US 20120277430A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0277430 A1 TANGUCH et al. (43) Pub. Date: Nov. 1, 2012

(54) PYRIDAZINONE COMPOUNDS (52) U.S. Cl...... 544/238 (57) ABSTRACT (76) Inventors: Takahiko TANGUCHI, Cambridge (GB); Jun Kunitomo, The present invention provides a compound which has the Kanagawa (JP) effect of PDE inhibition, and which is useful as a medicament for preventing or treating schizophrenia or so on. A com pound of formula (I), wherein R1 represents a substituent; (21) Appl. No.: 13/543,296 R2 represents a hydrogen atom, or a Substituent; R3 repre sents a hydrogenatom, or a substituent; Ring. A represents an (22) Filed: Jul. 6, 2012 aromatic ring which can be substituted, and Ring Brepresents a 5-membered heteroaromatic ring which can be substituted, Related U.S. Application Data or a salt thereof. (62) Division of application No. 13/148,172, filed on Oct. 20, 2011, filed as application No. PCT/US2010/ (Io) 000307 on Feb. 4, 2010. (60) Provisional application No. 61/202,207, filed on Feb. 5, 2009, provisional application No. 61/213,927, filed on Jul 30, 2009.

Publication Classification (51) Int. Cl. CO7D 403/14 (2006.01) Patent Application Publication Nov. 1, 2012 Sheet 1 of 3 US 2012/0277430 A1

2.50 2.00 1.50 1.OO . 0.50 O.OO ... Vehicle 3 10 30 Compound A (mg/kg, i.p.)

Fig. 1A

0.25 0.20 - 0. 15 ------0. 10 0.05 -

0.00 - --- vehicle 3 Compound A

Fig. 1B

"control

OCompound A: 3

Z Compound A: 10

8 Compound A: 30

a Compound A:100 (in g/kg, ip.)

-30t O 0 min O to 90 m in

Fig. 2A Patent Application Publication Nov. 1, 2012 Sheet 2 of 3 US 2012/0277430 A1

control

Compound A: 3 2) Compound A: 10 Compound A: 30 (in g/kg, ip)

-30 to Omin O to 90 min

Fig. 2B

i

* O O O 1 3 10 30 RS O.3 Compound A (mg/kg, i.p.) MK-801 (0.3 mg/kg, s.c.) - Fig. 3 Patent Application Publication Nov. 1, 2012 Sheet 3 of 3 US 2012/0277430 A1

3000

2500

2000 squnooA??a?oe 1500 1000

-60 to 0 min O to 90 min

Fig. 4 US 2012/0277430 A1 Nov. 1, 2012

PYRIDAZINONE COMPOUNDS medications, D or D/5-HT, antagonists, mainly derives from their activation of the indirect pathway in the striatum. TECHNICAL FIELD As PDE10A inhibitors are able to activate this pathway, this Suggests that PDE10A inhibitors are promising as antipsy 0001. The present invention relates to pyridazinone com chotic drugs. The excessive D receptor antagonism in the pounds. brain by Dantagonists causes problems of extrapyramidal side effects and hyperprolactinaemia. However the expres sion of PDE10A is limited to these striatal pathways in the BACKGROUND OF THE INVENTION brain, thus side effects by PDE10A inhibitors were expected to be weaker compared with current Dantagonists. Regard 0002 Phosphodiesterases (PDEs) are a superfamily of ing hyperprolactinaemia, PDE10A inhibitors would produce enzymes encoded by 21 genes and Subdivided into 11 distinct no prolactin elevation due to lack of D receptor antagonism families according to structural and functional properties. in the pituitary. Moreover, the presence of PDE10A in a direct These enzymes metabolically inactivate the ubiquitous intra pathway makes it likely that PDE10A inhibition will have cellular second messengers, cyclic adenosine monophos some advantage over current Dantagonists; the direct path phate (cAMP) and cyclic guanosine monophosphate way is thought to promote desired action, and activation of (cGMP): PDEs selectively catalyze the hydrolysis of the this pathway by PDE10A inhibitors may counteract extrapy 3'-ester bond, forming the inactive 5'-monophosphate. On the ramidal symptoms induced by excessive D receptor antago basis of substrate specificity, the PDE families can be further nism. In addition, activation of this pathway could facilitate striatal-thalamic outflow, promoting the execution of proce classified into three groups: i) the cAMP-PDEs (PDE4, dural Strategies. Furthermore, enhancement of second mes PDE7, PDE8), ii) the coMP-PDEs (PDE5, PDE6 and PDE9), senger levels without blockade of dopamine and/or other and iii) the dual-substrate PDEs (PDE1, PDE2, PDE3, neurotransmitter receptors may also provide therapeutic PDE10 and PDE11). advantages with fewer adverse side-effects compared with 0003. The cAMP and coMP are involved in the regulation current antipsychotics (e.g., hyperprolactinaemia and weight of virtually every physiological process Such as pro-inflam gain). This unique distribution and function in the brain indi matory mediator production and action, ion channel function, cates that PDE10A represents an important new target for the muscle relaxation, learning and memory formation, differen treatment of neurological and psychiatric disorders, in par tiation, apoptosis, lipogenesis, glycogenolysis and gluconeo ticular psychotic disorders like Schizophrenia. genesis. Especially, in neurons, these second messengers 0005. As a phosphodiesterase (PDE)10 inhibitor, a com have important role in the regulation of synaptic transmission pound represented by the formula: as well as in neuronal differentiation and survival (Nat. Rev. Drug Discov. 2006, vol. 5: 660-670). Regulation of these processes by cAMP and ccjMP are accompanied by activa tion of protein kinase A(PKA) and protein kinase G (PKG), which in turn phosphorylate a variety of substrates, including transcription factors, ion channels and receptors that regulate a variety of physiological processes. Intracellular cAMP and cGMP concentrations seem to be temporally, spatially, and functionally compartmentalized by regulation of adenyl and guanyl cyclases in response to extracellular signaling and their degradation by PDEs (Circ. Res. 2007, vol. 100(7): 0006 wherein Z is 950-966). PDEs provide the only means of degrading the cyclic nucleotides cAMP and ccjMP in cells, thus PDEs play an essential role in cyclic nucleotide signaling. Thereby, i PDEs could be promising targets for various therapeutic 21 drugs. Y N X 0004 Phosphodiesterase 10A (PDE10A) was discovered y 1 n n Nx N X in 1999 by three independent groups (Proc. Natl. Acad. Sci. USA 1999, vol.96: 8991-8996, J. Biol. Chem. 1999, vol. 274: Y Y 18438-18445, Gene 1999, vol. 234: 109-117). Expression N4N4 studies have shown that PDE10A has the most restricted 0007) was disclosed in WO2006/072828 Pamphlet. distribution within the all known PDE families; the PDE10A 0008 Further, as aphosphodiesterase (PDE)10 inhibitor, a mRNA is highly expressed only in brain and testes (Eur. J. compound represented by the general formula Biochem. 1999, vol. 266: 1118-1127, J. Biol. Chem. 1999, (I) vol. 274: 18438-18445). In the brain, mRNA and protein of PDE10A are highly enriched in medium spiny neurons (MSNs) of the striatum (Eur. J. Biochem. 1999, vol. 266: 1118-1127, Brain Res. 2003, vol. 985: 113-126). MSNs are classified into two groups: the MSN that express D dopam ine receptors responsible for a direct (striatonigral) pathway and the MSN that express D dopamine receptors responsible for an indirect (striatopallidal) pathway. The function of direct pathway is to plan and execution, while indirect path way is to act as a brake on behavioral activation. As PDE10A expresses in both MSNs, PDE10A inhibitors could activate both of these pathways. The antipsychotic efficacy of current 0009 was also disclosed in WO2008/001182 Pamphlet.

US 2012/0277430 A1 Nov. 1, 2012

I0059) R' is a hydrogen atom, or a methyl group, and 0090 8 0060 Ra is a hydrogen atom, or a Cacyclic hydrocar 0091. The compound according to any one of the above mentioned 1 to 7, wherein bon group which can be substituted, a compound of formula: 0092 R represents 0093 a hydrogenatom, or a Coalkoxy group which can be substituted. 0094. 9 0.095 The compound according to any one of the above mentioned 1 to 8, wherein (0096 R represents 0097 a hydrogen atom, or a Coalkoxy group. 0.098 (10) 0099. The compound according to any one of the above mentioned 1 to 9), wherein 0100 R represents 0101 a hydrogen atom. 01.02 11 0061 wherein 0103) The compound according to any one of the above 0062 Ring A" is a benzene ring which can be substituted mentioned 1 to 10, wherein by halogen, and 0104 Ring. A represents 0063 R'" is an acyl group 0105 a benzene ring which can be substituted by 1 to 5 0064 are excluded: substituents selected from 0065 or a salt thereof. 0106 (1) a halogen atom, 0107 (2) a Co alkyl group which can be substituted, 0.066 (2) 0.108 (3) a Coalkoxy group which can be substituted, 0067. The compound according to the above-mentioned 0109 (4) a 4- to 6-membered heterocyclic group contain 1 or 2, wherein ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa 0068 R represents toms which can be substituted, 0069 a halogen atom, a hydroxy group, a Co alkyl 0110 (5) a C- alkylsulfonyl group which can be substi group which can be substituted, or a Co to alkoxy group tuted, which can be substituted. I0111 (6) a C-, cycloalkyl group which can be substituted, 0070 (3) 0112 (7) a cyano group, 0071. The compound according to the above-mentioned 0113 (8) a carbamoyl group which can be substituted, 1 or 2, wherein 0114 (9) a Co alkylsulfonyloxy group which can be 0072 R represents substituted, 0073 a Coalkoxy group which can be substituted by 0115 (10) a C-7 cycloalkyl-C alkynyl group which can one or more Substituents selected from a halogen atom, a be substituted, Coalkoxy group, and a C-7 cycloalkyl group. 0116 (11) a tetrahydropyranyl group which can be substi 0074 (4) tuted, 0075. The compound according to the above-mentioned 0117 (12) a dihydropyranyl group which can be substi 1 or 2, wherein tuted, 0076 R represents 0118 (13) a mono-(Co alkyl-carbonyl)-amino group 0077 a Coalkoxy group. which can be substituted, 0078 [5] 0119 (14) a Coalkoxy-carbonyl group which can be 007.9 The compound according to any one of the above substituted, mentioned 1 to 4, wherein I0120 (15) a Co alkylsulfinyl group which can be sub 0080) R' represents stituted, and 0081 a phenyl group which can be substituted by 1 to 5 I0121 (16) a C- alkylsulfanyl group which can be sub Substituents selected from a halogenatom, a Coalkyl group stituted. which can be substituted, and a Coalkoxy group which can 0.122 12 be substituted. I0123. The compound according to any one of the above 0082 (6 mentioned 1 to 11, wherein 0083. The compound according to any one of the above 0.124 Ring. A represents 0.125 a benzene ring which can be substituted by 1 to 5 mentioned 1 to 5, wherein substituents selected from 0084) R' represents 0.126 (1) a halogen atom, 0085 a phenyl group which can be substituted by 1 to 5 I0127 (2) a Co alkyl group which can be substituted, Substituents selected from a halogen atom, a Co alkyl I0128 (3) a Coalkoxy group which can be substituted, group, and a Coalkoxy group. I0129 (4) a C-, cycloalkyl group, 0.086 7 0.130 (5) a halogeno Co alkylsulfonyloxy group, 0087. The compound according to any one of the above 0131 (6) a C-7 cycloalkyl-C alkynyl group, and mentioned 1 to 6, wherein I0132 (7) a 4- to 6-membered heterocyclic group contain I0088 R' represents ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa 0089 a phenyl group which can be substituted by 1 to 5 toms which can be substituted by one or more substituents halogen atoms. selected from a halogenatom, a hydroxy group, an oxo group, US 2012/0277430 A1 Nov. 1, 2012

a Coalkoxy-carbonyl group, a Coalkoxy group which (0162 18 can be substituted, and a Co alkyl group which can be 0163 The compound according to any one of the above substituted. mentioned 1 to 17, wherein 0133 13 0164 Ring B represents 0134. The compound according to any one of the above 0.165 a pyrazole ring. mentioned 1 to 12, wherein (0166 (19) 0135 Ring. A represents 0167. The compound according to the above-mentioned 0.136 a benzene ring which can be substituted by 1 to 5 2, wherein substituents selected from (0168 R' represents 0.137 (1) a halogen atom, 0169 a phenyl group which can be substituted by 1 to 5 I0138 (2) a Coalkyl group which can be substituted by 1 Substituents selected from a halogenatom, a Coalkyl group to 3 halogen atoms, which can be substituted, and a Coalkoxy group which can I0139 (3) a Coalkoxy group which can be substituted by be substituted, 1 to 3 halogen atoms, (0170 R represents 0140 (4) a C-7 cycloalkyl group, 0171 a halogen atom, a hydroxy group, a Co alkyl 0141 (5) a halogeno Coalkylsulfonyloxy group, group which can be substituted, or a Co alkoxy group 0142 (6) a C-7 cycloalkyl-C alkynyl group, and which can be substituted, 0143 (7) a 4- to 6-membered heterocyclic group contain (0172 R represents ing 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroa 0173 a hydrogenatom, or a Coalkoxy group which can toms which can be substituted by 1 to 4 substituents selected be substituted, from a halogenatom, a hydroxy group, an oxo group, a Co 0.174 Ring. A represents alkoxy-carbonyl group, a Coalkoxy group which can be 0.175 a benzene ring which can be substituted by 1 to 5 Substituted by halogen, and a Co alkyl group which can be substituents selected from Substituted by halogen. 0176 (1) a halogen atom, 0144. 14 (0177 (2) a Co alkyl group which can be substituted, 0145 The compound according to any one of the above 0.178 (3) a Coalkoxy group which can be substituted, mentioned 1 to 13, wherein 0179 (4) a 4- to 6-membered heterocyclic group contain 0146 Ring. A represents ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa 0147 a benzene ring which is substituted with toms which can be substituted, 0148 (1) (i) 1 or 2 halogen atoms, or (ii) one Coalkoxy 0180 (5) a Co alkylsulfonyl group which can be substi group, and tuted, 0149 (2) one 4- to 6-membered heterocyclic group con 0181 (6) a C-, cycloalkyl group which can be substituted, taining 0 or 1 oxygen atom, and 1 to 3 nitrogen atoms as 0182 (7) a cyano group, heteroatoms which can be substituted by 1 to 4 substituents 0183 (8) a carbamoyl group which can be substituted, selected from a halogenatom, a hydroxy group, an oxo group, 0.184 (9) a Co alkylsulfonyloxy group which can be a Coalkoxy-carbonyl group, a Coalkoxy group which substituted, can be substituted by halogen, and a Co alkyl group which 0185 (10) a C-7 cycloalkyl-C alkynyl group which can can be substituted by halogen. be substituted, 0150 15 0186 (11) a tetrahydropyranyl group which can be substi 0151. The compound according to the above-mentioned tuted, 14, wherein 0187 (12) a dihydropyranyl group which can be substi 0152 the 4- to 6-membered heterocyclic group containing tuted, 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroatoms 0188 (13) a mono-(Co alkyl-carbonyl)-amino group represents which can be substituted, 0153 a morpholino group, a pyrrolyl group, a dihydropy 0189 (14) a Coalkoxy-carbonyl group which can be rrolyl group, a pyrazolyl group, a dihydropyrazolyl group, a substituted, piperidyl group, anaZetidinyl group, a pyrrolidinyl group, an (0190 (15) a Co alkylsulfinyl group which can be sub oxazolidinyl group, an imidazolyl group or an imidazolidinyl stituted, and group. (0191 (16) a Co alkylsulfanyl group which can be sub 0154 16 stituted, and 0155 The compound according to any one of the above (0192 Ring B represents mentioned 1 to 15, wherein 0193 an imidazole ring, a pyrazole ring, a triazole ring or 0156 Ring B represents a tetrazole ring, each of which can be further substituted with O157 an imidazole ring, a pyrazole ring, a triazole ring or 1 to 3 substituents selected from a halogen atom, and a Co a tetrazole ring, each of which can be further substituted with alkyl group which can be substituted by halogen. 1 to 3 Substituents selected from a halogen atom, and a Co (0194 20 alkyl group which can be substituted by halogen. 0.195 The compound according to the above-mentioned 0158 17 19, wherein. 0159. The compound according to any one of the above 0196. Ring. A represents mentioned 1 to 16, wherein 0.197 a benzene ring which can be substituted by 1 to 5 0160 Ring B represents substituents selected from 0161 a pyrazole ring which can be further substituted with 0198 (1) a halogen atom, 1 to 3 Substituents selected from a halogen atom, and a Co 0199 (2) a Co alkyl group which can be substituted, alkyl group which can be substituted by halogen. 0200 (3) a Coalkoxy group which can be substituted, US 2012/0277430 A1 Nov. 1, 2012

0201 (4) a C-7 cycloalkyl group, can be substituted by halogen, and a Co alkyl group which 0202 (5) a halogeno Co alkylsulfonyloxy group, can be substituted by halogen, 0203 (6) a C-7 cycloalkyl-C alkynyl group, and 0236 Ring B represents 0204 (7) a 4- to 6-membered heterocyclic group contain 0237 a pyrazole ring. ing 0 or 1 oxygenatom; and 1 to 3 nitrogenatoms as heteroa 0238 23 toms which can be substituted by one or more substituents 0239. The compound according to the above-mentioned selected from a halogenatom, a hydroxy group, an oxo group, 22, wherein a Coalkoxy-carbonyl group, a Coalkoxy group which 0240 the 4- to 6-membered heterocyclic group containing can be substituted, and a C- alkyl group which can be 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroatoms substituted. represents 0205 21 0241 a morpholino group, a pyrrolyl group, a dihydropy 0206. The compound according to the above-mentioned rrolyl group, a pyrazolyl group, a dihydropyrazolyl group, a 2, wherein piperidyl group, anaZetidinyl group, a pyrrolidinyl group, an 0207) R' represents oxazolidinyl group, an imidazolyl group or an imidazolidinyl 0208 a phenyl group which can be substituted by 1 to 5 group. Substituents selected from a halogen atom, a Co alkyl 0242 24 group, and a Coalkoxy group, 0243 The compound according to the above-mentioned 0209 R represents 1, wherein 0210 a Coalkoxy group which can be substituted by 0244) R' represents one or more Substituents selected from a halogen atom, a 0245 an aromatic group which can be substituted, Coalkoxy group, and a C-7 cycloalkyl group, 0246 Ring. A represents 0211 R represents 0247 an aromatic ring which is substituted with 0212 a hydrogen atom, or a Coalkoxy group, 0248 (a) one substituent selected from 0213 Ring. A represents 0249 (1) a C-7 cycloalkyl group which can be substituted, 0214) a benzene ring which can be substituted by 1 to 5 and substituents selected from 0215 (1) a halogen atom, 0250 (2) a 4- to 6-membered heterocyclic group contain 0216 (2) a Coalkyl group which can be substituted by 1 ing 1 to 5 heteroatoms selected from a nitrogenatom, a Sulfur to 3 halogen atoms, atom, and an oxygen atom which can be substituted, and 0217 (3) a Coalkoxy group which can be substituted by (0251 (b) one or more further substituents. 1 to 3 halogen atoms, 0252) 25 0218 (4) a C-7 cycloalkyl group, 0253) The compound according to the above-mentioned 0219 (5) a halogeno Co alkylsulfonyloxy group, 24, wherein 0220 (6) a C-7 cycloalkyl-C alkynyl group, and 0254) R' represents 0221 (7) a 4- to 6-membered heterocyclic group contain 0255 a phenyl group which can be substituted, ing 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroa (0256 R represents toms which can be substituted by 1 to 4 substituents selected 0257 a hydrogenatom, a halogen atom, a hydroxy group, from a halogenatom, a hydroxy group, an oxo group, a Co a Coalkyl group which can be substituted, or a Coalkoxy alkoxy-carbonyl group, a Coalkoxy group which can be group which can be substituted, Substituted by halogen, and a Co alkyl group which can be 0258 R represents Substituted by halogen, 0259 a hydrogenatom, or a Coalkoxy group which can 0222 Ring B represents be substituted, 0223 a pyrazole ring which can be further substituted with 0260 Ring. A represents 1 to 3 substituents selected from a halogen atom, and a Co 0261 a benzene ring which alkyl group which can be substituted by halogen. 0262 is substituted with one substituent selected from 0224 (22 0263 (1) a C-7 cycloalkyl group which can be substituted, 0225. The compound according to the above-mentioned 0264 (2) a dihydropyranyl group which can be substi 2, wherein tuted, 0226) R' represents 0265 (3) a tetrahydropyranyl group which can be substi 0227 a phenyl group which can be substituted by 1 to 5 tuted, and halogen atoms, 0266 (4) a 4- to 6-membered heterocyclic group contain 0228 R represents ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa 0229 a Coalkoxy group, toms which can be substituted, 0230 R represents 0267 and can be substituted by further substituents, and 0231 a hydrogen atom, 0268 Ring B represents 0232 Ring. A represents 0269 an imidazole ring, a pyrazole ring, a triazole ring, a 0233 a benzene ring which is substituted with tetrazole ring, an isoxazole ring, an 1.3-oxazole ring, a furan 0234 (1) (i) 1 or 2 halogen atoms, or (ii) one Coalkoxy ring, or a thiophene ring, each of which can be substituted. group, and 0270 26 0235 (2) one 4- to 6-membered heterocyclic group con 0271 The compound according to the above-mentioned taining 0 or 1 oxygen atom, and 1 to 3 nitrogen atoms as 25, wherein heteroatoms which can be substituted by 1 to 4 substituents 0272 the 4- to 6-membered heterocyclic group containing selected from a halogenatom, a hydroxy group, an oxo group, 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroatoms a Coalkoxy-carbonyl group, a Coalkoxy group which represents US 2012/0277430 A1 Nov. 1, 2012

