alkynyl” for R³include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, and decynyl. In particular, propynyl is preferred.

The alkynyl moiety of “alkynyloxy”, “alkynyloxycarbonyl”, “alkynylcarbonyl”, “alkynylsulfinyl”, “alkynylsulfonyl” and “alkynylthio” has the same meaning as defined above for “alkynyl”.

Preferred examples of “alkynyloxy” for R³include undecynyloxy.

The term “non-aromatic carbocyclic group” includes cyclic saturated hydrocarbon groups having 3 to 8 carbon atoms, groups wherein such cyclic saturated hydrocarbon ring is fused with further one or two 3- to 8-membered rings, cyclic unsaturated aliphatic hydrocarbon groups having 3 to 8 carbon atoms, and groups wherein such cyclic unsaturated aliphatic hydrocarbon ring is fused with further one or two 3- to 8-membered rings.

Specific examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. In particular, a cyclic saturated hydrocarbon group having 3 to 6 carbon atoms and a cyclic saturated hydrocarbon group having 5 or 6 carbon atoms are preferred.

Specific examples of the ring to be fused with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocyclic rings, such as cycloalkane ring (for example: cyclohexane, cyclopentane) and cycloalkene ring (for example: cyclohexene, cyclopentene); non-aromatic heterocyclic rings, such as piperidine ring, piperazine ring and morpholine ring; aromatic carbocyclic rings, such as benzene ring and naphthalene ring; and aromatic heterocyclic rings, such as pyridine ring, pyrimidine ring, pyrrole ring and imidazole ring. The cyclic saturated hydrocarbon group having 3 to 8 carbon atoms should be involved in the linkage of such fused ring.

Specific examples of the ring to be fused with the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include carbocyclic rings: such as aromatic carbocyclic rings (for example: benzene ring, naphthalene ring) and non-aromatic carbocyclic rings (for example: cycloalkane rings such as cyclohexane ring and cyclopentane ring, cycloalkene rings such as cyclohexene ring and cyclopentene ring); and heterocyclic rings: such as aromatic heterocyclic rings (for example: pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring) and non-aromatic heterocyclic rings (for example: piperidine ring, piperazine ring, morpholine ring). The cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms should be involved in the linkage of such fused ring.

Examples of the non-aromatic carbocyclic group include the following groups. These groups may have a substituent group at any substitutable position.

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Specific examples of “non-aromatic carbocyclic group” for R¹include cycloalkyl and cycloalkenyl. In particular, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are preferable.

Specific examples of “non-aromatic carbocyclic group” for R⁴include cycloalkyl and cycloalkenyl. In particular, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl are preferable.

The non-aromatic carbocyclic ring moiety of “non-aromatic carbocyclyloxy”, “non-aromatic carbocyclyloxycarbonyl”, “non-aromatic carbocyclylcarbonyl”, “non-aromatic carbocyclylsulfinyl”, “non-aromatic carbocyclylsulfonyl” and “non-aromatic carbocyclylthio” has the same meaning as defined above for “non-aromatic carbocyclic group”.

Specific examples of “non-aromatic carbon ring oxy” for R⁴include cycloalkyloxy and cycloalkenyloxy. In particular, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy are preferable.

The term “aromatic carbocyclic group” includes monocyclic or polycyclic aromatic carbocyclic groups and groups wherein such monocyclic or polycyclic aromatic carbocyclic ring is fused with further one or two 3- to 8-membered rings. Specific examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl and phenanthryl. Particularly, phenyl is preferred.

Specific examples of the ring to be fused with the monocyclic or polycyclic aromatic carbocyclic group include non-aromatic carbocyclic rings such as cycloalkane rings (for example: cyclohexane ring, cyclopentane ring), and cycloalkene rings (for example: cyclohexene ring, cyclopentene ring); and non-aromatic heterocyclic rings such as piperidine ring, piperazine ring and morpholine ring. The monocyclic or polycyclic aromatic carbocyclic group should be involved in the linkage of such fused ring.

Examples of the aromatic carbocyclic groups include the following groups. These groups may have a substituent group at any possible position.

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Specific examples of “aromatic carbocyclic group” for R¹include phenyl, naphthyl, anthryl and phenanthryl. In particular, phenyl is preferred.

Specific examples of “aromatic carbocyclic group” for R³include phenyl, naphthyl, anthryl and phenanthryl. In particular, phenyl is preferred.

The aromatic carbocyclic ring moiety of “aromatic carbocyclyloxy”, “aromatic carbocyclyloxycarbonyl”, “aromatic carbocyclylcarbonyl”, “aromatic carbocyclylcarbonyl”, “aromatic carbocyclylsulfinyl”, “aromatic carbocyclylsulfonyl” and “aromatic carbocyclylthio” has the same meaning as defined above for “aromatic carbocyclic ring”.

Preferred examples of “aromatic carbocyclyloxy” for R⁴include phenyloxy and naphthyloxy.

The term “aromatic heterocyclic group” means monocyclic or polycyclic aromatic heterocyclic groups having one or more heteroatoms selected from O, S and N in the ring and groups wherein such monocyclic or polycyclic aromatic heterocyclic ring is fused with further one or two 3- to 8-membered rings.

Preferred examples of the monocyclic aromatic heterocyclic group include 5- or 6-membered aromatic heterocyclic groups such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl.

Preferred examples of the polycyclic aromatic heterocyclic group include aromatic heterocyclic groups fused with a 5- or 6-membered ring, such as bicyclic aromatic heterocyclic group (for example: indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl), and tricyclic aromatic heterocyclic group (for example: carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl). Any ring of the polycyclic aromatic heterocyclic group may be involved in the linkage.

Specific examples of the ring to be fused with the monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocyclic rings such as cycloalkane ring (for example: cyclohexane ring, cyclopentane ring), cycloalkene rings (for example: cyclohexene ring, cyclopentene ring); non-aromatic heterocyclic rings such as piperidine ring, piperazine ring and morpholine ring. The monocyclic or polycyclic aromatic heterocyclic group should be involved in the linkage of such fused ring.

Examples of the aromatic heterocyclic groups include the following groups. These groups may have a substituent group at any possible position.

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Specific examples of “aromatic heterocyclic group” for R⁴include bicyclic heterocyclic groups aromatic ring such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl; and carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl and dibenzofuryl. In particular, furyl, thiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzofuryl and benzothiophenyl are preferable.

The aromatic heterocyclic ring moiety of “aromatic heterocyclyloxy”, “aromatic heterocyclyloxycarbonyl”, “aromatic heterocyclylcarbonyl”, “aromatic heterocyclylsulfinyl”, “aromatic heterocyclylsulfonyl” and “aromatic heterocyclylthio” has the same meaning as defined above for “aromatic heterocyclic group”.

The term “non-aromatic heterocyclic group” means monocyclic or polycyclic non-aromatic heterocyclic groups having one or more heteroatoms selected from O, S and N in the ring and groups wherein such non-aromatic heterocyclic ring is fused with further one or two 3- to 8-membered rings.

Specific examples of the monocyclic non-aromatic heterocyclic group include dioxanyl, thiiranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, oxadiadinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl and thiazolidyl.

Specific examples of the polycyclic non-aromatic heterocyclic group include indolinyl, isoindolinyl, chromanyl, isochromanyl and isomannyl. Any ring of the polycyclic non-aromatic heterocyclic group may be involved in the linkage.

Examples of the non-aromatic heterocyclic groups include the following groups.

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Specific examples of “non-aromatic heterocyclic group” for R⁴include dioxanyl, thiiranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperidino, piperazinyl, piperazino, morpholinyl, morpholino, oxadiadinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and azepanyl. In particular, azetidinyl, piperidinyl, piperazinyl, morpholinyl, morpholino and azepanyl are preferable.

The non-aromatic heterocyclic ring moiety of “non-aromatic heterocyclyloxy”, “non-aromatic heterocyclyloxycarbonyl”, “non-aromatic heterocyclylcarbonyl”, “non-aromatic heterocyclylsulfinyl”, “non-aromatic heterocyclylsulfonyl” and “non-aromatic heterocyclylthio” has the same meaning as defined above for “non-aromatic heterocyclic group”.

Preferred examples of “non-aromatic heterocyclyloxy” for R⁴include piperidinyloxy.

The substituted or unsubstituted non-aromatic carbocyclic groups and the substituted or unsubstituted non-aromatic heterocyclic groups are optionally substituted with one or two oxo, thioxo or substituted or unsubstituted imino.

Examples of the substituent group for “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted non-aromatic carbocyclic group”, “substituted aromatic carbocyclic group”, “substituted aromatic heterocyclic group” and “substituted non-aromatic heterocyclic group” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azido, formyl, amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, substituted carbamoyl, substituted sulfamoyl, substituted amidino, a group of formula: —O—R^x, a group of formula: —O—C(═O)—R^x, a group of formula: —C(═O)—R^x, a group of formula: —C(═O)—O—R^x, a group of formula: —S—R^xor a group of formula: —SO₂—R^xwherein R^xis alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, carbamoyl, sulfamoyl or amidino. One or more of these substituent groups may occur at any substitutable position.

Specific examples of the substituent group for “substituted alkyl” in R²include hydroxy, amino and alkylamino.

Specific examples of the substituent group for “substituted alkyl” in R³include hydroxy, carboxy, aromatic carbocyclic group, alkylcarbonylamino, alkyloxy, alkyloxycarbonyl, alkylaminocarbonyl.

Specific examples of the substituent group for “substituted alkyl” in R⁴include hydroxy, phenylalkyloxy and phenylcarbonyloxy.

Specific examples of the substituent group for “substituted alkyl” in R⁵include halogen, hydroxy, cyano, alkyloxy, non-aromatic carbocyclic group, aromatic carbocyclic group, halo aromatic carbocyclic group, alkyl aromatic carbocyclic group, trihaloalkyl aromatic carbocyclic group, trihaloalkyloxy aromatic carbocyclic group, carboxy aromatic carbocyclic group, alkyloxycarbonyl aromatic carbocyclic group, alkyloxycarbonylalkyl aromatic carbocyclic group, alkylaminoalkyloxy aromatic carbocyclic group, aromatic heterocyclyl-aromatic carbocyclic group, aromatic heterocyclyloxy-aromatic carbocyclic group, alkylsulfonyl aromatic carbocyclic group, aromatic carbocyclyloxy-aromatic carbocyclic group, non-aromatic heterocyclylalkyloxy aromatic carbocyclic group, aromatic carbocyclyloxy-aromatic carbocyclic group, aromatic carbocyclyloxyalkyl aromatic carbocyclic groups, aromatic carbocyclyl-aromatic carbocyclic group, dihaloalkylsulfonyl, aromatic heterocyclic group, alkylcarbonyl, alkyloxycarbonyl, non-aromatic carbocyclylcarbamoyl, alkylaminocarbonyl, alkylcarbonyloxy, alkylamino, carboxyalkyloxy and alkylsulfonyloxy.

Specific examples of the substituent group for “substituted alkyloxy” in R⁴include alkyloxy, aromatic carbocyclic group, alkylcarbonyl-aromatic carbocyclic group, non-aromatic carbocyclic group, halo non-aromatic carbocyclic group and alkyloxycarbonyl-non-aromatic heterocyclic group.

Specific examples of the substituent group for “substituted alkenyl” in R⁴include aromatic carbocyclic group.

Specific examples of the substituent group for “substituted alkenyl” in R⁵include halogen.

Specific examples of the substituent group for “substituted alkynyl” in R³include hydroxy.

Specific examples of the substituent group for “substituted alkynyl” in R⁴include alkyloxy.

Specific examples of the substituent group for “substituted aromatic carbocyclic group” in R¹include halogen, cyano, carboxy, trihaloalkyl, non-aromatic carbocyclic group, alkyloxy, dihaloalkyloxy, aromatic carbocyclyloxy, alkylamino, alkyloxycarbonyl and non-aromatic heterocyclic group.

Specific examples of the substituent group for “substituted aromatic carbocyclic group” in R⁴include cyano, halogen, hydroxy, carboxy, sulfo, amino, alkyl, hydroxyalkyl, alkyloxyalkyl, alkyloxy, hydroxyalkyloxy, halo aromatic carbocyclic group, alkyl non-aromatic heterocyclic group, alkylcarbonylaminoalkyl non-aromatic heterocyclic group, alkylthio, alkylcarbonyl, alkyloxycarbonyl, non-aromatic heterocyclylcarbonyl, alkyloxy non-aromatic heterocyclylcarbonyl, alkylcarbonyl non-aromatic heterocyclylcarbonyl, hydroxy non-aromatic heterocyclylcarbonyl, alkylsulfonyl non-aromatic heterocyclylcarbonyl, haloalkylaminocarbonyl, hydroxyalkylaminocarbonyl, alkylaminocarbonyl, aminoalkylaminocarbonyl, hydroxyalkylaminocarbonyl, aminosulfonylalkylaminocarbonyl, alkylsulfonylalkylaminocarbonyl, carbamoyl, alkylcarbamoyl, haloalkylcarbamoyl, cyanoalkylcarbamoyl, hydroxyalkylcarbamoyl, non-aromatic heterocyclylalkylcarbamoyl, alkyl non-aromatic heterocyclylalkylcarbamoyl, alkylcarbamoyl, non-aromatic carboncyclylalkylcarbamoyl, aminoalkylcarbamoyl, hydroxyalkylcycloalkylcarbamoyl, non-aromatic heterocyclylaminoalkylcarbamoyl, alkyloxyalkylcarbamoyl, alkylaminoalkylcarbamoyl, hydroxyalkylcarbamoyl, hydroxyalkyloxyalkylcarbamoyl, hydroxyalkyl(alkyl)carbamoyl, dihydroxyalkylcarbamoyl, alkylcarbonylalkylcarbamoyl, non-aromatic heterocyclylcarbonylalkylcarbamoyl, alkylcarbonylaminoalkylcarbamoyl, alkylsulfonylalkylcarbamoyl, sulfamoyl aromatic carbocyclylalkyl, alkylsulfonyl aromatic heterocyclylalkyl, aromatic heterocyclyl-aromatic heterocyclylalkyl, non-aromatic heterocyclylsulfonylalkylcarbamoyl, sulfamoyl alkylcarbamoyl, nitro aromatic carbocyclylalkyl, non-aromatic carbocyclylcarbamoyl, alkyloxy aromatic carbocyclylcarbamoyl, aromatic heterocyclylalkylcarbamoyl, alkyl non-aromatic carbocyclyl-carbamoyl, hydroxyalkyl non-aromatic carbocyclylcarbamoyl, non-aromatic heterocyclylcarbamoyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, hydroxyalkylaminosulfonyl, non-aromatic heterocyclylsulfonyl, alkylamino, alkylcarbonylamino, non-aromatic heterocyclylcarbonylamino and alkylsulfonylamino.

Specific examples of the substituent group for “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” and “substituted imino” include hydroxy, cyano, formyl, alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic groups, non-aromatic heterocyclic group, carbamoyl, sulfamoyl, amidino, a group of formula: —O—R, a group of formula: —C(═O)—R, a group of formula: —C(═O)—O—R and a group of formula: —SO₂—R wherein R is alkyl, haloalkyl, alkenyl, alkynyl, non-aromatic carbocyclic group, aromatic carbocyclic group, aromatic heterocyclic group or non-aromatic heterocyclic group. One or two of these substituent groups may occur at any substitutable position.

Specific examples of the substituent group for “substituted amino” in R⁴include alkyl, hydroxyalkyl, alkyloxyalkyl, carboxyalkyl, alkylaminoalkyl, aromatic carbocyclylalkyl, alkyloxy aromatic carbocyclylalkyl, alkyloxycarbonylalkyl, carboxy aromatic carbocyclylalkyl, alkylamino aromatic carbocyclylalkyl, methylenedioxy aromatic carbocyclylalkyl, aromatic heterocyclylalkyl, alkyl aromatic heterocyclylalkyl, non-aromatic heterocyclylalkyl, alkyl non-aromatic heterocyclylamino, alkylcarbonylaminoalkyl, non-aromatic carbocyclic groups and alkylaminosulfonyl.

Preferred embodiments of the invention are described below.

Preferred embodiments of the substituent groups for R¹to R⁵in formula (I) are described below. Compounds having possible combination of the substituent groups in the following (Ia) to (Io) are preferable.

R¹is, preferably, (Ia) substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group; more preferably, (Ib) substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group; particularly, (Ic) non-aromatic carbocyclic groups optionally substituted with one or more substituents selected from Substituent Group B consisting of halogen, cyano, alkyl substituted with halogen, alkyl substituted with 1-6 halogens and alkyloxy substituted with 1-6 halogens, aromatic carbocyclic groups optionally substituted with one or more substituents selected from Substituent Group B, non-aromatic heterocyclic groups optionally substituted with one or more substituents selected from Substituent Group B, or aromatic heterocyclic groups optionally substituted with one or more substituents selected from Substituent Group B.

R²is, preferably, (Id) hydrogen, halogen, hydroxy, formyl, carboxy, cyano or substituted or unsubstituted alkyl; more preferably, (Id) halogen or substituted or unsubstituted alkyl; particularly, (Ie) hydrogen.

R³is, preferably, (If) hydrogen, halogen, cyano, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted amino; more preferably, (Ig) hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; particularly, (Ih) hydrogen.

R⁴is, preferably, (Ii) substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted amino; more preferably, (Ik) substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group; particularly, (Il) substituted or unsubstituted aromatic carbocyclic group or substituted or unsubstituted aromatic heterocyclic group.

R⁵is, preferably, (Im) C1-C3 alkyl or C4-C8 alkyl substituted with one or more substituents selected from Substituent Group A consisting of halogen, cyano, hydroxy, formyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, substituted or unsubstituted aromatic heterocyclylsulfonyl, and substituted or unsubstituted amino; more preferably (In) C1-C8 alkyl optionally substituted with one or more substituents selected from Substituent Group C consisting of halogen, cyano, substituted or unsubstituted alkylcarbonyl and substituted or unsubstituted alkyloxycarbonyl; particularly (Io) C4-C8 alkyl optionally substituted with one or more substituents selected from Substituent Group C.

The compounds of formula (I) are not limited to specific isomers and include all possible isomers (e.g., keto-enol isomers, imine-enamine isomers, diastereoisomers, enantiomers, rotamers or the like), racemates or mixtures thereof.

One or more hydrogen, carbon and/or other atoms in the compounds of formula (I) may be replaced with isotopes of hydrogen, carbon and/or other atoms respectively. Examples of the isotopes include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I and ³⁶Cl respectively. The compounds of formula (I) include compounds replaced with these isotopes. The compounds replaced with the above isotopes are useful as pharmaceuticals and include all of radiolabeled compounds of the compound of formula (I). The present invention also includes a method of radiolabeling in the manufacture of the radiolabeled compounds. Such radiolabeled compounds are useful in the studies for metabolized drug pharmacokinetics and binding assay and also as a diagnostic tool.

A radiolabeled compound of the compounds of formula (I) can be prepared using methods well-known in the art. For example, a tritium-labeled compound of formula (I) can be prepared by introducing a tritium into a compound of formula (I), through a catalytic dehalogenation using a tritium. This method comprises reacting with an appropriately-halogenated precursor of the compound of formula (I) with tritium gas in the presence of an appropriate catalyst, such as Pd/C, and in the presence or absent of a base. The other appropriate methods for preparing a tritium-labeled compound can be found in “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. A ¹⁴C-labeled compound can be prepared by using a raw material having ¹⁴C carbon.

Pharmaceutically acceptable salts of the compounds of formula (I) include, for example, salts with alkaline metals such as lithium, sodium, potassium and the like; alkaline earth metals such as calcium, barium and the like; magnesium; transition metals such as zinc, iron and the like; ammonium; organic bases such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline and the like; amino acids; inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid and the like; and organic acids such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethane sulfonic acid and the like, particularly salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid and methanesulfonic acid. These salts can be formed according to conventional methods.

