Fluorene compound and pharmaceutical use thereof

Abstract

The present invention provides an agent for the prophylactic or treatment of diabetes, diabetic complications, insulin resistance syndrome, metabolic syndrome, hyperglycemia, dyslipidemia, atherosclerosis, cardiac failure, cardiomyopathy, myocardial ischemia, brain ischemia, cerebral apoplexy, pulmonary hypertension, hyperlactacidemia, mitochondrial disease, mitochondrial encephalomyopathy or cancer, namely, a PDHK inhibitor and the like. A compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof: wherein each symbol is as defined in the specification.

1 . (canceled) 
     
     
         2 . A method of making a compound of formula [Vd] by reacting a compound of formula [Vb] and a compound of formula [Vc]: 
       
         
           
           
               
               
           
         
         wherein: 
         Hal 1  is a halogen atom; 
         Rx is a hydrogen atom or an alkyl group; 
         R a  is: 
         (1) a hydrogen atom; or 
         (2) a halogen atom; 
         R b0  is a substituent that can be converted to R b , wherein R b  is: 
         (1) a hydrogen atom; 
         (2) a halogen atom; 
         (3) a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from group A; 
         (4) a C 2-6  alkenyl group optionally substituted by 1 to 5 substituents independently selected from group C; 
         (5) a C 2-6  alkynyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (6) a cyano group; 
         (7) —C(═O)—R b1 , wherein R b1  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from group B; 
         (8) —C(═O)—OR b2 , wherein R b2  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (9) —C(═O)—NR b3 R b4 , wherein each of R b3  and R b4  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (10) —C(═O)—NR b5 —OR b6 , wherein each of R b5  and R b6  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (11) —OR b7 , wherein R b7  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (12) —NR b8 R b9 , wherein each of R b8  and R b9  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (13) —NR b10 —C(═O)—R b11 , wherein each of R b10  and R b11  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (14) —NR b12 —C(═O)—OR b13 , wherein R b12  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the Group B, and R b13  is a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (15) —O—C(═O)—NR b14 R b15 , wherein each of R b14  and R b15  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; or 
         (16) a group represented by the following formula: 
       
       
         
           
           
               
               
           
         
         wherein: 
         Y b  is: 
         (i) a single bond; 
         (ii) a C 1-6  alkylene; 
         (iii) a C 2-6  alkenylene; 
         (iv) —O—(CH 2 ) n1 —, wherein n1 is an integer of 0 to 4; 
         (v) —O—(CH 2 ) n2 —C(═O)—, wherein n2 is an integer of 0 to 4; 
         (vi) —C(═O)—; or 
         (vii) —NR b16 , wherein R b16  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         ring T is: 
         (i) a C 6-10  aryl group; 
         (ii) a C 3-10  cycloalkyl group; 
         (iii) a C 5-10  bridged cycloalkyl group; 
         (iv) a monocyclic aromatic heterocyclic group, which contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms; or 
         (v) a monocyclic non-aromatic heterocyclic group, which contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms; 
         each R is independently a substituent selected from group D; and 
         p is an integer of 0 to 4; 
         R c  is: 
         (1) a hydrogen atom; 
         (2) a halogen atom; 
         (3) a C 1-6  alkyl group; 
         (4) —C(═O)—OR c1 , wherein R c1  is a hydrogen atom or a C 1-6  alkyl group; 
         (5) —OR c2 , wherein R c2  is a hydrogen atom or a C 1-6  alkyl group; 
         (6) —NR c3 R c4 , wherein each of R c3  and R c4  is independently selected from a hydrogen atom and a C 1-6  alkyl group; or 
         (7) —NR c5 —C(═O)—R c6 , wherein each of R c5  and R c6  is independently selected from a hydrogen atom and a C 1-6  alkyl group; 
         each R e  is independently selected from: 
         (1) a halogen atom; and 
         (2) a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; and 
         n is an integer of 0 to 3; 
         wherein the group A is: 
         (a) a halogen atom; 
         (b) a cyano group; 
         (c) —C(═O)—R A1 , wherein R A1  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (d) —C(═O)—OR A2 , wherein R A2  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (e) —C(═O)—NR A3 R A4 , wherein each of R A3  and R A4  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (f) —C(═O)—NR A5 —OR A6 , wherein each of R A5  and R A6  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (g) —OR A7 , wherein R A7  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (h) —NR A8 R A9 , wherein each of R A8  and R A9  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (i) —NR A10 —C(═O)—R A11  wherein each of R A10  and R A11  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (j) —NR A12 —C(═O)—OR A13 , wherein R A12  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B, and R A13  is a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (k) —S(═O) 2 —R A14 , wherein R A14  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; 
         (l) —S(═O) 2 —OR A15 , wherein R A15  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group B; or 
         (m) —Si—(CH 2 —CH 3 ) 3 ; 
         wherein the group B is: 
         (a) a halogen atom; 
         (b) a cyano group; 
         (c) —C(═O)—R B1 , wherein R B1  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (d) —C(═O)—OR B2 , wherein R B2  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (e) —C(═O)—NR B3 R B4 , wherein each of R B3  and R B4  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (f) —C(═O)—NR B5 —OR B6 , wherein each of R B5  and R B6  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (g) —OR B7 , wherein R B7  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (h) —NR B8 R B9 , wherein each of R B8  and R B9  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (i) —NR B10 —C(═O)—R B11 , wherein each of R B10  and R B11  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (j) —NR B12 —S(═O) 2 R B13 , wherein each of R B12  and R B13  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (k) —NR B14 —C(═O)—OR B15 , wherein R B14  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C, and R B15  is a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C; 
         (l) —S(═O) 2 —R B16 , wherein R B16  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C, or 
       