0273 a morpholino group, a pyrrolyl group, a dihydropy piperidyl group, anaZetidinyl group, a pyrrolidinyl group, an rrolyl group, a pyrazolyl group, a dihydropyrazolyl group, a oxazolidinyl group, an imidazolyl group or an imidazolidinyl piperidyl group, anaZetidinyl group, a pyrrolidinyl group, an group. 0314 30 oxazolidinyl group, an imidazolyl group, an imidazolidinyl 0315 1-2-fluoro-4-(3,3,4,4-tetrafluoropyrrolidin-1-yl) group, an isoxazolyl group, a pyridyl group, a piperazinyl phenyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)py group, or a thiazolyl group. ridazin-4(1H)-one, or a salt thereof. 0274 (27) 0316 (31 0275. The compound according to the above-mentioned 0317 1-2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl-5- 24, wherein methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- 0276 the further substituents are 1 to 4 substituents one, or a salt thereof. 0318 32 selected from 0319 1-4-(3,4-difluoro-1H-pyrrol-1-yl)-2-fluorophe 0277 (1) a halogen atom, nyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin 0278 (2) an oxo group, 4(1H)-one, or a salt thereof. 0279 (3) a hydroxy group, 0320 33 0280 (4) a Co alkyl group which can be substituted, 0321 1-2-fluoro-4-(1H-pyrazol-1-yl)phenyl-5-meth 0281 (5) a Coalkoxy group which can be substituted, oxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, 0282 (6) a Coalkylsulfonyl group, or a salt thereof. 0322 (34 0283 (7) a morpholin-4-yl sulfonyl group, 0323 1-4-(4-chloro-1H-pyrazol-1-yl)-2-fluorophenyl 0284 (8) a cyano group, 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4 0285 (9) a carbamoyl group, (1H)-one, or a salt thereof. 0286 (10) a halogeno Co alkylsulfonyloxy group, 0324 (35) 0287 (11) a C-7 cycloalkyl-C alkynyl group, 0325 1-2-fluoro-4-(2-oxo-1,3-oxazolidin-3-yl)phenyl 0288 (12) a di-Clio alkyl-amino group, 5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4 (1H)-one, or a salt thereof 0289 (13) a mono-(Co alkyl-carbonyl)-amino group, 0326) 36 0290 (14) a Coalkoxy-carbonyl group, 0327 3-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-1-2- 0291 (15) a phenoxy group, fluoro-4-(1H-pyrazol-1-yl)phenyl-5-methoxypyridazin 0292 (16) a Co alkylsulfinyl group, 4(1H)-one, or a salt thereof. 0293 (17) a di-Clio alkyl-amino group, 0328 (37 0294 (18) a benzimidazole-2-yloxy group, and 0329. 3-1-(3-chlorophenyl)-1H-pyrazol-5-yl)-1-(2- 0295 (19) a benzimidazole-2-yl sulfonyl group. fluoro-4-(1H-pyrazol-1-yl)phenyl-5-methoxypyridazin 4(1H)-one, or a salt thereof. 0296 28 0330 38 0297. The compound according to the above-mentioned 0331 1-4-(4,4-dimethyl-2-oxopyrrolidin-1-yl)-2-fluo 24, wherein rophenyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)py 0298) R' represents ridazin-4(1H)-one, or a salt thereof. 0332 39 0299 a phenyl group which can be substituted by 1 to 5 0333 1-4-(5,5-dimethyl-2-oxo-1,3-oxazolidin-3-yl)-2- halogen atoms, fluorophenyl-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl) 0300 R represents pyridazin-4(1H)-one, or a salt thereof. 0301 a hydrogen atom or a Coalkoxy group, 0334 40 0302 R represents 0335 5-methoxy-1-2-methoxy-4-(1H-pyrazol-1-yl)phe 0303 a hydrogen atom, nyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one, 0304 Ring. A represents or a salt thereof. 0336 41 0305 a benzene ring, 0337. A prodrug of the compound according to according 0306 which is substituted with one 4- to 6-membered to any one of the above-mentioned 1 to 40 heterocyclic group containing 0 or 1 oxygenatom, and 1 to 3 0338 42 nitrogen atoms as heteroatoms which can be substituted by 1 0339. A medicament comprising the compound according to 4 Substituents selected from a halogen atom, a hydroxy to according to any one of the above-mentioned 1 to 40 or group, an oxo group, halogeno Coalkoxy group, a Co a prodrug thereof. alkoxy-carbonyl, and a Co alkyl group which can be Sub 0340 (43 stituted by halogen, 0341. A medicament comprising a compound of formula 0307 and which can be further substituted with 1 or 2 (Io): Substituents selected from a halogenatom and a Coalkoxy group, and 0308 Ring B represents (Io) 0309 a pyrazole ring. 0310 |29 0311. The compound according to the above-mentioned 28, wherein 0312 the 4- to 6-membered heterocyclic group containing 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroatoms represents 0313 a morpholino group, a pyrrolyl group, a dihydropy rrolyl group, a pyrazolyl group, a dihydropyrazolyl group, a US 2012/0277430 A1 Nov. 1, 2012

0342 wherein 0375 wherein 0343 R' represents 0376) R' represents 0344 a substituent, (0345 R represents 0377 a substituent, 0346 a hydrogen atom, or a substituent, 0378 R represents 0347 R represents 0379 a hydrogen atom, or a substituent, 0348 a hydrogen atom, or a substituent, (0380 R represents 0349 Ring. A represents 0381 a hydrogen atom, or a substituent, 0350 an aromatic ring which can be substituted, and 0382 Ring. A represents 0351 Ring B represents 0383 an aromatic ring which can be substituted, and 0352 a 5-membered heteroaromatic ring which can be 0384 Ring B represents substituted, 0353 or a salt thereof, or a prodrug thereof. 0385 a 5-membered heteroaromatic ring which can be 0354 44 substituted, 0355 The medicament according to the above-mentioned 0386 or a salt thereof, or a prodrug thereof 43 which is an agent for inhibiting phosphodiesterase 10A. (0387 as a medicament. 0356 45 0388 (48) 0357 The medicament according to the above-mentioned 43 which is for preventing or treating schizophrenia. 0389. Use of a compound of formula (I): 0358) 46 0359 A method of preventing or treating schizophrenia comprising administrating an effective amount of a com (Io) pound of formula (Io):

(Io)

0390 wherein 0391) R' represents 0392 a substituent, 0393 R’ represents 0360 wherein 0394 a hydrogen atom, or a substituent, 0361) R' represents 0395 R represents 0362 a substituent, 0396 a hydrogen atom, or a substituent, 0363 R’ represents 0397 Ring. A represents 0364 a hydrogen atom, or a substituent, 0398 an aromatic ring which can be substituted, and 0365 R represents 0399 Ring B represents 0366 a hydrogen atom, or a substituent, 0367 Ring. A represents 04.00 a 5-membered heteroaromatic ring which can be 0368 an aromatic ring which can be substituted, and substituted, 0369 Ring B represents 04.01 or a salt thereof, or a prodrug thereof 0370 a 5-membered heteroaromatic ring which can be 0402 in the manufacture of a medicament for preventing substituted, or treating schizophrenia. 0371 or a salt thereof, or a prodrug thereof 0403 Besides, the present invention also provides the fol 0372 to a mammal. lowing features. 0373) 47 0404 1" 0374. Use of a compound of formula (I): 0405. A compound represented by the formula (I):

(Io) (I) US 2012/0277430 A1 Nov. 1, 2012

0406 wherein 0428 4' (0407) R' represents a substituent, 0429. A medicament comprising a compound represented (0408 R represents a hydrogenatom or a substituent, by the formula (I): 04.09 R represents a hydrogenatom or a substituent, 0410 Ring. A represents an aromatic ring which can be

(Io) Substituted, and 0411 Ring B represents a 5-membered aromatic hetero cyclic ring which can be substituted; 0412 provided that the following compounds are excluded: 0413 a compound represented by the formula:

0430 wherein 0431) R' represents a substituent, 0432 R represents a hydrogenatom or a substituent, 0433) R' represents a hydrogenatom or a substituent, 0434 Ring. A represents an aromatic ring which can be Substituted, and 0435 Ring B represents a 5-membered aromatic hetero cyclic ring which can be substituted, 0414 wherein 0436 or a salt thereof. 0415 Ring. A represents a benzene ring which can be 0437. 5") substituted by one substituent selected from halogen and 0438. The medicament described as in the above-men alkyl, tioned 4" which is an agent for inhibiting phosphodiesterase 0416) R' represents (1) ethyl or (2) phenyl which can be 10A. substituted by one or more substituents selected from fluorine and trifluoromethyl, 0439 (6) 0440 The medicament described as in the above-men 0417 R represents hydrogen or methyl, and tioned 4" which is for preventing or treating schizophrenia. 0418 Ra represents a hydrogen atom or a C acyclic hydrocarbon group which can be substituted; and 0441 7 a compound represented by the formula: 0442. A method for preventing or treating schizophrenia 0419 which comprises administering an effective amount of a com pound represented by the formula (I):

(Io)

0420 wherein 0421 Ring A" represents a benzene ring which can be Substituted by halogen, and 0443 wherein 0422) R'" represents an acyl group; 0444) R' represents a substituent, 0423 or a salt thereof. 0445) R' represents a hydrogenatom or a substituent, 0424 2 0446 R represents a hydrogenatom or a substituent, 0425. A prodrug of the compound described as in the 0447 Ring. A represents an aromatic ring which can be above-mentioned 1. Substituted, and 0426 (3') 0448 Ring B represents a 5-membered aromatic hetero 0427. A medicament comprising the compound described cyclic ring which can be substituted, as in the above-mentioned 1" or the prodrug thereof. 0449 or a salt thereof. US 2012/0277430 A1 Nov. 1, 2012

0450 8 0472 FIG. 2. Graphs showing dose-dependent inhibition 0451. Use of a compound represented by the formula (I): of methamphetamine (MAP)- or MK-801-induced hyperlo comotion by compound A. The compound A decreased spon taneous locomotion (-30-0 min).

(Io) 0473 FIG. 3. A graph showing reversal of MK-801-in duced PPI deficits at 82 dB prepulse by compound A. 0474 FIG. 4. A graph showing inhibition of MK-801 induced hyperlocomotion by compounds in mice. DETAILED DESCRIPTION OF THE INVENTION 0475. The present invention will be explained in detail below. 0476 Unless otherwise specifically stated, in this specifi cation, examples of the "halogen' include fluorine, chlorine, bromine and iodine. 0477. Unless otherwise specifically stated, in this specifi cation, the phrase “can be halogenated' or the term “halo 0452 wherein geno” means that one or more (e.g., 1 to 3) halogenatoms can 0453 R' represents a substituent, be present as Substituents. 0454) R' represents a hydrogenatom or a substituent, 0478 Unless otherwise specifically stated, in this specifi 0455 R represents a hydrogenatom or a substituent, cation, examples of the “alkyl (group) include Co alkyl 0456 Ring. A represents an aromatic ring which can be (group). - 0479. Unless otherwise specifically stated, in this specifi Substituted, and cation, examples of the “Clio alkyl (group) include methyl, 0457 Ring B represents a 5-membered aromatic hetero ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclic ring which can be substituted, pentyl, isopentyl, neopentyl, and hexyl. 0458 or a salt thereof 0480. Unless otherwise specifically stated, in this specifi 0459 as a medicament. cation, the term "Coalkyl (group) that can be halogenated 0460 (9) means Coalkyl (group) which can be substituted by halo 0461) Use of a compound represented by the formula (I): gen, and examples thereof include trifluoromethyl. 0481. Unless otherwise specifically stated, in this specifi cation, examples of the “alkenyl (group) include C- alk (Io) enyl (group). 0482 Unless otherwise specifically stated, in this specifi cation, examples of the “Coalkenyl (group) include vinyl, 1-propen-1-yl, 2-propen-1-yl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, and 5-hexen-1-yl. 0483 Unless otherwise specifically stated, in this specifi cation, examples of the alkynyl (group) include C- alky nyl (group). 0484 Examples of “C, alkynyl (group)” include ethy nyl, 1-propyn-1-yl, 2-propyn-1-yl 4-pentyn-1-yl, and 5-hexyn-1-yl. 0485 Unless otherwise specifically stated, in this specifi 0462 wherein cation, examples of the “C-7 cycloalkyl-C alkynyl 0463) R' represents a substituent, (group) include cyclopropylethyl. 0464) R' represents a hydrogenatom or a substituent, 0486. Unless otherwise specifically stated, in this specifi 0465) R' represents a hydrogenatom or a substituent, cation, examples of the “C., cycloalkyl (group) include 0466 Ring. A represents an aromatic ring which can be cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Substituted, and 0487. Unless otherwise specifically stated, in this specifi 0467 Ring B represents a 5-membered aromatic hetero cation, examples of the "Caryl (group) include phenyl, cyclic ring which can be substituted, 1-naphthyl 2-naphthyl 2-biphenylyl, 3-biphenylyl, 4-biphe 0468 or a salt thereof nylyl, and 2-anthryl. 0469 in the manufacture of a medicament for preventing 0488. Unless otherwise specifically stated, in this specifi or treating schizophrenia. cation, examples of “Caralkyl (group) include benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl 2-naphthylm Advantageous Effects of Invention ethyl, 2,2-diphenylethyl 3-phenylpropyl, 4-phenylbutyl, 0470 The compound of the present invention has a PDE 5-phenylpentyl, 2-biphenylmethyl, 3-biphenylmethyl, and inhibitory activity and is useful as a drug for preventing or 4-biphenylmethyl. treating Schizophrenia, etc. 0489. Unless otherwise specifically stated, in this specifi cation, examples of “Caryl-Coalkenyl (group) include BRIEF DESCRIPTION OF DRAWINGS styryl. 0490 Unless otherwise specifically stated, in this specifi 0471 FIG. 1. Graphs showing dose-dependent elevation cation, the "heterocyclic group” (and a heterocyclic moiety in of cAMP (FIG. 1A) and coMP (FIG. 1B) contents in the a Substituent) is a non-aromatic heterocyclic group, or a het mouse striatum by compound A. eroaryl group (i.e., aromatic heterocyclic group), and US 2012/0277430 A1 Nov. 1, 2012

examples thereof include 3- to 14-membered heterocyclic 0492 saturated or unsaturated 3- to 14-membered non group having 1 to 5 hetero atoms selected from nitrogen, aromatic heterocyclic group having 1 to 5 hetero atoms Sulfur and oxygen. This "heterocyclic group' can be mono selected from nitrogen, Sulfur and oxygen Such as tetrahydro cyclic, bicyclic or tricyclic. furyl, oxazolidinyl, imidazolinyl (e.g., 1-imidazolinyl, 2-imi 0491 Examples of the “3- to 14-membered heterocyclic dazolinyl, 4-imidazolinyl), aziridinyl (e.g., 1-aziridinyl, group' include 3- to 14-membered aromatic heterocyclic 2-aziridinyl), aZetidinyl (e.g., 1-aZetidinyl, 2-azetidinyl), pyr group having 1 to 5 hetero atoms selected from nitrogen, rolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), Sulfur and oxygen Such as pyrrolyl (e.g., 1-pyrrolyl 2-pyrro piperidinyl (e.g., 1-piperidinyl, 2-piperidinyl, 3-piperidinyl), lyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., aZepanyl (e.g., 1-azepanyl, 2-azepanyl, 3-azepanyl, 4-aZepa 2-thienyl, 3-thienyl), pyrazolyl (e.g., 1-pyrazolyl 3-pyra nyl), azocanyl (e.g., 1-azocanyl, 2-azocanyl, 3-azocanyl. Zolyl, 4-pyrazolyl), imidazolyl (e.g., 1-imidazolyl, 2-imida 4-azocanyl), piperazinyl (e.g., 1,4-piperazin-1-yl, 1.4-piper Zolyl, 4-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isox azin-2-yl), diazepinyl (e.g., 1,4-diazepin-1-yl, 1,4-diazepin azolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 2-yl, 1,4-diazepin-5-yl, 1,4-diazepin-6-yl), diazocanyl (e.g., 5-oxazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 1,4-diazocan-1-yl, 1,4-diazocan-2-yl, 1,4-diazocan-5-yl, 5-isothiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 1,4-diazocan-6-yl, 1.5-diazocan-1-yl, 1.5-diazocan-2-yl, 5-thiazolyl), triazolyl (e.g., 1,2,3-triazol-4-yl, 1,2,4-triazol 1.5-diazocan-3-yl), tetrahydropyranyl (e.g., tetrahydropyran 3-yl), oxadiazolyl (e.g., 1,2,4-oxadiazol-3-yl, 1,2,4-oxadia 4-yl), morpholinyl (e.g., 4-morpholinyl), thiomorpholinyl Zol-5-yl), thiadiazolyl (e.g., 1,2,4-thiadiazol-3-yl, 1,2,4-thia (e.g., 4-thiomorpholinyl), 2-oxazolidinyl, dihydrofuryl, dihy diazol-5-yl), tetrazolyl pyridyl (e.g., 2-pyridyl, 3-pyridyl, dropyranyl, and dihydroquinolyl. 4-pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridaZinyl), 0493. Unless otherwise specifically stated, in this specifi pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidi cation, examples of the “5- to 10-membered heterocyclic nyl), pyrazinyl, indolyl, isoindolyl (e.g., 1-isoindolyl, groups' include those having 5- to 10-members among the 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl, aforementioned “3- to 14-membered heterocyclic group'. 6-isoindolyl, 7-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 0494. Unless otherwise specifically stated, in this specifi 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), benzo cation, examples of the 'aromatic heterocyclic group' (and blfuranyl (e.g., 2-benzobfuranyl, 3-benzobfuranyl, an aromatic heterocyclic moiety in a substituent) include the 4-benzobfuranyl, 5-benzobfuranyl, 6-benzobfuranyl, “3- to 14-membered aromatic heterocyclic group having 1 to 7-benzobfuranyl), benzocfuranyl (e.g., 1-benzocfura 5 hetero atoms selected from nitrogen, Sulfur and oxygen as nyl, 4-benzocfuranyl, 5-benzocfuranyl), benzobthienyl exemplified above as said "heterocyclic group'. (e.g., 2-benzobthienyl, 3-benzob thienyl, 4-benzob thie 0495. Unless otherwise specifically stated, in this specifi nyl, 5-benzobthienyl, 6-benzobthienyl, 7-benzob thie cation, examples of the “non-aromatic heterocyclic group' nyl), benzoic thienyl (e.g., 1-benzocthienyl, 4-benzoc (and an aromatic heterocyclic moiety in a substituent) include thienyl, 5-benzoic thienyl), indazolyl (e.g., 1-indazolyl, the “saturated or unsaturated 3- to 14-membered non-aro 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-inda matic heterocyclic group having 1 to 5 hetero atoms selected Zolyl, 7-indazolyl), benzimidazolyl (e.g., 1-benzimidazolyl, from nitrogen, Sulfur and oxygen as exemplified above as 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl), said “heterocyclic group'. 1.2-benzoisoxazolyl (e.g., 1,2-benzisoxazol-3-yl, 1,2-ben 0496 Unless otherwise specifically stated, in this specifi Zisoxazol-4-yl, 1,2-benzisoxazol-5-yl, 1.2-benzisoxazol-6- cation, examples of the “saturated heterocyclic group” (and a yl, 1.2-benzisoxazol-7-yl), benzoxazolyl(e.g., 2-benzox saturated heterocyclic moiety in a Substituent) include those azolyl, 4-benzoxazolyl, 5-benzoxazolyl, 6-benzoxazolyl, saturated among said “non-aromatic heterocyclic group'. 7-benzoxazolyl), 1,2-benzoisothiazolyl (e.g., 1,2-ben Specific examples thereof include tetrahydrofuryl, morpholi Zisothiazol-3-yl, 1,2-benzisothiazol-4-yl, 1,2-benzisothia nyl, thiomorpholinyl, piperidinyl, pyrrolidinyl, and piperazi Zol-5-yl, 1,2-benzisothiazol-6-yl, 1,2-benzisothiazol-7-yl), nyl group. benzothiazolyl (e.g., 2-benzothiazolyl, 4-benzothiazolyl, 0497. Unless otherwise specifically stated, in this specifi 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), iso cation, examples of the “5- to 6-membered saturated hetero quinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, cyclic group' (and a saturated heterocyclic moiety in a Sub 5-isoquinolyl), quinolyl (e.g., 2-quinolyl, 3-quinolyl, stituent) include those having 5- to 6-members among said 4-quinolyl, 5-quinolyl, 8-quinolyl), cinnolinyl (e.g., 3-cinno “saturated heterocyclic group'. linyl, 4-cinnolinyl, 5-cinnolinyl, 6-cinnolinyl, 7-cinnolinyl, 8-cinnolinyl), phthalazinyl (e.g., 1-phthalazinyl, 4-phthalazi 0498. Unless otherwise specifically stated, in this specifi nyl, 5-phthalazinyl, 6-phthalazinyl, 7-phthalazinyl, 8-ph cation, examples of the “alkoxy (group) include Co thalazinyl), quinazolinyl (e.g., 2-quinazolinyl, 4-quinazoli alkoxy (group). nyl, 5-quinazolinyl, 6-quinazolinyl, 7-quinazolinyl, 0499. Unless otherwise specifically stated, in this specifi 8-quinazolinyl), quinoxalinyl (e.g., 2-quinoxalinyl, 3-qui cation, examples of the “Coalkoxy (group) include meth noxalinyl, 5-quinoxalinyl, 6-quinoxalinyl, 7-quinoxalinyl, oxy; ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec 8-quinoxalinyl), pyrazolo 1.5-alpyridyl (e.g., pyrazolo 1.5- butoxy, pentyloxy and hexyloxy. 1pyridin-2-yl, pyrazolo 1.5-alpyridin-3-yl pyrazolo 1.5-a 0500 Unless otherwise specifically stated, in this specifi pyridin-4-yl, pyrazolo 1.5-alpyridin-5-yl, pyrazolo 1.5-a cation, examples of the "C-7 cycloalkyloxy (group) include pyridin-6-yl, pyrazolo 1.5-alpyridin-7-yl), imidazol-2-a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexy pyridyl (e.g., imidazol-2-alpyridin-2-yl, imidazol-2-a loxy. pyridin-3-yl, imidazol-2-alpyridin-5-yl, imidazol-2-a 0501 Unless otherwise specifically stated, in this specifi pyridin-6-yl, imidazol-2-alpyridin-7-yl, imidazol-2-a cation, examples of the "Caryloxy (group) include phe pyridin-8-yl); and nyloxy, 1-naphthyloxy and 2-maphthyloxy. US 2012/0277430 A1 Nov. 1, 2012