The compounds of formula (I) of the invention or salts thereof may exist in a form of solvate (e.g., hydrates or the like) and/or crystal polymorphs. The present invention encompasses those various solvates and crystal polymorphs. The “solvates” may be those wherein any numbers of solvent molecules (e.g., water molecules or the like) are coordinated with the compounds of formula (I). When the compounds of formula (I) or pharmaceutically acceptable salts thereof are allowed to stand in the atmosphere, the compounds may absorb water, resulting in attachment of adsorbed water or formation of hydrates. Recrystallization of the compounds of formula (I) or pharmaceutically acceptable salts thereof may produce crystal polymorphs.

The compounds of formula (I) of the invention may form prodrugs. Such prodrugs are encompassed by the present invention. Prodrugs are derivatives of the compounds of the invention with a chemically or metabolically degradable group(s), and the compounds are converted to a pharmaceutically active compound of the invention through solvolysis or under physiological conditions in vivo. The prodrugs include compounds that are converted to a compound of the invention through enzymatic oxidation, reduction, hydrolysis or the like under physiological conditions in vivo, compounds that are converted to a compound of the invention through hydrolysis by gastric acid, and the like. Methods for selecting and preparing suitable prodrug derivatives are described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. The prodrugs themselves may have some activity.

in case where the compound or a pharmaceutically acceptable salt thereof of the invention has hydroxyl group(s), the prodrugs may be acyloxy derivatives and sulfonyloxy derivatives that are prepared by, for example, reacting a compound having hydroxyl group(s) with suitable acyl halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonyl anhydride or mixed anhydride, or by reacting with a condensing agent. Examples include CH₃COO—, C₂H₅COO—, tert-BuCOO—, C₁₅H₃₁COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH₂CH₂COO—, CH₃CH(NH₂)COO—, CH₂N(CH₃)₂COO—, CH₃SO₃—, CH₃CH₂SO₃—, CF₃SO₃—, CH₂FSO₃—, CF₃CH₂SO₃—, p-CH₃O-PhSO₃—, PhSO₃— and p-CH₃PhSO₃—.

The term “chronic kidney disease” means a condition where either or both of

kidney disorder (urine abnormalities such as proteinuria, e.g., microalbuminuria, abnormal urinary sediment, abnormal finding of clinical imaging such as single kidney and polycystic kidney disease, decreased renal function such as increased serum creatinine, electrolyte abnormalities such as hypokalemia due to tubular damage, and abnormal finding of renal tissue biopsy) and

(2) deterioration in renal function less than 60 mL/min/1.73 m²of GFR (glomerular filtration rate)

is present for over three months.

The compounds of the invention are produced according to general procedures as described below. Also, the compounds of the invention can be prepared according to other methods based on the knowledge in Organic Chemistry.

Preparation of Compound a4

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Step 1

The compound a2 is reacted in a solution of Compound a1 in the presence or absence of a base to obtain Compound a3.

Examples of Compound a2 include halides and alkyloxysulfonyl compounds, and Compound a2 may be used in 1 to 10 equivalents, preferably 1 to 3 equivalents.

Examples of the base include sodium hydride, and the base may be used in 1 to 5 equivalents of Compound a1.

Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

The reaction temperature may be room temperature to 200° C., preferably from room temperature to reflux temperature.

The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

Step 2

The compound a4 can be obtained by reacting the solution of Compound a3 with an alkylating agent in the presence of a base.

Examples of the alkylating agent include haloalkyl and alkyltriflate, and the alkylating agent may be used in 1 to 5 equivalents of Compound a3.

Examples of the base include cesium carbonate, potassium carbonate, sodium hydride and tetrabutylammonium fluoride, and the base may be used in 1 to 10 equivalents, preferably 3 to 5 equivalents of Compound a3.

Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran.

The reaction temperature may be room temperature to 200° C., preferably room temperature to reflux temperature.

The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

Preparation of Compound a2

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Step 1

The compound a6 can be obtained by reacting a solution of Compound a5 with an alkyl metal in the presence or absence of silane compound.

Examples of the alkyl metal include methyl lithium, and the alkyl metal may be used in 1 to 10 equivalents, preferably 3 to 5 equivalents of Compound a5.

Examples of the silane compound include trimethylsilyl chloride and trimethylsilyl bromide, and the silane compound may be used in 1 to 30 equivalents, preferably 5 to 15 equivalents of Compound a5.

Examples of the solvent include tetrahydrofuran, diethyl ether and dimethoxyethane.

The reaction temperature may be −20° C. to 50° C., preferably a temperature under ice-cooling to room temperature.

The reaction time may be 0.1 to 24 hours, preferably 1 to 5 hours.

Step 2

The compound a2 can be obtained by reacting the solution of Compound a6 with a brominating agent.

Examples of the brominating agent include bromine, tetrabutylammonium tribromide, pyridinium tribromide, N-bromosuccinimide, and the brominating agent may be used in 1 to 10 equivalents, preferably in 1 to 5 equivalents of Compound a6.

Examples of the solvent include methanol, acetonitrile, chloroform, methylene chloride, acetic acid and tetrahydrofuran.

The reaction temperature may be −20° C. to 50° C., preferably 0° C. to room temperature.

The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

Preparation of Compound a9

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Step 1

The compound 8 can be obtained by reacting a solution of Compound a7 with a formylating agent.

Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and 1,2-dichloroethane.

Examples of the formylating agent include (Chloromethylene)dimethyliminium chloride, or N,N-dimethylformamide or N-methyl-N-phenylformamide in combination with phosphorous oxychloride, and the formylating agent may be used in 1 to 5 equivalents, preferably, 1 to 3 equivalents of Compound a7.

The reaction temperature may be −20° C. to 50° C., preferably 0° C. to room temperature.

The reaction time may be 0.1 to 10 hours, preferably 1 to 5 hours.

Step 2

The compound a9 can be obtained by reacting Compounds a8 with a reducing agent.

Examples of the reducing agent include sodium borohydride, lithium borohydride, and lithium aluminum hydride, and the reducing agent may be used in 0.05 to 10 molar equivalents, preferably 0.1 to 3 equivalents of Compound a8.

Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, tetrahydrofuran, diethyl ether, dichloromethane and water, and the solvent may be used alone or in combination.

The reaction temperature may be 0° C. to reflux temperature, preferably 20° C. to room temperature.

The reaction time may be 0.2 to 24 hours, preferably 0.5 to 2 hours.

Preparation of Compound a12

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Step 1

A solution of compound a10 is reacted with an amine (R^4aNH₂wherein R^4ais as defined above) in the presence of a base to obtain Compound a11.

Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, ethanol and acetonitrile.

Examples of the base include 1,8-diazabicyclo[5,4,0]-7-undecene, sodium hydrogen carbonate, and the like, and the base may be used in 1 to 5 equivalents, preferably 1 to 3 equivalents, of Compound a10.

The amine (R^4aNH₂) may be used in 1 to 5 equivalents, preferably 1 to 3 equivalents, of Compound a10.

The reaction temperature may be 0° C. to reflux temperature, preferably room temperature to 100° C.

The reaction time may be 0.1 to 48 hours, preferably 1 to 24 hours.

Step 2

The solution of compound a11 is reacted with an alkylating agent (R³—Y wherein Y is a leaving group such as halogen and R³is as defined above) in the presence of a base to obtain Compound a12.

Examples of the solvent include N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone and tetrahydrofuran, and the like.

Examples of the base include potassium carbonate, cesium carbonate, and sodium hydride, etc., and the base may be used in 1 to 5 equivalents, preferably 1 to 3 equivalents, of Compound a11.

Examples of the alkylating agent (R³—Y) include alkyl iodides alkyl bromides and the like, and the alkylating agent may be used in 1 to 5 equivalents, preferably 1 to 3 equivalents, of Compound a11.

The reaction temperature may be 0° C. to reflux temperature, preferably room temperature to 100° C.

The reaction time may be 0.1 to 48 hours, preferably 1 to 24 hours.

Preparation of Compound a16

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Wherein

Ring A is substituted or unsubstituted non-aromatic carbocyclic ring, substituted or unsubstituted aromatic carbocyclic ring, substituted or unsubstituted non-aromatic heterocyclic ring, substituted or unsubstituted aromatic heterocyclic ring;

R¹represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group;

R²and R³are each independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylnylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl or substituted or unsubstituted aromatic heterocyclylsulfonyl;

R^4band R^4Care independently hydrogen, halogen, hydroxy, cyano, formyl, carboxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted amino, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclyloxy, substituted or unsubstituted aromatic carbocyclyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aromatic heterocyclyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted non-aromatic carbocyclylthio, substituted or unsubstituted aromatic carbocyclylthio, substituted or unsubstituted non-aromatic heterocyclylthio, substituted or unsubstituted aromatic heterocyclylthio, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylnylsulfinyl, substituted or unsubstituted non-aromatic carbocyclylsulfinyl, substituted or unsubstituted aromatic carbocyclylsulfinyl, substituted or unsubstituted non-aromatic heterocyclylsulfinyl, substituted or unsubstituted aromatic heterocyclylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted alkynylsulfonyl, substituted or unsubstituted non-aromatic carbocyclylsulfonyl, substituted or unsubstituted aromatic carbocyclylsulfonyl, substituted or unsubstituted non-aromatic heterocyclylsulfonyl, or substituted or unsubstituted aromatic heterocyclylsulfonyl;

R⁵is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group or substituted or unsubstituted aromatic heterocyclic group; q is an integer of 1 to 5.

Step 1

A solution of compound a13 is reacted with an amine in the presence of a base, a condensing agent and additives to obtain Compound a14.

The amine may be used in 1 to 5 equivalents, preferably 1 to 3 equivalents, of Compound a13.

Examples of the solvent include methylene chloride, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, tetrahydrofuran, and the like.

Examples of the bases include triethylamine, diisopropylethylamine and the like, and the base may be used in 1 to 10 equivalents, preferably 1 to 5 equivalents, of Compound a13.

Examples of the additive include 1-hydroxybenzotriazole and the like, and the additive may be used in 0.1 to 2 equivalents, preferably 0.2 to 0.5 equivalents, of Compound a13.

Examples of the condensing agent include 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate and the like, and the condensing agent may be used in 1 to 5 equivalents, preferably 1 to 3 equivalents, of Compound a13. The reaction temperature may be 0° C. to reflux temperature, preferably room temperature.

The reaction time may be 0.1 to 48 hours, preferably 1 to 24 hours.

Step 2

The solution of Compound a14 is reacted with a deprotecting agent to obtain Compound a15.

Examples of the solvent include methylene chloride, tetrahydrofuran and the like.

Examples of the deprotecting agent include boron tribromide, boron trichloride, trimethylsilane iodide, palladium on carbon and the like, and the deprotecting agent may be used in 0.005 to 10 equivalents, preferably 0.01 to 5 equivalents, of Compound a13.

The reaction temperature may be −78° C. to room temperature, preferably −78° C. to 0° C.

The reaction time may be 0.1 to 48 hours, preferably 1 to 24 hours.

Step 3

The solution of Compound a15 is reacted with an alkylating agent in the presence of a base to obtain Compound a16.

The alkylating agent may be used in 1 to 20 equivalents, preferably 1 to 10 equivalents, of Compound a15.

Examples of the solvents include 2-propanol and the like.

Examples of the base include sodium carbonate and the like, and the base may be used in 1 to 30 equivalents, preferably 1 to 10 equivalents, of Compound a15.

The reaction temperature may be 0° C. to reflux temperature.

The reaction time may be 0.1 to 48 hours, preferably 1 to 12 hours.

Preparation of Compound a17

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A solution of Compound a10 is reacted with a boronic acid or boronic acid ester in the presence of a base and a metal catalyst to obtain Compound a17.

Examples of the boronic acid include aromatic carbocyclic boronic acids, non-aromatic carbocyclic boronic acids, aromatic heterocyclic boronic acids, non-aromatic heterocyclic boronic acids and boronic acid esters thereof, and the boronic acid may be used in 1-10 equivalents, preferably 1 to 3 equivalents.

Examples of the metal catalyst include [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex, palladium acetate and the like, and the catalyst may be used in 0.01 to 0.5 equivalents, preferably 0.05 to 0.2 equivalents, of Compound a10.

Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate and the like, and the base may be used in 1 to 10 equivalents, preferably 3 to 5 equivalents, of Compound a10.

Examples of the solvent include N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, and the like.

The reaction temperature may be room temperature to reflux temperature, preferably room temperature to 100° C.

The reaction time may be 0.1 to 24 hours, preferably 1 to 12 hours.

The compound of the invention thus obtained may be purified and crystallized in a variety of solvents. Examples of the solvent to be used include alcohols (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ethers (diethyl ether, diisopropyl ether, etc.), methyl acetate, ethyl acetate, chloroform, methylene chloride, tetrahydrofuran, N,N-dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water, or a mixture thereof. The compound may be dissolved in the solvent under heating, and the impurities are removed. The solution is then gradually cooled and filtered to collect the precipitated solid or crystal.

The compound of the present invention has autotaxin inhibitory activity. Accordingly, the pharmaceutical composition containing the compound of the present invention is useful as a therapeutic and/or prophylactic agent for diseases involving autotaxin. The diseases involving autotaxin include, for example, chronic kidney disease, urinary excretion failure, renal fibrosis, interstitial pneumonitis or pulmonary fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis, angiogenesis, cancer, formation, growth and propagation of tumor, arteriosclerosis, ocular diseases, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, restenosis, wound healing, transplant rejection and the like. The pharmaceutical composition containing the compound of the invention is useful as a therapeutic agent and/or preventive agent for these diseases.

The compounds of the invention may have a utility as a pharmaceutical, as well as autotaxin inhibitory effect, characterized by any of or all of the features as follows:

a) weak inhibitory effect on CYP enzymes (e.g., CYP1A2, CYP2C9, CYP3A4, etc.);

b) good pharmacokinetics, such as high bioavailability and appropriate clearance;

c) low toxicity (e.g., anemia-induced action);

d) high metabolic stability;

e) high water solubility;

f) high brain migration;

g) free of gastrointestinal disorders (e.g., hemorrhagic enteritis, gastrointestinal ulcers, gastrointestinal bleeding, etc.).

Also, the compound of the invention has low affinity for ENPP1, ENPP3 to 7 receptors and high selectivity for ENPP2 receptor.

The pharmaceutical composition of the invention may be administered orally or parenterally. The pharmaceutical composition may be administered orally in a formulation as conventionally used including tablets, granules, powders, capsules, pills, solutions, syrups, buccal or sublingual.

The pharmaceutical composition may be administered parenterally in a formulation as conventionally used including injections such as intramuscular or intravenous injection, suppositories, transdermal absorbents, inhalants, etc.

The pharmaceutical composition may be prepared by mixing an effective amount of the compound of the invention with various pharmaceutical additives suitable for the formulation, such as excipients, binders, moistening agents, disintegrants, lubricants, diluents and the like. For injections, an active ingredient together with a suitable carrier may be sterilized to obtain a pharmaceutical composition.

Examples of the excipients include lactose, saccharose, glucose, starch, calcium carbonate, crystalline cellulose and the like. Examples of the binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin, polyvinylpyrrolidone and the like. Examples of the disintegrants include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar, sodium lauryl sulfate and the like. Examples of the lubricants include talc, magnesium stearate, macrogol and the like. For base materials of suppositories, cacao oil, macrogol, methylcellulose and the like may be used. Solubilizing agents, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents and the like, which are commonly used, may be added when the composition is prepared as solutions, emulsified or suspended injections. Sweetening agents, flavors and the like, which are commonly used, may be added for oral formulation.

The dosage of the pharmaceutical composition of the invention is determined in the light of the age and weight of the patient, the type and severity of the disease to be treated, and the route for administration and the like. In the case of oral administration to adults, the dosage is usually in the range of 0.05 to 100 mg/kg/day, preferably 0.1 to 10 mg/kg/day. In the case of parenteral administration, the dosage is variable depending on the administration route, but is usually 0.005 to 10 mg/kg/day, preferably in the range of 0.01 to 1 mg/kg/day. The dosage may be administered in single or divided doses.

The present invention is further explained by the following Examples and Test Examples, which are not intended to limit the scope of the present invention.

The abbreviations as used herein represent the following meanings.

Me: methyl

Et: ethyl

Bu: butyl

Ph: phenyl

PPh3, TPP: triphenylphosphine

AcOEt: ethyl acetate

DMF: N,N-dimethylformamide

TFA: trifluoroacetic acid

DMSO: dimethyl sulfoxide

THF: tetrahydrofuran

DIEA, Hunig's Base: N,N-diisopropylethylamine

TBAF: tetrabutylammonium fluoride

SEM: 2-(trimethylsilyl)ethoxymethyl

OAc: acetic acid group

mCPBA: meta-chloroperbenzoic acid

NMP: 1-methylpyrrolidin-2-one

LAH: lithium aluminum hydride

DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene

DCM: methylene chloride

TEA: triethylamine

TMS: tetramethylsilane

NMR analysis of the compounds obtained in the Example was carried out at 400 MHz, using deuterated dimethyl sulfoxide (d6-DMSO) or deuterochloroform (CDCl₃).

LC/MS was measured under the following conditions.

[Method A]
Column: ACQUITY UPLC BEH C18 (1.7 μm i.d. 2.1×50 mm) (Waters)

Flow rate: 0.8 mL/min

UV detection wavelength: 254 nm

Mobile Phase:

[A]0.1% formic acid in water

[B]0.1% formic acid in acetonitrile

Gradient: linear gradient from 10% to 100% [B] over 3.5 minutes, and then 100% [B] was maintained for 0.5 minutes.

[Method B]
Column: Shim-pack XR-ODS (2.2 μm, i.d. 50×3.0 mm) (Shimadzu)

Flow rate: 1.6 mL/min

UV detection wavelength: 254 nm

Mobile Phase:

[A]0.1% formic acid in water

[B]0.1% formic acid in acetonitrile

Gradient: linear gradient from 10% to 100% [B] over 3 minutes, and then 100% [B] was maintained for 1 minute.

Example 1
Synthesis of 2-(4-chlorophenyl)-7-methyl-8-pentyl-imidazo[1,2-a]pyrimidin-5(8H)-one (3)

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Step 1:

To a solution of 2-amino-4-hydroxy-6-methylpyrimidine (1, 250 mg, 2.00 mmol) in N,N-dimethylformamide (10 mL) was added 2-bromo-1-(4-chlorophenyl)ethanone (467 mg, 2.00 mmol), and the solution was heated to reflux for 4 hours under argon atmosphere. The reaction was cooled to room temperature, and the precipitate was collected by filtration to yield 2-(4-chlorophenyl)-7-methyl-imidazo[1,2-a]pyrimidin-5(8H)-one (2, 301 mg, yield: 58%) as a pale yellow solid.

1H-NMR (δ ppm TMS/DMSO-d6) 8.13 (s, 1H), 7.94 (d, 2H, J=8.1 Hz), 7.48 (d, 2H, J=8.1 Hz), 5.65 (s, 1H), 2.30 (s, 3H).

Step 2:

To a solution of the compound (2, 130 mg, 0.500 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (652 mg, 2.00 mmol) and 1-bromopentane (151 mg, 1.00 mmol), and the solution was stirred at room temperature for 24 hours. The reaction mixture was concentrated. The residue was dissolved in methylene chloride, and washed with water and brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (methylene chloride) to yield 2-(4-chlorophenyl)-7-methyl-8-pentylimidazo[1,2-a]pyrimidin-5(8H)-one (3, 132 mg, yield: 80%) as a colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6) 8.17 (s, 1H), 7.97 (d, 2H, J=8.1 Hz), 7.48 (d, 2H, J=8.1 Hz), 5.77 (s, 1H), 4.25 (t, 2H, J=7.1 Hz), 2.46 (s, 3H), 1.85-1.72 (m, 2H), 1.42-1.33 (m, 4H), 0.90 (t, 3H, J=6.6 Hz).

Compounds (4) to (19) were prepared in a similar manner.

TABLE 1

Compound
Structure
1H-NMR

4

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(δ ppm TMS/DMSO-d6) 8.19 (s, 1H), 7.98 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 5.78 (s, 1H), 3.81 (s, 3H), 2.44 (s, 3H).