       (m) —S(═O) 2 —OR B17 , wherein R B17  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group C;
 wherein the group C is: 
 (a) a halogen atom; 
 (b) —C(═O)—R C1 , wherein R C1  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 halogen atoms; 
 (c) —C(═O)—OR C2 , wherein R C2  is a hydrogen atom or a C 1-6  alkyl group; and 
 (d) —OR C3 , wherein R C3  is a hydrogen atom or a C 1-6  alkyl group; 
 wherein the group D is: 
 (a) a halogen atom; 
 (b) a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from group E; 
 (c) a C 1-6  alkyl group substituted by a C 6-10  aryl group optionally substituted by 1 to 5 substituents independently selected from group F; 
 (d) a C 1-6  alkyl group substituted by a C 3-10  cycloalkyl optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (e) a C 1-6  alkyl group substituted by a C 5-10  bridged cycloalkyl optionally substituted by 1 to substituents independently selected from the group F; 
 (f) a C 1-6  alkyl group substituted by a monocyclic aromatic heterocyclic group optionally substituted by 1 to 5 C 1-6  alkyl groups, where the monocyclic aromatic heterocyclic group contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms; 
 (g) a C 3-10  cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (h) a C 5-10  bridged cycloalkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (i) a cyano group; 
 (j) —C(═O)—R D1 , wherein R D1  is a hydrogen atom, a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E, or a monocyclic non-aromatic heterocyclic group optionally substituted by 1 to 5 substituents independently selected from the group F, where the monocyclic non-aromatic heterocyclic group contains 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and has 3 to 7 ring-constituting atoms; 
 (k) —C(═O)—OR D2 , wherein R D2  is a hydrogen atom, or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (l) —C(═O)—NR D3 R D4 , wherein each of R D3  and R D4  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (m) —C(═O)—NR D5 —OR D6 , wherein each of R D5  and R D6  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (n) —OR D7 , wherein R D7  is a hydrogen atom, or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (o) —NR D8 R D9 , wherein each of R D8  and R D9  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (p) —NR D10 —C(═O)—R D11 , wherein each of R D10  and R D11  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (q) —NR D12 —C(═O)—OR D13 , wherein R D12  is a hydrogen atom, or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E, and R D13  is a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; 
 (r) —S(═O) 2 —R D14 , wherein R D14  is a hydrogen atom, or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E; or 
 (s) —S(═O) 2 —OR D15 , wherein R D15  is a hydrogen atom, or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group E, 
 wherein the group E is: 
 (a) a halogen atom; 
 (b) a cyano group; 
 (c) —C(═O)—R E1 , wherein R E1  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (d) —C(═O)—OR E2 , wherein R E2  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (e) —C(═O)—NR E3 R E4 , wherein each of R E3  and R E4  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (f) —C(═O)—NR E5 —OR E6 , wherein each of R E5  and R E6  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (g) —OR E7 , wherein R E7  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (h) —NR E8 R E9 , wherein each of R E8  and R E9  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (i) —NR E10 —C(═O)—R E11 , wherein each of R E10  and R E11  is independently selected from a hydrogen atom and a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (j) —NR E12 —C(═O)—OR E13 , wherein R E12  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F, and R E13  is a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (k) —S(═O) 2 —R E14 , wherein R E14  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; 
 (l) —S(═O) 2 —OR E5 , wherein R E15  is a hydrogen atom or a C 1-6  alkyl group optionally substituted by 1 to 5 substituents independently selected from the group F; or 
 (m) —NR E16 —S(═O) 2 —R E17 , wherein each of R E16  and R E17  are is a hydrogen atom or a C 1-6  alkyl group; and 
 wherein the group F is: 
 (a) —(CH 2 ) nF1 —C(═O)—OR F1 , wherein R F1  is a hydrogen atom or a C 1-6  alkyl group, and nF1 is an integer of 0 to 4; or 
 (b) —(CH 2 ) nF2 —OR F2 , wherein R F2  is a hydrogen atom or a C 1-6  alkyl group, and nF2 is an integer of 0 to 4.