0502. Unless otherwise specifically stated, in this specifi methylsulfanyl, ethylsulfanyl, propylsulfanyl, isopropylsul cation, examples of the “C. aralkyloxy (group) include fanyl, butylsulfanyl, sec-butylsulfanyl, and tert-butylsulfa benzyloxy and phenethyloxy. nyl. 0503. Unless otherwise specifically stated, in this specifi 0519 Unless otherwise specifically stated, in this specifi cation, examples of the “alkyl-carbonyloxy (group) include cation, examples of the "C-7 cycloalkylsulfanyl (group) Coalkyl-carbonyloxy (group). include cyclopropylsulfanyl, cyclobutylsulfanyl, cyclopen 0504. Unless otherwise specifically stated, in this specifi tylsulfanyl and cyclohexylsulfanyl. cation, examples of the “Clio alkyl-carbonyloxy (group) 0520. Unless otherwise specifically stated, in this specifi include acetoxy and propionyloxy. cation, examples of the “Carylsulfanyl (group)” include 0505. Unless otherwise specifically stated, in this specifi phenylsulfanyl, 1-naphthylsulfanyl and 2-naphthylsulfanyl. cation, examples of the “alkoxy-carbonyloxy (group) 0521. Unless otherwise specifically stated, in this specifi include Coalkoxy-carbonyloxy (group). cation, examples of the “C. aralkylsulfanyl (group) 0506 Unless otherwise specifically stated, in this specifi include benzylsulfanyl and phenethylsulfanyl. cation, examples of the "Coalkoxy-carbonyloxy (group) 0522 Unless otherwise specifically stated, in this specifi include methoxycarbonyloxy, ethoxycarbonyloxy, propoxy cation, examples of the heterocyclic moiety of the "heterocy carbonyloxy and butoxycarbonyloxy. clic-sulfanyl (group) include those similar to said "hetero 0507 Unless otherwise specifically stated, in this specifi cyclic group'. Specifically, examples of the "heterocyclic cation, examples of the "mono-alkyl-carbamoyloxy (group) sulfanyl (group) include 5- to 14-membered heterocyclic include mono-Cio alkyl-carbamoyloxy (group). Sulfanyl (group) having 1 to 5 hetero atoms selected from 0508 Unless otherwise specifically stated, in this specifi nitrogen, Sulfur and oxygen. cation, examples of the “mono-Cio alkyl-carbamoyloxy 0523. Unless otherwise specifically stated, in this specifi (group) include methylcarbamoyloxy and ethylcarbamoy cation, examples of the “alkyl-carbonyl (group) include loxy. Co alkyl-carbonyl. 0509 Unless otherwise specifically stated, in this specifi 0524. Unless otherwise specifically stated, in this specifi cation, examples of the “di-alkyl-carbamoyloxy (group) cation, examples of the “Clio alkyl-carbonyl (group) include di-Clio alkyl-carbamoyloxy (group). include acetyl, propionyl and pivaloyl. 0510 Unless otherwise specifically stated, in this specifi 0525. Unless otherwise specifically stated, in this specifi cation, examples of the “di-Clio alkyl-carbamoyloxy cation, examples of the “C-7 cycloalkyl-carbonyl (group) (group) include dimethylcarbamoyloxy and diethylcarbam include cyclopropylcarbonyl, cyclopentylcarbonyl and oyloxy. cyclohexylcarbonyl group. 0511 Unless otherwise specifically stated, in this specifi 0526. Unless otherwise specifically stated, in this specifi cation, examples of the “C. aryl-carbonyloxy (group) cation, examples of the "Caryl-carbonyl (group) include include benzoyloxy and naphthylcarbonyloxy. benzoyl, 1-naphthoyl and 2-maphthoyl group. 0512 Unless otherwise specifically stated, in this specifi 0527 Unless otherwise specifically stated, in this specifi cation, examples of the "mono- or di-Caryl-carbamoy cation, examples of the “C. aralkyl-carbonyl (group) loxy (group) include phenylcarbamoyloxy and naphthylcar include phenylacetyl and 3-phenylpropionyl group. bamoyloxy. 0528. Unless otherwise specifically stated, in this specifi 0513. Unless otherwise specifically stated, in this specifi cation, examples of the heterocyclic moiety of the "heterocy cation, examples of the heterocyclic moiety of the "heterocy clic-carbonyl (group) include those similar to said "hetero clic-oxy (group) include those similar to said "heterocyclic cyclic group'. Specifically, examples thereof include 3- to group' are included. Specifically, examples of the "heterocy 14-membered heterocyclic-carbonyl (group) having 1 to 5 clic-oxy (group) include 5- to 14-membered heterocyclic hetero atoms selected from nitrogen, Sulfur and oxygen. Fur oxy (group) having 1 to 5 hetero atoms selected from nitro ther, specific examples thereof include picolinoyl, nicotinoyl, gen, Sulfur and oxygen. isonicotinoyl 2-thenoyl, 3-thenoyl 2-furoyl, 3-furoyl, 0514. Unless otherwise specifically stated, in this specifi 1-morpholinylcarbonyl, 4-thiomorpholinylcarbonyl, aziri cation, examples of the aromatic heterocyclic moiety of the din-1-ylcarbonyl, aziridin-2-ylcarbonyl, aZetidin-1-ylcarbo "heterocyclic-oxy (group) include those similar to the “aro nyl, aZetidin-2-ylcarbonyl, pyrrolidine-1-ylcarbonyl, pyrroli matic heterocyclic group’ as examples of said "heterocyclic dine-2-ylcarbonyl, pyrrolidine-3-ylcarbonyl, piperidine-1- group'. Specifically, examples of the 'aromatic heterocyclic ylcarbonyl, piperidine-2-ylcarbonyl, piperidine-3- oxy (group) include 3- to 14-membered aromatic heterocy ylcarbonyl, azepan-1-ylcarbonyl, azepan-2-ylcarbonyl, clic-oxy (group) having 1 to 5 hetero atoms selected from aZepan-3-ylcarbonyl, azepan-4-ylcarbonyl, azocan-1-ylcar nitrogen, Sulfur and oxygen. bonyl, azocan-2-ylcarbonyl, azocan-3-ylcarbonyl, azocan-4- 0515. Unless otherwise specifically stated, in this specifi ylcarbonyl, 1.4-piperazine-1-ylcarbonyl, 1,4-piperazine-2- cation, examples of the “Clio alkylsulfonyloxy (group) ylcarbonyl, 1,4-diazepan-1-ylcarbonyl, 1,4-diazepan-2- include methylsulfonyloxy and ethylsulfonyloxy. ylcarbonyl, 1,4-diazepan-5-ylcarbonyl, 1,4-diazepan-6- 0516. Unless otherwise specifically stated, in this specifi ylcarbonyl, 1,4-diazocan-1-ylcarbonyl, 1,4-diazocan-2- cation, examples of the "halogeno Co alkylsulfonyloxy ylcarbonyl, 1,4-diazocan-5-ylcarbonyl, 1,4-diazocan-6- (group) include halogeno methylsulfonyloxy and halogeno ylcarbonyl, 1.5-diazocan-1-ylcarbonyl, 1.5-diazocan-2- ethylsulfonyloxy. ylcarbonyl and 1,5-diazocan-3-ylcarbonyl. 0517. Unless otherwise specifically stated, in this specifi 0529 Unless otherwise specifically stated, in this specifi cation, examples of the “alkylsulfanyl (group) include Co cation, examples of the “carboxy (group) that can be esteri alkylsulfanyl (group). fied include carboxy, alkoxy-carbonyl which can be substi 0518. Unless otherwise specifically stated, in this specifi tuted, Caryloxy-carbonyl which can be substituted, C cation, examples of the “Clio alkylsulfanyl (group) include aralkyloxy-carbonyl which can be substituted, silyloxy-car US 2012/0277430 A1 Nov. 1, 2012

bonyl which can be substituted (e.g., TMS-O CO. , TES 0545 Unless otherwise specifically stated, in this specifi O CO. , TBS-O CO. , TIPS-O CO. , TBDPS-O cation, examples of the “Clio alkyl-carbamoyl (group) CO , etc.) include methylcarbamoyl, ethylcarbamoyl and propylcar 0530 Unless otherwise specifically stated, in this specifi bamoyl. cation, examples of the “alkoxy-carbonyl (group) include 0546. Unless otherwise specifically stated, in this specifi methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and cation, examples of the "mono- or di-alkylamino (group) tert-butoxycarbonyl. include mono- or di-Clio alkylamino (group). 0531. Unless otherwise specifically stated, in this specifi 0547. Unless otherwise specifically stated, in this specifi cation, examples of the “C. aryloxy-carbonyl (group) cation, examples of the "mono- or di-Clio alkylamino include phenoxycarbonyl. (group) include methylamino, ethylamino, propylamino, 0532 Unless otherwise specifically stated, in this specifi dimethylamino and diethylamino. cation, examples of the “C, aralkyl-carbonyl (group) 0548. Unless otherwise specifically stated, in this specifi include benzyloxycarbonyl and phenethyloxycarbonyl. cation, examples of the “alkyl-carbonylamino (group) 0533. Unless otherwise specifically stated, in this specifi include Coalkyl-carbonylamino. cation, examples of the alkylsulfonyl (group) include Co 0549. Unless otherwise specifically stated, in this specifi alkylsulfonyl (group). cation, examples of the Co alkyl-carbonylamino (group) 0534 Unless otherwise specifically stated, in this specifi include acetylamino, propionylamino and pivaloylamino. cation, examples of the “Clio alkylsulfonyl (group) include 0550 Unless otherwise specifically stated, in this specifi methylsulfonyl and ethylsulfonyl. cation, examples of the heterocyclic moiety of the "heterocy 0535. Unless otherwise specifically stated, in this specifi clic-amino (group) those similar to said "heterocyclic cation, examples of the “C-7 cycloalkylsulfonyl (group) group”. Examples of the "heterocyclic-amino (group) include cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopen include 2-pyridyl-amino. tylsulfonyl and cyclohexylsulfonyl. 0551 Unless otherwise specifically stated, in this specifi 0536. Unless otherwise specifically stated, in this specifi cation, examples of the "heterocyclic-carbonyl' of the “het cation, examples of the “Carylsulfonyl (group) include erocyclic-carbonylamino (group) those similar to said "het phenylsulfonyl, 1-naphthylsulfonyl and 2-maphthylsulfonyl. erocyclic-carbonyl. Examples of the "heterocyclic 0537. Unless otherwise specifically stated, in this specifi carbonylamino (group) include pyridyl-carbonylamino. cation, examples, of the heterocyclic moiety of the "hetero 0552. Unless otherwise specifically stated, in this specifi cyclic-sulfonyl (group)' include those similar to said “het cation, examples of the "heterocyclic (group) of the "hetero erocyclic group'. Specifically, examples of the "heterocyclic cyclic-oxycarbonylamino (group) include those similar to sulfonyl (group) include 5- to 14-membered heterocyclic said “heterocyclic group”. Examples of the "heterocyclic Sulfonyl (group) having 1 to 5 hetero atoms selected from oxycarbonylamino (group) include 2-pyridyl-oxycarbony nitrogen, Sulfur and oxygen lamino. 0538 Unless otherwise specifically stated, in this specifi 0553. Unless otherwise specifically stated, in this specifi cation, examples of the Saturated heterocyclic moiety of the cation, examples of the "heterocyclic (group) of the "hetero “saturated heterocyclic-sulfonyl (group) include those simi cyclic-sulfonylamino (group) include those similar to said lar to said “heterocyclic group'. Specifically, examples of the "heterocyclic group”. Examples of the "heterocyclic-sulfo "heterocyclic-sulfonyl (group) include 5- to 14-membered nylamino (group) include 2-pyridyl-Sulfonylamino. heterocyclic-Sulfonyl (group) having 1 to 5 hetero atoms 0554. Unless otherwise specifically stated, in this specifi selected from nitrogen, Sulfur and oxygen. cation, examples of the “alkoxy-carbonylamino (group) 0539 Unless otherwise specifically stated, in this specifi include Coalkoxy-carbonylamino. cation, examples of the “alkylsulfinyl (group) include Co 0555. Unless otherwise specifically stated, in this specifi alkylsulfinyl (group). cation, the Co alkoxy-carbonylamino (group) include 0540 Unless otherwise specifically stated, in this specifi methoxycarbonylamino, ethoxycarbonylamino, propoxycar cation, examples of the "Coalkylsulfinyl (group) include bonylamino and butoxycarbonylamino. methylsulfinyl and ethylsulfinyl. 0556. Unless otherwise specifically stated, in this specifi 0541. Unless otherwise specifically stated, in this specifi cation, examples of the “alkyl-sulfonylamino (group) cation, examples of the “C., cycloalkylsulfinyl (group) include Coalkyl-sulfonylamino. include cyclopropylsulfinyl, cyclobutylsulfinyl, cyclopentyl 0557. Unless otherwise specifically stated, in this specifi Sufinyl, and cyclohexysulfinyl. cation, examples of the “Clio alkyl-sulfonylamino (group) 0542 Unless otherwise specifically stated, in this specifi include methylsulfonylamino and ethylsulfonylamino. cation, examples of the "Carylsulfinyl (group) include 0558 Unless otherwise specifically stated, in this specifi phenylsulfinyl, 1-naphthylsulfinyl and 2-maphthylsulfinyl. cation, examples of the "mono- or di-C-7 cycloalkylamino 0543. Unless otherwise specifically stated, in this specifi (group) include cyclopropylamino, cyclopentylamino and cation, examples of the heterocyclic moiety of the "heterocy cyclohexylamino. clic-sulfinyl (group) include those similar to said “heterocy 0559. Unless otherwise specifically stated, in this specifi clic group'. Specifically, examples of the "heterocyclic cation, examples of the “C-7 cycloalkyl-carbonylamino sulfinyl (group) include 5- to 14-membered heterocyclic (group) include cyclopropylcarbonylamino, cyclopentyl Sulfinyl (group) having 1 to 5 hetero atoms selected from carbonylamino and cyclohexylcarbonylamino. nitrogen, Sulfur and oxygen. 0560. Unless otherwise specifically stated, in this specifi 0544 Unless otherwise specifically stated, in this specifi cation, examples of the “C-7 cycloalkyloxy-carbonylamino cation, examples of the “alkyl-carbamoyl (group) include (group) include cyclopropoxycarbonylamino, cyclopenty Co alkyl-carbamoyl (group). loxycarbonylamino and cyclohexyloxycarbonylamino. US 2012/0277430 A1 Nov. 1, 2012

0561 Unless otherwise specifically stated, in this specifi 0594 (25) a C- alkylsulfonyloxy (group) which can be cation, examples of the "C-7 cycloalkyl-sulfonylamino Substituted (e.g., halogeno Co alkylsulfonyloxy (group) (group) include cyclopropylsulfonylamino, cyclopentylsul which can be substituted); fonylamino and cyclohexylsulfonylamino. 0595 (26) a mercapto group: 0562 Unless otherwise specifically stated, in this specifi 0596 (27) an alkylsulfanyl group which can be substi cation, examples of the "mono- or di-C arylamino tuted; (group) include phenylamino and diphenylamino. 0597 (28) a C-7 cycloalkylsulfanyl group which can be substituted; 0563. Unless otherwise specifically stated, in this specifi 0598 (29) a Carylsulfanyl group which can be substi cation, examples of the "mono- or di-C7 aralkylamino tuted; (group) include benzylamino. 0599 (30) a Cz-aralkylsulfanyl group which can be sub 0564 Unless otherwise specifically stated, in this specifi stituted; cation, examples of the "Caryl-carbonylamino (group) 0600 (31) a heterocyclic-sulfanyl group which can be include benzoylamino and naphthoylamino. substituted; 0565. Unless otherwise specifically stated, in this specifi 0601 (32) a formyl group: cation, examples of the "Caryl-sulfonylamino (group) 0602 (33) an alkyl-carbonyl group which can be substi include phenylsulfonylamino, 2-naphthylsulfonylamino and tuted; 1-naphthylsulfonylamino. 0603 (34) a C-7 cycloalkylcarbonyl group which can be 0566 Symbols in the aforementioned formulas (Formula substituted; I) and Formula (I)) will be explained below. 0604 (35) a Carylcarbonyl group which can be sub 0567. In the aforementioned formula, R' represents a sub stituted; stituent. 0605 (36) a Cz aralkylcarbonyl group which can be 0568 Examples of the substituent represented by R' substituted; include substituents selected from the below described sub 0606 (37) a heterocyclic-carbonyl group which can be stituent group A. substituted; 0569. Substituent Group A 0607 (38) an alkylsulfonyl group which can be substi 0570 (1) a halogen atoms; tuted; 0571 (2) a nitro group: 0608 (39) a C-7 cycloalkylsulfonyl group which can be 0572 (3) a cyano group; substituted; 0573 (4) a carboxy group that can be esterified; 0609 (40) a Carylsulfonyl group which can be substi 0574 (5) an alkyl group which can be substituted; tuted; 0575 (6) an alkenyl group which can be substituted; 0610 (41) a heterocyclic-sulfonyl group which can be 0576 (7) an alkynyl group which can be substituted (e.g., substituted; an C, cycloalkyl-C alkynyl group which can be substi 0611 (42) an alkylsulfinyl group which can be substi tuted; tuted; 0577 (8) a C-7 cycloalkyl group which can be substituted; 0612 (43) a C-7 cycloalkylsulfinyl group which can be substituted; 0578 (9) a Caryl group which can be substituted; 0613 (44) a Carylsulfinyl group which can be substi 0579 (10) a Cz-aralkyl group which can be substituted; tuted; 0580 (11) a Caryl-C alkenyl group which can be 0614 (45) a heterocyclic-sulfinyl group which can be sub substituted; stituted; 0581 (12) a heterocyclic group which can be substituted; 0615 (46) a sulfo group: 0582 (13) a hydroxy group: 0616 (47) a sulfamoyl group: 0583 (14) an alkoxy group which can be substituted; 0.617 (48) a sulfinamoyl group; 0584) (15) a C-7 cycloalkyloxy group which can be sub 0618 (49) a sulfenamoyl group; stituted; 0619 (50) a thiocarbamoyl group: 0585 (16) a Caryloxy group which can be substituted; 0620 (51) a carbamoyl group which can be substituted 0586 (17) a C- aralkyloxy group which can be substi e.g., alkyl-carbamoyl group which can be substituted tuted; 0621 (52) an amino group which can be substituted e.g., 0587 (18) an alkyl-carbonyloxy group which can be sub 0622 amino, stituted; 0623 mono- or di-alkylamino group which can be substi tuted, 0588 (19) an alkoxy-carbonyloxy group which can be 0624 mono- or di-C-7 cycloalkylamino group which can substituted; be substituted, 0589 (20) a mono-alkyl-carbamoyloxy group which can 0625 mono- or di-C arylamino group which can be be substituted; substituted, 0590 (21) a di-alkyl-carbamoyloxy group which can be 0626 mono- or di-C7-caralkylamino group which can be substituted; substituted, 0591 (22) a Caryl-carbonyloxy group which can be 0627 heterocyclic amino group which can be substituted, substituted; 0628 Caryl-carbonylamino group which can be Sub 0592 (23) a mono- or di-Caryl-carbamoyloxy group stituted, which can be substituted; 0629 formylamino, 0593 (24) a heterocyclic-oxy group which can be substi 0630 alkyl-carbonylamino group which can be substi tuted (e.g., aromatic heterocyclic-oxy group which can be tuted (e.g., mono-(Coalkyl-carbonyl)-amino group which substituted) can be substituted), US 2012/0277430 A1 Nov. 1, 2012