5

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(δ ppm TMS/DMSO-d6) 8.22 (s, 1H), 7.98 (d, 2H, J = 8.7 Hz), 7.47 (d, 2H, J = 8.7 Hz), 5.77 (s, 1H), 4.33 (q, 2H, J = 7.2 Hz), 2.47 (s, 3H), 1.37 (t, 3H, J = 7.2 Hz).

6

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(δ ppm TMS/DMSO-d6) 8.17 (s, 1H), 7.97 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 5.77 (s, 1H), 4.23 (t, 2H, J = 7.2 Hz), 2.47 (s, 3H), 1.89-1.75 (m, 2H), 0.97 (t, 3H, J = 7.2 Hz).

7

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(δ ppm TMS/DMSO-d6) 8.18 (s, 1H), 7.98 (d, 2H, J = 8.1 Hz), 7.48 (d, 2H, J = 8.1 Hz), 5.78 (s, 1H), 4.28 (t, 2H, J = 7.3 Hz), 2.47 (s, 3H), 1.83-1.70 (m, 2H), 1.48-1.34 (m, 2H), 0.96 (t, 3H, J = 7.3 Hz).

8

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(δ ppm TMS/DMSO-d6) 8.14 (s, 1H), 7.94 (d, 2H, J = 8.1 Hz), 7.45 (d, 2H, J = 8.1 Hz), 5.75 (s, 1H), 4.24 (t, 2H, J = 7.3 Hz), 2.44 (s, 3H), 1.83-1.68 (m, 2H), 1.42-1.23 (m, 6H), 0.85 (t, 3H, J = 6.6 Hz).

TABLE 2

Compound
Structure
1H-NMR

9

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(δ ppm TMS/DMSO-d6) 8.17 (s, 1H), 7.97 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 5.77 (s, 1H), 4.25 (t, 2H, J = 7.2 Hz), 2.46 (s, 3H), 1.85-1.70 (m, 2H), 1.44-1.19 (m, 8H), 0.86 (t, 3H, J = 5.4 Hz).

10

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(δ ppm TMS/DMSO-d6) 8.15 (s, 1H), 7.95 (d, 2H, J = 8.8 Hz), 7.44 (d, 2H, J = 8.8 Hz), 5.75 (s, 1H), 4.24 (t, 2H, J = 8.0 Hz), 2.44 (s, 3H), 1.83-1.68 (m, 2H), 1.44-1.25 (m, 10H), 0.83 (t, 3H, J = 6.6 Hz).

11

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8.13 (s, 1H), 7.94 (d, 2H, J = 8.1 Hz), 7.43 (d, 2H, J = 8.1 Hz), 5.74 (s, 1H), 4.22 (t, 2H, J = 8.0 Hz), 2.43 (s, 3H), 1.83-1.65 (m, 2H), 1.40-1.12 (m, 12H), 0.81 (t, 3H, J = 7.3 Hz).

12

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(δ ppm TMS/DMSO-d6) 8.15 (s, 1H), 7.95 (d, 2H, J = 8.0 Hz), 7.45 (d, 2H, J = 8.0 Hz), 5.75 (s, 1H), 4.25 (t, 2H, J = 7.3 Hz), 2.44 (s, 3H), 1.85-1.67 (m, 2H), 1.42-1.12 (m, 14H), 0.82 (m, 3H).

13

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(δ ppm TMS/DMSO-d6) 8.24 (s, 1H), 7.95 (d, 2H, J = 8.1 Hz), 7.45 (d, 2H, J = 8.1 Hz), 7.40-7.22 (m, 5H), 5.85 (s, 1H), 5.62 (s, 2H), 2.35 (s, 3H).

TABLE 3

Compound
Structure
1H-NMR

14

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(δ ppm TMS/DMSO-d6) 7.84 (s, 1H), 7.81 (d, 2H, J = 8.1 Hz), 7.38 (d, 2H, J = 8.1 Hz), 5.67 (s, 1H), 5.82 (s, 1H), 4.34- 4.05 (m, 1H), 3.28-3.00 (m, 2H), 2.45 (s, 3H), 2.07-1.90 (m, 2H), 1.88-1.68 (m, 3H), 1.53-1.27 (m, 3H).

15

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(δ ppm TMS/DMSO-d6) 8.20 (s, 1H), 7.96 (d, 2H, J = 8.8 Hz), 7.47 (d, 2H, J = 8.8 Hz), 6.14-5.98 (m, 1H), 5.81 (s, 1H), 5.27-5.06 (m, 2H), 4.97 (s, 2H), 2.42 (s, 3H).

16

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(δ ppm TMS/DMSO-d6) 8.22 (s, 1H), 7.99 (d, 2H, J = 8.8 Hz), 7.48 (d, 2H, J = 8.8 Hz), 5.86 (s, 1H), 5.20 (s, 2H), 3.53 (s, 1H), 2.55 (s, 3H).

17

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(δ ppm TMS/DMSO-d6) 8.11 (s, 1H), 8.03-7.95 (m, 2H), 7.29- 7.22 (m, 2H), 5.76 (s, 1H), 4.25 (t, 2H, J = 7.5 Hz), 2.46 (s, 3H), 1.85-1.72 (m, 2H), 1.43-1.32 (m, 4H), 0.90 (t, 3H, J = 6.6 Hz).

18

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(δ ppm TMS/DMSO-d6) 8.18 (s, 1H), 7.91 (d, 2H, J = 8.1 Hz), 7.61 (d, 2H, J = 8.1 Hz), 5.78 (s, 1H), 4.27 (t, 2H, J = 7.2 Hz), 2.47 (s, 3H), 1.85-1.74 (m, 2H), 1.41-1.33 (m, 4H), 0.90 (t, 3H, J = 6.6 Hz).

TABLE 4

Compound
Structure
1H-NMR

19

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(δ ppm TMS/DMSO-d6) 8.10 (s, 1H), 7.84 (d, 2H, J = 8.1 Hz), 7.23 (d, 2H, J = 8.1 Hz), 5.76 (s, 1H), 4.30-4.19 (m, 2H), 2.46 (s, 3H), 2.33 (s, 3H), 1.92-1.73 (m, 2H), 1.43-1.29 (m, 4H), 0.90 (t, 3H, J = 6.6 Hz).

Example 2
2-(4-chlorophenyl)-7-methyl-5-oxoimidazo[1,2-a]pyrimidin-8(5H)-yl)acetic acid ethyl ester (20)

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Step 1:

To a solution of the compound (2, 130 mg, 0.500 mmol) in N,N-dimethylformamide (5 mL) was added cesium carbonate (652 mg, 2.00 mmol) and bromoacetic acid ethyl ester (167 mg, 1.00 mmol), and the solution was stirred for 12 hours at room temperature. The reaction mixture was concentrated. The residue was dissolved in methylene chloride, and washed with water and brine. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (methylene chloride) to yield 2-(4-chlorophenyl)-7-methyl-5-oxoimidazo[1,2-a]pyrimidin-8(5H)-yl)acetic acid ethyl ester (20, 143 mg, yield: 83%) as a colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6) 8.23 (s, 1H), 7.94 (d, 2H, J=8.8 Hz), 7.47 (d, 2H, J=8.8 Hz), 5.87 (s, 1H), 5.19 (s, 2H), 4.22 (q, 2H, J=7.3 Hz), 2.39 (s, 3H), 1.23 (t, 3H, J=7.3 Hz).

Compounds (21) to (124) were prepared in a similar manner.

TABLE 5

Compound
Structure
1H-NMR

21

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(δppm TMS/DMSO-d6) 8.22 (s, 1H), 7.94 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 5.87 (s, 1H), 5.25 (s, 2H), 3.75 (s, 3H), 2.39 (s, 3H).

22

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(δppm TMS/DMSO-d6) 8.21 (s, 1H), 7.92 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.42-7.32 (m, 5H), 5.86 (s, 1H), 5.26 (m, 4H), 2.39 (s, 3H).

23

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(δppm TMS/DMSO-d6) 8.21 (s, 1H), 7.94 (d, 2H, J = 8.8 Hz), 7.47 (d, 2H, J = 8.8 Hz), 5.85 (s, 1H), 2.37 (s, 3H), 1.44 (s, 9H).

24

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(δppm TMS/DMSO-d6) 8.37 (m, 1H), 8.19 (s, 1H), 7.95 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 5.82 (s, 1H), 4.96 (s, 2H), 3.19-3.08 (m, 2H), 2.34 (s, 3H), 1.05 (t, 3H, J = 6.6 Hz).

25

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(δppm TMS/DMSO-d6) 8.19 (d, 1H, J = 1.4 Hz), 7.97-7.89 (m, 2H), 7.47 (d, 2H, J = 8.1 Hz), 5.82 (s, 1H), 5.27 (d, 2H, J = 9.5 Hz), 3.56-3.44 (q, 1H, J = 6.6 Hz), 3.14 (s, 1.5 H), 2.32 (d, 3H, J = 4.4 Hz), 1.32 (t, 1.5H, J = 6.6 Hz), 1.04 (t, 1.5H, J = 6.6 Hz).

TABLE 6

Compound
Structure
1H-NMR

26

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(δppm TMS/DMSO-d6) 8.18 (s, 1H), 7.96 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 5.77 (s, 1H), 4.45 (t, 2H, J = 5.1 Hz), 3.80 (t, 2H, J = 5.1 Hz), 3.44 (q, 2H, J = 7.2 Hz), 1.04 (t, 3H, J = 6.6 Hz).

27

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(δppm TMS/CDCl3) 7.85 (s, 1H), 7.79 (d, 2H, J = 8.8 Hz), 7.37 (d, 2H, J = 8.8 Hz), 5.69 (s, 1H), 4.50 (t, 2H, J = 5.1 Hz), 4.45-4.10 (m, 4H), 3.97 (t, 2H, J = 5.1 Hz), 3.80-3.52 (m, 7H), 2.51 (s, 3H).

28

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(δppm TMS/DMSO-d6) 8.19 (s, 1H), 7.93 (d, 2H, J = 8.1 Hz), 7.46 (d, 2H, J = 8.1 Hz), 5.83 (s, 1H), 2.71 (q, 2H, J = 7.2 Hz), 2.28 (s, 3H), 1.04 (t, 3H, J = 7.2 Hz).

29

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(δppm TMS/DMSO-d6) 8.18 (s, 1H), 7.97 (d, 2H, J = 8.1 Hz), 7.48 (d, 2H, J = 8.1 Hz), 5.80 (s, 1H), 4.59-4.43 (m, 4H), 2.48 (s, 3H), 1.91 (s, 3H).

30

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(δppm TMS/DMSO-d6) 8.17 (s, 1H), 8.00-7.93 (m, 2H), 7.30- 7.19 (m, 2H), 5.86 (s, 1H), 5.19 (s, 2H), 4.22 (q, 2H, J = 6.6 Hz), 2.38 (s, 3H), 1.24 (t, 3H, J = 6.6 Hz).

TABLE 7

Compound
Structure
1H-NMR

31

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(δppm TMS/DMSO-d6) 8.24 (s, 1H), 7.88 (d, 2H, J = 8.7 Hz), 7.61 (d, 2H, J = 8.7 Hz), 5.87 (s, 1H), 5.19 (s, 2H), 4.22 (q, 2H, J = 7.2 Hz), 2.38 (s, 3H), 1.23 (t, 3H, J = 7.2 Hz).

32

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(δppm TMS/DMSO-d6) 8.03 (s, 1H), 7.84 (d, 2H, J = 8.8 Hz), 6.97 (d, 2H, J = 8.8 Hz), 5.84 (s, 1H), 5.18 (s, 2H), 4.22 (q, 2H, J = 6.6 Hz), 3.78 (s, 3H), 2.38 (s, 3H), 1.23 (t, 3H, J = 6.6 Hz).

33

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(δppm TMS/DMSO-d6) 8.28 (s, 1H), 8.11 (s, 1H), 7.93 (d, 1H, J = 8.1 Hz), 7.54-7.30 (m, 2H), 5.87 (s, 1H), 5.19 (s, 2H), 4.23 (q, 2H, J = 7.3 Hz), 2.39 (s, 3H), 1.24 (t, 3H, J = 7.3 Hz).

34

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(δppm TMS/DMSO-d6) 8.34 (s, 1H), 8.15 (s, 1H), 7.90 (d, 1H, J = 8.1 Hz), 7.66 (d, 1H, J = 8.1 Hz), 5.87 (s, 1H), 5.19 (s, 2H), 4.22 (q, 2H, J = 6.6 Hz), 2.38 (s, 3H), 1.24 (t, 3H, J = 6.6 Hz).

35

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(δppm TMS/DMSO-d6) 7.92 (d, 2H, J = 7.3 Hz), 7.46-7.37 (m, 2H), 7.35-7.27 (m, 1H), 5.86 (s, 1H), 5.19 (s, 2H), 4.22 (q, 2H, J = 6.6 Hz), 2.39 (s, 3H), 1.24 (t, 3H, J = 6.6 Hz).

TABLE 8

Compound
Structure
1H-NMR

36

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(δppm TMS/CDCl3) 8.25 (d, 2H, J = 8.8 Hz), 8.02-7.97 (m, 3H), 6.71 (d, 2H, J = 8.8 Hz), 5.76 (s, 1H), 5.07 (s, 2H), 4.31 (q, 2H, J = 7.3 Hz), 2.38 (s, 3H), 1.33 (t, 3H, J = 7.3 Hz).

37

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(δppm TMS/CDCl3) 8.74 (s, 1H), 8.17-8.07 (m, 2H), 7.97 (s, 1H), 7.61-7.52 (m, 1H), 5.80 (s, 1H), 5.11 (s, 2H), 4.32 (q, 2H, J = 7.3 Hz), 2.38 (s, 3H), 1.35 (t, 3H, J = 7.3 Hz) .

38

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(δppm TMS/CDCl3) 7.71 (s, 1H), 7.64 (d, 2H, J = 8.8 Hz), 6.71 (d, 2H, J = 8.8 Hz), 5.73 (s, 1H), 5.07 (s, 2H), 4.28 (q, 2H, J = 7.3 Hz), 3.75 (brs, 2H), 2.33 (s, 3H), 1.31 (t, 3H, J = 7.3 Hz).

39

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(δppm TMS/CDCl3) 7.82 (s, 1H), 7.24-7.16 (m, 3H), 6.67- 6.61 (m, 1H), 5.76 (s, 1H), 5.10 (s, 2H), 4.29 (q, 2H, J = 7.3 Hz), 3.73 (brs, 2H), 2.36 (s, 3H), 1.32 (t, 3H, J = 7.3 Hz).

40

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(δppm TMS/DMSO-d6) 8.22 (s, 1H), 7.80-7.70 (m, 4H), 7.35- 7.27 (m, 1H), 5.87 (s, 1H), 5.18 (s, 2H), 4.21 (qd, 2H, J = 7.3, 2.2 Hz), 2.38 (s, 3H), 1.23 (td, 3H, J = 7.3, 2.2 Hz).

TABLE 9

Compound
Structure
1H-NMR

41

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(δppm TMS/CDCl3) 7.79 (s, 1H), 7.71 (d, 2H, J = 7.8 Hz), 7.33 (d, 2H, J = 8.0 Hz), 5.72 (s, 1H), 5.10 (s, 2H), 2.60 (t, 2H, J = 7.2 Hz), 2.24 (s, 3H), 1.76-1.73 (m, 2H), 1.00 (t, 3H, J = 7.3 Hz).

42

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(δppm TMS/CDCl3) 7.60 (d, 2H, J = 8.0 Hz), 7.48 (s, 1H), 7.27 (d, 2H, J = 8.0 Hz), 5.42 (s, 1H), 4.43 (d, 1H, J = 3.0 Hz), 4.33-4.28 (m, 2H), 4.01 (dd, 1H, J = 14.1, 9.3 Hz), 2.41 (s, 3H), 1.63-1.56 (m, 4H), 1.03 (t, 3H, J = 6.7 Hz).

43

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(δppm TMS/CDCl3) 7.84-7.81 (m, 3H), 7.38 (d, 2H, J = 8.3 Hz), 5.87-5.85 (m, 1H), 5.70 (s, 1H), 5.14-5.08 (m, 2H), 4.30 (t, 2H, J = 7.8 Hz), 2.43 (s, 3H), 2.24 (q, 2H, J = 6.9 Hz), 2.04-1.96 (m, 2H).

44

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(δppm TMS/CDCl3) 7.86 (s, 1H), 7.79 (d, 2H, J = 8.0 Hz), 7.37 (d, 2H, J = 7.9 Hz), 6.49 (d, 1H, J = 13.9 Hz), 6.33- 6.31 (m, 1H), 5.76 (s, 1H), 2.39 (s, 3H), 2.33 (q, 2H, J = 7.2 Hz), 1.63-1.60 (m, 2H), 1.06 (t, 3H, J = 7.3 Hz).

45

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(δppm TMS/CDCl3) 7.85 (s, 1H), 7.81 (d, 2H, J = 7.8 Hz), 7.38 (d, 2H, J = 7.5 Hz), 5.70 (s, 1H), 4.31 (t, 2H, J = 7.8 Hz), 3.70 (t, 2H, J = 6.3 Hz), 2.44 (s, 3H), 1.96-1.88 (m, 2H), 1.73-1.66 (m, 2H), 1.59- 1.55 (m, 4H).

TABLE 10

Compound
Structure
1H-NMR

46

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(δppm TMS/CDCl3) 7.81 (s, 1H), 7.75 (d, 2H, J = 7.9 Hz), 7.35 (d, 2H, J = 7.9 Hz), 5.69 (s, 1H), 4.32-4.31 (m, 2H), 3.99 (m, 1H), 2.42 (s, 3H), 1.97-1.95 (m, 2H), 1.58-1.54 (m, 2H), 1.25 (s, 3H).

47

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(δppm TMS/CDCl3) 7.84 (s, 1H), 7.72 (d, 2H, J = 8.2 Hz), 7.37 (d, 2H, J = 8.2 Hz), 5.76 (s, 1H), 4.79 (t, 1H, J = 11.6 Hz), 4.16 (d, 1H, J = 11.6 Hz), 3.37-3.34 (m, 1H), 2.47 (s, 3H), 2.31 (t, 1H, J = 8.0 Hz), 1.97-1.94 (m, 1H), 1.82 (d, 1H, J = 8.0 Hz), 1.62-1.48 (m, 2H), 0.91 (t, 3H, J = 8.0 Hz) .

48

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(δppm TMS/CDCl3) 7.85 (s, 1H), 7.80 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.3 Hz), 5.72 (s, 1H), 4.53 (t, 2H, J = 8.0 Hz), 3.16 (t, 2H, J = 8.0 Hz), 2.51 (s, 3H), 2.34 (t, 3H, J = 8.0 Hz), 0.87 (t, 3H, J = 8.0 Hz) .

49

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(δppm TMS/CDCl3) 7.85 (s, 1H), 7.80 (d, 2H, J = 7.5 Hz), 7.38 (d, 2H, J = 7.8 Hz), 5.71 (s, 1H), 4.82-4.76 (m, 1H), 4.35 (t, 2H, J = 7.8 Hz), 2.45 (s, 3H), 2.06-1.98 (m, 2H), 1.82-1.72 (m, 2H), 1.41-1.35 (m, 3H) .