0631 C., cycloalkyl-carbonylamino group which can be lamino, C-7 cycloalkyl, Co alkoxy, formyl, Co alkyl substituted, carbonyl, C-7 cycloalkyl-carbonyl, Cea aryl-carbonyl, 0632 heterocyclic-carbonylamino group which can be C7-caralkyl-carbonyl, Coalkoxy-carbonyl, C-aryloxy substituted, carbonyl, C7 aralkyloxy-carbonyl, Co alkylsulfanyl. 0633 C., cycloalkyloxy-carbonylamino group which Co alkylsulfinyl, Co alkylsulfonyl, carbamoyl, thiocar can be substituted, bamoyl, mono- ordi-Clio alkylcarbamoyl, mono- or di-Ca 0634 heterocyclic-oxycarbonylamino group which can aryl-carbamoyl and so on); be substituted, 0668 (f) a Caryloxy group which can be substituted 0635 carbamoylamino group which can be substituted, (the “C. aryloxy group' can be substituted with one or 0636 alkylsulfonylamino group which can be substituted, more substituents selected from halogen, hydroxy, cyano, 0637 C., cycloalkyl-sulfonylamino group which can be amino, Co alkyl that can behalogenated, mono- or di-Co substituted, alkylamino, mono- or di-Co-1 arylamino, mono- or di-C7 0638 heterocyclic sulfonylamino group which can be aralkylamino, C-7 cycloalkyl, Co alkoxy, formyl, Co substituted, alkyl-carbonyl, C., cycloalkyl-carbonyl, C. aryl-carbo 0639 Carylsulfonylamino group which can be substi nyl, C7-caralkyl-carbonyl, Coalkoxy-carbonyl, C-ary tuted loxy-carbonyl, C7 aralkyloxy-carbonyl, Co alkylsulfa 0640. Among the aforementioned substituent group A, nyl, Co alkylsulfinyl, alkylsulfonyl, carbamoyl, i.e., particularly, thiocarbamoyl, mono- or di-Clio alkylcarbamoyl, mono- or 0641 the “alkoxy-carbonyl group which can be substi di-Caryl-carbamoyl and so on); tuted’, 0669 (g) a C- aralkyloxy group which can be substi 0642 the “alkyl group which can be substituted, tuted (the "Czaralkyloxy group' can be substituted with 0643 the “alkenyl group which can be substituted’, one or more Substituents selected from halogen atoms, 0644 the “alkynyl group which can be substituted’, hydroxy, cyano, amino, Co alkyl that can be halogenated, 0645 the “alkoxy group which can be substituted’, mono- or di-Clio alkylamino, mono- or di-Carylamino, 0646 the “alkyl-carbonyloxy group which can be substi mono- or di-C7-6 aralkylamino, C-7 cycloalkyl, Co tuted’, alkoxy, formyl, Co alkyl-carbonyl, C., cycloalkyl-carbo 0647 the “alkoxy-carbonyloxy group which can be sub nyl, C-14 aryl-carbonyl, C7-16 aralkyl-carbonyl, Co stituted’, alkoxy-carbonyl, Caryloxy-carbonyl, C. aralkyloxy 0648 the “mono-alkyl-carbamoyloxy group which can be carbonyl, Coalkylsulfanyl, Coalkylsulfinyl, Coalkyl substituted’, Sulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Clio alky 0649 the “dialkyl-carbamoyloxy group which can be sub lcarbamoyl, mono- or di-Caryl-carbamoyl and so on); stituted’, 0670 (h) a mono- or di-5- to 10-membered heterocyclic 0650 the “alkylsulfanyl group which can be substituted”. group having 1 to 4 hetero atoms selected from nitrogen, 0651 the “alkylcarbonyl group which can be substituted”. Sulfur and oxygen (e.g., furyl, pyridyl, thienyl, pyrrolidino, 0652 the “alkylsulfonyl group which can be substituted”. 1-piperidinyl, 4-piperidyl, piperazinyl, 1-morpholinyl, 0653 the “alkylsulfinyl group which can be substituted. 4-thiomorpholinyl, azepan-1-yl, azocan-1-yl, azonan-1-yl, 0654 the “alkyl-carbamoyl group which can be substi 3,4-dihydroisoquinoline-2-yl and the like) which can be sub tuted’, stituted (the “mono- or di-5- to 10-membered heterocyclic 0655 the “mono- or di-alkylamino group which can be group having 1 to 4 hetero atoms selected from nitrogen, substituted’, sulfur and oxygen can be substituted with one or more sub 0656 the “alkyl-carbonylamino group which can be sub stituents selected from halogen, hydroxy, cyano, amino, Co stituted’, alkyl that can be halogenated, mono- or di-Clio alkylamino, 0657 the “mono-(Co alkyl-carbonyl)-amino group mono- or di-C arylamino, mono- or di-C7 aralky which can be substituted lamino, C-7 cycloalkyl, Co alkoxy, formyl, Co alkyl 0658 the “alkoxy-carbonylamino group which can be carbonyl, C-7 cycloalkyl-carbonyl, Cea aryl-carbonyl, substituted', and C7-caralkyl-carbonyl, Coalkoxy-carbonyl, C-aryloxy 0659 the “alkylsulfonylamino group which can be substi carbonyl, C. aralkyloxy-carbonyl, Co alkylsulfanyl. tuted’, Coalkylsulfinyl, alkylsulfonyl, carbamoyl, thiocarbamoyl. 0660 substituents thereof may be selected from, for mono- or di-Clio alkylcarbamoyl, mono- or di-C aryl example, the following substituent group B. The number of carbamoyl group and so on); the Substituents ranges from 1 to the maximum number which 0671 (i) an amino group which can be substituted e.g., can be substituted, more preferably from 1 to 3 and further Amino group which can be substituted by one or two sub preferably 1. stituents selected from the group consisting of Co alkyl, 0661 Substituent Group B C2-alkenyl, C-aryl, C7-6 aralkyl, heterocyclic group and 0662. Substituent group B consists of heterocyclic-alkyl group (The Coalkyl, C2-alkenyl, C-14 0663 (a) a halogenatom; aryl, C7-caralkyl, heterocyclic group and heterocyclic-alkyl 0664 (b) a hydroxy group; group can be substituted with halogenatoms, hydroxy, cyano, 0665 (c) a nitro group; amino, Co alkyl that can be halogenated (not the alkyl and 0666 (d) a cyano group; alkenyl Substituents), mono- or di-Clio alkylamino, mono 0667 (e) a Caryl group which can be substituted (the or di-Carylamino, mono- or di-C7 aralkylamino, C-7 "Caryl group' can be substituted with one or more Sub cycloalkyl, Co alkoxy, formyl, Co alkyl-carbonyl, C-7 stituents selected from halogen, hydroxy, cyano, amino, Co cycloalkyl-carbonyl, Caryl-carbonyl, C. aralkyl-car alkyl that can be halogenated, mono- or di-Clio alkylamino, bonyl, Co alkoxy-carbonyl, C-7 cycloalkyloxy-carbonyl, mono- or di-Co-1 arylamino, mono- or di-C7-6 aralky C-1 aryloxy-carbonyl, C7-6 aralkyloxy-carbonyl, Co US 2012/0277430 A1 Nov. 1, 2012 alkylsulfanyl, C-7 cycloalkylsulfanyl, Co alkylsulfinyl, 0706 the “aromatic heterocyclic-oxy which can be sub C-7 cycloalkylsulfinyl, Co alkylsulfonyl, C-7 cycloalkyl stituted’, Sulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Clio alky 0707 the “C., cycloalkylsulfanyl which can be substi lcarbamoyl, mono- or di-Caryl-carbamoyl group). “Het tuted’, erocyclic” and "heterocyclic” in "heterocyclic-alkyl are the 0708 the “Carylsulfanyl which can be substituted’, same as the aforementioned "heterocyclic group'; 0709 the “C, aralkylsulfanyl which can be substi 0672 () a C-7 cycloalkyl; tuted’, 0710 the "heterocyclic-sulfanyl which can be substi 0673 (k) a C- alkoxy which can be substituted (the tuted’, “Coalkoxy” can be substituted with one or more substitu 0711 the “C., cycloalkyl-carbonyl which can be substi ents selected from halogen, hydroxy, amino, mono- or di-C. tuted’, 10 alkylamino, mono- or di-Carylamino, C-7 cycloalkyl, 0712 the “Caryl-carbonyl which can be substituted, Coalkoxy, formyl, Co alkyl-carbonyl, C-7 cycloalkyl 0713 the “C, aralkyl-carbonyl which can be substi carbonyl, C-aryl-carbonyl, C7 aralkyl-carbonyl, Co tuted’, alkoxy-carbonyl, C-aryloxy-carbonyl, C. aralkyloxy 0714 the "heterocyclic-carbonyl which can be substi carbonyl, Co alkylsulfanyl, Co alkylsulfinyl, Co alkyl tuted’, Sulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Clio alky 0715 the “C., cycloalkylsulfonyl which can be substi lcarbamoyl, mono- or di-Caryl-carbamoyl, and so on); tuted’, 0674) (1) a formyl; 0716 the “Carylsulfonyl which can be substituted, 0675 (m) a Co alkyl-carbonyl (e.g., acetyl); 0717 the "heterocyclic-sulfonyl which can be substi 0676 (n) a C-7 cycloalkyl-carbonyl: tuted’, 0677 (o) a Caryl-carbonyl: 0718 the “C., cycloalkylsulfinyl which can be substi 0678 (p) a Cz-aralkyl-carbonyl: tuted’, 0679 (q) a Coalkoxy-carbonyl: 0719 the “Carylsulfinyl which can be substituted’, 0680 (r) a Caryloxy-carbonyl: 0720 the "heterocyclic-sulfinyl which can be substi 0681 (s) a C- aralkyloxy-carbonyl: tuted’, 0682 (t) a Coalkylsulfanyl: 0721 the “carbamoyl group which can be substituted, 0683 (u) a Coalkylsulfinyl: 0722 the “amino group which can be substituted’, 0684 (v) a Coalkylsulfonyl: 0723 the “mono- or di-C., cycloalkylamino group which 0685 (w) a carbamoyl: can be substituted, 0686 (x) a thiocarbamoyl; 0724 the "mono- or di-Carylamino group which can 0687 (y) a mono-Cio alkylcarbamoyl (e.g., methylcar be substituted, bamoyl ethylcarbamoyl, etc.); 0725 the “mono- or di-C7 aralkylamino group which 0688 (Z) a di-Clio alkylcarbamoyl (e.g., dimethylcar can be substituted, bamoyl, diethylcarbamoyl ethylmethylcarbamoyl, etc.); 0726 the "heterocyclic amino group which can be substi 0689 (aa) a mono- or di-Caryl-carbamoyl (e.g., phe tuted, nylcarbamoyl, 1-naphthylcarbamoyl 2-naphthylcarbamoyl, 0727 the "Caryl-carbonylamino group which can be etc.); and substituted, 0690 (bb) a mono- or di-5- to 7-membered heterocyclic 0728 the “C., cycloalkyl-carbonylamino group which carbamoyl having 1 to 4 hetero atoms selected from nitrogen, can be substituted, Sulfur and oxygen (e.g., 2-pyridylcarbamoyl 3-pyridylcar 0729 the "heterocyclic-carbonylamino group which can bamoyl, 4-pyridylcarbamoyl, 2-thienylcarbamoyl, 3-thienyl be substituted, carbamoyl, etc.). 0730 the “C., cycloalkyloxy-carbonylamino group 0691 Among the aforementioned substituent group A, which can be substituted, i.e., particularly, 0731 the "heterocyclic-oxycarbonylamino group which 0692 the “Cea aryloxy-carbonyl which can be substi can be substituted, tuted’, 0732 the “carbamoylamino group which can be substi 0693 the "Czaralkyloxy-carbonyl which can be substi tuted, tuted’, 0733 the “alkylsulfonylamino group which can be substi tuted, 0694 the “C., cycloalkyl-C alkynyl which can be sub 0734 the “C., cycloalkyl-sulfonylamino group which stituted’, can be substituted, 0695 the “C., cycloalkyl which can be substituted, 0735 the "heterocyclic sulfonylamino group which can be 0696 the “Caryl which can be substituted, Substituted, and 0697 the “Cz aralkyl which can be substituted, (0736 the "Carylsulfonylamino group which can be 0698 the "Caryl-C alkenyl which can be substi substituted, tuted’, 0737 substituents thereof may be selected from, for 0699 the "heterocyclic group which can be substituted’, example, the aforementioned Substituent group B and the (0700 the “C., cycloalkyloxy which can be substituted”. following substituent group B'. The number of substituents 0701 the “Caryloxy which can be substituted’, ranges from 1 to the maximum number which can be substi 0702 the “Cz aralkyloxy which can be substituted”. tuted, more preferably from 1 to 3 substituents and further 0703 the "Caryl-carbonyloxy which can be substi preferably 1 substituent. tuted’; (0738. Substituent Group B' 0704 the “mono- or di-C aryl-carbamoyloxy which (0739 Substituent group B' consists of can be substituted’, 0740 (a) Coalkyl, which can be substituted by one or (0705 the “heterocyclic-oxy which can be substituted”, more substituents selected from halogen, hydroxy, cyano, US 2012/0277430 A1 Nov. 1, 2012 amino, mono- or di-Clio alkylamino, mono- or di-Cary 0762 an alkylsulfonyl group which can be substituted, lamino, mono- or di-C. aralkylamino, C-7 cycloalkyl, and Coalkoxy, formyl, Co alkyl-carbonyl, C-7 cycloalkyl 0763 an amino group which can be substituted carbonyl, C-aryl-carbonyl, C7 aralkyl-carbonyl, Co 0764) are preferable. alkoxy-carbonyl, C-aryloxy-carbonyl, C. aralkyloxy 0765. The number of substituents ranges from 1 to the carbonyl, Co alkylsulfanyl, Co alkylsulfinyl, Co alkyl maximum number which can be substituted, more preferably Sulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Clio alky from 1 to 3 substituents and further preferably 1 substituent. lcarbamoyl, mono- or di-Caryl-carbamoyl, and so on; 0766. In particular, for example, aromatic group which 0741 (b) Calkenyl, which can be substituted by one or can be substituted are desirable as R. The 'aromatic group more Substituents selected from halogen, hydroxy, cyano, which can be substituted include "Caryl which can be amino, mono- or di-Clio alkylamino, mono- or di-Cary substituted” and "heteroaryl which can be substituted lamino, mono- or di-C. aralkylamino, C-7 cycloalkyl, among the Substituents listed above. Coalkoxy, formyl, Co alkyl-carbonyl, C-7 cycloalkyl 10767 R' is, for example, preferably a phenyl group which carbonyl, C-aryl-carbonyl, C7 aralkyl-carbonyl, Co is substituted by one or more alkoxy-carbonyl, C-aryloxy-carbonyl, C. aralkyloxy 0768 (preferably, 1 to 5) substituents selected from carbonyl, Co alkylsulfanyl, Co alkylsulfinyl, Co alkyl 0769 (a) Co alkyl group (e.g., isopropyl, isobutyl), and Sulfonyl, carbamoyl, thiocarbamoyl, mono- or di-Clio alky (0770 (b) halogen atoms (e.g., chlorine, fluorine), Co lcarbamoyl, mono- or di-Caryl-carbamoyl, and so on; and alkyl group (e.g., methyl), Co alkoxy group (e.g., meth 0742 (c) C. alkynyl, which can be substituted by one or oxy). more substituents selected from halogen atoms, hydroxy, (0771. In the aforementioned formula, R represents a cyano, amino, mono- or di-Clio alkylamino, mono- or di-C- hydrogen atom or a Substituent. 14 arylamino, mono- or di-C7-6 aralkylamino, C-7 (0772. Examples of the substituent represented by R cycloalkyl, Co alkoxy, formyl, Co alkyl-carbonyl, C-7 include substituents selected from the aforementioned sub cycloalkyl-carbonyl, Caryl-carbonyl, C7 aralkyl-car stituent group A. bonyl, Coalkoxy-carbonyl, C-14 aryloxy-carbonyl, C7 (0773) Among them, R is, for example, preferably aralkyloxy-carbonyl, Co alkylsulfanyl, Co alkylsulfinyl, 0774 a halogen atom, Co alkylsulfonyl, carbamoyl, thiocarbamoyl, mono- or (0775 a hydroxy group, di-Clio alkylcarbamoyl, mono- or di-Caryl-carbamoyl 0776 an alkyl group which can be substituted, or group, and so on. 0777 an alkoxy group which can be substituted. 0743. Among them, R' is, for example, preferably (0778. Among them, specifically, R is, for example, 0744 an alkyl group which can be substituted, 0779 preferably a halogenatom, a hydroxy group, a Co 0745 a C-7 cycloalkyl group which can be substituted, alkyl group which can be substituted, or a Coalkoxy group 0746 a Caryl group which can be substituted, which can be substituted, 0747 a non-aromatic heterocyclic group which can be 0780 more preferably a Coalkoxy group which can be substituted, or substituted by one or more substituents selected from a halo 0748 a heterocyclic group which can be substituted. gen atom, a Coalkoxy group, and a C-7 cycloalkyl group. and 0749 Among them, specifically, R is, for example, 0781 further preferably a Coalkoxy group. 0750 preferably a phenyl group which can be substituted 10782. In another aspect of the present invention, as R, in by 1 to 5 substituents selected from a halogen atom, a Co particular, for example, alkyl group which can be substituted, a Coalkoxy group 0783 (i) a hydrogenatom, which can be substituted, 0784 (ii) a halogen atom, 0751 more preferably a phenyl group which can be sub 0785 (iii) a hydroxy group, stituted by 1 to 5 substituents selected from a halogenatom, a 0786 (iv) an alkyl group which can be substituted by one Coalkyl group, and a Coalkoxy group, and or more substituents selected from halogen atoms, hydroxy 0752 further preferably a phenyl group which can be sub group, amino group, and alkoxy group, stituted by 1 to 5 halogenatoms. 0787 (v) an amino group that can be mono- or di-substi 0753. In another aspect of the present invention, as R', in tuted with alkyl group, or particular, for example, 0788 (vi) analkoxy group which can be substituted by one 0754) a 5- or 6-membered aromatic group (preferably phe or more substituents selected from cyano group, amino nyl group, pyridyl group) which can be substituted by one or group, alkoxy group, hydroxy group, halogen atoms and C-7 more substituents selected from cycloalkyl group 0755 a halogen atom (preferably, a chlorine atom, a fluo 0789 is preferable, and, for example, rine atom), 0790 (i) a hydrogenatom, 0756 a cyano group, 0791 (ii) a hydroxy group, (0757 a hydroxy group, 0792 (iii) a C- alkyl group (e.g., methyl), or 0793 (iv) a Co alkoxy group (e.g., methoxy, ethoxy, 0758 an alkyl group (preferably, methyl group, isobutyl isopropoxy, cyclopropylmethoxy, difluoromethoxy) which group) which can be substituted, can be substituted by one or more substituents selected from 0759 an alkoxy group (preferably methoxy group) which halogen atoms and C-7 cycloalkyl group can be substituted, 0794) is more preferable. 0760 an alkylsulfanyl group which can be substituted, 0795. In the aforementioned formula, R represents a 0761 an alkylsulfinyl group which can be substituted, hydrogen atom or a Substituent. US 2012/0277430 A1 Nov. 1, 2012

0796. Examples of the substituents represented by R imidazole, benzoxazole, benzisoxazole, benzothiazole, ben include substituents selected from the aforementioned sub Zisothiazole, 1 H-benzotriazole, quinoline, isoquinoline, stituent group A. cinnoline, quinazoline, quinoxaline, phthalazine, naphthyri 0797. Among them, R is, for example, preferably dine, purine, pteridine, carbazole, C-carboline, B-carboline, 0798 a halogen atom, Y-carboline, acridine, phenoxazine, phenothiazine, phena 0799 a hydroxy group, Zine, phenoxathiin, thianthrene, phenanthridine, phenanthro 0800 an alkyl group which can be substituted, or line, indolizine, pyrrolopyridine, pyrrolo 1.2-bipyridazine, 0801 an alkoxy group which can be substituted. 0821 1 H-pyrrolo2,3-bipyrazine, pyrazolo 1.5-alpyri 0802. Among them, specifically, R is, for example, dine, imidazol-2-alpyridine, imidazo 1.2-bipyridazine, 0803 preferably a hydrogenatom, or a Coalkoxy group imidazol-2-alpyrimidine, 1,2,4-triazolo 4.3-alpyridine, 1.2, which can be substituted, 4-triazolo 4,3-bipyridazine and the like). 0804 more preferably a hydrogenatom, or a Coalkoxy 0822. When the “(ii) aromatic heterocyclic ring contain group, and ing 1 to 4 hetero atoms selected from nitrogen, oxygen, and 0805 further preferably a hydrogen atom. Sulfur contains nitrogen, the aromatic heterocyclic ring can (0806. In another aspect of the present invention, as R, in form an N-oxide. particular, for example, 0823. Among them, preferred is benzene, pyridine, 0807 (i) hydrogen atom, pyridazine, pyrimidine, pyrazine, pyridine N-oxide, 1,2,3- 0808 (ii) halogen atoms, triazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3,4-tetrazine, 1.2, 0809 (iii) alkyl group which can be substituted by one or 3.5-tetrazine, 1,2,4,5-tetrazine, pyrrole, furan, thiophene, more Substituents selected from halogen atoms, hydroxy pyrazole, imidazole, isoxazole, isothiazole, 1.3-oxazole, 1.3- group, amino group, and alkoxy group, thiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, 1.2.3-Oxa 0810 (iv) amino group that can be mono- or di-substituted diazole, 1,2,3-thiadiazole, naphthalene, quinoline, quinaZo with alkyl group, or line, quinoxaline, benzofuran, benzothiophene, benzoxazole, 0811 (vi) alkoxy group, and for example, benzothiazole, benzimidazole, indole, 1H-indazole, 1H-pyr 0812 is preferable, and, for example, rolo2,3-bipyrazine, 1 H-pyrrolopyridine, 1H-imidazopyri 0813 a hydrogen atom and a C- alkyl group (e.g., dine, 1H-imidazopyrazine, triazine, isoquinoline, benzothia methyl) diazole, benzisoxazole, benzisothiazole, indazole, purine, 0814 is more preferable. isoquinoline, phthalazine, naphthyridine, cinnoline, pteridine 0815. In the aforementioned formula, Ring. A represents or the like, especially preferred is, for example, benzene or an aromatic ring which can be substituted. pyridine, and most preferred is benzene. 0816. The 'aromatic ring of the “aromatic ring which can 0824. The substituents of the “aromatic ring which can be be substituted” is preferably a 5 to 16-membered aromatic substituted as represented by the ring A, for example, ring, more preferably a 5 to 6-membered aromatic ring, and include the substituents selected from the aforementioned further preferably a 6-membered aromatic ring. Substituent group A. 0817. The 'aromatic ring of the “aromatic ring which can 0825. In particular, preferred examples of the substituents be substituted represented by the ring A, for example, of the “aromatic ring which can be substituted include includes (i) an aromatic cyclic hydrocarbon, (ii) an aromatic 0826 (1) a halogen atom, heterocyclic ring containing 1 to 4 heteroatoms selected from 0827 (2) a Co alkyl group which can be substituted, nitrogen, oxygen and Sulfur. 0828 (3) a Coalkoxy group which can be substituted, 0818 Said “(i) aromatic cyclic hydrocarbon, for example, 0829 (4) a 4- to 6-membered heterocyclic group contain includes Caromatic cyclic hydrocarbons such as benzene, ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa naphthalene, anthracene, phenanthrene, acenaphthylene toms which can be substituted, (preferably C-2 aromatic cyclic hydrocarbons, particularly 0830 (5) a C- alkylsulfonyl group which can be substi benzene is preferable). tuted, 0819 Said “(ii) aromatic heterocyclic ring containing 1 to 0831 (6) a C-7 cycloalkyl group which can be substituted, 4 hetero atoms selected from nitrogen, oxygen, and Sulfur, for 0832 (7) a cyano group, example, includes 5- or 6-membered aromatic monocyclic 0833 (8) a carbamoyl group which can be substituted, type heterocyclic rings Such as furan, thiophene, pyrrole, 0834 (9) a Co alkylsulfonyloxy group which can be 1.3-oxazole, isoxazole, 1.3-thiazole, isothiazole, imidazole, substituted, pyrazole, 1.2.3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiaz ole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thia 0835 (10) a C-7 cycloalkyl-C alkynyl group which can diazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, be substituted, pyridazine, pyrimidine, pyrazine, 1,2,3-triazine, 1.3.5-triaz 0836 (11) a tetrahydropyranyl group which can be substi ine, 1,2,4-triazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, 1.2.4. tuted, 5-tetrazine and the like; and 0837 (12) a dihydropyranyl group which can be substi 0820) 8 to 16-membered (preferably 8 to 12-membered) tuted, aromatic condensed heterocyclic rings (preferably heterocy 0838 (13) a mono-(Co alkyl-carbonyl)-amino group clic rings formed by condensation of 1 to 2 said 5- to 6-mem which can be substituted, bered aromatic monocyclic heterocyclic rings (preferably 1 0839 (14) a Coalkoxy-carbonyl group which can be ring) with 1 to 2 benzene rings (preferably 1 ring), or hetero substituted, cyclic rings formed by condensation of 2 to 3 said identical 5 0840 (15) a Co alkylsulfinyl group which can be sub to 6-membered aromatic monocyclic heterocyclic rings or stituted, different heterocyclic rings) such as benzofuran, isobenzofu 0841 (16) a C- alkylsulfanyl group which can be sub ran, benzothiophene, indole, isolindole, 1H-indazole, benz stituted, and so on. US 2012/0277430 A1 Nov. 1, 2012

0842. As it is apparent for a person of ordinary skill in the 0869 (7) a 4- to 6-membered heterocyclic group contain art, the '4- to 6-membered heterocyclic group containing 0 or ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa 1 oxygen atom, and 1 to 3 nitrogen atoms as heteroatoms of toms which can be substituted by one or more substituents the “4- to 6-membered heterocyclic group containing 0 or 1 selected from a halogenatom, a hydroxy group, an oxo group, oxygenatom, and 1 to 3 nitrogenatoms as heteroatoms which a Coalkoxy-carbonyl group, a Coalkoxy group which can be substituted is included in the "heterocyclic group of can be substituted, and a C- alkyl group which can be the "heterocyclic group which can be substituted”. substituted. 0843. The number of substituents preferably ranges from 0870 Ring A is, for example, more preferably 1 to 5. 0871 a benzene ring which can be substituted by 1 to 5 0844. The number of the substituents of the "heterocyclic substituents selected from group which can be substituted” is one or more, preferably in 0872 (1) a halogen atom, the range of 1 to 5, more preferably in the range of 1 to 3. 0873 (2) a Coalkyl group which can be substituted by 1 further preferably one or two. to 3 halogen atoms, 0845 When the number of the substituents is two or more, 0874) (3) a Coalkoxy group which can be substituted by the Substituents on the Ring. A can be combined to form a ring 1 to 3 halogen atoms, which can be substituted. The “ring of the “ring which can be 0875 (4) a C-7 cycloalkyl group, substituted include a 5- to 6-membered heterocyclic ring 0876 (5) a halogeno Co alkylsulfonyloxy group, containing one nitrogen atom or two oxygen atoms as het 0877 (6) a C-7 cycloalkyl-C alkynyl group, and erOatOmS. 0878 (7) a 4- to 6-membered heterocyclic group contain 0846. The “ring can be substituted by one or more (pref ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa erably, 1 to 5) substituents selected from the Substituent toms which can be substituted by 1 to 4 substituents selected group A. from a halogenatom, a hydroxy group, an oxo group, a Co 0847. In another aspect of the present invention, preferred alkoxy-carbonyl group, a Coalkoxy group which can be examples of the Substituents of the 'aromatic ring which can Substituted by halogen, and a Co alkyl group which can be be substituted represented by Ring A include Substituted by halogen. 0848 a halogen atoms (preferably halogen atom) 0879 Ring A is, for example, further preferably 0849 a cyano group, 0880 a benzene ring which is substituted with 0850 a hydroxy group, 0881 (1) (i) 1 or 2 halogenatoms, or (ii) one Coalkoxy 0851 an alkyl group which can be substituted (preferably group, and Co alkyl group which can be substituted by 1 to 3 halogen 0882 (2) one 4- to 6-membered heterocyclic group con atoms e.g., trifluoromethyl group), taining 0 or 1 oxygen atom, and 1 to 3 nitrogen atoms as 0852 aalkoxy group which can be substituted (preferably heteroatoms which can be substituted by 1 to 4 substituents Coalkoxy group which can be substituted by 1 to 3 halogen selected from a halogenatom, a hydroxy group, an oxo group, atoms e.g., methoxy group, difluoromethoxy group), a Coalkoxy-carbonyl group, a Coalkoxy group which 0853 a carbamoyl group can be substituted by halogen, and a Co alkyl group which 0854 a heterocyclic-oxy group (preferably 5- to 10-mem can be substituted by halogen. bered heterocyclic-oxy group containing 1 to 3 hetero atoms 0883. Here, as the “one 4- to 6-membered heterocyclic selected from nitrogen, oxygen and Sulfur e.g., benzimida group containing 0 or 1 oxygen atom, and 1 to 3 nitrogen Zolyloxy group), atoms as heteroatoms', for example, preferred is a mor 0855 an alkylsulfanyl group which can be substituted, pholino group, a pyrrolyl group, a dihydropyrrolyl group, a 0856 an alkylsulfinyl group which can be substituted, pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, 0857 an alkylsulfonyl group which can be substituted an aZetidinyl group, a pyrrolidinyl group, an oxazolidinyl (preferably Co alkylsulfonyl group e.g., methylsulfonyl group, an imidazolyl group or an imidazolidinyl group. group), 0884. In another aspect of the present invention, as ring A, 0858 a heterocyclic-sulfonyl group (preferably 5- to in particular, for example, 6-membered saturated heterocyclic-Sulfonyl group contain 0885 preferred is a 5- to 6-membered aromatic group ing 1 to 3 hetero atoms selected from nitrogen, oxygen and which can be substituted by one or more substituents selected Sulfur e.g., morpholinylsulfonyl group), from halogen atoms, cyano group, hydroxy group, alkyl 0859 an amino group which can be substituted, group which can be substituted, alkoxy group which can be 0860 a cycloalkyl group (preferably C-7 cycloalkyl e.g., Substituted, carbamoyl group, alkylsulfanyl group which can cyclohexyl) and saturated heterocyclic group (preferably 5 be substituted, alkylsulfinyl group which can be substituted, to 6-membered saturated heterocyclic group containing 1 to 3 alkylsulfonyl group which can be substituted, heterocyclic hetero atoms selected from nitrogen, oxygen and Sulfur e.g., Sulfonyl group, amino group which can be substituted, morpholinyl group and piperidyl group). cycloalkyl group, and Saturated heterocyclic group, and 0861 Ring A is, for example, preferably 0886 further specifically, preferred is a 5- to 6-membered 0862 a benzene ring which can be substituted by 1 to 5 aromatic group (e.g., phenyl, pyridyl) which can be substi substituents selected from tuted by one or more substituents selected from 0863 (1) a halogen atom, 0887 (a) a halogenatom (e.g., chlorine, fluorine), 0864 (2) a Co alkyl group which can be substituted, 0888 (b) a Cyano group, 0865 (3) a Coalkoxy group which can be substituted, 0889 (c) a Coalkyl group which can be substituted by 1 0866 (4) a C-7 cycloalkyl group, to 3 halogen atoms (e.g., methyl, trifluoromethyl), 0867 (5) a halogeno Coalkylsulfonyloxy group, 0890 (d) a C-7 cycloalkyl group (e.g., methyl, trifluorom 0868 (6) a C-7 cycloalkyl-C alkynyl group, and ethyl), US 2012/0277430 A1 Nov. 1, 2012

0891 (e) a Coalkoxy group which can be substituted by (0905 Compound (I-A) 1 to 3 halogen atoms (e.g., difluoromethoxy, methoxy), 0906. The above described compound (I), wherein 0892 (f) a 5- to 10-membered heterocyclic group contain (0907) R' represents ing 1 to 3 hetero atoms selected from nitrogen, oxygen and 0908 a phenyl group which can be substituted by 1 to 5 Sulfur (e.g., morpholinyl, benzimidazolyl, piperidinyl), Substituents selected from a halogenatom, a Coalkyl group which can be substituted, and a Coalkoxy group which can 0893 (g) a Co alkyl-sulfonyl group (e.g., methylsulfo be substituted, nyl), (0909 R represents 0894 (h) a 5- to 10-membered heterocyclic-sulfonyl 0910 a halogen atom, a hydroxy group, a Co alkyl group containing 1 to 3 hetero atoms selected from nitrogen, group which can be substituted, or a Co alkoxy group oxygen and Sulfur (e.g., morpholinylsulfonyl), and which can be substituted, (i) a carbamoyl group. (0911 R represents 0895 0912 a hydrogenatom, or a Coalkoxy group which can 0896. In the aforementioned formula, the ring B repre be substituted, sents a “5-membered aromatic heterocyclic ring which can be 0913 Ring. A represents substituted'. 0914 a benzene ring which can be substituted by 1 to 5 0897 Examples of the “5-membered aromatic heterocy substituents selected from clic ring which can be substituted’ represented by the ring B 0915 (1) a halogen atom, include 5-membered aromatic heterocyclic rings containing 1 0916 (2) a Co alkyl group which can be substituted, to 4 hetero atoms (preferably 1 to 2 atoms) selected from 0917 (3) a Coalkoxy group which can be substituted, nitrogen, oxygen and Sulfur Such as pyrrole, furan, thiophene, 0918 (4) a 4- to 6-membered heterocyclic group contain pyrazole, imidazole, isoxazole, isothiazole, 1.3-oxazole, 1.3- ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa thiazole, triazole (e.g., 1.23-triazole, 1,2,4-triazole), tetra toms which can be substituted, Zole, oxadiazole (e.g., 1.2.3-oxadiazole), and thiadiazole 0919 (5) a C- alkylsulfonyl group which can be substi (e.g., 1,2,3-thiadiazole). Among them, pyrazole, triazole, and tuted, tetrazole are preferable, and pyrazole is most preferable. 0920 (6) a C-7 cycloalkyl group which can be substituted, 0898. As the substituents of the “5-membered aromatic 0921 (7) a cyano group, heterocyclic represented by the ring B, for example, the sub 0922 (8) a carbamoyl group which can be substituted, 0923 (9) a Co alkylsulfonyloxy group which can be stituents selected from the aforementioned substituent group substituted, A can be included. 0924 (10) a C-7 cycloalkyl-C alkynyl group which can (0899 Preferable examples of the substituents include a be substituted, halogen atom, an alkyl group which can be substituted and a 0925 (11) a tetrahydropyranyl group which can be substi Caryl group which can be substituted, more preferable tuted, examples thereof include a halogenatom, an alkyl group, and 0926 (12) a dihydropyranyl group which can be substi a C- aryl group, further preferable examples thereof tuted, include an alkyl group (e.g., methyl). 0927 (13) a mono-(Co alkyl-carbonyl)-amino group 0900 Also preferably, the ring B does not have such a which can be substituted, substituent. In other words, the ring B has only substituents 0928 (14) a Co alkoxy-carbonyl group which can be shown in the general formula of (I). The ring B is preferably substituted, a 5-membered nitrogen-containing aromatic heterocyclic 0929 (15) a Co alkylsulfinyl group which can be sub ring having 1 to 3 hetero atoms selected from nitrogen, oxy stituted, and gen and Sulfur, which can be substituted by a Co alkyl 0930 (16) a C- alkylsulfanyl group which can be sub group (e.g., methyl)(e.g., pyrazole, triazole, tetrazole). stituted, and 0901. As the Ring B, preferred is an imidazole ring, a 0931 Ring B represents pyrazole ring, a triazole ring or a tetrazole ring, each of which 0932 an imidazole ring, pyrazole ring, a triazole ring or a can be further substituted with 1 to 3 substituents selected tetrazole ring, each of which can be further substituted with 1 from a halogen atom, and a Co alkyl group which can be to 3 Substituents selected from a halogen atom, and a Co Substituted by halogen, more preferred is a pyrazole ring alkyl group which can be substituted by halogen. which can be further substituted with 1 to 3 substituents 0933 Compound (I-B) selected from a halogen atom, and a Co alkyl group which 0934. The above described compound (I-A), wherein can be substituted by halogen, especially preferred is a pyra 0935 Ring. A represents Zole ring. 0936 a benzene ring which can be substituted by 1 to 5 0902. In another aspect of the present invention, the ring B substituents selected from is preferably a 5-membered nitrogen-containing aromatic 0937 (1) a halogen atom, heterocyclic ring having 1 to 3 nitrogenatoms (e.g., pyrazole, 0938 (2) a Co alkyl group which can be substituted, triazole, tetrazole), which can be substituted by a Co alkyl 0939 (3) a Coalkoxy group which can be substituted, group (e.g., methyl) 0940 (4) a C-7 cycloalkyl group, 0903. Further preferably, examples of the substituents, 0941 (5) a halogeno Co alkylsulfonyloxy group, moieties and rings as explained in the present specification 0942 (6) a C-7 cycloalkyl-C alkynyl group, and are used in combination. 0943 (7) a 4- to 6-membered heterocyclic group contain 0904 For example, the following compounds, i.e., com ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa pounds (Io-A); (Io-B), (Io-C). (Io-D), (Io-E). (Io-F), and (Io-G) toms which can be substituted by one or more substituents are preferable as a compound (I). selected from a halogenatom, a hydroxy group, an oxo group, US 2012/0277430 A1 Nov. 1, 2012 20 a Coalkoxy-carbonyl group, a Coalkoxy group which an aZetidinyl group, a pyrrolidinyl group, an oxazolidinyl can be substituted, and a Co alkyl group which can be group, an imidazolyl group or an imidazolidinyl group. substituted. 0978 Compound (I-E) 0944 Compound (I-C) 0979 The above described compound (I), wherein 0945. The above described compound (I), wherein 0980) R' represents (0946) R' represents 0981 an aromatic group which can be substituted, 0947 a phenyl group which can be substituted by 1 to 5 0982 Ring. A represents Substituents selected from a halogen atom, a Co alkyl 0983 an aromatic ring which is substituted with group, and a Coalkoxy group, 0984 (a) one substituent selected from 0948 R represents 0985 (1) a C-7 cycloalkyl group which can be substituted, 0949 a Coalkoxy group which can be substituted by and one or more Substituents selected from a halogen atom, a 0986 (2) a 4- to 6-membered heterocyclic group contain Coalkoxy group, and a C-7 cycloalkyl group, ing 1 to 5 heteroatoms selected from a nitrogenatom, a Sulfur 0950 R represents atom, and an oxygen atom which can be substituted, and 0951 a hydrogen atom, or a Coalkoxy group, 0987) (b) one or more further substituents. 0952 Ring. A represents 0988. Here, especially preferably, the further substituents 0953 a benzene ring which can be substituted by 1 to 5 are 1 to 4 substituents selected from substituents selected from 0989 (1) a halogen atom, 0954 (1) a halogen atom, 0990 (2) an oxo group, 0955 (2) a Coalkyl group which can be substituted by 1 0991 (3) a hydroxy group, to 3 halogen atoms, 0992 (4) a Co alkyl group which can be substituted, 0956 (3) a Coalkoxy group which can be substituted by 0993 (5) a Coalkoxy group which can be substituted, 1 to 3 halogen atoms, 0994 (6) a Co alkylsulfonyl group, 0957 (4) a C-7 cycloalkyl group, 0995 (7) a morpholin-4-yl sulfonyl group, 0958 (5) a halogeno Co alkylsulfonyloxy group, 0996 (8) a cyano group, 0959 (6) a C-7 cycloalkyl-C alkynyl group, and 0997 (9) a carbamoyl group, 0960 (7) a 4- to 6-membered heterocyclic group contain 0998 (10) a halogeno Coalkylsulfonyloxy group, ing 0 or 1 oxygenatom, and 1 to 3 nitrogenatoms as heteroa 0999 (11) a C-7 cycloalkyl-C alkynyl group, toms which can be substituted by 1 to 4 substituents selected from a halogenatom, a hydroxy group, an oxo group, a Co 1000 (12) a di-Clio alkyl-amino group, alkoxy-carbonyl group, a Coalkoxy group which can be 1001 (13) a mono-(Co alkyl-carbonyl)-amino group, Substituted by halogen, and a Co alkyl group which can be 1002 (14) a Coalkoxy-carbonyl group, Substituted by halogen, 1003 (15) a phenoxy group, 0961 Ring B represents 1004 (16) a Co alkylsulfinyl group, 0962 a pyrazole ring which can be further substituted with 1005 (17) a di-Clio alkyl-amino group, 1 to 3 Substituents selected from a halogen atom, and a Co 1006 (18) a benzimidazole-2-yloxy group, and alkyl group which can be substituted by halogen. 1007 (19) a benzimidazole-2-yl sulfonyl group. 0963 Compound (I-D) 1008 Compound (I-F) 0964. The above described compound (I), wherein 1009 The above described compound (I-E), wherein 0965) R' represents 1010) R' represents 0966 a phenyl group which can be substituted by 1 to 5 1011 a phenyl group which can be substituted, halogen atoms, 1012 R represents 0967 R represents 1013 a hydrogenatom, a halogen atom, a hydroxy group, 0968 a Coalkoxy group, a Coalkyl group which can be substituted, or a Coalkoxy 0969 R represents group which can be substituted, 0970 a hydrogen atom, 1014 R represents 0971 Ring. A represents 1015 a hydrogenatom, or a Coalkoxy group which can 0972 a benzene ring which is substituted with be substituted, 0973 (1) (i) 1 or 2 halogenatoms, or (ii) one alkoxy group, 1016 Ring. A represents and 1017 a benzene ring which 0974 (2) one 4- to 6-membered heterocyclic group con 1018 is substituted with one substituent selected from taining 0 or 1 oxygen atom, and 1 to 3 nitrogen atoms as 1019 (1) a C-, cycloalkyl group which can be substituted, heteroatoms which can be substituted by 1 to 4 substituents 1020 (2) a dihydropyranyl group which can be substi selected from a halogenatom, a hydroxy group, an oxo group, tuted, a Co alkoxy-carbonyl group, a Coalkoxy group which 1021 (3) a tetrahydropyranyl group which can be substi can be substituted by halogen, and a Co alkyl group which tuted, and can be substituted by halogen, 1022 (4) a 4- to 6-membered heterocyclic group contain 0975 Ring B represents ing 0 or 1 oxygenatom, and 1 to 3 nitrogen atoms as heteroa 0976 a pyrazole ring. toms which can be substituted, and can be substituted by 0977 Here, as the “one 4- to 6-membered heterocyclic further substituents, and group containing 0 or 1 oxygen atom, and 1 to 3 nitrogen 1023 Ring B represents atoms as heteroatoms', for example, preferred is a mor 1024 an imidazole ring, a pyrazole ring, a triazole ring, a pholino group, a pyrrolyl group, a dihydropyrrolyl group, a tetrazole ring, an isoxazole ring, an 1.3-oxazole ring, a furan pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, ring, or a thiophene ring, each of which can be substituted. US 2012/0277430 A1 Nov. 1, 2012

1025 Here, as the “one 4- to 6-membered heterocyclic 1049 Ring B represents a 5-membered aromatic hetero group containing 0 or 1 oxygen atom, and 1 to 3 nitrogen cyclic ring which can be substituted. atoms as heteroatoms', for example, preferred is a mor 1050 Compound (I-I) pholino group, a pyrrolyl group, a dihydropyrrolyl group, a 1051 Compound (I), wherein pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, 1052 Ring A is a 5- to 6-membered aromatic ring (e.g., an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl phenyl pyridyl) which can be substituted by one or more group, animidazolyl group, an imidazolidinyl group, an isox substituents selected from azolyl group, a pyridyl group, a piperazinyl group, or a thia 1053 (a) halogen atoms (e.g., chlorine, fluorine, iodine) Zolyl group. 1054 (b) cyano group 1026 Compound (Io-G) 1055 (c) Co. alkyl group which can be substituted by 1 1027. The Compound (Io-E), or the Compound (I-F), to 3 halogen atoms (e.g., methyl, trifluoromethyl), wherein 1056 (d) C., cycloalkyl group (e.g., methyl, trifluorom 1028) R' represents ethyl), 1029 a phenyl group which can be substituted by 1 to 5 1057 (e) Coalkoxy group which can be substituted by 1 halogen atoms, to 3 halogen atoms (e.g., difluoromethoxy, methoxy), 1030 R represents 1058 (f) 5- to 10-membered heterocyclic group contain 1031 a hydrogen atom or a Coalkoxy group, ing 1 to 3 hetero atoms selected from nitrogen, oxygen and 1032 R represents Sulfur (e.g., morpholinyl, benzimidazolyl, piperidinyl), 1033 a hydrogen atom, 1034 Ring. A represents 1059 (g) Coalkyl-sulfonyl group (e.g., methylsulfonyl) 1035 a benzene ring, 1060 (h) 5- to 10-membered heterocyclic-sulfonyl group 1036 which is substituted with one 4- to 6-membered containing 1 to 3 hetero atoms selected from nitrogen, oxygen heterocyclic group containing 0 or 1 oxygenatom, and 1 to 3 and Sulfur (e.g., morpholinylsulfonyl), nitrogen atoms as heteroatoms which can be substituted by 1 1061 (i) carbamoyl group, to 4 Substituents selected from a halogen atom, a hydroxy 1062) R' represents group, an oxo group, halogeno Coalkoxy group, a Co 1063 (a) Co alkyl group (e.g., isopropyl, isobutyl), or alkoxy-carbonyl, and a Co alkyl group which can be Sub 1064 (b) halogen atoms (e.g., chlorine, fluorine), Co stituted by halogen, alkyl group (e.g., methyl) Coalkoxy group (e.g., methoxy). 1037 and which can be further substituted with 1 or 2 1065 R represents Substituents selected from a halogenatom and a Coalkoxy 1066 (a) hydrogen group, and 1067 (b) hydroxy group 1038 Ring B represents 1068 (c) Co alkyl group (e.g., methyl), or 1039 a pyrazole ring. 1069 (d) Coalkoxy group which can be substituted by 1040 Here, as the “one 4- to 6-membered heterocyclic one or more substituents selected from halogen atoms and group containing 0 or 1 oxygen atom, and 1 to 3 nitrogen C-7 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, atoms as heteroatoms', for example, preferred is a mor cyclopropylmethoxy, difluoromethoxy), pholino group, a pyrrolyl group, a dihydropyrrolyl group, a 1070 R represents pyrazolyl group, a dihydropyrazolyl group, a piperidyl group, 1071 hydrogen, or Co alkyl group (e.g., methyl), an azetidinyl group, a pyrrolidinyl group, an oxazolidinyl 1072 the ring B is preferably a 5-membered nitrogen group, an imidazolyl group or an imidazolidinyl group. containing aromatic heterocyclic ring having 1 to 3 nitrogen 1041. In another aspect of the present invention, the fol atoms (e.g., pyrazole, triazole, tetrazole), which can be Sub lowing compounds, i.e., compounds (Io-H) and (Io-I) are stituted by a Co alkyl group (e.g., methyl) preferable as a compound (I). 1073 Preferably, the compound (I) does not include the 1042 Compound (Io-H) following compounds or salts thereof: 1043 Compound (I), wherein 1074 1-(2-chlorophenyl)-6-methyl-3-(5-thioxo-4-3- 1044 wherein (trifluoromethyl)phenyl-4,5-dihydro-1H-1,2,4-triazol-3- 1045) R' represents alkyl group which can be substituted, ylpyridazin-4(1H)-one, alkoxy group which can be substituted, cycloalkyl group 1075 1-(4-chlorophenyl)-3-4-(2-fluorophenyl)-5- which can be substituted, or aromatic group which can be thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl-6-methylpy substituted, ridazin-4(1H)-one, 1046 R represents a hydrogen atom, a hydroxy group, 1076) 1-(4-chlorophenyl)-6-methyl-3-(5-thioxo-4-3- alkyl group which can be substituted, or alkoxy group which (trifluoromethyl)phenyl-4,5-dihydro-1H-1,2,4-triazol-3- can be substituted, ylpyridazin-4(1H)-one, 1047 R represents a hydrogenatom or alkyl group which 1077 1-(4-chlorophenyl)-3-4-(2-fluorophenyl)-5-(me can be substituted, thylsulfanyl)-4H-1,2,4-triazol-3-yl-6-methylpyridazin-4 1048 Ring. A represents a 5- or 6-membered aromatic ring (1H)-one, which can be substituted by one or more substituents selected 1078 1-(4-chlorophenyl)-6-methyl-3-(5-(methylsulfa from halogen atoms, cyano group, hydroxy group, alkyl nyl)-4-3-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- group which can be substituted, alkoxy group which can be ylpyridazin-4(1H)-one, Substituted, carbamoyl group, alkylsulfanyl group which can 1079 1-(2-chlorophenyl)-6-methyl-3-(5-(methylsulfa be substituted, alkylsulfinyl group which can be substituted, nyl)-4-3-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3- heterocyclic-Sulfonyl group, amino group which can be Sub ylpyridazin-4(1H)-one, stituted, cycloalkyl group, and Saturated heterocyclic group, 1080 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1-phenylpy and ridazin-4(1H)-one,