TABLE 11

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

50

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Method A
1.83
342

51

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Method A
2.00
344

52

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Method A
1.92
344

53

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Method A
2.57
368

54

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Method A
2.68
364

TABLE 12

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

55

embedded image

Method A
2.46
368

56

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Method A
2.81
330

57

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Method A
2.80
342

58

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Method A
2.94
356

59

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Method A
2.46
370

TABLE 13

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

60

embedded image

Method A
2.69
364

61

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Method A
1.89
344

62

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Method A
2.09
373

63

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Method A
2.05
341

64

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Method A
2.63
364

TABLE 14

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

65

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Method A
2.42
356

66

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Method A
2.43
314

67

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Method A
2.70
364

68

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Method A
1.89
359

69

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Method A
2.31
384

TABLE 15

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

70

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Method A
1.29
331

71

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Method A
2.73
330

72

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Method A
2.37
360

73

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Method A
2.51
374

74

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Method A
2.62
388

TABLE 16

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

75

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Method A
1.43
359

76

embedded image

Method A
2.49
346

77

embedded image

Method A
2.64
328

78

embedded image

Method A
2.54
316

79

embedded image

Method A
2.75
330

TABLE 17

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

80

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Method A
2.34
360

81

embedded image

Method A
2.92
344

82

embedded image

Method A
2.67
364

83

embedded image

Method A
2.43
314

84

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Method B
2.30
424

TABLE 18

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

85

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Method A
1.76
463

86

embedded image

Method A
2.62
422

87

embedded image

Method A
2.92
344

88

embedded image

Method A
2.68
426

89

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Method A
1.77
451

TABLE 19

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

90

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Method A
2.81
402

91

embedded image

Method A
2.08
428

92

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Method A
2.48
458

93

embedded image

Method A
2.96
442

94

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Method A
2.28
334

TABLE 20

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

95

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Method A
2.99
392

96

embedded image

Method A
2.08
424

97

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Method A
2.85
446

98

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Method A
2.18
355

99

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Method A
2.04
394

TABLE 21

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

100

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Method A
2.13
382

101

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Method A
2.63
386

102

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Method A
2.81
400

103

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Method A
2.45
408

104

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Method A
2.89
418

TABLE 22

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

105

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Method A
2.08
428

106

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Method A
1.97
327

107

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Method A
2.26
344

108

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Method A
2.33
432

109

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Method A
1.49
351

TABLE 23

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

110

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Method A
1.82
393

111

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Method A
2.71
454

112

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Method A
2.42
422

113

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Method A
2.38
464

114

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Method A
2.07
351

TABLE 24

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

115

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Method A
2.73
418

116

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Method A
2.75
418

117

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Method A
1.61
351

118

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Method A
2.05
344

119

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Method A
2.52
386

TABLE 25

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

120

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Method A
2.90
456

121

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Method A
2.55
368

122

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Method A
2.82
434

123

embedded image

Method A
3.09
406

124

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Method A
2.24
346

Example 3
8-(4-chlorophenyl)-2-propylimidazo[1,2-a]pyrimidin-5(8H)-one (127)

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Step 1:

To a solution of 2-aminopyrimidin-4-ol (125, 333 mg, 3.00 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride under ice-cooling (60 wt %, 132 mg, 3.30 mmol), and the mixture was stirred at room temperature for 30 minutes. A solution of 1-bromopentan-2-one (495 mg, 3.00 mmol, prepared according to Bioorg. Med. Chem. 15 (2007) 3225-3234) in N,N-dimethylformamide (4 mL) was added under ice-cooling, and the mixture was stirred for 1 hour. To the reaction mixture was added sodium hydroxide solution (2 mol/L, 1 mL), and the mixture was stirred at room temperature for 30 minutes. Hydrochloric acid (2 mol/L, 1.1 mL) was added, and the mixture was extracted four times with chloroform/methanol (9:1). The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform/methanol) to yield 2-propylimidazo[1,2-a]pyrimidin-5(8H)-one (126, 275 mg, yield: 52%) as a colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6) 7.94 (s, 1H), 7.85 (d, LH, J=6.5 Hz), 7.34 (s, 1H), 5.76 (d, 1H, J=6.3 Hz), 2.57 (t, 2H, J=7.4 Hz), 1.67-1.64 (m, 2H), 0.91 (t, 3H, J=7.3 Hz).

Step 2:

To a solution of the compound (126, 25 mg, 0.14 mmol) in N,N-dimethylformamide (0.8 mL) was added potassium carbonate (23 mg, 0.17 mmol) and 4-chlorobenzyl bromide (44 mg, 0.21 mmol), and the mixture was stirred at 50° C. for 6 hours. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to yield 8-(4-chlorophenyl)-2-propylimidazo[1,2-a]pyrimidin-5(8H)-one (127, 30 mg, yield: 70%) as a colorless solid.

1H-NMR (δ ppm TMS/CDCl3) 7.34-7.30 (m, 6H), 5.78 (d, 1H, J=7.5 Hz), 5.31 (s, 2H), 2.64 (t, 2H, J=7.5 Hz), 1.78-1.69 (m, 2H), 1.00 (t, 3H, J=7.3 Hz).

Compounds (128) and (129) were prepared in a similar manner.

TABLE 26

Com-

pound
Structure
1H-NMR

128

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(δppm TMS/CDCl3) 7.38 (s, 1H), 7.25 (d, 2H, J = 7.5 Hz), 7.02 (d, 2H, J = 7.5 Hz), 6.95 (d, 1H, J = 7.8 Hz), 5.61 (d, 1H, J = 7.5 Hz), 4.36 (t, 2H, J = 6.7 Hz), 3.17 (t, 2H, J = 6.7 Hz), 2.65 (t, 2H, J = 7.5 Hz), 1.80 (s, 1H), 1.76-1.72 (m, 2H), 1.01 (t, 3H, J = 7.3 Hz).

129

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(δppm TMS/CDCl3) 7.37 (s, 1H), 7.29-7.26 (m, 4H), 7.10 (d, 2H, J = 8.0 Hz), 5.76 (d, 1H, J = 7.8 Hz), 4.18 (t, 2H, J = 7.2 Hz), 2.70-2.62 (m, 4H), 2.27-2.19 (m, 2H), 1.78- 1.70 (m, 2H), 1.01 (t, 3H, J = 7.4 Hz).

Example 4
4-(5-oxo-8-(4,4,4-trifluorobutyl)-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-5,8-dihydroimidazo[1,2-a]pyrimidine-7-yl)benzamide (136)

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Step 1:

To a solution of (1r,4r)-4-(trifluoromethyl)cyclohexanecarboxylic acid (130, 2.00 g, 10.2 mmol) in tetrahydrofuran (75 mL) was added methyl lithium in tetrahydrofuran (1.14 mol/L, 36 mL, 41 mmol) under ice-cooling, and the mixture was stirred for 2 hours under cooling. Chlorotrimethylsilane (26 mL, 204 mmol) was added, and the reaction mixture was warmed to room temperature. Hydrochloric acid (1 mol/L, 75 mL) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was extracted twice with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product of 1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethanone (131) (1.97 g).

Step 2:

To a solution of the crude product of the compound (131) (1.10 g) in methanol (7 mL) was added bromine (0.29 mL, 5.7 mmol) in methanol (3 mL) under ice-cooling, and the mixture was stirred at room temperature for 6 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product of 2-bromo-1-((1r,4r)-4-(trifluoromethyl)cyclohexyl)ethanone (132) (2.3 g).

Step 3:

To a solution of 2-amino-6-chloropyrimidin-4-ol (133, 200 mg, 1.37 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60 wt %, 55 mg, 1.4 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of the crude product of the compound (132) (670 mg) in N,N-dimethylformamide (2 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 5 hours. Sodium hydroxide solution (2 mol/L, 1.27 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. HCl (2 mol/L, 1.4 mL) and water (50 mL) were added, and the reaction mixture was extracted twice with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure to yield the crude product of 7-chloro-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)imidazo[1,2-a]pyrimidin-5(8H)-one (134)(615 mg).

Step 4:

To a solution of the crude product of the compound (134) (300 mg) in N,N-dimethylformamide (4.5 mL) was added sodium hydride (60 wt %, 32 mg, 0.80 mmol) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added 4-bromo-1,1,1-trifluorobutane (0.25 mL, 2.0 mmol), and the mixture was stirred at 100° C. for 3 hours. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product of 7-chloro-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)imidazo[1,2-a]pyrimidin-5(8H)-one (135) (101 mg), and then about half of which (50 mg) was purified by silica gel chromatography (hexane/ethyl acetate) to yield the compound (135, 11 mg, yield from the compound (133): 8%) as a pale brown solid.

1H-NMR (δ ppm TMS/DMSO-d6) 7.34 (s, 1H), 6.11 (s, 1H), 4.44 (t, 2H, J=7.3 Hz), 2.44-2.53 (m, 3H), 2.28-2.30 (br m, 1H), 1.99-2.07 (m, 6H), 1.41-1.43 (m, 4H).

Step 5:

To a solution of the crude product of the compound (135) (50 mg),4-carbamoylphenylboronic acid (29 mg, 0.18 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (9.5 mg, 0.012 mmol) in N,N-dimethylformamide (1 mL) was added aqueous sodium carbonate (2 mol/L, 0.23 mL), and the mixture was stirred at 100° C. for 20 minutes. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give 4-(5-oxo-8-(4,4,4-trifluorobutyl)-2-((1r,4r)-4-(trifluoromethyl)cyclohexyl)-5,8-dihydroimidazo[1,2-a]pyrimidin-7-yl)benzamide (136, 2.4 mg, yield from the compound (133): 1%) as a yellow oil.

LC/MS (Method B) Retention Time=2.19 min, Found Mass [M+H]=515.

Compounds (137) to (166) were prepared in a similar manner.

TABLE 27

Compound
Structure
1H-NMR

137

embedded image

(δppm TMS/DMSO-d6) 7.26 (s, 1H), 5.71 (s, 1H), 4.16-4.19 (m, 2H), 2.50-2.52 (br m, 1H), 2.43 (s, 3H), 2.31 (br s, 1H), 2.10-2.13 (br m, 2H), 1.94- 1.97 (br m, 2H), 1.70-1.73 (br m, 2H), 1.32-1.42 (m, 8H), 0.88 (t, 3H, J = 10.0 Hz).

138

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(δppm TMS/DMSO-d6) 8.12 (s, 1H), 7.95 (d, 2H, J = 7.8 Hz), 7.42 (t, 2H, J = 7.5 Hz), 7.31-7.33 (m, 1H), 5.77 (s, 1H), 4.27 (t, 2H, J = 7.0 Hz), 2.47 (s, 2H), 1.79-1.81 (m, 2H), 1.37-1.39 (m, 4H), 0.91 (t, 3H, J = 7.0 Hz).

TABLE 28

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

139

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Method A
2.44
302

140

embedded image

Method A
2.34
336

141

embedded image

Method A
2.71
388

142

embedded image

Method A
2.58
352

143

embedded image

Method A
2.52
336

TABLE 29

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

144

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Method A
2.13
302

145

embedded image

Method A
3.17
378

146

embedded image

Method A
2.29
336

147

embedded image

Method A
2.40
330

148

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Method A
1.92
379

TABLE 30

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

149

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Method A
2.19
338

150

embedded image

Method A
2.64
336

151

embedded image

Method A
2.38
368

152

embedded image

Method A
2.21
326

153

embedded image

Method A
2.53
346

TABLE 31

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

154

embedded image

Method A
2.51
324

155

embedded image

Method A
2.30
362

156

embedded image

Method A
2.54
380

157

embedded image

Method A
2.05
321

158

embedded image

Method A
2.58
364

TABLE 32

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

159

embedded image

Method A
1.67
367

160

embedded image

Method A
2.24
368

161

embedded image

Method A
2.48
364

162

embedded image

Method A
2.25
332

163

embedded image

Method A
2.20
314

TABLE 33

Reten-

tion

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

164

embedded image

Method B
2.37
517

165

embedded image

Method B
1.81
640

166

embedded image

Method A
1.95
340

Example 5
2-(4-chlorophenyl)-3-hydroxymethyl-7-methyl-8-pentylimidazo[1,2-a]pyrimidin-5(8H)-one (168)

embedded image

To a solution of the compound (3, 150 mg, 0.455 mmol) in N,N-dimethylformamide (1.5 mL) was added (chloromethylene)dimethylammoniumiminium chloride (146 mg, 1.14 mmol), and the solution was stirred at room temperature for 90 minutes. Saturated aqueous sodium bicarbonate (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layer was washed twice with water, dried with anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to yield 2-(4-chlorophenyl)-7-methyl-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidine-3-carbaldehyde (167, 151 mg, yield: 93%) as a yellow solid.

1H-NMR (δ ppm TMS/CDCl3) 11.00 (s, 1H), 8.16 (d, 2H, J=8.4 Hz), 7.43 (d, 2H, J=8.3 Hz), 5.88 (s, 1H), 4.32 (t, 2H, J=7.8 Hz), 2.48 (s, 3H), 1.85-1.87 (m, 2H), 1.42-1.44 (m, 4H), 0.95 (t, 3H, J=10.0 Hz).

Step 2:

To a solution of the compound (167, 20 mg, 0.056 mmol) in methanol (0.5 mL) was added sodium borohydride (4.2 mg, 0.11 mmol), and the solution was stirred at room temperature for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was triturated in diisopropyl ether to yield 2-(4-chlorophenyl)-3-hydroxymethyl-7-methyl-8-pentylimidazo[1,2-a]pyrimidin-5(8H)-one (168, 13 mg, yield: 66%) as a colorless solid.

1H-NMR (δ ppm TMS/CDCl3) 7.62 (d, 2H, J=8.0 Hz), 7.42 (d, 2H, J=8.0 Hz), 5.71 (s, 1H), 4.93 (d, 2H, J=7.5 Hz), 4.27 (t, 2H, J=7.8 Hz), 4.14 (t, 1H, J=7.4 Hz), 2.44 (s, 3H), 1.86-1.84 (m, 2H), 1.43-1.40 (m, 4H), 0.95-0.93 (m, 3H).

Compounds (169) to (173) were prepared in a similar manner.

TABLE 34

Compound
Structure
1H-NMR

169

embedded image

(δppm TMS/DMSO-d6) 7.64 (dd, 4H, J = 15.2, 8.6 Hz), 5.62 (s, 1H), 4.18 (t, 2H, J = 7.7 Hz), 2.78 (s, 3H), 2.41 (s, 3H), 1.76-1.74 (m, 2H), 1.35- 1.33 (m, 4H), 0.89 (t, 3H, J = 6.8 Hz).

170

embedded image

(δppm TMS/DMSO-d6) 7.68 (d, 2H, J = 8.0 Hz), 7.51 (d, 2H, J = 7.8 Hz), 5.61 (s, 1H), 4.18 (t, 2H, J = 7.7 Hz), 2.78 (s, 3H), 2.40 (s, 3H), 1.74- 1.76 (m, 2H), 1.33-1.35 (m, 4H), 0.87 (t, 3H, J = 6.8 Hz).

171

embedded image

(δppm TMS/CDCl3) 8.00 (d, 2H, J = 8.5 Hz), 7.41 (d, 2H, J = 8.5 Hz), 5.61 (s, 1H), 4.22 (t, 2H, J = 7.8 Hz), 2.39 (s, 3H), 1.84-1.82 (m, 2H), 1.42- 1.41 (m, 4H), 0.94 (t, 3H, J = 6.8 Hz).

172

embedded image

(δppm TMS/CDCl3) 7.70 (d, 2H, J = 8.3 Hz), 7.37 (d, 2H, J = 8.2 Hz), 5.64 (s, 1H), 4.21- 4.25 (m, 4H), 2.38 (s, 3H), 1.80-1.82 (br m, 4H), 1.37- 1.40 (br m, 4H), 0.92 (s, 3H).

173

embedded image

(δppm TMS/CDCl3) 7.82 (d, 2H, J = 8.4 Hz), 7.41 (d, 2H, J = 8.2 Hz), 5.62 (s, 1H), 4.24 (t, 2H, J = 7.8 Hz), 4.13 (s, 2H), 2.39 (s, 3H), 2.25 (s, 6H), 1.83-1.85 (m, 2H), 1.39- 1.42 (m, 4H), 0.94 (t, 3H, J = 10.0 Hz).

Example 7
Synthesis of methyl 4-((2-(4-chlorophenyl)-6-methyl-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-ylamino)methyl)benzoate (178)

embedded image

To a solution of 2-amino-6-chloro-pyrimidin-4-ol (174, 25 g, 172 mmol) in N,N-dimethylformamide (250 mL) was added sodium hydride (60 wt %, 7.56 g, 189 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. A solution of 2-bromo-1-(4-chlorophenyl)ethanone (40 g, 172 mmol) in N,N-dimethylformamide (100 mL) was added to the solution in the iced bath, and the mixture was stirred at room temperature for 2 hours. Sodium hydroxide solution (2 mol/L, 125 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 45 minutes. Hydrochloric acid (2 mol/L, 138 mL) and water (250 mL) were added, and the precipitated solid was collected by filtration to yield a crude product of 7-chloro-2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-5(8H)-one (175) (20 g).

Step 2

To crude product of the compound (175) (20 g) in N,N-dimethylformamide (300 mL) were added sodium hydride (60 wt %, 3.43 g, 86.0 mmol) and 1-bromopentane (32.4 g, 214 mmol), and the solution was stirred at 100° C. for 6 hours. After cooling to room temperature, the addition of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to yield 7-chloro-2-(4-chlorophenyl)-8-pentylimidazo[1,2-a]pyrimidin-5(8H)-one (176, 8.4 g, yield from the compound (174): 14%) as a colorless solid.

1H-NMR (δ ppm TMS/CDCl3) 7.85 (s, 1H), 7.80 (d, 2H, J=8.5 Hz), 7.39 (d, 2H, J=8.5 Hz), 5.99 (s, 1H), 4.51 (t, 2H, J=7.8 Hz), 1.91 (t, 2H, J=7.4 Hz), 1.44-1.43 (m, 4H), 0.95 (t, 3H, J=6.9 Hz).

Step 3

To a solution of the compound (176, 500 mg, 1.43 mmol) in N,N-dimethylformamide (10 mL) were added 1,8-diazabicyclo[5,4,0]-7-undecene (435 mg, 2.86 mmol) and methyl 4-aminomethyl benzoate (472 mg, 2.86 mmol), and the mixture was stirred at 80° C. for 24 hours. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to yield methyl 4-((2-(4-chlorophenyl)-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-ylamino)methyl)benzoate (177, 554 mg, yield: 81%) as a colorless solid.

1H-NMR (δ ppm TMS/CDCl3) 8.05 (d, 2H, J=7.8 Hz), 7.76-7.73 (m, 3H), 7.39-7.36 (m, 4H), 5.12 (t, 1H, J=5.1 Hz), 4.95 (s, 1H), 4.46 (d, 2H, J=4.9 Hz), 4.32 (t, 2H, J=7.6 Hz), 3.92 (s, 3H), 1.90-1.82 (m, 2H), 1.43-1.41 (m, 4H), 0.92 (t, 3H, J=6.0 Hz).

Step 4

To a solution of the compound (177, 160 mg, 0.334 mmol) in N,N-dimethylformamide (3 mL) were added potassium carbonate (69 mg, 0.50 mmol) and methyl iodide (52 mg, 0.37 mmol), and the mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol) to yield methyl 4-((2-(4-chlorophenyl)-6-methyl-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-ylamino)methyl)benzoate (178, 75 mg, yield: 46%) as a colorless solid.

1H-NMR (δ ppm TMS/CDCl3) 8.06 (d, 2H, J=7.7 Hz), 7.81-7.80 (m, 3H), 7.41-7.37 (m, 4H), 4.40 (d, 2H, J=6.7 Hz), 4.28 (t, 2H, J=7.6 Hz), 3.93-3.91 (m, 4H), 2.02 (s, 3H), 1.88-1.81 (m, 2H), 1.37-1.29 (m, 4H), 0.89 (t, 3H, J=6.7 Hz).

Compounds (179) to (361) were prepared in a similar manner.

TABLE 35

Compound
Structure
1H-NMR

179

embedded image

(δppm TMS/DMSO-d6) 8.11 (s, 1H), 7.98 (d, 2H, J = 8.3 Hz), 7.46 (d, 2H, J = 8.0 Hz), 4.34 (s, 2H), 3.15 (s, 2H), 2.37 (s, 3H), 1.76 (s, 2H), 1.38 (s, 4H), 0.91 (s, 3H).

180

embedded image

(δppm TMS/CDCl3) 7.82 (d, 3H, J = 9.5 Hz), 7.38 (d, 2H, J = 8.3 Hz), 4.36 (t, 2H, J = 7.8 Hz), 2.96 (t, 2H, J = 7.4 Hz), 2.67 (t, 2H, J = 7.4 Hz), 2.52 (s, 3H), 1.84 (s, 2H), 1.44 (d, 4H, J = 3.5 Hz), 0.95 (t, 3H, J = 6.4 Hz).

181

embedded image

(δppm TMS/DMSO-d6) 8.16 (s, 1H), 7.99 (d, 2H, J = 7.8 Hz), 7.78 (s, 1H), 7.48 (d, 2H, J = 7.8 Hz), 4.37 (s, 2H), 3.43 (s, 5H), 3.06 (d, 3H, J = 6.3 Hz), 2.40 (s, 3H), 1.78 (s, 2H), 1.39 (s, 4H), 0.99 (t, 3H, J = 7.2 Hz), 0.91 (s, 3H).

182

embedded image

(δppm TMS/DMSO-d6) 8.22 (s, 1H), 8.01 (d, 2H, J = 8.0 Hz), 7.47 (dd, 4H, J = 19.4, 7.7 Hz), 7.39 (d, 1H, J = 7.0 Hz), 7.30 (d, 2H, J = 7.5 Hz), 4.38 (t, 2H, J = 7.5 Hz), 2.31 (s, 3H), 1.85 (s, 2H), 1.42 (s, 4H), 0.92 (s, 3H).

183

embedded image

(δppm TMS/DMSO-d6) 8.25 (s, 1H), 7.98 (d, 2H, J = 8.0 Hz), 7.49 (d, 2H, J = 8.3 Hz), 5.33 (s, 1H), 4.34 (s, 4H), 2.69 (s, 3H), 1.81 (s, 2H), 1.38 (s, 4H), 0.90 (s, 3H).

TABLE 36

Compound
Structure
1H-NMR

184

embedded image

(δppm TMS/DMSO-d6) 8.36 (s, 1H), 7.99 (d, 2H, J = 7.8 Hz), 7.51 (d, 2H, J = 7.8 Hz), 4.39 (t, 2H, J = 7.8 Hz), 2.73 (s, 3H), 1.83 (s, 2H), 1.40 (s, 4H), 0.91 (s, 3H).

185

embedded image

(δppm TMS/DMSO-d6) 8.10 (s, 1H), 7.96 (d, 2H, J = 8.3 Hz), 7.46 (d, 2H, J = 8.3 Hz), 4.26 (t, 2H, J = 7.7 Hz), 2.43 (s, 3H), 1.76 (s, 2H), 1.38 (s, 4H), 0.90 (t, 3H, J = 6.7 Hz).

186

embedded image

(δppm TMS/CDCl3) 7.90 (s, 1H), 7.82 (d, 2H, J = 8.3 Hz), 7.40-7.38 (m, 3H), 5.82 (d, 1H, J = 7.5 Hz), 4.23 (t, 2H, J = 7.3 Hz), 1.95 (t, 2H, J = 7.2 Hz), 1.40-1.39 (m, 4H), 0.93 (t, 3H, J = 6.7 Hz).

187

embedded image

(δppm TMS/CDCl3) 7.80-7.77 (m, 3H), 7.36 (d, 2H, J = 8.0 Hz), 5.29 (s, 1H), 4.32 (t, 2H, J = 7.7 Hz), 3.38 (t, 4H, J = 6.0 Hz), 2.03 (t, 4H, J = 6.0 Hz), 1.87-1.85 (m, 2H), 1.39-1.29 (m, 4H), 0.90 (t, 3H, J = 7.0 Hz).

188

embedded image

(δppm TMS/CDCl3) 7.78-7.76 (m, 3H), 7.35 (d, 2H, J = 8.3 Hz), 5.01 (s, 1H), 4.49 (t, 1H, J = 5.0 Hz), 4.25 (t, 2H, J = 7.7 Hz), 3.19 (q, 2H, J = 6.4 Hz), 1.84-1.72 (m, 5H), 1.04 (t, 3H, J = 7.4 Hz), 0.94 (t, 3H, J = 6.4 Hz).

TABLE 37

Compound
Structure
1H-NMR

189

embedded image

(δppm TMS/CDCl3) 7.80-7.79 (m, 3H), 7.37 (d, 2H, J = 8.0 Hz), 5.24 (s, 1H), 4.30 (t, 2H, J = 7.4 Hz), 4.10 (t, 2H, J = 6.3 Hz), 1.91-1.86 (m, 4H), 1.40- 1.39 (m, 4H), 1.10 (t, 3H, J = 7.4 Hz), 0.93 (t, 3H, J = 6.7 Hz).

190

embedded image

(δppm TMS/DMSO-d6) 8.11 (s, 1H), 7.94 (d, 2H, J = 8.3 Hz), 7.88 (d, 2H, J = 8.3 Hz), 7.46 (d, 2H, J = 8.0 Hz), 7.20 (d, 1H, J = 8.0 Hz), 5.44 (s, 1H), 4.20 (t, 2H, J = 7.0 Hz), 3.23 (t, 2H, J = 6.7 Hz), 3.03 (br s, 3H), 2.78 (t, 2H, J = 7.0 Hz), 2.62 (br s, 2H), 1.79-1.77 (m, 2H), 1.33-1.22 (m, 4H), 0.84 (t, 3H, J = 7.0 Hz).

191

embedded image

(δppm TMS/CDCl3) 7.79 (d, 3H, J = 7.8 Hz), 7.37 (d, 2H, J = 8.0 Hz), 5.44 (s, 1H), 4.25 (t, 2H, J = 7.3 Hz), 3.73 (s, 4H), 3.06 (s, 4H), 2.69 (s, 3H), 2.61 (d, 2H, J = 6.8 Hz), 2.56 (d, 2H, J = 7.0 Hz), 2.51 (s, 4H), 1.84 (s, 2H), 1.39-1.29 (m, 4H), 0.91 (t, 3H, J = 7.0 Hz).

TABLE 38

Com-

pound
Structure
1H-NMR

192

embedded image

(δ ppm TMS/DMSO-d6) 12.94 (s, 1H), 7.94-7.90 (m, 5H), 7.84 (t, 1H, J = 5.7 Hz), 7.49 (d, 2H, J = 7.7 Hz), 7.44 (d, 2H, J = 7.3 Hz), 4.69 (s, 1H), 4.55 (d, 2H, J = 5.0 Hz), 4.34 (t, 2H, J = 7.4 Hz), 1.79-1.77 (m, 2H), 1.40-1.37 (m, 4H), 0.90 (t, 3H, J = 6.0 Hz).

193

embedded image

(δ ppm TMS/CDC13) 7.79-7.78 (m, 3H), 7.37 (d, 2H, J = 8.3 Hz), 5.25 (s, 1H), 4.51-4.49 (m, 1H), 4.30 (t, 2H, J = 7.5 Hz), 2.67-2.65 (m, 2H), 2.38- 2.35 (m, 5H), 2.14-2.09 (m, 2H), 1.98-1.94 (m, 2H), 1.86- 1.82 (m, 2H), 1.41-1.38 (m, 4H), 0.93 (t, 3H, J = 6.5 Hz).

194

embedded image

13.08 (s, 1H), 8.14 (d, 1H, J = 2.1 Hz), 8.01 (d, 2H, J = 7.0 Hz), 7.92 (d, 2H, J = 7.0 Hz), 7.63 (d, 2H, J = 6.8 Hz), 7.45 (d, 2H, J = 7.0 Hz), 5.57 (s, 1H), 5.45 (s, 2H), 4.25 (t, 2H, J = 6.3 Hz), 1.78-1.75 (m, 2H), 1.27-1.19 (m, 4H), 0.81 (t, 3H, J = 5.8 Hz).

TABLE 39

Com-

pound
Structure
1H-NMR

195

embedded image

(δ ppm TMS/CDC13) 8.07 (d, 2H, J = 7.5 Hz), 7.82-7.79 (m, 3H), 7.39-7.37 (m, 4H), 5.48 (s, 1H), 4.31 (t, 2H, J = 7.5 Hz), 4.25 (s, 2H), 3.94 (s, 3H), 2.72 (s, 3H), 1.89-1.85 (m, 2H), 1.38-1.32 (m, 4H), 0.91 (t, 3H, J = 6.8 Hz).

196

embedded image

(δ ppm TMS/CDC13) 7.78- 7.76 (m, 3H), 7.35 (d, 2H, J = 8.0 Hz), 4.83 (s, 1H), 4.19-4.13 (m, 6H), 2.47-2.40 (m, 2H), 1.90-1.82 (m, 2H), 1.42-1.36 (m, 4H), 0.94 (t, 3H, J = 6.9 Hz).

197

embedded image

(δ ppm TMS/DMSO-d6) 13.01 (s, 1H), 8.14 (s, 1H), 7.97-7.95 (m, 4H), 7.49-7.47 (m, 4H), 5.48 (s, 1H), 4.38 (s, 2H), 4.24 (t, 2H, J = 7.5 Hz), 2.73 (s, 3H), 1.81-1.78 (m, 2H), 1.32-1.16 (m, 4H), 0.83 (t, 3H, J = 7.2 Hz).

TABLE 40

Com-

pound
Structure
1H-NMR

198

embedded image

(δ ppm TMS/DMSO-d6) 8.11 (d, 3H, J = 8.3 Hz), 7.94 (d, 2H, J = 7.8 Hz), 7.87-7.89 (m, 1H), 7.73 (d, 2H, J = 8.3 Hz), 7.51 (d, 2H, J = 7.8 Hz), 4.73 (s, 1H), 4.54-4.57 (m, 2H), 4.41 (t, 2H, J = 6.9 Hz), 2.65 (t, 2H, J = 6.9 Hz), 1.90- 1.92 (m, 2H), 1.69-1.71 (m, 2H).

TABLE 41

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

199

embedded image

Method A
2.30
387

200

embedded image

Method A
3.10
430

201

embedded image

Method A
3.46
472

202

embedded image

Method A
2.99
416

203

embedded image

Method A
3.31
420

TABLE 42

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

204

embedded image

Method A
3.41
386

205

embedded image

Method A
3.10
358

206

embedded image

Method A
2.89
348

207

embedded image

Method A
2.57
374

208

embedded image

Method A
2.97
344

TABLE 43

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

209

embedded image

Method A
2.29
387

210

embedded image

Method A
3.10
430

211

embedded image

Method A
3.31
420

212

embedded image

Method A
2.89
348

213

embedded image

Method A
2.58
374

TABLE 44

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

214

embedded image

Method A
2.89
402

215

embedded image

Method A
3.36
458

216

embedded image

Method A
2.89
402

217

embedded image

Method A
3.47
472

218

embedded image

Method A
1.72
389

TABLE 45

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

219

embedded image

Method A
3.26
435

220

embedded image

Method A
3.36
552

221

embedded image

Method A
2.66
371

222

embedded image

Method A
2.23
375

TABLE 46

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

223

embedded image

Method A
3.33
504

224

embedded image

Method A
2.91
399

225

embedded image

Method A
1.80
443

226

embedded image

Method A
2.81
451

227

embedded image

Method A
2.44
457

TABLE 47

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

228

embedded image

Method A
2.74
424

229

embedded image

Method A
2.61
422

230

embedded image

Method A
3.18
387

231

embedded image

Method A
2.84
359

232

embedded image

Method A
2.75
414

TABLE 48

Com-

Retention
Mass

pound
Structure
LC/MS
Time [min]
[M + H]

233

embedded image

Method A
2.53
428

234

embedded image

Method A
2.76
401

235

embedded image

Method A
2.62
402

236

embedded image

Method A
2.26
416

237

embedded image

Method A
2.93
464

TABLE 49

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

238

embedded image

Method A
2.51
444

239

embedded image

Method A
2.87
427

240

embedded image

Method A
2.54
485

241

embedded image

Method A
2.39
471

242

embedded image

Method A
2.49
442

TABLE 50

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

243

embedded image

Method A
2.88
472

244

embedded image

Method A
2.74
484

245

embedded image

Method A
3.35
512

246

embedded image

Method A
3.27
399

247

embedded image

Method A
3.34
413

TABLE 51

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

248

embedded image

Method A
2.47
345

249

embedded image

Method A
2.77
465

250

embedded image

Method A
2.53
389

251

embedded image

Method A
2.95
435

252

embedded image

Method A
3.08
425

TABLE 52

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

253

embedded image

Method A
2.17
419

254

embedded image

Method A
2.45
400

255

embedded image

Method A
3.46
413

256

embedded image

Method A
3.08
399

257

embedded image

Method A
3.48
399

TABLE 53

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

258

embedded image

Method A
3.08
399

259

embedded image

Method A
3.08
399

260

embedded image

Method A
3.34
400

261

embedded image

Method A
3.33
436

262

embedded image

Method A
3.84
458

TABLE 54

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

263

embedded image

Method A
3.87
444

264

embedded image

Method A
2.81
409

265

embedded image

Method A
3.58
484

266

embedded image

Method A
3.25
464

267

embedded image

Method A
3.60
440

TABLE 55

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

268

embedded image

Method A
2.80
415

269

embedded image

Method A
2.84
390

270

embedded image

Method A
2.85
388

271

embedded image

Method A
3.72
482

272

embedded image

Method A
3.14
374

TABLE 56

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

273

embedded image

Method A
2.97
409

274

embedded image

Method A
2.36
387

275

embedded image

Method A
3.74
470

276

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Method A
3.72
481

277

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Method A
3.48
442

TABLE 57

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

278

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Method A
3.51
503

279

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Method A
3.85
496

280

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Method A
3.62
455

281

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Method A
3.55
456

282

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Method A
2.07
455

TABLE 58

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

283

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Method A
2.40
483

284

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Method A
1.73
445

285

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Method A
2.04
474

286

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Method A
2.02
477

287

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Method A
2.35
506

TABLE 59

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

288

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Method
1.72
467

A

289

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Method
2.01
496

A

290

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Method A
2.46
523

TABLE 60

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

291

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Method A
2.99
511

292

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Method
2.88
549

A

293

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Method A
2.31
414

294

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Method A
2.48
456

TABLE 61

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

295

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Method A
2.47
456

296

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Method A
2.81
549

297

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Method A
2.86
507

298

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Method A
2.61
492

299

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Method A
2.58
511

TABLE 62

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

300

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Method A
3.43
412

301

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Method A
2.73
428

302

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Method A
2.06
442

303

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Method A
3.57
426

304

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Method A
2 .60
414

TABLE 63

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

305

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Method A
3.53
474

306

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Method A
3.20
460

307

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Method A
3.94
480

308

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Method A
3.41
440

309

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Method A
2.85
382

TABLE 64

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

310

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Method A
3.03
434

311

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Method A
3.23
527

312

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Method A
3.06
525

313

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Method A
3.08
525

314

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Method A
3.10
525

TABLE 65

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

315

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Method A
3.26
484

316

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Method A
3.10
513

317

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Method A
3.10
508

318

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Method A
2.91
503

319

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Method A
2.71
456

TABLE 66

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

320

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Method A
3.39
474

321

embedded image

Method A
3.09
434

322

embedded image

Method A
3.44
488

323

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Method A
3.09
452

324

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Method A
3.05
540

TABLE 67

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

325

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Method A
3.28
474

326

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Method A
2.31
499

327

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Method A
3.19
461

328

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Method A
2.30
428

329

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Method A
2.28
426

TABLE 68

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

330

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Method A
2.21
426

331

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Method A
2.23
426

332

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Method A
2.21
440

333

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Method B
2.31
373

334

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Method A
2.49
429

TABLE 69

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

335

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Method A
1.90
536

336

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Method A
2.51
495

337

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Method A
2.37
526

338

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Method A
2.51
500

339

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Method A
2.25
486

TABLE 70

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

340

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Method A
2.51
514

341

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Method A
2.30
539

342

embedded image

Method A
1.90
522

343

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Method A
2.32
569

TABLE 71

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

344

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Method A
2.35
527

345

embedded image

Method A
2.32
528

346

embedded image

Method A
2.34
500

347

embedded image

Method A
2.58
584

348

embedded image

Method A
2.28
486

TABLE 72

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

349

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Method A
2.37
526

350

embedded image

Method A
2.48
528

351

embedded image

Method A
2.62
570

352

embedded image

Method A
1.90
485

353

embedded image

Method A
2.34
500

TABLE 73

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

354

embedded image

Method A
2.28
514

355

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Method A
2.35
514

356

embedded image

Method A
2.34
514

357

embedded image

Method B
2.61
435

358

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Method B
2.46
387

TABLE 74

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

359

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Method B
2.98
487

360

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Method B
3.12
515

361

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Method B
2.46
387

Example 8
N-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-(2-(4-chlorophenyl)-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-yl)benzamide (365)

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Step 1:

To a solution of compound (176, 1.82 g, 5.20 mmol) in N,N-dimethylformamide (55 mL) were added 4-carboxyphenylboronic acid (1.29 g, 7.79 mmol), [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (424 mg, 0.520 mmol) and aqueous sodium carbonate (2 mol/L, 15.6 mL), and the mixture was stirred at 100° C. for 2 hours. After cooling to room temperature, water was added, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol) to yield 4-(2-(4-chlorophenyl)-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-yl)benzoic acid (362, 1.65 g, yield: 73%) as a colorless solid.

LC/MS (Method A) Retention Time=2.75 min, Found Mass [M+H]=436.

Step 2:

To a solution of the compound (362, 400 mg, 0.918 mmol) in methylene chloride (6 mL) were added benzyl 2-aminoethyl carbamate (267 mg, 1.38 mmol), 1-hydroxybenzotriazole (25 mg, 0.18 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (367 mg, 1.38 mmol) and triethylamine (0.636 mL, 4.59 mmol), and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to yield benzyl 2-(4-(2-(4-chlorophenyl)-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-yl)benzamide)ethylcarbamate (363, 422 mg, yield: 75%) as a yellow solid.

LC/MS (Method B) Retention Time=2.74 min, Found Mass [M+H]=612.

Step 3

To a solution of the compound (363, 152 mg, 0.248 mmol) in methylene chloride (5 mL) was added a solution of boron tribromide in methylene chloride (1 mol/L, 0.50 mL, 0.50 mmol) was added at −78° C., and the mixture was stirred for at 0° C. 4 hours. Methanol in water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (chloroform/methanol) to yield N-(2-aminoethyl)-4-(2-(4-chlorophenyl)-5-oxo-8-pentyl-5,8-dihydroimidazo[1,2-a]pyrimidin-7-yl)benzamide (364, 90 mg, yield: 76%) as a yellow solid.

1H-NMR (δ ppm TMS/DMSO-d6) 8.78 (t, 1H, J=5.3 Hz), 8.30 (s, 1H), 8.04-8.01 (m, 4H), 7.78-7.74 (m, 6H), 7.50 (d, 2H, J=7.5 Hz), 5.74 (s, 1H), 4.11 (t, 2H, J=7.2 Hz), 3.04-3.01 (m, 2H), 1.64-1.62 (m, 2H), 1.13-1.05 (m, 4H), 0.74 (t, 3H, J=6.8 Hz).

Step 4

To a solution of the compound (364, 30 mg, 0.063 mmol) in 2-propanol (1.5 mL) were added sodium carbonate (67 mg, 0.63 mmol) and 3,3-bis(chloromethyl) oxetane (97 mg, and 0.63 mmol), and the mixture was stirred at 140° C. for 2 hours. After cooling the mixture to room temperature, hydrochloric acid (1 mol/L) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform/methanol) to yield N-(2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-4-(2-(4-chlorophenyl)-5-oxo-8-pentyl-5,8-dihydro-imidazo[1,2-a]pyrimidine-7-yl)benzamide (365, 13 mg, yield: 37%) of a colorless solid.

1H-NMR (δ ppm TMS/CDCl3) 7.99 (d, 2H, J=7.5 Hz), 7.93 (s, 1H), 7.85 (d, 2H, J=7.3 Hz), 7.52 (d, 2H, J=7.3 Hz), 7.40 (d, 2H, J=7.5 Hz), 5.75 (s, 1H), 4.76 (s, 4H), 4.15 (t, 2H, J=7.8 Hz), 3.60 (s, 4H), 3.52 (q, 2H, J=5.3 Hz), 2.78 (t, 2H, J=5.3 Hz), 1.73-1.70 (m, 2H), 1.23-1.16 (m, 4H), 0.81 (t, 3H, J=6.8 Hz).

Compound (366) to (867) were prepared in a similar manner.