US 2012/0277430 A1 Nov. 1, 2012

Preferable examples of salts with inorganic acids include salts 1130. The symbols used for the compounds in the reaction with hydrochloric acid, hydrobromic acid, nitric acid, sulfu schemes indicate the same meanings as mentioned above. In ric acid, phosphoric acid and the like. Preferable examples of this specification, a methyl group (CH) is sometimes abbre salts with organic acids include salts with formic acid, acetic viated as Me. The compounds in the schemes can include Salts acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic thereof in the cases when salts can be formed and Such salts acid, tartaric acid, maleic acid, citric acid, Succinic acid, malic are similar to the salts of the compound (I). Further, the acid, methanesulfonic acid, benzenesulfonic acid, p-toluene compound obtained in each process can be used directly in the sulfonic acid and the like. Preferable examples of salts with form of a reaction mixture or as a crude product in the fol basic amino acids include salts with arginine, lysine, orni lowing reactions. However, it can be isolated from the reac thine and the like. Preferable examples of salts with acidic tion mixture according to the ordinary method. The product amino acids include salts with aspartic acid, glutamic acid itself can be easily purified by the known means of isolation and the like. Among them, salts that are pharmacologically Such as extraction, concentration, neutralization, filtration, acceptable are preferable. For example, in the case when distillation, recrystallization and chromatography. Alterna acidic functional group are present in the compound, for tively, if the compound in the schemes is commercially avail example, inorganic salts including alkali metal salts (e.g., able, a commercial product can be used directly and in addi Sodium salts, etc.) and alkali earth metal salts (e.g., calcium tion, those which are manufactured by the known methods or salts, magnesium salts, barium salts, etc.) and ammonium by a comparable method can be used. If the compound as a salts are preferable. In contrast, in the case when basic func raw material contains amino, carboxy, hydroxyl or heterocy tional group are present in the compound, for example, salts clic group, the group can be protected by a protective group with inorganic acids such as hydrochloric acid, hydrobromic that is generally used in the peptide chemistry. In this case, if acid, nitric acid, Sulfuric acid, phosphoric acid, etc. or salts desirable, target compound can be obtained by removing the with organic acid Such as acetic acid, phthalic acid, fumaric protective group. The protective group can be introduced or acid, oxalic acid, tartaric acid, maleic acid, citric acid, suc removed by the known methods, for example, based on the cinic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. methods described in “Protective Groups in Organic Synthe are preferable. sis, 3 Edition” (by Theodora W. Greene, Peter G. M. Wuts, 1122. If the compound (I) includes isomers such as tau published in 1999 by Wiley-Interscience Corporation). tomers, optical isomers, Steric isomers, reverse isomers and 1131 Examples of “X” include halogen anions (e.g., rotational isomers, one of the other isomers or mixture are chlorine anion, bromine anion, iodine anion, etc.), nitrate ion, also included in the compound of the present invention. Fur and phosphate ion. ther, if the compound (I) has an optical isomer, the optical 1132. In these manufacturing methods, Substituent con isomer separated from the racemate is included in the com versions of each substituents of R' to Rand each substituents pound (I). on the Rings A and B be carried out according to the aperse 1123. The compound (I) can be obtained in the crystal known method, for example, the method described in “Com form. Either single crystalline form or crystalline mixture can prehensive Organic Transformations” (by Richard C. Larock, be included in the compound (I). published in 1999 by Wiley-VCH). 1124. The compound of the formula (I) can be a pharma 1133. The following respective processes can be carried ceutically acceptable co-crystal or a co-crystal salt. The term out without a solvent or the raw materials can be dissolved or “co-crystal' or “co-crystal salt” as used herein means a crys Suspended in an appropriate solvent prior to the reaction. In talline material composed of two or more unique Solids at this case, one kind of Solvent can be used independently or room temperature, each of which has distinctive physical two or more solvents can be combined at an appropriate ratio. characteristics such as structure, melting point, and heats of Specific examples of the solvents to be used in the manufac fusion, hygroscopicity, Solubility, and stability. A co-crystal turing methods of the present compound are given specifi or a co-crystal salt can be obtained according to a per se cally as follows: known co-crystallization method. 1134 Alcohols: methanol, ethanol, 1-propanol, 2-pro 1125. The compound (I) can be provided as a solvate (for panol, tert-butyl alcohol, 2-methoxyethanol, etc. example, hydrate) or as a non-Solvate and both are included in 1135 Ethers: diethyl ether, diisopropyl ether, diphenyl the compound (I). ether, tetrahydrofuran, 1.4-dioxane, 1,2-dimethoxyethane, 1126) The compounds labeled with isotopes (e.g., H. H. etc. 'C, C, F, S, 'I, etc.) are also included in the com 1136 Aromatic hydrocarbons: benzene, chlorobenzene, pound (I). toluene, Xylene, etc. 1127. Manufacturing Methods 1137 Saturated hydrocarbons: cyclohexane, hexane, etc. 1128. The compound of the present invention and the 1138 Amides: N,N-dimethylformamide, N,N-dimethy compound as raw materials can be manufactured by the lacetamide, hexamethylphosphoric triamide, etc. known means, for example, by the methods shown in the following schemes. Hereinafter, “room temperature' indi 1139 Halogenated hydrocarbons: dichloromethane, chlo cates a temperature generally ranging from 0 to 35° C. and “a roform, carbon tetrachloride, 1,2-dichloroethane, etc. low temperature' indicates a temperature generally from -78 1140 Nitriles: acetonitrile, propionitrile, etc. to O C. 1141 Sulfoxides: dimethylsulfoxide, etc. 1129. The compound (I) can be obtained, for example, by 1142 Aromatic organic bases: pyridine, lutidine, etc. the method explained below or by a comparable method 1143 Acid anhydrides: acetic anhydride, etc. thereto. The methods of manufacturing the compound (I) is 1144 Organic acids: formic acid, acetic acid, propionic explained below by explaining the methods of manufacturing acid, trifluoroacetic acid, methanesulfonic acid, etc. the compounds (I-a), (I-b), (I-c). (I-d). (I-e), (I-g), (I-h), (I-i), 1145 Inorganic acids: hydrochloric acid, sulfuric acid, and (I-) included in the compound (I). etc. US 2012/0277430 A1 Nov. 1, 2012 24

1146 Esters: methyl acetate, ethyl acetate, butyl acetate, triphenylphosphine, and 4,5-bis(diphenylphosphino)-9.9- etc. dimethylxanthene are exemplified. As the “copper catalysts’. 1147 Ketones: acetone, methyl ethyl ketone, etc. for example, cuprous iodide (CuI), and copper oxide (Cu2O) 1148 Specific examples of bases or deoxidizers that are can be used. The "copper catalyst” can be used in an amount used in the manufacturing methods for the compound of the ranging from about 0.1 to 1 moland preferably from 0.1 to 0.5 present invention are given as follows: mol relative to 1 mol of the reaction substrate. In addition, the 1149 Inorganic bases: sodium hydroxide, potassium "copper catalyst” can be used along with a ligand Such as hydroxide, magnesium hydroxide, etc. N,N'-dimethylethane-1,2-diamine, trans-1,2-diaminocyclo 1150 Basic salts: sodium carbonate, potassium carbonate, hexane and Salicylaldoxime. Such a ligand is used in an cesium carbonate, calcium carbonate, sodium hydrogen car amount ranging from about 0.1 to 4 mol and preferably from bonate, etc. 1151. Organic bases: triethylamine, diisopropylethy 0.1 to 2 mol relative to 1 mol of the reaction substrate. As the lamine, tributylamine, cyclohexyldimethylamine, pyridine, “base', sodium tert-butoxide or potassium phosphate can be lutidine, 4-dimethylaminopyridine, N,N-dimethylaniline, used and the amount ranges from about 1 to 10 mol and N-methylpiperidine, N-methylpyrrolidine, N-methylmor preferably from 1 to 3 mol relative to 1 mol of the reaction pholine, 1,5-diazabicyclo[4.30-5-nonene, 1,4-diazabicyclo Substrate. It is advantageous to carry out the present reaction 2.2.2]octane, 1,8-diazabicyclo[5.4.0-7-undecene, imida in the absence of a solvent or in the presence of an inert Zole, etc. solvent in the reaction. The solvent to be used is not particu 1152 Metal alkoxides: sodium methoxide, sodium ethox larly limited as long as the reaction proceeds, but for example, ide, potassium tert-butoxide, etc. ethers, nitriles and the like are desirable. It is desirable to 1153 Alkali metal hydrides: sodium hydride, potassium carry out the reaction generally at room temperature or under hydride, etc. reflux conditions by heating and preferably under reflux con 1154 Metal amides: sodium amide, lithium diisopropyla ditions by heating. The reaction time generally ranges from mide, lithium hexamethyldisilazide, etc. 0.5 to 48 hours and preferably from 1 to 24 hours. 1155 Organic lithium reagents: methyl lithium, n-butyl 1162. This coupling reaction can be carried out by the lithium, sec-butyl lithium, tert-butyl lithium, etc. methods described in “Cross-Coupling Reactions: A Practi 1156 Specific examples of acids or acid catalysts that are cal Guide (Topics in Current Chemistry) (Springer) “Experi used in the manufacturing methods for the compound of the mental Organic Metallic Chemistry for Synthesizing Chem present invention are given as follows: ists' (Kodansha) and "Organic Synthesis using Transition 1157 Inorganic acids: hydrochloric acid, sulfuric acid, Metals” (Kagaku Dojin) or by a comparable method. nitric acid, hydrobromic acid, phosphoric acid, etc. 1163 The compounds (I-a), (I-b), (I-c). (I-d), (I-e), (I-g), 1158 Organic acids: acetic acid, trifluoroacetic acid, (I-h), (I-i), and (I-), each of which is included in the com oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic pound (I) can be prepared by the manufacturing method A. acid, citric acid. Succinic acid, methanesulfonic acid, p-tolu manufacturing method B, manufacturing method C, manu enesulfonic acid, 10-camphorsulfonic acid, etc. facturing method D. manufacturing methodE, manufacturing 1159 Lewis acids: trifluoroboron ether complex, Zinc method F. manufacturing method G. manufacturing method iodide, anhydrous aluminum chloride, anhydrous Zinc chlo H. manufacturing method I or manufacturing method Jas ride, anhydrous iron chloride, etc. explained below. 1160. When binding "heterocyclic compounds”, “car 1164. The symbols in each general formula in the reaction bamate compounds”, “acetylene derivatives”, “boronic acid schemes represent the same meanings as mentioned above derivatives', or “organotin compounds' to Ring A having a unless otherwise specifically mentioned. leaving group, the product can be produced by a coupling 1165 Manufacturing Method A reaction in the presence of a base using both palladium cata lyst and copper catalyst or one of them. The "heterocyclic compounds' include an imidazole ring compound, pyrazole NH2 NX ring compound, pyrrolidine ring compound, aZetidine ring Process 1 compound, a pyrrolidone ring compound, piperidone ring Her -- compound, etc., the "carbamate compounds' include oxazolidone ring compound, etc., the "acetylene derivatives' (II) (III) O O include cyclopropylacetylene, etc. the “boronic acid deriva Process 2 tives” include (1-methyl-1H-pyrazol-4-yl)boronic acid pina He col esters, etc., the “organotin compounds' includes 2-(tribu - us Me tylstannyl)-1,3-oxazole, etc. (IV) 1161. As the “palladium catalyst”, for example, tris O O (dibenzylideneacetone)dipalladium(0), tetrakistriph enylphosphinepalladium(0) and the like can be used. The Me Me palladium catalyst can be used in an amount ranging from Process 3 about 0.01 to 1 mol and preferably from 0.05 to 0.2 mol N He relative to 1 mol of the reaction substrate. The “palladium catalyst” can be used in combination with phosphine ligands. When the phosphine ligand is used, it is used in an amount ranging from about 0.01 to 4 mol and preferably from 0.05 to 5 1 mol relative to 1 mol of the reaction substrate. As the (V) “phosphine ligand’, for example, a phosphine ligand Such as US 2012/0277430 A1 Nov. 1, 2012 25

1167. Manufacturing Method C -continued

Process 4 -- RNHNH Process 5

(VI)

Process 7 -e-

1166 Manufacturing Method B

H

NX O O Process 2 -is2 Me -- -e- N N Me ulus OR4 Me + RNHNH ->Process 8 (III) (VIII) (VII) O O

Process 3

NHNH

1168. Manufacturing Method D

Process 6 RNH, -> Process 5 (xii) + RNH --> (XII) US 2012/0277430 A1 Nov. 1, 2012 26

-continued -continued

Process 9 Process 13 -> -e-

Process 3 -e-

(XVI) (I-d)

1169 Manufacturing Method El --

NX O O Process 2 -- rulus Her OMe XXIII (III) (XVII) ( ) O O R2

OMe Process 3 HN1 N

() RNHNH -Process I 4 - (XVIII) (VII)

Process 11 He

1170. Manufacturing Method F.

Process 12 Process 14 He- He US 2012/0277430 A1 Nov. 1, 2012 27

-continued -continued

Process 12 Ho

(XXVI) (I-f)

1171. Manufacturing Method G Process 3 ---

NX O O O -- lulu HeProcess 2 MeO OMe (III) (XXVII)

O O O OMe

MeO OMe Process 17 --

Process 4 Process 19 -as Process 18 RNHNH, T R1 -e- (VII)

Process 18 Process 11 -e- Hs US 2012/0277430 A1 Nov. 1, 2012 28

1173. Manufacturing Method I -continued

Process 23

(2) indicates text missing or illegible when filed

1172. Manufacturing Method H

Process 20

1174. Manufacturing Method J

Process 24 -e- Process 21 d) (XXV)

Process 22 -es Process 25 Her

(XXXVIII)

Process 26 US 2012/0277430 A1 Nov. 1, 2012 29

in the reaction. These solvents are not limited as long as the

-continued reaction proceeds, but a mixed solvent of alcohols and water is desirable. 1187. It is desirable to carry out the reaction generally at room temperature or at a low temperature while being cooled in an ice bath. 1188 The reaction time generally ranges from 5 seconds to 24 hours and preferably ranges from 5 seconds to 1 hour. 1189 R is a Co alkyl group which can be substituted, and preferably a methyl group, or an ethyl group. In this process, R represents a Co alkyl group which can be sub (I-) stituted or a Coalkoxy group which can be substituted. 1190 Process 3 is a method of producing a compound 1175 Process 1 is a method of producing a compound (III) (VI), a compound (X), a compound (XIX), a compound by reacting a compound (II) with a diazotization agent. If (XXIII) or a compound (XXXIV) from the compound (V), desirable, the reaction can be carried out in the presence of an the compound (IX), the compound (XVIII), the compound acid. (XXII) or the compound (XXXIII). The reaction can be car 1176 Examples of a diazotization agent are as follows: ried out in the presence of N,N-dimethylformamide dimethy alkali metal nitrites such as Sodium nitrite and potassium lacetal and the like as a solvent. nitrite: C. nitrous acid alkyl esters such as t-butyl nitrite and 1191. This process can be carried out by the method isoamyl nitrite, nitrosyl chloride, nitrosyl Sulfate, and nitro described in the Journal of Heterocyclic Chemistry, 1981, 18, gen monoxide. Among them, Sodium nitrite is desirable from 333-334 or by a comparable method. the standpoint that it can be obtained easily at a low cost. 1192. It is desirable to carry out the reaction generally Further, nitrous acid alkyl esters are desirable from the stand under reflux conditions by heating and preferably at 100° C. point that the reactivity is enhanced. In this case, since an to 150° C. alkali metal nitrite is solid at room temperature, it is dissolved 1193. The reaction time generally ranges from 1 to 10 in advance in water prior to its use. hours and preferably from 1 to 5 hours. 1177. As the “acid, for example, hydrochloric acid, sul 1194 Process 4 is a method of producing a compound furic acid and acetic acid are applicable and they can be also (I-a), a compound (I-e) or a compound (XXXV) by placing used as a mixture. the compound (VII) together with the compound (VI), the 1178 From the standpoint of increasing reactivity and compound (XXIII) or the compound (XXXIV). economical efficiency, the amount of a diazotization agent 1195 The amount of the compound (VII) to be used ranges from 1 to 5 mol and preferably from 1 to 2 mol relative ranges from approximately 1 to 10 mol and preferably from to 1 mol of the compound (II). It is desirable to carry out the approximately 2 to 5 mol relative to 1 mol of the compound reaction generally at room temperature or at a low tempera (VI), the compound (XXIII) or the compound (XXXIV). ture and preferably at a temperature ranging from -30°C. to 1196. It is advantageous to carry out the reaction in the OO C. absence of a solvent or in the presence of an inert Solvent in 1179 The reaction time generally ranges from 1 minute to the reaction. The solvent to be used is not limited as long as 3 hours and preferably from 1 minute to 1 hour. the reaction proceeds, but alcohols, organic acids or mixed 1180. It is advantageous to carry out the present reaction in solvents thereof are desirable. the absence of a solvent or in the presence of an inert solvent 1197. It is desirable to carry out the reaction generally in in the reaction. These solvents are not limited as long as the an ice bath, at room temperature, or under reflux conditions reaction proceeds, but water is preferred. by heating and preferably at 0°C. to 150° C. 1181 Process 2 is a method of producing a compound (V), 1198. The reaction time generally ranges from 0.1 to 10 a compound (IX), a compound (XVIII) or a compound (XX hours and preferably from 0.5 to 5 hours. VIII) by placing a compound (III) together with a compound 1199. This process can be carried out by the method (IV), a compound (VIII), a compound (XVII) or a compound described in the Journal of Heterocyclic Chemistry, 1981, 18, (XXVII). 333-334 or by a comparable method. 1182. This process can be carried out by the method 1200. In this process, R' represents a Co alkyl group described in Tetrahedron Lett., 2008, 49(14), 2262-2264 or which can be substituted, a C-7 cycloalkyl group which can by a comparable method. If desirable, the reaction can be be substituted, oran aromatic group which can be substituted. carried out in the presence of a base. 1201 Process 5 is a method of producing a compound (XI) 1183. The amount of the compounds (IV), (VIII), (XVII) by reacting the compound (X) with hydrazine, a method of or (XXVII) to be used ranges from approximately 1 to 5 mol producing a compound (XIII) by reacting the compound (X) and preferably from 1 to 2 mol relative to 1 mol of the with ammonia, or a method of producing a compound (XV) compound (III). by reacting the compound (X) with an amine compound 1184 As the “base', for example, sodium acetate can be (XII). used. 1202. The amount of hydrazine, ammonia and the amine 1185. The amount of the “base' to be used generally compound (XII) to be used ranges from approximately 1 to 10 ranges from 1 to 10 equivalents and preferably from 2 to 6 mol and preferably from approximately 2 to 5 mol relative to equivalents relative to the compound (III). 1 mol of the compound (X). 1186 It is advantageous to carry out the present reaction in 1203. It is advantageous if the reaction is carried out in the the absence of a solvent or in the presence of an inert solvent absence of a solvent or in the presence of an inert Solvent in US 2012/0277430 A1 Nov. 1, 2012 30 the reaction. The solvent is not limited as long as the reaction 1220. The reaction time generally ranges from 0.5 to 3 proceeds, but for example, alcohols or ethers are desirable. hours and preferably from 0.5 to 1 hour. 1204. It is desirable to carry out the reaction generally 1221. This process can be carried out by the method under heated conditions and preferably at 50° C. to 100° C. described in Org. Lett., 2004, 6 (17), 2969-2971 or by a 1205 The reaction time generally ranges from 1 to 10 comparable method. hours and preferably from 1 to 5 hours. 1222 Process 7 is a method of producing a compound 1206. This process can be carried out by the method (XIV) from the compound (XIII). The product can be pro described in the Journal of Heterocyclic Chemistry, 1981, 18, duced in the presence of N,N-dimethylformamide dimethy 333-334 or by a comparable method. lacetal as a solvent. 1207 Further, a method of heating under microwave con 1223. It is desirable to carry out the reaction generally ditions or a method of heating in the presence of trimethyl under heated conditions and preferably at 100° C. to 150° C. aluminum as an activator is applicable. 1224. The reaction time generally ranges from 0.1 to 5 1208. The reaction temperature in the case when heating hours and preferably from 0.1 to 1 hour. under microwave conditions range generally from 50° C. to 1225. This process can be carried out by the method 150° C. and preferably from 100° C. to 130° C. The reaction described in Arch. Pharm. Chem. Life Sci., 2007, 340, 17-25 time generally ranges from 10 to 60 min. and preferably from or by a comparable method. 10 to 20 min. It is advantageous to carry out the reaction in the 1226 Process 8 is a method of producing a compound absence of a solvent or using an inert Solvent in the reaction. (I-c) by placing the compound (XIV) together with a hydra The Solvent is not limited as long as the reaction proceeds, but zine compound (VII). The reaction can be carried out in the for example, alcohols or ethers are desirable. presence of an organic acid. 1209 If the reaction is carried out in the presence of trim 1227. The amount of the hydrazine compound (VII) to be ethylaluminum as an activator, trimethyl aluminum is used in used ranges from about 1 to 5 mol and preferably from 1 to 2 an amount ranging from approximately 1 to 5 mol and pref mol relative to 1 mol of the compound (XIV). erably from about 1 to 3 mol relative to 1 mol of the com 1228. As the “organic acid', for example, acetic acid can pound (X). It is advantageous to carry out the reaction in the be used. absence of a solvent or using an inert Solvent in the reaction. 1229. The amount of the organic acid to be used is similar The Solvent is not limited as long as the reaction proceeds, but to the amount when it is generally used as a solvent. methylene chloride is desirable. It is desirable to carry out the 1230. It is desirable to carry out the reaction generally reaction generally under heated conditions and preferably at under heated conditions and preferably at 100° C. to 130°C. 50° C. to 100°C. The reaction time generally ranges from 1 to 1231. The reaction time generally ranges from 0.5 to 3 15 hours and preferably from 1 to 10 hours. hours and preferably from 0.5 to 1 hour. 1210 Process 6 is a method of producing a compound 1232. This process can be carried out by the method (I-b) by placing the compound (XI) together with an amine described in Arch. Pharm. Chem. Life Sci., 2007, 340, 17-25 compound (XII). or by a comparable method. 1211. In the case when R is a hydrogen, the compound 1233 Process 9 is a method of producing a compound (XI) is reacted with N,N-dimethylformamide dimethylacetal (XVI) from the compound (XV). The reaction can be carried or the like, and Subsequently reacted with an amine com out in the presence of 1H-benzod 1.2.3 triazole and an acid pound (XII) under an acidic condition without isolation to halide. produce a compound (I-b). In contrast, if R is a methyl group, 1234. It is advantageous to carry out the reaction in the the compound (XI) is reacted with N,N-dimethylacetamide absence of a solvent or using an inert Solvent in the reaction. dimethylacetal and the reaction is carried out with an amine The solvent is not particularly limited as long as the reaction compound (XII) under an acidic condition as mentioned proceeds, but for example, halogenated hydrocarbons are above to produce a compound (I-b). desirable. 1212 The amount of N,N-dimethylformamide dimethy 1235. The amount of 1H-benzod1.2.3 triazole to be lacetal or N,N-dimethylacetamide dimethylacetal to be used used ranges from about 1 to 10 mol and preferably from 1 to ranges from about 1 to 5 mol and preferably from about 1 to 5 mol relative to 1 mol of the compound (XV). 2 mol relative to 1 mol of the compound (XI). 1236. As the “acid halide', for example, thionyl chloride 1213. It is desirable to carry out the reaction generally can be used. under heated conditions and preferably at 50° C. to 100° C. 1237. The amount of the “acid halide' to be used ranges 1214. The reaction time generally ranges from 0.5 to 3 from about 1 to 5 equivalents and preferably from 1 to 2 hours and preferably from 0.5 to 1 hour. equivalents relative to the compound (XV). 1215. It is advantageous to carry out the reaction in the 1238. It is desirable to carry out the reaction under reflux absence of a solvent or using an inert Solvent in the reaction. conditions by heating and it is also possible to carry out the The Solvent is not limited as long as the reaction proceeds, but reaction in a short time under microwave conditions. If the for example, nitriles are desirable. reaction is carried out under microwave conditions, the reac 1216. The amount of an amine compound (XII) to be used tion time ranges from 0.1 to 1 hour at 80 watts and preferably ranges from about 1 to 5 mol and preferably from 1 to 2 mol from 0.1 to 0.3 hours. relative to 1 mol of the compound (XI). 1239. This process can be carried out by the method 1217. As the “acid', for example, acetic acid can be used. described in Synthesis, 2007, 1204-1208 or by a comparable 1218. As for the amount of an acid to be used, it is desir method. able to use the same amount as acetonitrile used as a solvent 1240 Process 10 is a method of producing a compound in the aforementioned reaction. (I-d) from the compound (XVI). The product can be produced 1219. It is desirable to carry out the reaction generally by reacting an acid as well as Sodium azide in the presence of under heated conditions and preferably at 100°C. to 130° C. a phase transfer catalyst. US 2012/0277430 A1 Nov. 1, 2012