TABLE 75

Compound
Structure
1H-NMR

366

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(δ ppm TMS/CDCl3) 7.93 (s, 1H), 7.85 (d, 2H, J = 8.5 Hz), 7.54 (d, 3H, J = 6.3 Hz), 7.41 (t, 4H, J = 8.5 Hz), 5.77 (s, 1H), 4.17 (t, 2H, J = 7.8 Hz), 1.74-1.72 (m, 2H), 1.23-1.16 (m, 5H), 0.80 (t, 3H, J = 6.9 Hz).

367

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(δ ppm TMS/CDCl3) 7.81-7.79 (m, 3H), 7.38 (d, 2H, J = 7.8 Hz), 5.92 (s, 1H), 4.67 (d, 2H, J = 6.3 Hz), 4.32 (t, 2H, J = 7.8 Hz), 1.89-1.86 (m, 2H), 1.43-1.40 (m, 4H), 0.94 (t, 3H, J = 6.4 Hz).

368

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(δ ppm TMS/CDCl3) 7.93 (s, 1H), 7.84 (d, 2H, J = 8.3 Hz), 7.44-7.39 (m, 4H), 7.23 (d, 1H, J = 8.3 Hz), 5.74 (s, 1H), 4.16 (t, 2H, J = 7.8 Hz), 1.73-1.71 (m, 2H), 1.22-1.15 (m, 4H), 0.82 (t, 3H, J = 6.9 Hz).

369

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(δ ppm TMS/CDCl3) 7.86 (s, 1H), 7.82 (d, 2H, J = 8.0 Hz), 7.38 (d, 2H, J = 8.0 Hz), 5.71 (s, 1H), 4.29 (t, 2H, J = 7.8 Hz), 2.64 (t, 2H, J = 7.7 Hz), 1.88-1.86 (m, 2H), 1.77-1.73 (m, 2H), 1.44-1.43 (m, 4H), 1.09 (t, 3H, J = 7.3 Hz), 0.96 (t, 3H, J = 6.3 Hz).

370

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(δ ppm TMS/CDCl3) 9.78 (s, 1H), 7.95 (s, 1H), 7.85 (d, 2H, J = 7.8 Hz), 7.41 (d, 2H, J = 7.8 Hz), 6.37 (s, 1H), 4.78 (t, 2H, J = 7.8 Hz), 1.86-1.83 (m, 2H), 1.43-1.42 (m, 4H), 0.94 (t, 3H, J = 6.4 Hz).

TABLE 76

Compound
Structure
1H-NMR

371

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(δ ppm TMS/CDCl3) 7.87 (s, 1H), 7.82 (d, 2H, J = 7.3 Hz), 7.38-7.36 (m, 7H), 5.91 (s, 1H), 4.63 (s, 2H), 4.49 (s, 2H), 4.31 (t, 2H, J = 7.7 Hz), 1.87-1.84 (m, 2H), 1.37-1.35 (m, 4H), 0.92 (t, 3H, J = 5.6 Hz).

372

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(δ ppm TMS/DMSO-d6) 8.25 (s, 1H), 7.99 (d, 2H, J = 8.3 Hz), 7.49 (d, 2H, J = 8.0 Hz), 6.01 (s, 1H), 4.47 (t, 2H, J = 7.2 Hz), 1.85-1.82 (m, 2H), 1.33- 1.31 (m, 4H), 0.88 (t, 3H, J = 6.4 Hz).

373

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(δ ppm TMS/CDCl3) 8.64 (s, 2H), 7.93 (s, 1H), 7.84 (d, 2H, J = 8.3 Hz), 7.40 (d, 2H, J = 8.3 Hz), 5.76 (s, 1H), 4.19-4.15 (m, 5H), 1.78-1.74 (m, 2H), 1.28-1.22 (m, 4H), 0.86 (t, 3H, J = 6.9 Hz).

374

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(δ ppm TMS/DMSO-d6) 8.62-8.65 (m, 1H), 8.33 (s, 1H), 8.00- 8.02 (m, 4H), 7.72 (d, 2H, J = 7.7 Hz), 7.51 (d, 2H, J = 7.9 Hz), 5.77 (s, 1H), 4.10-4.13 (m, 2H), 3.57-3.59 (m, 4H), 3.35-3.42 (m, 4H), 2.43 (s, 4H), 1.62-1.64 (m, 2H), 1.07- 1.09 (br m, 4H), 0.73 (t, 3H, J = 6.7 Hz).

375

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(δ ppm TMS/CDCl3) 8.01-8.03 (m, 5H), 7.69 (d, 2H, J = 7.8 Hz), 7.56 (d, 2H, J = 7.8 Hz), 6.20 (brs, 1H), 5.81 (s, 1H), 5.70 (brs, 1H), 4.23 (t, 2H, J = 6.8 Hz), 2.32 (t, 2H, J = 6.8 Hz), 1.88-1.91 (br m, 2H), 1.57 (br s, 2H).

TABLE 77

Compound
Structure
1H-NMR

376

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(δ ppm TMS/CDCl3) 7.99-8.02 (m, 6H), 7.69 (d, 2H, J = 8.0 Hz), 7.54 (d, 2H, J = 7.5 Hz), 7.08 (s, 1H), 5.81 (s, 1H), 4.23 (t, 2H, J = 7.4 Hz), 3.76-3.79 (br m, 5H), 3.63- 3.64 (m, 2H), 2.69 (t, 2H, J = 6.9 Hz), 2.59 (s, 4H), 2.32 (t, 2H, J = 6.9 Hz), 1.89-1.92 (br m, 2H), 1.57-1.59 (m, 2H).

377

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(δ ppm TMS/CDCl3) 8.01-8.05 (br m, 5H), 7.78 (s, 1H), 7.69 (d, 2H, J = 8.0 Hz), 7.52 (d, 2H, J = 7.8 Hz), 5.80 (s, 1H), 4.23 (t, 2H, J = 7.4 Hz), 3.67-3.68 (m, 2H), 2.78 (t, 2H, J = 7.8 Hz), 2.46 (s, 6H), 2.32 (t, 2H, J = 6.9 Hz), 1.88-1.91 (br m, 2H), 1.57- 1.59 (m, 2H).

378

embedded image

(δ ppm TMS/DMSO-d6) 8.57 (t, 1H, J = 5.3 Hz), 8.32 (s, 1H), 8.03-8.02 (m, 4H), 7.70 (d, 2H, J = 7.5 Hz), 7.50 (d, 2H, J = 7.3 Hz), 5.76 (s, 1H), 4.14 (t, 2H, J = 7.0 Hz), 3.40-3.39 (m, 2H), 2.41 (q, 4H, J = 7.4 Hz), 2.19 (s, 6H), 1.78-1.71 (m, 2H), 1.44-1.37 (m, 2H).

379

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(δ ppm TMS/DMSO-d6) 8.31 (s, 1H), 8.15 (s, 1H), 8.05-8.03 (m, 4H), 7.69 (d, 2H, J = 7.8 Hz), 7.56 (s, 1H), 7.50 (d, 2H, J = 8.0 Hz), 5.77 (s, 1H), 4.14 (t, 2H, J = 6.9 Hz), 2.40 (t, 2H, J = 6.9 Hz), 1.78-1.71 (m, 2H), 1.44-1.37 (m, 2H).

380

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(δ ppm TMS/DMSO-d6) 8.60 (t, 1H, J = 5.8 Hz), 8.31 (s, 1H), 8.02 (t, 4H, J = 8.0 Hz), 7.70 (d, 2H, J = 7.8 Hz), 7.49 (d, 2H, J = 8.0 Hz), 5.76 (s, 1H), 4.14 (t, 2H, J = 7.2 Hz), 3.58 (t, 4H, J = 4.1 Hz), 2.41-2.39 (m, 6H), 1.76-1.73 (m, 2H), 1.44-1.36 (m, 2H).

TABLE 78

Compound
Structure
1H-NMR

381

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(δ ppm TMS/DMSO-d6) 8.57 (t, 1H, J = 6.1 Hz), 8.32 (s, 1H), 8.03-8.01 (m, 4H), 7.70 (d, 2H, J = 7.8 Hz), 7.51 (d, 2H, J = 7.8 Hz), 5.75 (s, 1H), 4.17 (t, 2H, J = 7.3 Hz), 3.40 (q, 2H, J = 6.3 Hz), 2.43 (t, 2H, J = 6.7 Hz), 2.19 (s, 8H), 1.94-1.90 (m, 2H).

382

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(δ ppm TMS/DMSO-d6) 8.33 (s, 1H), 8.18 (s, 1H), 8.06-8.03 (m, 4H), 7.70 (d, 2H, J = 7.5 Hz), 7.60-7.50 (m, 4H), 5.77 (s, 1H), 4.16 (t, 2H, J = 7.2 Hz), 2.25-2.19 (m, 2H), 1.94- 1.90 (m, 2H).

383

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(δ ppm TMS/DMSO-d6) 8.63 (t, 1H, J = 5.3 Hz), 8.33 (s, 1H), 8.04-8.02 (m, 4H), 7.71 (d, 2H, J = 7.5 Hz), 7.52 (d, 2H, J = 7.5 Hz), 5.77 (s, 1H), 4.17 (t, 2H, J = 6.3 Hz), 3.60-3.57 (m, 4H), 2.43 (br s, 4H), 2.25-2.20 (m, 2H), 1.94- 1.90 (m, 2H).

384

embedded image

(δ ppm TMS/DMSO-d6) 8.57 (t, 1H, J = 5.5 Hz), 8.51 (s, 1H), 8.20 (d, 2H, J = 7.5 Hz), 8.02 (d, 2H, J = 7.8 Hz), 7.90 (d, 2H, J = 7.3 Hz), 7.70 (d, 2H, J = 7.5 Hz), 5.78 (br s, 1H), 4.15 (t, 2H, J = 7.0 Hz), 3.39 (q, 2H, J = 6.4 Hz), 2.44-2.35 (m, 4H), 2.19 (s, 6H), 1.79- 1.71 (m, 2H), 1.45-1.38 (m, 2H).

385

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(δ ppm TMS/DMSO-d6) 8.51 (s, 1H), 8.21 (d, 2H, J = 7.8 Hz), 8.16 (s, 1H), 8.06 (d, 2H, J = 7.5 Hz), 7.90 (d, 2H, J = 7.8 Hz), 7.70 (d, 2H, J = 7.5 Hz), 7.57 (s, 1H), 5.79 (s, 1H), 4.15 (t, 2H, J = 6.9 Hz), 2.40 (t, 2H, J = 6.9 Hz), 1.78-1.73 (m, 2H), 1.45-1.37 (m, 2H).

TABLE 79

Compound
Structure
1H-NMR

386

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(δ ppm TMS/DMSO-d6) 8.60 (t, 1H, J = 5.4 Hz), 8.50 (s, 1H), 8.20 (d, 2H, J = 7.5 Hz), 8.01 (d, 2H, J = 7.5 Hz), 7.89 (d, 2H, J = 7.5 Hz), 7.70 (d, 2H, J = 7.5 Hz), 5.78 (s, 1H), 4.14 (t, 2H, J = 7.0 Hz), 3.58 (t, 4H, J = 4.3 Hz), 2.42-2.39 (m, 6H), 1.79-1.71 (m, 2H), 1.43-1.41 (m, 2H).

387

embedded image

(δ ppm TMS/DMSO-d6) 8.60 (t, 1H, J = 5.2 Hz), 8.54 (br s, 1H), 8.20 (d, 2H, J = 8.3 Hz), 8.03 (d, 2H, J = 8.0 Hz), 7.92 (d, 2H, J = 8.2 Hz), 7.71 (d, 2H, J = 8.0 Hz), 5.79 (br s, 1H), 4.17 (t, 2H, J = 7.0 Hz), 3.41-3.40 (m, 2H), 2.42 (t, 2H, J = 6.7 Hz), 2.30-2.19 (m, 8H), 1.94-1.92 (m, 2H).

388

embedded image

(δ ppm TMS/DMSO-d6) 8.53 (s, 1H), 8.21-8.19 (m, 3H), 8.06 (d, 2H, J = 7.7 Hz), 7.92 (d, 2H, J = 7.4 Hz), 7.70 (d, 2H, J = 7.5 Hz), 7.60 (s, 1H), 5.79 (s, 1H), 4.17 (t, 2H, J = 7.8 Hz), 2.29-2.16 (m, 2H), 1.94-1.90 (m, 2H).

389

embedded image

(δ ppm TMS/DMSO-d6) 8.62 (t, 1H, J = 5.8 Hz), 8.54 (s, 1H), 8.18 (d, 2H, J = 7.8 Hz), 8.03 (d, 2H, J = 7.8 Hz), 7.92 (d, 2H, J = 7.3 Hz), 7.71 (d, 2H, J = 7.7 Hz), 5.79 (s, 1H), 4.17 (t, 2H, J = 7.3 Hz), 3.58 (t, 4H, J = 4.3 Hz), 3.43 (q, 2H, J = 6.0 Hz), 2.45 (br s, 4H), 2.27-2.20 (m, 2H), 1.93- 1.91 (m, 2H).

390

embedded image

(δ ppm TMS/DMSO-d6) 8.62 (t, 1H, J = 5.3 Hz), 8.29 (s, 1H), 8.01 (t, 4H, J = 7.7 Hz), 7.69 (d, 2H, J = 7.5 Hz), 7.50 (d, 2H, J = 7.8 Hz), 5.75 (s, 1H), 4.78 (t, 1H, J = 5.4 Hz), 4.11 (t, 2H, J = 7.5 Hz), 3.54 (q, 2H, J = 6.0 Hz), 1.64-1.61 (m, 2H), 1.13-1.09 (m, 5H), 0.73 (t, 3H, J = 6.8 Hz).

TABLE 80

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

391

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Method A
3.00
434

392

embedded image

Method A
3.42
432

393

embedded image

Method A
3.48
448

394

embedded image

Method A
2.76
422

395

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Method A
3.22
422

TABLE 81

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

396

embedded image

Method A
3.22
422

397

embedded image

Method A
3.20
422

398

embedded image

Method A
3.25
418

399

embedded image

Method A
3.36
435

400

embedded image

Method A
2.99
417

TABLE 82

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

401

embedded image

Method A
2.76
485

402

embedded image

Method A
2.73
463

403

embedded image

Method A
3.01
382

404

embedded image

Method A
3.18
436

405

embedded image

Method A
2.52
435

TABLE 83

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

406

embedded image

Method A
2.84
489

407

embedded image

Method A
2.67
393

408

embedded image

Method A
3.42
396

409

embedded image

Method A
2.58
394

410

embedded image

Method A
2.64
393

TABLE 84

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

411

embedded image

Method A
2.82
408

412

embedded image

Method A
2.56
515

413

embedded image

Method A
2.12
506

414

embedded image

Method A
3.05
356

415

embedded image

Method A
3.46
398

TABLE 85

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

416

embedded image

Method A
2.22
490

417

embedded image

Method A
2.66
382

418

embedded image

Method A
2.93
399

419

embedded image

Method A
2.69
464

420

embedded image

Method A
3.59
519

TABLE 86

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

421

embedded image

Method A
3.14
477

422

embedded image

Method A
2.84
407

423

embedded image

Method A
2.93
386

424

embedded image

Method A
2.59
409

425

embedded image

Method A
2.03
495

TABLE 87

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

426

embedded image

Method A
2.53
409

427

embedded image

Method A
2.47
493

428

embedded image

Method A
3.06
525

429

embedded image

Method A
2.18
472

430

embedded image

Method A
2.93
541

TABLE 88

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

431

embedded image

Method A
2.80
485

432

embedded image

Method A
3.35
438

433

embedded image

Method A
2.79
470

434

embedded image

Method A
2.76
449

435

embedded image

Method A
3.52
420

TABLE 89

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

436

embedded image

Method A
2.73
493

437

embedded image

Method A
2.77
520

438

embedded image

Method A
2.94
514

439

embedded image

Method A
2.12
506

440

embedded image

Method A
2.86
485

TABLE 90

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

441

embedded image

Method A
2.80
485

442

embedded image

Method A
3.77
448

443

embedded image

Method A
3.25
410

444

embedded image

Method A
3.23
410

445

embedded image

Method A
3.20
477

TABLE 91

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

446

embedded image

Method A
2.93
450

447

embedded image

Method A
3.03
434

448

embedded image

Method A
2.45
448

449

embedded image

Method A
2.69
566

450

embedded image

Method A
3.02
449

TABLE 92

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

451

embedded image

Method A
2.50
531

452

embedded image

Method A
2.94
541

453

embedded image

Method C
2.97
464

454

embedded image

Method A
2.94
454

455

embedded image

Method A
2.39
423

TABLE 93

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

456

embedded image

Method A
3.05
423

457

embedded image

Method A
2.89
411

458

embedded image

Method A
3.22
457

459

embedded image

Method A
2.43
409

460

embedded image

Method A
3.05
423

TABLE 94

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

461

embedded image

Method A
2.78
423

462

embedded image

Method A
2.83
418

463

embedded image

Method A
2.14
410

464

embedded image

Method C
2.74
612

TABLE 95

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

465

embedded image

Method A
2.65
488

466

embedded image

Method A
2.26
512

467

embedded image

Method A
2.29
523

468

embedded image

Method A
3.07
491

469

embedded image

Method A
3.08
511

TABLE 96

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

470

embedded image

Method A
2.4
520

471

embedded image

Method A
3.03
541

472

embedded image

Method A
2.47
519

473

embedded image

Method A
2.69
505

TABLE 97

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

474

embedded image

Method A
2.47
546

475

embedded image

Method A
2.72
481

476

embedded image

Method A
2.46
493

477

embedded image

Method A
2.71
507

TABLE 98

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

478

embedded image

Method A
2.87
477

479

embedded image

Method A
2.74
507

480

embedded image

Method A
2.43
523

481

embedded image

Method A
2.47
493

482

embedded image

Method A
2.29
509

TABLE 99

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

483

embedded image

Method A
2.9
489

484

embedded image

Method A
2.75
473

485

embedded image

Method A
2.1
562

486

embedded image

Method A
2.31
509

487

embedded image

Method A
2.31
509

TABLE 100

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

488

embedded image

Method A
2.67
502

489

embedded image

Method A
2.1
504

490

embedded image

Method A
2.59
491

491

embedded image

Method A
2.97
630

TABLE 101

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

492

embedded image

Method A
2.6
553

493

embedded image

Method A
2.59
567

494

embedded image

Method A
2.54
541

495

embedded image

Method A
2.61
449

TABLE 102

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

496

embedded image

Method A
2.54
520

497

embedded image

Method A
2.72
519

498

embedded image

Method A
2.65
582

499

embedded image

Method A
2.46
542

TABLE 103

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

500

embedded image

Method A
2.62
491

501

embedded image

Method A
2.66
612

502

embedded image

Method A
2.63
519

503

embedded image

Method A
2.58
545

TABLE 104

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

504

embedded image

Method A
2.31
509

505

embedded image

Method A
2.09
543

506

embedded image

Method A
2.88
515

507

embedded image

Method A
2.43
526

508

embedded image

Method A
2.23
540

TABLE 105

Reten-

tion
Mass

Com-

Time
[M +

pound
Structure
LC/MS
[min]
H]

509

embedded image

Method A
2.88
610

510

embedded image

Method A
2.17
544

511

embedded image

Method A
2.12
543

512

embedded image

Method A
2.63
618

TABLE 106

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

513

embedded image

Method A
2.78
596

514

embedded image

Method A
2.09
529

515

embedded image

Method A
2.21
564

516

embedded image

Method A
2.4
547

517

embedded image

Method A
2.5
576

TABLE 107

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

518

embedded image

Method A
2.97
570

519

embedded image

Method A
2.72
603

520

embedded image

Method A
2.28
620

TABLE 108

Retention

Com-

Time

pound
Structure
LC/MS
[min]
Mass [M + H]

521

embedded image

Method A
2.62
604

522

embedded image

Method A
2.07
492

523

embedded image

Method A
2.09
529

524

embedded image

Method A
2.1
596

TABLE 109

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

525

embedded image

Method A
2.08
515

526

embedded image

Method A
3.17
450

527

embedded image

Method A
3.32
559

528

embedded image

Method B
2.79
393

TABLE 110

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

529

embedded image

B
2.95
449

530

embedded image

B
2.61
419

531

embedded image

B
2.09
511

532

embedded image

B
2.44
452

533

embedded image

B
2.29
438

TABLE 111

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

534

embedded image

B
2.37
523

535

embedded image

B
1.74
562

536

embedded image

A
2.20
509

TABLE 112

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

537

embedded image

B
1.56
387

538

embedded image

B
1.61
415

539

embedded image

B
1.68
542

540

embedded image

B
1.84
473

541

embedded image

B
3.07
497

TABLE 113

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

542

embedded image

B
1.64
528

543

embedded image

B
1.68
514

544

embedded image

B
2.31
460

545

embedded image

B
1.57
438

546

embedded image

B
2.43
439

TABLE 114

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

547

embedded image

B
2.55
475

548

embedded image

B
1.64
542

549

embedded image

B
2.97
501

550

embedded image

B
2.98
501

551

embedded image

B
2.93
501

TABLE 115

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

552

embedded image

B
2.98
501

553

embedded image

B
3.05
515

554

embedded image

B
3.13
515

555

embedded image

B
3.13
515

556

embedded image

B
2.95
500

TABLE 116

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

557

embedded image

B
2.57
440

558

embedded image

B
2.70
346

559

embedded image

B
2.95
500

560

embedded image

B
2.67
415

561

embedded image

B
2.96
415

TABLE 117

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

562

embedded image

B
2.53
475

563

embedded image

B
2.67
475

564

embedded image

B
2.65
487

565

embedded image

B
2.85
487

566

embedded image

B
2.71
521

TABLE 118

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

567

embedded image

B
2.88
521

568

embedded image

B
2.75
557

569

embedded image

B
2.47
507

570

embedded image

B
1.63
459

571

embedded image

B
2.50
528

TABLE 119

Retention

Time
Mass

Compound
Structure
LC/MS
min
[M + H]

572

embedded image

B
1.56
401

573

embedded image

C
2.16
515

574

embedded image

C
2.13
501

575

embedded image

B
1.79
459

576

embedded image

C
1.77
473

TABLE 120

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

577

embedded image

C
1.91
445

578

embedded image

B
1.98
529

579

embedded image

A
2.26
518

580

embedded image

A
2.29
518

581

embedded image

A
2.00
516

TABLE 121

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

582

embedded image

A
2.03
516

583

embedded image

A
2.46
546

584

embedded image

A
2.52
546

585

embedded image

A
2.19
544

586

embedded image

A
2.24
544

TABLE 122

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

587

embedded image

A
2.43
447

588

embedded image

A
2.47
447

589

embedded image

A
2.11
445

590

embedded image

A
2.13
445

591

embedded image

A
2.59
546

TABLE 123

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

592

embedded image

A
2.69
546

593

embedded image

A
2.32
544

594

embedded image

A
2.36
544

595

embedded image

A
2.83
574

596

embedded image

A
2.96
574

TABLE 124

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

597

embedded image

A
2.57
572

598

embedded image

A
2.61
572

599

embedded image

A
2.60
443

600

embedded image

A
2.65
443

601

embedded image

A
2.27
403

TABLE 125

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

602

embedded image

A
2.43
403

603

embedded image

A
2.12
446

604

embedded image

A
2.79
443

605

embedded image

A
2.60
443

606

embedded image

A
2.73
443

TABLE 126

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

607

embedded image

A
2.34
417

608

embedded image

A
2.65
443

609

embedded image

A
2.24
460

610

embedded image

A
2.37
415

611

embedded image

A
2.39
431

TABLE 127

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

612

embedded image

A
2.79
443

613

embedded image

A
2.50
443

614

embedded image

A
2.50
615

615

embedded image

A
2.35
514

616

embedded image

A
2.37
514

TABLE 128

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

617

embedded image

A
2.11
474

618

embedded image

A
2.20
474

619

embedded image

A
2.71
615

620

embedded image

A
2.71
615

621

embedded image

A
2.55
514

TABLE 129

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

622

embedded image

A
2.35
514

623

embedded image

A
2.40
514

624

embedded image

A
2.37
514

625

embedded image

A
2.23
486

626

embedded image

A
2.55
514

TABLE 130

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

627

embedded image

A
2.49
601

628

embedded image

A
2.35
500

629

embedded image

A
2.37
500

630

embedded image

A
2.09
460

631

embedded image

A
2.70
601

TABLE 131

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

632

embedded image

A
2.70
601

633

embedded image

A
2.55
500

634

embedded image

A
2.35
500

635

embedded image

A
2.41
500

636

embedded image

A
2.37
500

TABLE 132

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

637

embedded image

A
2.23
472

638

embedded image

A
2.55
500

639

embedded image

A
2.68
544

640

embedded image

A
2.86
544

641

embedded image

A
2.86
544

TABLE 133

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

642

embedded image

A
2.34
553

643

embedded image

A
1.98
539

644

embedded image

A
1.94
541

645

embedded image

A
1.92
499

646

embedded image

A
1.92
513

TABLE 134

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

647

embedded image

A
1.97
525

648

embedded image

A
1.97
539

649

embedded image

A
1.75
568

650

embedded image

A
1.92
525

651

embedded image

A
2.03
555

TABLE 135

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

652

embedded image

A
1.74
582

653

embedded image

A
1.99
541

654

embedded image

A
1.96
583

655

embedded image

A
2.94
599

656

embedded image

A
1.94
527

TABLE 136

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

657

embedded image

A
2.07
597

658

embedded image

A
1.87
444

659

embedded image

A
1.85
444

660

embedded image

A
1.85
444

661

embedded image

A
1.99
499

TABLE 137

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

662

embedded image

A
1.87
515

663

embedded image

A
1.86
515

664

embedded image

A
1.85
515

665

embedded image

A
1.87
501

666

embedded image

A
1.85
501

TABLE 138

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

667

embedded image

A
1.85
501

668

embedded image

A
2.48
595

669

embedded image

A
1.68
429

670

embedded image

A
1.69
429

671

embedded image

A
3.14
471

TABLE 139

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

672

embedded image

A
2.18
516

673

embedded image

A
2.50
540

674

embedded image

A
2.39
514

675

embedded image

A
2.33
500

676

embedded image

A
2.55
542

TABLE 140

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

677

embedded image

A
2.44
540

678

embedded image

A
1.35
500

679

embedded image

A
2.34
512

680

embedded image

A
2.31
542

681

embedded image

A
2.38
542

TABLE 141

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

682

embedded image

B
3.01
500

683

embedded image

A
2.56
514

684

embedded image

A
2.43
585

685

embedded image

A
2.57
514

686

embedded image

A
2.34
530

TABLE 142

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

687

embedded image

A
2.36
530

688

embedded image

A
2.83
568

689

embedded image

A
2.62
528

690

embedded image

A
2.57
514

691

embedded image

A
2.83
568

TABLE 143

Retention

Com-

Time
Mass

pound
Structure
LC/MS
[min]
[M + H]

692

embedded image

A
2.56
514

693

embedded image

A
2.52
526

694

embedded image

A
2.43
539

695

embedded image

A
2.30
539

696

embedded image

A
2.83
568

TABLE 144

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

697

embedded image

A
2.21
511

698

embedded image

A
2.22
525

699

embedded image

A
2.37
513

700

embedded image

A
2.21
511

701

embedded image

A
2.18
525

TABLE 145

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

702

embedded image

A
2.21
511

703

embedded image

A
2.36
527

704

embedded image

A
2.21
499

705

embedded image

A
2.15
511

706

embedded image

A
2.81
526

TABLE 146

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

707

embedded image

A
2.43
539

708

embedded image

A
2.21
511

709

embedded image

A
2.23
499

710

embedded image

A
2.26
525

711

embedded image

A
2.26
525

TABLE 147

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

712

embedded image

A
2.16
511

713

embedded image

B
2.45
520

714

embedded image

A
2.17
431

715

embedded image

A
2.48
427

716

embedded image

A
2.71
441

TABLE 148

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

717

embedded image

A
2.61
338

718

embedded image

A
2.69
420

719

embedded image

A
2.69
416

720

embedded image

A
2.6
402

721

embedded image

A
1.89
566

TABLE 149

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

722

embedded image

A
2.60
542

723

embedded image

A
2.50
528

724

embedded image

A
2.81
626

725

embedded image

A
2.63
576

726

embedded image

A
2.80
626

TABLE 150

Retention

Time

Compound
Structure
LC/MS
[min]
Mass [M + H]

727

embedded image

A
2.86
652

728

embedded image

A
2.62
542

729

embedded image

A
2.41
514

730

embedded image

A
2.68
556

731

embedded image

A
2.51
528

TABLE 151

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

732

embedded image

A
2.56
562

733

embedded image

A
2.60
542

734

embedded image

A
2.83
582

735

embedded image

A
2.69
590

736

embedded image

A
2.73
576

TABLE 152

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

737

embedded image

A
2.34
500

738

embedded image

A
2.63
542

739

embedded image

A
2.43
514

740

embedded image

A
2.64
576

741

embedded image

C
2.85
557

TABLE 153

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

742

embedded image

C
2.85
557

743

embedded image

A
2.44
596

744

embedded image

A
2.08
506

745

embedded image

A
2.51
610

746

embedded image

A
2.39
562

TABLE 154

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M + H]

747

embedded image

A
2.20
534

748

embedded image

A
2.14
520

749

embedded image

A
2.20
612

750

embedded image

A
1.86
522

751

embedded image

A
2.27
626

TABLE 155

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

752

embedded image

A
2.15
578

753

embedded image

A
1.96
550

754

embedded image

A
1.91
536

755

embedded image

A
2.18
534

756

embedded image

A
1.81
444

TABLE 156

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

757

embedded image

A
2.27
548

758

embedded image

A
2.14
500

759

embedded image

A
1.93
472

760

embedded image

A
1.86
458

761

embedded image

A
1.95
550

TABLE 157

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

762

embedded image

A
1.57
460

763

embedded image

A
2.05
564

764

embedded image

A
1.90
516

765

embedded image

A
1.69
488

766

embedded image

A
1.64
474

TABLE 158

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

767

embedded image

A
1.98
520

768

embedded image

A
1.58
430

769

embedded image

A
2.07
534

770

embedded image

A
1.90
486

771

embedded image

A
1.64
444

TABLE 159

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

772

embedded image

A
1.78
536

773

embedded image

A
1.40
446

774

embedded image

A
1.72
502

775

embedded image

A
2.41
592

776

embedded image

A
2.03
502

TABLE 160

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

777

embedded image

A
2.48
606

778

embedded image

A
2.37
558

779

embedded image

A
2.10
516

TABLE 161

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

780

embedded image

A
1.69
458

781

embedded image

A
1.51
474

782

embedded image

A
1.46
460

783

embedded image

A
2.38
496

784

embedded image

A
2.54
572

TABLE 162

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

785

embedded image

A
2.57
540

786

embedded image

A
2.53
554

787

embedded image

A
2.56
572

788

embedded image

A
2.34
510

789

embedded image

A
2.50
561

TABLE 163

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

790

embedded image

A
2.25
509

791

embedded image

A
2.68
572

792

embedded image

A
2.56
540

793

embedded image

A
2.55
550

794

embedded image

A
2.40
526

TABLE 164

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

795

embedded image

A
2.28
510

796

embedded image

A
2.53
588

797

embedded image

A
2.51
541

798

embedded image

A
2.57
550

799

embedded image

A
2.44
511

TABLE 165

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

800

embedded image

A
2.62
554

801

embedded image

A
2.48
550

802

embedded image

A
3.47
427

803

embedded image

A
3.49
475

804

embedded image

A
3.49
427

TABLE 166

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

805

embedded image

A
2.94
512

806

embedded image

A
3.21
528

807

embedded image

A
2.65
480

808

embedded image

A
3.40
413

809

embedded image

A
2.67
457

TABLE 167

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

810

embedded image

A
3.07
397

811

embedded image

A
3.39
413

812

embedded image

A
3.40
413

813

embedded image

A
3.49
476

814

embedded image

A
3.40
413

TABLE 168

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

815

embedded image

B
2.69
554

816

embedded image

B
2.44
500

817

embedded image

B
1.97
522

818

embedded image

B
3.00
478

819

embedded image

B
2.04
394

TABLE 169

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

820

embedded image

B
2.66
450

821

embedded image

B
2.54
489

822

embedded image

B
2.81
462

823

embedded image

B
2.44
434

824

embedded image

B
2.19
461

TABLE 170

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

825

embedded image

B
2.54
492

826

embedded image

B
2.46
490

827

embedded image

B
2.21
414

828

embedded image

B
2.51
442

829

embedded image

B
2.21
452

TABLE 171

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

830

embedded image

B
2.19
466

831

embedded image

B
2.26
480

832

embedded image

B
2.22
480

833

embedded image

A
2.02
501

834

embedded image

A
2.39
466

TABLE 172

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

835

embedded image

A
2.35
438

836

embedded image

A
2.68
495

837

embedded image

A
2.08
524

838

embedded image

A
2.14
497

839

embedded image

A
2.44
491

TABLE 173

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

840

embedded image

A
2.5
556

841

embedded image

A
2.01
470

842

embedded image

A
2.19
510

843

embedded image

A
2.07
457

844

embedded image

A
1.99
487

TABLE 174

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

845

embedded image

A
2.2
443

846

embedded image

A
2.17
469

847

embedded image

A
2.06
496

848

embedded image

A
2.45
547

849

embedded image

A
2.18
519

TABLE 175

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

850

embedded image

A
2.49
511

851

embedded image

A
2.21
427

852

embedded image

A
1.79
538

853

embedded image

A
1.82
526

854

embedded image

A
2.03
501

TABLE 176

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

855

embedded image

A
2.12
520

856

embedded image

A
2.22
469

857

embedded image

A
2.18
485

858

embedded image

A
2.13
495

859

embedded image

A
2.18
495

TABLE 177

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

860

embedded image

A
2.25
481

861

embedded image

A
2.19
515

862

embedded image

A
2.41
508

863

embedded image

A
2.3
509

864

embedded image

A
2.17
563

TABLE 178

Retention

Time
Mass

Compound
Structure
LC/MS
[min]
[M+H]

865

embedded image

A
2.28
483

866

embedded image

A
2.45
547

867

embedded image

A
2.68
495

Test Example 1
(Method A) Evaluation of Autotaxin Inhibitor

Solution A containing 25 mM Tris-HCl buffer (pH7.5), 100 mM NaCl, 5 mM MgCl₂and 0.1% BSA was prepared. Mouse autotaxin enzyme (purchased from R&D System) was diluted with Solution A, and 5 μL of which was added to a solution of test compound in DMSO. Furthermore, 5 μl of 0.5 μM TG-mTMP in Solution A was added and allowed to react at room temperature for 2 hours. 5 μl of 150 mM EDTA in Solution A was added to quench the reaction, and a fluorescent dye TokyoGreen, which was produced by the reaction, was detected. The fluorescence was detected using ViewLux (PerkinElmer, Inc.) with an excitation wavelength of 480 nm and a fluorescence wavelength of 540 nm.

The percent inhibition of the test compound was calculated by assuming the sample with no test compound as 0% inhibition and the sample with no enzyme as 100% inhibition, and the percent inhibitions at different concentrations of the test compound were plotted to obtain a concentration-dependent curve. The IC50 value, which is the concentration of the test compound that resulted in 50% inhibition, was determined from the curve.

embedded image

Test Example 2
(Method B) Evaluation of Autotaxin Inhibitor

Solution A containing 25 mM Tris-HCl buffer (pH7.5), 100 mM NaCl, 5 mM MgCl₂and 0.1% BSA was prepared. Human autotaxin enzyme (purchased from R&D System) was diluted with Solution A, and 5 μL of which was added to a solution of test compound in DMSO. Furthermore, 5 μl of 0.5 μM TG-mTMP in Solution A was added and allowed to react at room temperature for 2 hours. 5 μl of 150 mM EDTA in Solution A was added to quench the reaction, and the fluorescent dye TokyoGreen, which was produced by the reaction, was detected. The fluorescence was detected using ViewLux (PerkinElmer, Inc.) with an excitation wavelength of 480 nm and a fluorescence wavelength of 540 nm.

Test Example 3
(Method C) Evaluation of Autotaxin Inhibitor

Solution B containing 100 mM Tris-HCl buffer (pH7.5), 150 mM NaCl, 5 mM MgCl₂and 0.05% Triton X-100 was prepared. Human autotaxin enzyme (purchased from R&D System) was diluted with Solution B, and 2.5 μL of which was added to a solution of test compound in DMSO. Furthermore, 2.5 μl of 200 μM 18:0 Lyso PC (purchased from Avanti Polar Lipids) in Solution B was added and allowed to react at room temperature for 2 hours. After completion of the reaction, 15 μL of the coline assay reagent (100 mM Tris-HCl buffer (pH7.5), 5 mM MgCl2, 77 μg/mL choline oxidase, 10 μg/mL peroxidase, 25 μM 10-acetyl-3,7-dihydroxyphenoxazine and excess autotaxin inhibitor) was added and allowed to react at room temperature for 20 minutes. The fluorescent dye Resorufin, which was produced by the reaction, was detected. The fluorescence was detected using ViewLux (PerkinElmer, Inc.) with an excitation wavelength of 531 nm and a fluorescence wavelength of 598 nm.

The results obtained by the test methods described above are shown in the following tables.