1241. It is advantageous to carry out the reaction using an 1259. The amount of the condensation agent to be used inert solvent in the reaction. The solvent to be used is not ranges from about 1 to 5 mol and preferably from 1 to 3 mol particularly limited as long as the reaction proceeds, but for relative to 1 mol of the compound (XX) or the compound example, it is desirable to use a halogenated hydrocarbon, a (XXXI). solvent mixed with water and the like. 1260. A base such as triethylamine or N,N-diisopropyl 1242. As the “phase transfer catalyst, for example, tetrabu ethylamine is preferably used in an amount ranging from tyl ammonium bromide can be used. about 1 to 10 mol and preferably from 2 to 3 mol relative to 1 1243. The amount of the “phase transfer catalyst” to be mol of the compound (XX) or the compound (XXXI). used ranges from about 0.1 to 1 equivalent and preferably 1261. It is desirable to carry out the reaction generally at from 0.1 to 0.3 equivalent relative to the compound (XVI). room temperature or under heated conditions and preferably 1244. The amount of sodium azide to be used ranges from at room temperature. about 1 to 5 mol and preferably from 1 to 3 mol relative to 1 mol of the compound (XVI). 1262 The reaction time generally ranges from 1 to 48 1245. As the “acid', for example, organic acids can be hours and preferably from 5 to 10 hours. used. 1263. The reaction with an acid halide is carried out in the 1246 The amount of the “acid' to be used ranges from presence of a base Such as triethylamine using N.O-dimeth about 1 to 5 equivalents and preferably from 1 to 2 equivalents ylhydroxylamine hydrochloride to synthesize a target prod relative to the compound (XVI). uct. 1247 The reaction temperature can range from 0° C. to 1264. It is advantageous to carry out this reaction without 100° C. and preferably at room temperature. using a solvent or using an inert solvent in the reaction. The 1248. The reaction time generally ranges from 0.1 to 48 Solvent to be used is not particularly limited as long as the hours and preferably from 10 to 24 hours. reaction proceeds, but for example, ethers, esters amides are 1249. This process can be carried out by the method desirable. described in Synthesis, 2007, 1204-1208 or by a comparable 1265. The amount of the base such as triethylamine ranges method. from about 1 to 10 mol and preferably from 2 to 3 mol relative 1250 Process 11 is a method of producing a compound to 1 mol of the compound (XX) or the compound (XXXI). (XX) or a compound (XXXI) from the compound (XIX) or 1266. It is desirable to carry out the reaction generally the compound (XXX). The reaction can be carried out under while cooling in an ice bath or at room temperature and an acidic or basic condition. It is advantageous to carry out preferably by cooling in an ice bath. this reaction without using a solvent or using an inert Solvent 1267. The reaction time generally ranges from 0.5 to 5 in the reaction. The solvent to be used is not particularly limited as long as the reaction proceeds, but for example, it is hours and preferably from 1 to 3 hours. desirable to use alcohols, a solvent mixed with water and 1268. Further, the compound (XXI) or the compound ethers. (XXXII) can be produced by reacting the compound (XIX) or the compound (XXX) with trimethyl aluminum and N.O- 1251. As the “acid, for example, inorganic acids can be dimethylhydroxylamine hydrochloride in the presence of an used. organic base. The amount of an organic base, trimethyl alu 1252. As the “base', for example, inorganic bases such as minum and N.O-dimethylhydroxylamine hydrochloride Sodium hydroxide or potassium hydroxide can be used. Fur ranges from about 1 to 10 mol and preferably from 2 to 5 mol ther, lithium hydroxide can also be used. relative to 1 mol of the compound (XIX) or the compound 1253. The amount of the acid or the base to be used ranges (XXX). It is advantageous to carry out this reaction without from about 1 to 10 mol and preferably from 1 to 5 mol relative using a solvent or using an inert solvent in the reaction. The to 1 mol of the compound (XIX) or the compound (XXX). Solvent to be used is not particularly limited as long as the 1254. It is desirable to carry out the reaction generally at reaction proceeds, but for example, halogenated hydrocar room temperature or under heated conditions and preferably bons are desirable. It is desirable to carry out the reaction at room temperature. generally by cooling in an ice bath or at room temperature and 1255. The reaction time generally ranges from 1 to 48 preferably by cooling in an ice bath. The reaction time gen hours and preferably from 3 to 10 hours. erally ranges from 1 to 24 hours and preferably from 1 to 5 1256 Process 12 is a method of producing a compound hours. (XXI) or a compound (XXXII) from the compound (XX) or the compound (XXXI). The product can be produced using 1269 Process 13 is a method of producing a compound N.O-dimethylhydroxylamine hydrochloride with a conden (XXII) or a compound (XXXIII) from the compound (XXI) sation agent in the presence of a base Such as triethylamine or or the compound (XXXII). The product can be produced N,N-diisopropylethylamine. Alternatively, a carboxylic acid using an “alkylating agent. Such as a Grignard reagent or an of the Substrate is converted to a corresponding acid halide organic lithium reagent. which is then reacted with N.O-dimethylhydroxylamine 1270. It is advantageous to carry out this reaction without hydrochloride to produce the target products. using a solvent or using an inert solvent in the reaction. The 1257. As the “condensation agent, for example, 1-ethyl Solvent to be used is not particularly limited as long as the 3-(3-dimethylaminopropyl)carbodiimide hydrochloride can reaction proceeds, but for example, ethers are desirable. be used in the presence of 1-hydroxybenzotriazole. 1271. The amount of the “alkylating agent' ranges from 1258. It is advantageous to carry out this reaction without about 1 to 10 mol and preferably from 2 to 3 mol relative to 1 using a solvent or using an inert Solvent in the reaction. The mol of the compound (XXI) or the compound (XXXII). Solvent to be used is not particularly limited as long as the 1272. It is desirable to carry out the reaction generally at reaction proceeds, but for example, nitriles, ethers and amides -78°C. or while cooling in an ice bath and preferably at -78° are desirable. C. US 2012/0277430 A1 Nov. 1, 2012 32

1273 R’ is a hydrogen atom, or a Coalkyl group which 1291. The amount of the compound (XXVI) to be used can be substituted, and preferably a hydrogen atom, or a ranges from approximately 1 to 10 mol and preferably from methyl group. approximately 1 to 3 mol relative to 1 mol of the compound 1274 R is a hydrogen atom, or a Coalkyl group which (XXV). can be substituted, and preferably a hydrogen atom, or a 1292. As the “base', potassium acetate or potassium car methyl group. bonate and the like can be used and its amount ranges from 1275. The reaction time generally ranges from 1 to 10 about 1 to 10 mol and preferably from 1 to 3 mol relative to 1 hours and preferably from 1 to 3 hours. mol of the compound (XXV). 1276 Process 14 is a method of producing a compound (XXIV) from the compound (XX). The product can be pro 1293 As the “palladium catalyst, bisdi-tert-butyl (4- duced using diphenylphosphoryl azide in the presence of a dimethylaminophenyl)phosphinedichloropalladium(II) or base Such as triethylamine. tetrakis(triphenylphosphine)palladium and the like can be 1277. It is advantageous to carry out this reaction without used and its amount ranges from about 0.01 to 0.5 mol and using a solvent or using an inert Solvent in the reaction. The preferably from 0.03 to 0.1 mol relative to 1 mol of the Solvent to be used is not particularly limited as long as the compound (XXV). reaction proceeds. For example, in the case when using tert 1294. It is advantageous to carry out this reaction without butanol as a solvent, a tert-butyl carbamate derivative is tem using a solvent or using an inert solvent in the reaction. The porarily obtained and its hydrolysis is carried out under an Solvent to be used is not particularly limited as long as the acidic condition to produce a compound (XXIV). Further, in reaction proceeds, but for example, alcohols, solvent mixture the case when using toluene as a solvent, an isocyanate as an with water, aromatic hydrocarbons, ethers, amides and the intermediate is hydrolyzed with an aqueous Sodium hydrox like are desirable. ide solution to produce a compound (XXIV). 1295. It is desirable to carry out the reaction generally at 1278. The amount of diphenylphosphoryl azide ranges room temperature or under reflux conditions by heating and from about 1 to 10 mol and preferably from 1 to 3 mol relative preferably under reflux conditions by heating. to 1 mol of the compound (XX). 1279. The amount of triethylamine ranges from about 1 to 1296. The reaction time generally ranges from 5 to 48 10 mol and preferably from 1 to 3 mol relative to 1 mol of the hours and preferably from 10 to 20 hours. compound (XX). 1297. This process can be carried out by the method 1280. It is desirable to carry out the reaction generally at described in Org. Lett. 2006, 8, 1787-1789 or by a compa room temperature or under reflux conditions by heating and rable method. preferably under reflux conditions by heating. 1298 R represents an alkoxy group which can be substi 1281. The reaction time generally ranges from 1 to 20 tuted or a hydroxyl group and the like. hours and preferably from 1 to 10 hours. 1299 Process 17 is a method of producing a compound 1282. This process can be carried out by the method (XXIX) from the compound (XXVIII) and the reaction can be described in Tetrahedron 1974, 30, 2151-2157 or by a com carried out in the presence of a base. parable method. 1300. As the base, basic salts, organic bases, metal alkox 1283 Process 15 is a method of producing a compound ides or metal amides and the like can be used and potassium (XXV) from the compound (XXIV). The product can be carbonate or sodium methoxide is desirable. The amount of produced using a nitrite in the presence of a copper salt. the base ranges from about 1 to 10 mol and preferably from 1 1284. It is advantageous to carry out this reaction without to 3 mol relative to 1 mol of the compound (XXVIII). It is using a solvent or using an inert Solvent in the reaction. The advantageous to carry out this reaction without using a sol Solvent to be used is not particularly limited as long as the vent or using an inert solvent in the reaction. The solvent to be reaction proceeds, but for example, amides are desirable. used is not particularly limited as long as the reaction pro 1285. As the "copper salt”, cupric bromide (CuBr) and ceeds, but for example, ethers or amides are desirable. It is the like can be used and its amount ranges from about 1 to 5 desirable to carry out the reaction generally at room tempera mol and preferably from 1 to 2 mol relative to 1 mol of the ture or under reflux conditions by heating and preferably at compound (XXIV). room temperature. 1286. As the “nitrite', isoamyl nitrite or pentyl nitrite and 1301 The reaction time generally ranges from 1 to 24 the like can be used and its amount ranges from about 1 to 10 hours and preferably from 2 to 4 hours. mol and preferably from 1 to 3 mol relative to 1 mol of the 1302 Process 18 is a method of producing a compound compound (XXIV). (XXX) or a compound (1-g) from the compound (XXIX) or 1287. It is desirable to carry out the reaction generally in the compound (XXXVI). an ice bath, at room temperature or under heated conditions 1303 Methylation can be carried out under the condition and preferably at a temperature ranging from 0 to 70° C. using trimethylsilyldiazomethane or methyl iodide in the 1288 The reaction time generally ranges from 1 to 10 presence of a base. hours and preferably from 1 to 5 hours. 1304. In the case when the reaction is carried out using 1289. This process can be carried out by the method trimethylsilyldiazomethane, trimethylsilyldiazomethane is described in U.S. Pat. No. 5,059.599 or by a comparable used in an amount ranging from about 10 to 50 mol and method. preferably from 5 to 20 mol relative to 1 mol of the compound 1290 Process 16 is a method of producing a compound (XXIX) or the compound (XXXVI) using a solvent such as (I-f) from the compound (XXV) and the compound (XXVI). methanol and the like. It is desirable to carry out the reaction The product can be produced using a palladium catalyst in the generally by cooling in an ice bath or under room temperature presence of a base. conditions and preferably by cooling in an ice bath. US 2012/0277430 A1 Nov. 1, 2012

1305 The reaction time generally ranges from 1 to 5 hours as long as the reaction proceeds, but for example, dimethyl and preferably from 1 to 2 hours. Sulfoxide, halogenated hydrocarbons, ethers and esters are 1306. In the case when using methyl iodide in the presence desirable. It is desirable to carry out the reaction generally ofa base, the reaction can be carried out using an ether solvent under low temperature conditions or at room temperature. in the presence of sodium hydroxide and the like. The reaction time generally ranges from 1 to 10 hours and 1307 Methyl iodide is used in an amount ranging from preferably from 1 to 3 hours. about 1 to 10 mol and preferably from 1 to 3 mol relative to 1 mol of the compound (XXIX) or the compound (XXXVI). In 1318. This process can be carried out by the method addition, a base such as Sodium hydroxide is also used in an described in Comprehensive Organic Transformations amount ranging from about 1 to 10 mol and preferably from (WILEY-VCH) or in Oxidation in Organic Chemistry 1 to 3 mol relative to 1 mol of the compound (XXIX) or the (American Chemical Society) by a comparable method. compound (XXXVI). It is desirable to carry out the reaction 1319 Process 22 is a method of producing a compound generally by cooling in an ice bath or under room temperature (I-h) from the compound (XXXVIII). Using C-tosyl benzyl conditions and preferably by cooling in an ice bath. isocyanide (Organic Syntheses, Coll. Vol. 10, p.692 (2004): 1308 The reaction time generally ranges from 1 to 5 hours Vol. 77, p198 (2000)), an 1,3-oxazole compound or an 1,3- and preferably from 1 to 2 hours. imidazole compound can be produced. In the case when 1309 Process 19 is a method of producing a compound producing “1.3-oxazole compound, the reaction is carried (XXXVI) from the compound (XXXV) and the product can out in the presence of a base Such as potassium carbonate. In be obtained using trimethylsilyl chloride in the presence of contrast, in the case when producing “1.3-imidazole com Sodium iodide. pound, the reaction is carried out in the presence of a base 1310 The amount of sodium iodide ranges from about 1 to Such as potassium carbonate along with the presence of aque 10 mol and preferably from 1 to 5 mol relative to 1 mol of the ous ammonia or an amine Such as methylamine. compound (XXXV). The amount of trimethylsilyl chloride 1320. A base Such as potassium carbonate, aqueous ranges from about 1 to 10 mol and preferably from 1 to 5 mol ammonia or methylamine is used in an amount ranging from relative to 1 mol of the compound (XXXV). about 1 to 10 moland preferably from 1 to 3 mol relative to the 1311. It is advantageous to carry out this reaction without compound (XXXVIII). It is advantageous to carry out this using a solvent or using an inert Solvent in the reaction. The reaction without using a solvent or using an inert Solvent in Solvent to be used is not particularly limited as long as the the reaction. The solvent to be used is not particularly limited reaction proceeds, but for example, nitriles are desirable. It is as long as the reaction proceeds, but for example, ethers, desirable to carry out the reaction generally at room tempera nitriles and amides are desirable. It is desirable to carry out the ture or under reflux conditions by heating and preferably reaction generally under low temperature conditions or at under reflux conditions by heating. The reaction time gener room temperature and preferably under room temperature ally ranges from 1 to 20 hours and preferably from 3 to 10 conditions. hours. 1321. The reaction time generally ranges from 5 to 30 1312 Process 20 is a method of producing a compound hours and preferably from 5 to 15 hours. (XXXVII) from the compound (XIX) and the product can be 1322 This process can be carried out by the method obtained using an appropriate reductant. described in New Edition: Heterocyclic Compounds (Kodan 1313 As the “reductant”, lithium aluminum hydride, disobutylaluminum hydride and the like can be used. It can sha) or by a comparable method. be used in an amount ranging from about 1 to 10 mol and 1323 Process 23 is a method of producing a compound preferably from 1 to 3 mol relative to 1 mol of the compound (I-i) from the compound (XXIV). As long as the reaction (XIX). It is advantageous to carry out this reaction without proceeds, it is not particularly limited, but after reacting with using a solvent or using an inert Solvent in the reaction. The an aqueous glyoxal Solution in an alcoholic solvent, under an Solvent to be used is not particularly limited as long as the acidic condition, the compound (XXIV) can be reacted with reaction proceeds, but for example, ethers are desirable. It is ammonium chloride and benzaldehyde to give the compound desirable to carry out the reaction generally at -78°C. or by (I-i). cooling in an ice bath and preferably at -78°C. 1324. An aqueous glyoxal Solution is used in an amount 1314. The reaction time generally ranges from 0.5 to 5 ranging from about 1 to 5 mol and preferably from 1 to 3 mol hours and preferably from 1 to 3 hours. relative to 1 mol of the compound (XXIV). It is desirable to 1315. This process can be carried out by the method carry out the reaction, generally under low temperature con described in Comprehensive Organic Transformations ditions or under room temperature conditions and preferably (WILEY-VCH) or by a comparable method. under room temperature conditions. 1316 Process 21 is a method of producing a compound 1325. The reaction time generally ranges from 5 to 30 (XXXVIII) from the compound (XXXVII) and the product hours and preferably from 10 to 20 hours. can be produced using an appropriate oxidation. 1326 Benzaldehyde and ammonium chloride are used in 1317. As the “oxidation', for example, Swern oxidation, an amount ranging from about 1 to 5 moland preferably from or oxidation using an oxidant Such as a Sulfur trioxide pyri 1 to 3 mol relative to 1 mol of the compound (XXIV). An acid dine complex, pyridinium chlorochromate and the like can be to be used is not particularly limited as long as the reaction used. When the oxidation using the oxidant is conducted, the proceeds, but for example, phosphoric acid and the like are oxidant is used in the amount ranging from about 1 to 10 mol desirable. It is desirable to carry out the reaction generally and preferably from 1 to 3 mol relative to 1 mol of the under room temperature conditions or under reflux conditions compound (XXXVII). It is advantageous to carry out this by heating and preferably under reflux conditions by heating. reaction without using a solvent or using an inert Solvent in The reaction time generally ranges from 5 to 40 hours and the reaction. The solvent to be used is not particularly limited preferably from 20 to 30 hours. US 2012/0277430 A1 Nov. 1, 2012 34