Test Method:
Method A: Test Example 1; Method B: Test Example 2; Method C: Test Example 3
Enzyme Inhibitory Activity:

A: IC50≦10 nM; B: 10 nM≦IC50≦100 nM; C: 100 nM≦IC50≦1000 nM; D: 1000 nM≦IC50

TABLE 179

Inhibitory

Compound
Assay Method
Activity

1
no data

2
no data

3
Method B
A

4
Method A
C

5
Method A
B

6
Method A
B

7
Method B
B

8
Method B
B

9
Method A
B

10
Method A
B

11
Method A
C

12
Method A
C

13
Method B
B

14
Method A
B

15
Method A
B

16
Method A
B

17
Method A
B

18
Method B
A

19
Method A
B

20
Method B
A

21
Method A
B

22
Method A
B

23
Method A
B

24
Method A
C

25
Method A
C

26
Method B
B

27
Method A
D

28
Method B
B

29
Method B
B

30
Method A
B

31
Method A
B

32
Method A
B

33
Method A
D

34
Method A
B

35
Method A
B

36
Method A
B

37
Method A
C

38
Method A
D

39
Method A
D

40
Method A
B

41
Method C
C

42
Method B
B

43
Method B
B

44
Method B
B

45
Method B
C

46
Method C
D

47
Method C
D

48
Method C
D

49
Method C
C

50
Method B
C

51
Method B
B

52
Method B
D

53
Method B
B

54
Method B
B

55
Method B
B

56
Method B
B

57
Method B
B

58
Method B
B

59
Method B
B

60
Method B
C

61
Method B
C

62
Method B
C

63
Method C
C

64
Method B
C

65
Method B
C

66
Method B
B

67
Method B
B

68
Method B
D

69
Method B
D

70
Method B
C

71
Method B
B

72
Method B
B

73
Method B
B

74
Method B
C

75
Method B
C

76
Method B
C

77
Method B
B

78
Method B
B

79
Method B
B

80
Method B
B

81
Method B
A

82
Method B
B

83
Method B
B

84
Method B
A

85
Method B
A

86
Method B
C

TABLE 180

Inhibitory

Compound
Assay Method
Activity

87
Method B
B

88
Method B
C

89
Method B
A

90
Method B
B

91
Method B
B

92
Method B
B

93
Method B
D

94
Method B
B

95
Method B
B

96
Method B
C

97
Method B
B

98
Method C
B

99
Method B
C

100
Method B
B

101
Method B
B

102
Method B
C

103
Method B
B

104
Method B
B

105
Method B
B

106
Method B
B

107
Method B
C

108
Method B
B

109
Method B
C

110
Method B
B

111
Method B
C

112
Method B
B

113
Method B
B

114
Method B
B

115
Method B
B

116
Method B
C

117
Method B
B

118
Method B
C

119
Method C
C

120
Method B
D

121
Method B
B

122
Method B
C

123
Method B
C

124
Method B
B

125
no data

126
no data

127
Method B
D

128
Method B
D

129
Method B
D

130
no data

131
no data

132
no data

133
no data

134
no data

135
Method C
D

136
Method C
C

137
Method C
C

138
Method B
C

139
Method B
C

140
Method B
C

141
Method B
B

142
Method B
B

143
Method B
C

144
Method B
C

145
Method B
D

146
Method B
C

147
Method B
D

148
Method B
D

149
Method B
C

150
Method B
C

151
Method B
D

152
Method B
B

153
Method B
D

154
Method B
B

155
Method B
B

156
Method B
A

157
Method B
A

158
Method B
B

159
Method B
D

160
Method B
C

161
Method B
A

162
Method B
C

163
Method B
C

164
Method C
B

165
Method C
B

166
Method C
D

167
Method B
C

168
Method B
C

169
Method B
B

170
Method B
B

171
Method B
B

172
Method B
D

TABLE 181

Inhibitory

Compound
Assay Method
Activity

173
Method B
D

174
no data

175
no data

176
Method B
B

177
Method B
B

178
Method B
A

179
Method B
B

180
Method B
A

181
Method B
A

182
Method B
D

183
Method B
B

184
Method B
D

185
Method B
C

186
Method B
B

187
Method B
B

188
Method B
B

189
Method B
B

190
Method C
B

191
Method B
A

192
Method C
B

193
Method B
A

194
Method C
B

195
Method B
A

196
Method B
A

197
Method C
B

198
Method C
B

199
Method B
B

200
Method B
A

201
Method B
A

202
Method C
B

203
Method B
B

204
Method B
C

205
Method B
B

206
Method B
B

207
Method C
B

208
Method B
B

209
Method B
C

210
Method B
C

211
Method B
D

212
Method B
D

213
Method B
C

214
Method B
A

215
Method B
A

216
Method B
D

217
Method B
C

218
Method B
B

219
Method C
B

220
Method B
B

221
Method B
B

222
Method B
B

223
Method B
B

224
Method B
B

225
Method B
A

226
Method B
B

227
Method B
A

228
Method B
B

229
Method B
B

230
Method B
A

231
Method B
A

232
Method B
A

233
Method B
B

234
Method B
A

235
Method B
B

236
Method B
B

237
Method B
B

238
Method B
A

239
Method B
B

240
Method B
A

241
Method B
A

242
Method C
B

243
Method B
A

244
Method B
B

245
Method B
B

246
Method B
B

247
Method B
B

248
Method B
B

249
Method B
B

250
Method B
B

251
Method B
B

252
Method B
B

253
Method B
B

254
Method B
A

255
Method B
A

256
Method B
A

257
Method B
A

258
Method B
B

TABLE 182

Inhibitory

Compound
Assay Method
Activity

259
Method B
B

260
Method B
B

261
Method B
C

262
Method B
C

263
Method B
C

264
Method B
C

265
Method B
D

266
Method B
C

267
Method B
C

268
Method B
A

269
Method B
A

270
Method B
C

271
Method B
D

272
Method B
B

273
Method B
C

274
Method B
A

275
Method B
B

276
Method B
B

277
Method B
B

278
Method B
B

279
Method B
B

280
Method B
B

281
Method B
B

282
Method C
B

283
Method B
A

284
Method C
B

285
Method B
A

286
Method B
A

287
Method B
A

288
Method C
B

289
Method B
A

290
Method C
C

291
Method C
C

292
Method C
C

293
Method C
C

294
Method C
C

295
Method C
C

296
Method C
C

297
Method C
C

298
Method C
C

299
Method C
B

300
Method C
C

301
Method C
C

302
Method C
B

303
Method C
D

304
Method C
C

305
Method C
D

306
Method C
B

307
Method C
D

308
Method C
B

309
Method C
B

310
Method C
C

311
Method C
C

312
Method C
B

313
Method C
C

314
Method C
D

315
Method C
C

316
Method C
B

317
Method C
D

318
Method C
C

319
Method C
B

320
Method C
C

321
Method C
C

322
Method C
D

323
Method C
C

324
Method C
C

325
Method C
C

326
Method C
A

327
Method C
C

328
Method C
C

329
Method C
C

330
Method C
C

331
Method C
C

332
Method C
C

333
Method C
C

334
Method C
D

335
Method C
C

336
Method C
B

337
Method C
B

338
Method C
B

339
Method C
B

340
Method C
B

341
Method C
B

342
Method C
C

343
Method C
B

344
Method C
C

TABLE 183

Inhibitory

Compound
Assay Method
Activity

345
Method C
A

346
Method C
B

347
Method C
B

348
Method C
A

349
Method C
A

350
Method C
A

351
Method C
B

352
Method C
D

353
Method C
A

354
Method C
A

355
Method C
A

356
Method C
A

357
Method C
C

358
Method C
C

359
Method C
C

360
Method C
D

361
Method C
D

362
Method C
B

363
Method C
B

364
Method C
B

365
Method C
B

366
Method B
B

367
Method B
A

368
Method B
A

369
Method B
A

370
Method B
A

371
Method B
B

372
Method B
B

373
Method C
B

374
Method B
A

375
Method C
B

376
Method C
B

377
Method C
B

378
Method C
B

379
Method B
A

380
Method B
A

381
Method C
B

382
Method C
B

383
Method C
B

384
Method B
A

385
Method B
A

386
Method B
A

387
Method C
B

388
Method C
B

389
Method B
A

390
Method C
B

391
Method C
B

392
Method B
C

393
Method B
B

394
Method C
B

395
Method B
B

396
Method B
B

397
Method B
A

398
Method B
B

399
Method B
B

400
Method B
A

401
Method C
B

402
Method B
A

403
Method B
B

404
Method B
A

405
Method C
B

406
Method C
C

407
Method C
B

408
Method B
B

409
Method C
B

410
Method B
A

411
Method B
A

412
Method C
B

413
Method C
B

414
Method B
B

415
Method B
B

416
Method B
A

417
Method B
B

418
Method B
B

419
Method B
A

420
Method B
B

421
Method B
B

422
Method B
B

423
Method B
B

424
Method B
A

425
Method C
B

426
Method B
A

427
Method C
B

428
Method C
C

429
Method C
B

430
Method C
B

TABLE 184

Inhibitory

Compound
Assay Method
Activity

431
Method C
B

432
Method C
C

433
Method C
B

434
Method C
C

435
Method C
C

436
Method C
B

437
Method C
B

438
Method C
B

439
Method C
B

440
Method C
C

441
Method C
C

442
Method C
D

443
Method C
C

444
Method C
C

445
Method C
C

446
Method C
C

447
Method C
B

448
Method C
B

449
Method C
B

450
Method C
B

451
Method C
B

452
Method C
B

453
Method C
C

454
Method C
B

455
Method C
C

456
Method C
B

457
Method C
B

458
Method C
C

459
Method C
B

460
Method C
C

461
Method C
B

462
Method C
B

463
Method C
B

464
Method C
B

465
Method C
B

466
Method C
B

467
Method C
B

468
Method C
C

469
Method C
B

470
Method C
B

471
Method C
C

472
Method C
B

473
Method C
B

474
Method C
B

475
Method C
B

476
Method C
B

477
Method C
B

478
Method C
B

479
Method C
B

480
Method C
B

481
Method C
B

482
Method C
A

483
Method C
B

484
Method C
B

485
Method C
B

486
Method C
A

487
Method C
A

488
Method C
B

489
Method C
B

490
Method C
A

491
Method C
C

492
Method C
B

493
Method C
B

494
Method C
B

495
Method C
B

496
Method C
B

497
Method C
B

498
Method C
B

499
Method C
B

500
Method C
B

501
Method C
B

502
Method C
B

503
Method C
B

504
Method C
B

505
Method C
A

506
Method C
B

507
Method C
B

508
Method C
B

509
Method C
B

510
Method C
A

511
Method C
B

512
Method C
A

513
Method C
B

514
Method C
A

515
Method C
B

516
Method C
B

TABLE 185

Inhibitory

Compound
Assay Method
Activity

517
Method C
B

518
Method C
C

519
Method C
B

520
Method C
B

521
Method C
B

522
Method C
B

523
Method C
B

524
Method C
B

525
Method C
B

526
Method C
C

527
Method C
D

528
Method C
C

TABLE 186

Inhibitory

Compound
Assay Method
Activity

529
Method C
C

530
Method C
B

531
Method C
A

532
Method C
B

533
Method C
A

534
Method C
A

535
Method C
A

536
Method C
A

537
Method C
B

538
Method C
C

539
Method C
B

540
Method C
B

541
Method C
C

542
Method C
C

543
Method C
B

544
Method C
C

545
Method C
C

546
Method C
B

547
Method C
B

548
Method C
C

549
Method C
B

550
Method C
C

551
Method C
C

552
Method C
C

553
Method C
C

554
Method C
C

555
Method C
B

556
Method C
B

557
Method C
B

558
Method C
C

559
Method C
B

560
Method C
B

561
Method C
D

562
Method C
C

563
Method C
C

564
Method C
B

565
Method C
C

566
Method C
B

567
Method C
D

568
Method C
B

569
Method C
A

570
Method C
A

571
Method C
C

572
Method C
B

573
Method C
B

574
Method C
B

575
Method C
B

576
Method C
B

577
Method C
A

578
Method C
B

579
Method C
B

580
Method C
A

581
Method C
A

582
Method C
A

583
Method C
A

584
Method C
A

585
Method C
A

586
Method C
A

587
Method C
D

588
Method C
C

589
Method C
D

590
Method C
C

591
Method C
C

592
Method C
B

593
Method C
B

594
Method C
B

595
Method C
C

596
Method C
B

597
Method C
B

598
Method C
B

599
Method C
B

600
Method C
A

601
Method C
C

602
Method C
C

603
Method C
C

604
Method C
C

605
Method C
C

606
Method C
D

607
Method C
B

608
Method C
B

609
Method C
B

610
Method C
D

611
Method C
B

612
Method C
C

613
Method C
B

614
Method C
C

TABLE 187

Assay
Inhibitory

Compound
Method
Activity

615
Method C
A

616
Method C
A

617
Method C
C

618
Method C
B

619
Method C
B

620
Method C
A

621
Method C
A

622
Method C
C

623
Method C
C

624
Method C
B

625
Method C
C

626
Method C
B

627
Method C
C

628
Method C
A

629
Method C
A

630
Method C
C

631
Method C
C

632
Method C
B

633
Method C
B

634
Method C
C

635
Method C
D

636
Method C
B

637
Method C
D

638
Method C
C

639
Method C
C

640
Method C
D

641
Method C
D

642
Method C
B

643
Method C
C

644
Method C
C

645
Method C
C

646
Method C
D

647
Method C
D

648
Method C
D

649
Method C
B

650
Method C
D

651
Method C
B

652
Method C
B

653
Method C
C

654
Method C
A

655
Method C
C

656
Method C
C

657
Method C
A

658
Method C
B

659
Method C
D

660
Method C
D

661
Method C
D

662
Method C
B

663
Method C
C

664
Method C
B

665
Method C
B

666
Method C
B

667
Method C
B

668
Method C
C

669
Method C
B

670
Method C
B

671
Method C
C

672
Method C
B

673
Method C
A

674
Method C
A

675
Method C
A

676
Method C
A

677
Method C
A

678
Method C
B

679
Method C
A

680
Method C
B

681
Method C
A

682
Method C
C

683
Method C
B

684
Method C
B

685
Method C
A

686
Method C
B

687
Method C
C

688
Method C
B

689
Method C
A

690
Method C
B

691
Method C
C

692
Method C
B

693
Method C
B

694
Method C
B

695
Method C
C

696
Method C
C

697
Method C
B

698
Method C
B

699
Method C
C

700
Method C
B

TABLE 188

Assay
Inhibitory

Compound
Method
Activity

701
Method C
C

702
Method C
B

703
Method C
B

704
Method C
B

705
Method C
C

706
Method C
B

707
Method C
C

708
Method C
B

709
Method C
C

710
Method C
C

711
Method C
C

712
Method C
C

713
Method C
B

714
Method C
C

715
Method C
B

716
Method C
C

717
Method C
C

718
Method C
B

719
Method C
C

720
Method C
C

721
Method C
B

722
Method C
A

723
Method C
A

724
Method C
A

725
Method C
B

726
Method C
A

727
Method C
C

728
Method C
A

729
Method C
A

730
Method C
A

731
Method C
A

732
Method C
A

733
Method C
A

734
Method C
A

735
Method C
A

736
Method C
A

737
Method C
A

738
Method C
A

739
Method C
A

740
Method C
A

741
Method C
B

742
Method C
B

743
Method C
A

744
Method C
B

745
Method C
A

746
Method C
A

747
Method C
B

748
Method C
A

749
Method C
A

750
Method C
B

751
Method C
A

752
Method C
A

753
Method C
A

754
Method C
A

755
Method C
C

756
Method C
C

757
Method C
B

758
Method C
B

759
Method C
B

760
Method C
B

761
Method C
C

762
Method C
D

763
Method C
B

764
Method C
B

765
Method C
C

766
Method C
B

767
Method C
C

768
Method C
D

769
Method C
B

770
Method C
C

771
Method C
C

772
Method C
C

773
Method C
D

774
Method C
B

775
Method C
A

776
Method C
A

777
Method C
A

778
Method C
A

779
Method C
A

TABLE 189

Assay
Inhibitory

Compound
Method
Activity

780
Method C
C

781
Method C
D

782
Method C
C

783
Method C
B

784
Method C
C

785
Method C
C

786
Method C
C

787
Method C
C

788
Method C
D

789
Method C
B

790
Method C
A

791
Method C
C

792
Method C
C

793
Method C
C

794
Method C
B

795
Method C
A

796
Method C
C

797
Method C
B

798
Method C
C

799
Method C
B

800
Method C
B

801
Method C
C

802
Method C
D

803
Method C
D

804
Method C
D

805
Method C
C

806
Method C
D

807
Method C
B

808
Method C
D

809
Method C
C

810
Method C
C

811
Method C
D

812
Method C
C

813
Method C
D

823
Method C
B

824
Method C
A

825
Method C
D

826
Method C
B

827
Method C
D

828
Method C
D

829
Method C
C

830
Method C
C

831
Method C
C

832
Method C
D

833
Method C
D

834
Method C
C

835
Method C
D

836
Method C
B

837
Method C
D

838
Method C
D

839
Method C
C

840
Method C
C

841
Method C
D

842
Method C
C

843
Method C
D

844
Method C
D

845
Method C
C

846
Method C
D

847
Method C
D

848
Method C
D

849
Method C
D

850
Method C
C

851
Method C
C

852
Method C
D

853
Method C
D

854
Method C
D

855
Method C
D

856
Method C
D

TABLE 190

Assay
Inhibitory

Compound
Method
Activity

814
Method C
C

815
Method C
A

816
Method C
B

817
Method C
A

818
Method C
D

819
Method C
C

820
Method C
B

821
Method C
C

822
Method C
D

857
Method C
D

858
Method C
B

859
Method C
D

860
Method C
C

861
Method C
B

862
Method C
B

863
Method C
C

864
Method C
D

865
Method C
C

TABLE 191

Assay
Inhibitory

Compound
Method
Activity

866
Method C
D

867
Method C
B

Test Example 4
CYP Inhibition Test

Using commercially available pooled human hepatic microsome, the compound was tested to assess inhibitory effect on the typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), specifically, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenyloin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6) and terfenedine hydroxylation (CYP3A4).

The reaction conditions were as follows.

Substrates:

- 0.5 μmol/L ethoxyresorufin (CYP1A2),
- 100 μmol/L tolbutamide (CYP2C9),
- 50 μmol/L S-mephenitoin (CYP2C19),
- 5 μmol/L dextromethorphan (CYP2D6),
- 1 μmol/L terfenedine (CYP3A4);
  
  Reaction Time: 15 minutes;

Reaction Temperature: 37° C.;

Enzyme: pooled human hepatic microsome 0.2 mg protein/mL;

Concentration of Test Compound: 1, 5, 10, 20 μmol/L (four points).

A test sample, which contains the substrate, human hepatic microsome and test compound at the amounts as described above in 50 mM Hepes buffer, was added to a 96-well plate.

The cofactor NADPH was added to initiate metabolism reaction. After the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by fluorescent multilabel counter. Tributamide hydroxide (CYP2C9 metabolite), mephenyloin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were determined by LC/MS/MS.

Only DMSO, which was the solvent for the test compound, was added to the reaction system as the control (100%). For each concentration of the test compound, the remaining activity (%) was calculated, and the IC50 was calculated by reverse presumption by a logistic model using the concentration and the inhibition rate.

Test Example 5
Metabolic Stability

Assessment of metabolic stability in hepatic microsomes:

To tris-hydrochloric acid buffer (pH 7.4), were added NADPH (the final concentration was 1 mM in case of oxidative metabolism), hepatic microsomes (the final concentration was 0.5 mg protein/mL) and test compound (the final concentration was 2 μM), and the mixture was reacted at 37° C. for 0 and 30 minutes. In case of conjugated glucuronic acid, UDPGA (the final concentration was 5 mM) was added instead of NADPH. The reaction was stopped by addition of acetonitrile/methanol=1/1 (v/v) (2 parts by volume of the reaction solution). After the centrifugation, the supernatant was measured by HPLC. By comparing the results obtained from the reactions for 0 and 30 minutes, the loss of the compound by metabolic reaction was calculated to assess the metabolic stability of the compound of the invention.

Test Example 6
Powder Solubility Test

Appropriate amount of test sample was put into appropriate container. To the container was added 200 μL each of JP-1 solution (sodium chloride 2.0 g, hydrochloric acid 7.0 mL and water to reach 1000 mL), JP-2 solution (phosphate buffer (pH 6.8) 500 mL and water 500 mL) and 20 mmol/L TCA (sodium taurocholate)/JP-2 solution (TCA 1.08 g and water to reach 100 mL). In the case that the test compound was dissolved after the addition of the test solution, bulk powder was added as appropriate. The container was sealed and shaken for 1 hour at 37° C. The mixture was filtered, and 100 μL of methanol was added to each 100-μL aliquot of the filtrate to make the filtrates two-fold diluted. The dilution ratio was changed if necessary. After checking if any bubble or precipitate occurred, the container was sealed and shaken. Quantification was performed by absolute calibration method using HPLC.

Formulation Examples

The following Formulation Examples are only exemplified and not intended to limit the scope of the invention.

Formulation Example 1
Tablets

Compound of formula (I)
15 mg

Starch
15 mg

Lactose
15 mg

Crystalline cellulose
19 mg

Polyvinyl alcohol
3 mg

Distilled water
30 ml

Calcium stearate
3 mg

The above ingredients except calcium stearate are uniformly mixed and milled to granulate, and dried to obtain a suitable size of granules. Then, the granules are added with calcium stearate and compressed to form a tablet.

Formulation Example 2
Capsules

Compound of formula (I)
10 mg

Magnesium stearate
10 mg

Lactose
80 mg

The above ingredients are mixed uniformly to obtain powders or fine granules, which are then filled in a capsule.

Formulation Example 3
Granules

Compound of formula (I)
30 g

Lactose
265 g

Magnesium Stearate
5 g

The above ingredients are mixed uniformly and compressed. The compressed mixture is milled, granulated and sieved to obtain the desired size of granules.

INDUSTRIAL APPLICABILITY

The present invention is applicable in the pharmaceutical field, for example, in the development and production of medicaments for the treatment of fibrotic diseases.

Number	Date	Country	Kind
2013-041176	Mar 2013	JP	national
2013-227215	Oct 2013	JP	national

8-SUBSTITUTED IMIDAZOPYRIMIDINONE DERIVATIVE HAVING AUTOTAXIN INHIBITORY ACTIVITY

Information

Publication Number

Date Filed

Date Published

Inventors

Original Assignees

CPC

International Classifications

Abstract

Description

Claims

Priority Claims (2)

PCT Information