1327. This process can be carried out by the method ture conditions. The reaction time generally ranges from 1 to described in New Edition: Heterocyclic Compounds (Kodan 48 hours and preferably from 5 to 20 hours. sha) or by a comparable method. 1333. This process can be carried out by the method 1328 Process 24 is a method of producing a compound described in “New Edition: Heterocyclic Compounds” (XXXIX) from the compound (XXV). As long as the reaction (Kodansha) or by a comparable method. proceeds, it is not particularly limited, but the product can be 1334) The compound (I-e) wherein R is a halogen atom produced by reacting the compound (XXV) with trimethyl (e.g., a bromine atom) can be produced by the following silylacetylene in an ether solvent such as tetrahydrofuran in method. Initially, the compound (V) is reacted with a reagent the presence of a palladium catalyst and a copper catalyst as such as N,N-dimethylformamide dimethyl acetal to obtain a well as a base. As the palladium catalyst, for example, bis compound (XXII) wherein R and R7 are hydrogen atoms. (triphenylphosphine)palladium (II)dichloride and the like The amount of the reagent such as N,N-dimethylformamide dimethyl acetal is about 1 to 5 mol, preferably 1 to 2 mol can be used. The palladium catalyst is used in an amount relative to 1 mol of the compound (V). It is desirable that this ranging from about 0.01 to 1 mol and preferably from 0.05 to reaction is carried out using an inert Solvent in the reaction 0.2 mol relative to 1 mol of the compound (XXV). In addition, (e.g., amides). It is desirable that the reaction is carry out at the palladium catalyst is used along with a phosphine ligand room temperature or while heating and preferably at a tem Such as triphenylphosphine. The phosphine ligand is used in perature ranging from 40 to 100° C. The reaction time gen an amount ranging from about 0.01 to 1 mol and preferably erally ranges from 1 to 20 hours, and preferably from 1 to 10 from 0.05 to 0.2 mol relative to 1 mol of the compound hours. Then, the obtained compound (XXII) is reacted with a (XXV). As the copper catalyst, for example, cuprous iodide halogen molecule (e.g., a bromine molecule) to introduce a (CuI) and the like can be used. The copper catalyst is used in halogen atom at R position of the compound (XXII). The an amount ranging from about 0.1 to 1 mol and preferably amount of the halogen molecule to be used ranges from about from 0.1 to 0.5 mol relative to 1 mol of the compound (XXV). 1 to 5 mol and preferably about 1 to 2 mol relative to 1 mol of Trimethylsilylacetylene is used in an amount ranging from the compound (XXII). It is desirable that this reaction is about 1 to 5 mol and preferably from 1 to 3 mol relative to 1 carried out using an inert Solvent in the reaction (e.g., organic mol of the compound (XXV). The reaction is carried out in acids). It is desirable that the reaction is carried out at room the presence of a base Such as triethylamine and the amount of temperature or at a low temperature and preferably at room a base to be used ranges from about 1 to 5 mol and preferably temperature. The reaction time generally ranges from 1 to 10 from 1 to 3 mol relative to 1 mol of the compound (XXV). It hours, and preferably from 1 to 3 hours. is desirable to carry out the reaction generally by heating at a 1335. The compound (I-e) wherein R is an alkyl group temperature ranging from 40 to 60°C. (e.g., a methyl group) can be produced by the following 1329. The reaction time generally ranges from 1 to 10 days method. Initially, the compound (XXII) is reacted with a and preferably from 5 to 7 days. reagent such as N,N-dimethylacetamide dimethyl acetal to 1330. This process can be carried out by the method obtain a compound (XIII). The amount of N,N-dimethylac described in Tetrahedron Lett., 1975, 16, 4467-4470 or by a etamide dimethyl acetal to be used ranges from about 1 to 30 comparable method. mol and preferably from 5 to 20 mol relative to 1 mol of the 1331 Process 25 is a method of producing a compound compound (XXII). This reaction is preferably carried out (XL) from the compound (XXXIX). As long as the reaction without using a solvent or using an inert solvent in the reac proceeds, it is not particularly limited, but the product can be tion. Further, it is desirable to carry out the reaction under produced by reacting the compound (XXXIX) with sodium reflux conditions by heating, or it is possible to be heated hydroxide aqueous solution or a fluoride ion Such as tetrabu under microwave conditions. The reaction temperature when tylammonium fluoride in an alcohol or an ether as a solvent. heating under microwave conditions generally ranges from The amount of aqueous sodium hydroxide solution or fluo 50° C. to 150° C. and preferably at a temperature ranging ride ion ranges from about 1 to 100 mol or greater and pref from 100° C. to 130° C. The reaction time generally ranges erably from 1 to 3 mol relative to 1 mol of the compound from 1 to 60 min. and preferably from 3 to 20 min. (XXXIX). It is desirable to carry out the reaction generally by 1336. The compound (I-e) wherein R is an alkyl group cooling in an ice bath or under room temperature conditions which is substituted by a fluorine atom (e.g., a trifluoromethyl and preferably under room temperature conditions. The reac group) can be produced by the following method. Initially, the tion time generally ranges from 0.5 to 5 hours and preferably compound (XXII) is reacted with an ester having an alkyl from 1 to 3 hours. group Substituted with a fluorine atom (e.g., ethyl trifluoro 1332 Process 26 is a method of producing a compound acetate) under basic conditions. The amount of the ester to be (I-) from the compound (XL). As long as the reaction pro used ranges from 1 to 20 mol and preferably from 1 to 10 mol ceeds, it is not particularly limited, but the product can be relative to 1 mol of the compound (XXII). This reaction is produced by reacting the compound (XL) with N-hydroxy carried out in the presence of a base such as Sodium methox benzenecarboximidoyl chloride in an ether as a solvent. ide and the amount of the base to be used ranges from about N-hydroxybenzenecarboximidoyl chloride is used in an 1 to 5 mol and preferably from 1 to 3 mol relative to 1 mol of amount ranging from about 1 to 5 mol and preferably from 1 the compound (XXII). It is desirable that this reaction is to 3 mol relative to 1 mol of the compound (XL). The present carried out using an inert Solvent in the reaction (e.g., ethers). reaction is carried out in the presence of a base such as It is desirable to carry out the reaction under ice cold condi triethylamine and the amount of a base to be used ranges from tions or at room temperature and preferably at room tempera about 1 to 5 mol and preferably from 1 to 3 mol relative to 1 ture. The reaction time generally ranges from 0.5 to 7 days mol of the compound (XL). It is desirable to carry out the and preferably from 1 to 3 days. Furthermore, the compound reaction generally by cooling in an ice bath or under room (I-e) can be produced by placing the reaction product along temperature conditions and preferably under room tempera with the compound (VII). The amount of the compound (VII) US 2012/0277430 A1 Nov. 1, 2012 to be used ranges from about 1 to 10 mol and preferably from in peptide chemistry can be introduced into these group. If about 2 to 5 mol relative to 1 mol of the raw material. It is preferable, the protective group is removed after the reaction advantageous to carry out this reaction without using a sol to be able to obtain a target compound. vent or using an inert solvent in the reaction. The solvent to be 1341. As a protective group for the amino group, for used is not particularly limited as long as the reaction pro example, formyl and the following group that can be respec ceeds, but for example, alcohols and organic acids or mixed tively Substituted can be used: Co alkylcarbonyl (e.g., solvents thereof are desirable. It is desirable to carry out the acetyl, ethylcarbonyl, etc.), phenylcarbonyl, Co alkyl-oxy reaction under ice cold conditions or at room temperature or carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), phe while heating and preferably at a temperature ranging from 0° nyloxycarbonyl, C. aralkyl-carbonyl (e.g., benzylcarbo C. to 150°C. The reaction time generally ranges from 0.1 to nyl, etc.), trityl, phthaloyl, or N,N-dimethylaminomethylene. 10 hours and preferably from 0.5 to 5 hours. This process can The Substituents to be used can include halogen (e.g., fluo be carried out by the method described in the Journal of rine, chlorine, bromine, iodine, etc.), Co alkyl-carbonyl Heterocyclic Chemistry, 1981, 18, 333-334 or by a compa (e.g., methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), rable method. nitro group and the like. The number of Substituents ranges 1337. The compound (I-e) wherein R is a halogen atom from 1 to 3. (e.g., a fluorine atom) can be produced by reacting the com 1342. As a protective group for the carboxyl group, for pound (I-e) wherein R is a hydrogen atom with a reagent example, the following group that can be respectively substi Such as a halogenating agent. For example, when introducing tuted can be used: Co alkyl (e.g., methyl, ethyl, n-propyl. a fluorine atom, 1-(chloromethyl)-4-fluoro-1,4-diazoniabi i-propyl. n-butyl, tert-butyl, etc.), phenyl, trityl, or silyl and cyclo[2.2.2]octane bis(tetrafluoroborate) (hereinafter the like. The Substituents to be used can include halogen (e.g., referred to as Selectfluor) can be used as a fluorinating agent. fluorine, chlorine, bromine, iodine, etc.), formyl, Co alkyl The amount of the Selectfluor to be used ranges from about 1 carbonyl (e.g., acetyl, ethylcarbonyl, butylcarbonyl, etc.), to 30 mol and preferably from 5 to 20 mol relative to 1 mol of nitro groups and the like. The number of Substituents ranges the compound (I). This reaction is preferably carried out from 1 to 3. using an inert Solvent in the reaction (e.g., nitriles, etc.). 1343. As a protective group for the hydroxyl group, for Further. It is desirable to carry out the reaction under ice cold example, the following group that can be respectively substi conditions or at room temperature and preferably at room tuted can be used: Co alkyl (e.g., methyl, ethyl, n-propyl. temperature. The reaction time generally ranges from 1 to 20 i-propyl. n-butyl, tert-butyl, etc.), phenyl, C-caralkyl (e.g., days and preferably from 5 to 15 days. benzyl, etc.), formyl, Co alkyl-carbonyl (e.g., acetyl, eth 1338. The compound (I-e) wherein R is an alkyl group ylcarbonyl, etc.), phenyloxycarbonyl, benzoyl, C-caralkyl (e.g., a methyl group) can be produced by the following carbonyl (e.g., benzylcarbonyl, etc.), pyranyl, furanyl, or silyl reaction. Initially, the compound (XXII) is reacted with an and the like. The substituents to be used can include halogen ester (e.g., methyl formate) under basic conditions. The ester (e.g., fluorine, chlorine, bromine, iodine, etc.), Co alkyl is works also as a solvent. This reaction is carried out in the (e.g., methyl, ethyl, n-propyl, etc.), phenyl, C7-oaralkyl (e.g., presence of a base Such as sodium methoxide, and the amount benzyl, etc.), nitro group and the like. The number of sub of the base to be used ranges from about 1 to 5 mol and stituents ranges from 1 to 4. preferably from 1 to 3 mol relative to 1 mol of the compound 1344. Further, as a method of removing the protective (XXII). Generally, it is desirable to carry out the reaction group, the known method or a comparable method can be under ice cold conditions or at room temperature and prefer used. For example, a method of treating with acids, bases, ably at room temperature. The reaction time generally ranges reduction, UV-light, hydrazine, phenylhydrazine, sodium from 1 to 20 hours and preferably from 2 to 10 hours. N-methyldithiocarbamate, tetrabutylammonium fluoride, 1339. The compound (I) can be produced by further palladium acetate and the like can be used. placing the reaction product along with the compound (VII). 1345. In each reaction in the manufacturing methods of The amount of the compound (VII) to be used ranges from said compounds (I-a), (I-b), (I-c). (I-d), (I-e), (I-g), (I-h), (I-i), about 1 to 10 mol and preferably from about 2 to 5 mol and (I-), or their salts, and in each reaction in the synthesis of relative to 1 mol of the raw material. It is advantageous to the raw material compounds, solvents that are generally carry out this reaction without using a solvent or using an inert known may be used during the reaction. solvent in the reaction. The solvent to be used is not particu 1346 For example, the following generally known sol larly limited as long as the reaction proceeds, but for example, vents can be used: alcohols and organic acids or mixed solvents thereof are 1347 ethers such as tetrahydrofuran, diethylether, 1.2- preferable. Generally, it is desirable to carry out the reaction dimethoxyethane, 1,4-dioxane and the like; under ice cold conditions or at room temperature or under reflux conditions by heating and preferably at a temperature 1348 esters such as ethyl acetate, butyl acetate and the ranging from 0° C. to 150° C. The reaction time generally like: ranges from 0.1 to 10 hours and preferably from 0.5 to 5 1349 aromatic hydrocarbons such as benzene, toluene hours. This process can be carried out by the method and the like; described in the Journal of Heterocyclic Chemistry, 1981, 18, 1350 aromatic heterocyclic compounds such as pyridine, 333-334 or by a comparable method. lutidine and the like; 1340. If the raw material compounds contain an amino 1351 amides such as N,N-dimethylformamide, N-meth group, a carboxyl group, a hydroxyl group as a Substituent, in ylpyrrolidone and the like: each reaction in the manufacturing methods of said com 1352 halogenated compounds such as chloroform, meth pounds (I-a), (I-b), (I-c). (I-d), (I-e), (I-g), (I-h), (I-i), and (I-). ylene chloride and the like: or salts thereof, and in each reaction in the synthesis of the raw 1353 alcohols such as methanol, ethanol, 2-propanol, 2.2- material compounds, a protective group that is generally used dimethylethanol and the like: US 2012/0277430 A1 Nov. 1, 2012 36

1354) aliphatic hydrocarbon compounds such as hexane, 1364) Prodrugs of the compound (I) include compounds heptane, petroleum ether and the like; wherein an amino group in the compound (I) is acylated, 1355 carboxylic acids such as formic acid, acetic acid and alkylated or phosphorylated (e.g., the amino group in the the like; and water. compound (I) is eicosanoylated, alanylated, pentylami 1356 Further, the solvents used in the reaction can be used nocarbonylated, (5-methyl-2-oxo-1, 3-dioxolen-4-yl)meth as a single solvent or as a solvent mixture of two kinds to 6 oxycarbonylated, tetrahydrofuranylated, pyrrolidylmethy kinds. lated, pivaloyloxymethylated or tert-butylated); the hydroxyl group in the compound (I) is acylated, alkylated, phospho 1357. Further, the reaction can be carried out in the pres rylated or borated (e.g., the hydroxyl group in the compound ence of amines such as triethylamine, N,N-diisopropylamine, (I) is acetylated, palmitoylated, propanoylated, pivaloylated, pyridine, N-methylmorpholine and the like or bases such as Succinylated, fumarylated, alanylated, dimethylaminometh Sodium hydroxide, potassium carbonate and the like. Alter ylcarbonylated); the carboxyl group in the compound (I) is natively, the reaction can be carried out in the presence of an esterified or amidated (e.g., the carboxyl group in the com acid Such as hydrochloric acid, Sulfuric acid, acetic acid and pound (I) is ethyl-esterified, phenyl-esterified, carboxym the like. ethyl-esterified, dimethylaminomethyl-esterified, pivaloy 1358. The compounds obtained by the aforementioned loxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, methods: (I-a), (I-b), (I-c). (I-d). (I-e), (I-f). (I-g), (I-h), (I-i), phthalidyl-esterified, (5-methyl-2-oxo-1,3-dioxolen-4-yl) and (I-) can be isolated or purified by the ordinary separation methyl-esterified, cyclohexyloxycarbonylethyl-esterified, or means such as recrystallization, distillation, chromatography methylamidated). These compounds, can be produced from and the like. If the compounds of the present invention: (I-a). the compound (I) by the known methods. Prodrugs of the (I-b), (I-c). (I-d), (I-e), (I-f). (I-g), (I-h), (I-i), and (I-) are compound (I) can be converted to the compound (I) under obtained in a free form, they can be converted to their salts by the physiological conditions as described in “Development of the known methods or by a comparable method (e.g., neutral Drugs' Vol. 7 Molecular Design published in 1990 by ization, etc.), or in reverse, if they are obtained in the salt Hirokawa Shoten, page 163 to 198. form, they can be converted to a free form or other salts by the 1365. The compound of the present invention has an known methods or by a comparable method. If the compound excellent PDE10A inhibitory activity and is useful for the obtained are racemates, they can be separated into a d-form following diseases and symptoms in mammals (e.g., humans, and 1-form by the ordinary optical separation means. cows, horses, dogs, cats, monkeys, mice, rats, etc. particularly 1359. The raw material compounds of the compounds in humans): (I-a), (I-b), (I-c). (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), and (I-) or 1366 psychotic disorder (e.g., brief psychotic disorder, salts thereofare not particularly limited as long as there are no shared psychotic disorder): interference with the reaction. Examples of such salts are 1367 psychosis induced by alcohol, amphetamine, can same as the salts of the compounds (I-a), (I-b), (I-c). (I-d), nabis, cocaine, hallucinogens, obesity, inhalants, opioids, or (I-e), (I-f). (I-g), (I-h), (I-i), and (I-). phencyclidine; 1360. In any of the above mentioned manufacturing meth 1368 delusional disorder; ods or processes, if desired, a compound (I) can be synthe 1369 anxiety disorder: sized by further applying one or combination of known reac tions such as protection/deprotection reactions, acylation 1370 movement disorder: reactions, alkylation reactions, hydrogenation reactions, oxi 1371 mood disorder: dation reactions, reduction reactions, carbon chain extension 1372 major depressive disorder; reactions, Substituent exchanging reactions, and so on. 1373 a major depressive disorder superimposed on a psy 1361) If the target products are obtained in the free form by chotic disorder comprising a delusional disorder or schizo the aforementioned reactions, they can be converted to the phrenia; corresponding salts by the ordinary methods, or if they are 1374 major depressive episode of the mild, moderate or obtained in the salt form, they can be converted to the free severe type; form or other salts by the ordinary methods. The compound 1375 manic or mixed mood episode: (I) obtained can be isolated from the reaction mixture and 1376 hypomanic mood episode: purified by the known means such as phase transfer, concen 1377 depressive episode with atypical features: tration, solvent extraction, fractional distillation, crystalliza 1378 depressive episode with melancholic features; tion, recrystallization, chromatography and the like. 1379 depressive episode with catatonic features; 1362. If the compound (I) is present as a configurational 1380 mood episode with postpartum onset; isomer, diastereomer, or conformer, if desired, they can be 1381 post-stroke depression; isolated respectively by the aforementioned isolation and 1382) dysthymic disorder; purification means. If the compound (I) is present as a race 1383 minor depressive disorder; mate, it can be separated to a d-form and 1-form by the ordinary optical separation means. 1384 autism 1363 As in the case of the compound (I), a prodrug of the 1385 drug addiction compound (I) can be used. The prodrug of the compound (I) 1386 neurodegenerative disorder; is a compound that is converted to a compound (I) by reac 1387 neurodegeneration associated with cerebral trauma; tions using enzymes or gastric acid under physiological con 1388 neurodegeneration associated with stroke; ditions in vivo. Namely, it includes a compound that is con 1389 neurodegeneration associated with cerebral infarct; Verted to a compound (I) by enzymatic oxidation, reduction 1390 hypoglycemia-induced neurodegeneration; and hydrolysis or a compound that is converted to a com 1391 neurodegeneration associated with epileptic sei pound (I) by hydrolysis using gastric acid. Zure; US 2012/0277430 A1 Nov. 1, 2012 37

1392 neurodegeneration associated with neurotoxin poi ous absorbent, ointment, lotion, patch, Suppositories (e.g., Soning: rectal Suppository, vaginal Suppository), pellets, transnasal 1393 multi-system atrophy; preparations, pulmonary preparations (inhalant), eye drops 1394 Alzheimer's disease: and the like, in an oral or parenteral route (e.g., intravenous, 1395 dementia: intramuscular, Subcutaneous, intraorgan, intranasal, intrader 1396 multi-infarct dementia: mal, ophthalmic instillation, intracerebral, intrarectal, intra 1397 alcoholic dementia or other drug-related dementia; vaginal, intraperitoneal, directly to lesion). 1398 dementia associated with intracranial tumors or 1428 Here, as a pharmaceutical acceptable carrier, com cerebral trauma; mon organic or inorganic carrier Substances are used as for 1399 dementia associated with Huntington's disease or mulation raw materials. Carriers are added as vehicles, lubri Parkinson's disease; cants, binders and disintegrants in the Solid formulations; and 1400 AIDS-related dementia: as solubilizing agents, Suspending agents, isotonization 1401 Fronto temperal dementia; agents, buffers and soothing agents in the liquid formulations. 1402 delirium; If desired, formulation additives such as antiseptics, antioxi 1403 amnestic disorder; dants, colorants, Sweeteners, etc. can be used. 1404 post-traumatic stress disorder; 1429 Favorable examples of the vehicles are as follows: 1405 mental retardation; lactose, Sucrose, D-mannitol, D-Sorbitol, starch, C.-Starch, 1406 learning disorder (e.g., reading disorder, mathemat dextrin, crystalline cellulose, low-substituted hydroxypropyl ics disorder, or a disorder of written expression); cellulose, Sodium carboxymethylcellulose, gum Arabic, pull 1407 attention-deficit/hyperactivity disorder; lulan, light silicic anhydride, synthetic aluminum silicate and 1408 age-related cognitive decline; magnesium metasilicic aluminate. 1409 premenstrual dysphoric disorder; 1430 Favorable examples of the lubricants include mag 1410 post-psychotic depressive disorder of schizophre nesium Stearate, calcium Stearate, talc and colloidal silica. n1a, 1431 Favorable examples of the binders are as follows: 1411 bipolar disorder comprising bipolar I disorder, bipo C-Starch, Sucrose, gelatin, gum Arabic, methylcellulose, car lar II disorder; boxymethylcellulose, sodium carboxymethylcellulose, crys 1412 cyclothymic disorder; talline cellulose, Sucrose, D-mannitol, trehalose, dextrin, pull 1413 Parkinson's disease: lulan, hydroxypropylcellulose, hydroxypropyl methyl 1414 Huntington's disease; cellulose and polyvinylpyrrolidone. 1415 paranoid: 1432 Favorable examples of the disintegrants are as fol 1416 schizophrenia (e.g., paranoid Schizophrenia, disor lows: lactose, Sucrose, starch, carboxymethylcellulose, cal ganized schizophrenia, disorganized schizophrenia, cata cium carboxymethylcellulose, croScarmellose Sodium, tonic schizophrenia, undifferentiated Schizophrenia, residual Sodium carboxymethyl starch, light silicic anhydride and Schizophrenia); low-substituted hydroxypropylcellulose. 1417 schizophreniform disorder; 1433) Favorable examples of the solvents are as follows: 1418 schizoaffective disorder of the delusional type or the water for injection, physiological saline, Linger solution, depressive type; alcohol, propylene glycol, polyethylene glycol, Sesame oil, 1419 personality disorder of the paranoid type: corn oil, olive oil and cottonseed oil. 1420 personality disorder of the schizoid type: 1434 Favorable examples of the solubilizing agents areas 1421 obesity; follows: polyethylene glycol, propylene glycol, D-mannitol, 1422 metabolic syndrome; trehalose, benzylbenzoate, ethanol, tris-aminomethane, cho 1423 non-insulin dependent diabetes (NIDDM): lesterol, triethanolamine, Sodium carbonate, Sodium citrate, 1424 glucose intolerance; Sodium salicylate and sodium acetate. 1425. In particular, the compound of the present invention 1435 Favorable examples of the suspending agents are as is useful for preventing or treating schizophrenia. follows: Surfactants such as Stearyl triethanolamine, sodium 1426 Since the compound of the present invention dem lauryl Sulfate, laurylamino propionic acid, lecithin, benzalko onstrates excellent metabolic stability, Superior therapeutic nium chloride, benzethonium chloride, and glycerin effects on the aforementioned diseases are expected even at a monostearate; hydrophilic polymers such as polyvinyl alco low dosage. hol, polyvinyl pyrrolidone, Sodium carboxymethylcellulose, 1427. The compound of the present invention can be methylcellulose, hydroxymethylcellulose, hydroxyethyl cel administered safely, as it is, or in a dosage form which is lulose and hydroxypropyl cellulose; polysorbates, and poly manufactured according to a perse known method for manu oxyethylene-hardened castor oil. facturing pharmaceutical formulations (e.g., methods 1436 Favorable examples of the isotonization agents described in Japanese Pharmacopoeia) Such as tablets (inclu include Sodium chloride, glycerin, D-mannitol, D-Sorbitol sive of Sugar coated tablet, film coated tablet, Sublingual and glucose. tablet, orally disintegrable tablet, and buccal), pills, powders, 1437. Favorable examples of the buffers include buffer granules, capsules (inclusive of Soft capsule, and microcap Solutions of phosphates, acetates, carbonates and citrates. Sule), troches, syrups, liquid dosage forms, emulsions, con 1438 Favorable examples of the soothing agents include trolled-release preparations (e.g., quick-release preparation, benzyl alcohol. Sustained-release preparation, Sustained-release microcap 1439. Favorable examples of antiseptics include para Sule), aerosols, films (e.g., orally disintegrable film, adhesive oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phen film for application to oral-cavity mucosa), injections (e.g., ethyl alcohol, dehydroacetic acid and Sorbic acid. Subcutaneous injection, intravenous injection, intramuscular 1440 Favorable examples of antioxidants include sulfites injection, intraperitoneal injection), drip infusion, percutane and ascorbates. US 2012/0277430 A1 Nov. 1, 2012

1441 Favorable examples of the colorants include water ease, including, but not limited to, Reminyl, Cognex, Aricept, soluble edible tar dyes (e.g., edible dyes such as Food Red No. Exelon, Akatinol, Neotropin, Eldepryl, Estrogen and 2 and No. 3, Food Yellow No. 4 and No. 5, Food Blue No. 1 Cliquinol; agents used in the treatment of dementia, includ and 2); water insoluble lake dyes (e.g., aluminum salts of the ing, but not limited to, Mellaril, Haldol, Risperdal, Cognex, aforementioned water soluble edible tar dyes), natural dyes Aricept, and Exelon; agents used in the treatment of epilepsy, (e.g., B-carotene, chlorophyll, red iron oxide). including, but not limited to, Dilantin, Luminal, Tegretol, 1442 Favorable examples of the Sweeteners include Depakote, Depakene, Zarontin, Neurontin, Barbita, Solfeton Sodium saccharin, dipotassium glycyrrhizate, aspartame and and Felbatol; agents used in the treatment of multiple sclero Stevia. sis, including, but not limited to, Detrol, Ditropan XL, Oxy 1443 The medical compositions of the present invention Contin, Betaseron, Avonex, AZathioprine, Trexall and Copax can be manufactured by the common methods in the field of one; agents used in the treatment of Huntington's disease, formulation technology, for example, methods listed in the including, but not limited to, Elavil, Tofranil, Norpramin, Japanese pharmacopoeia. Specific manufacturing methods Pamelor, Paxil, Prozac, Zoloft, Nitoman, Haldol, Thorazine, for formulations are described in detail below. Mellaril. Dogmatil, Seroquel, CloZaril, and Risperdal; agents 1444. The content of the compound of the present inven useful in the treatment of diabetes, including, but not limited tion in the medical compositions of the present invention to, PPAR ligands (e.g. agonists, antagonists, such as Rosigli varies based on the dosage forms, dosages of the compound of taZone, TroglitaZone and PioglitaZone), insulin secreta the present invention, etc. For example, the content approxi gogues (e.g., Sulfonylurea drugs, such as Glyburide, Glime mately ranges from 0.01 to 100 wt % and preferably from 0.1 piride, Chlopropamide, Tolbutamide, and Glipizide, and non to 95 wt % relative to the entire amount of the composition. Sulfonyl secretagogues), C-glucosidase inhibitors (such as 1445. The dosage of the compound of the present inven Acarbose, Miglitol, and Voglibose), insulin sensitizers (such tion depends upon injection targets, administration routes, as the PPAR-Yagonists, e.g., the glitazones; biguanides, PTP target diseases, symptoms, etc. For example, in the case of 1B inhibitors, DPP-IV inhibitors, and 11 beta-HSD inhibi oral administration in patients with Schizophrenia (adults, tors), hepatic glucose output lowering compounds (such as bodyweight of approximately 60kg), generally a single dose glucagon antagonists and metformin, e.g., Glucophage and ranges from approximately 0.1 to 20 mg/kg bodyweight, Glucophage XR), insulin and insulin derivatives (both long preferably from approximately 0.2 to 10 mg/kg bodyweight, and short acting forms and formulations of insulin); and anti further preferably from approximately 0.5 to 10 mg/kg body obesity drugs, including, but not limited to, B-3 agonists, weight, and this dosage is preferably administered once daily CB-1 agonists, neuropeptide Y5 inhibitors, Ciliary Neu or several times daily (e.g., 3 times). rotrophic Factor and derivatives (e.g., AXokine), appetite, 1446. The compounds can be administered as the sole Suppressants (e.g., Sibutramine), and lipase inhibitors (e.g., active agent or in combination with other pharmaceutical Orlistat). agents such as other agents used in the treatment of psychosis, 1448 The form of administration of concomitant drugs especially Schizophrenia and bipolar disorder, obsessive with the compound of the present invention is not particularly compulsive disorder, major depression, Parkinson's disease, limited and is acceptable as long as the compound of the Alzheimer's disease, cognitive impairment and/or memory present invention is combined with concomitant drugs at the loss, e.g., nicotinic C7 agonists, nicotinic C7 partial agonists, time of administration. Examples of Such forms of adminis nicotinic C.7 positive allosteric modulators, PDE2 inhibitors, tration are as follows: PDE4 inhibitors, PDE5 inhibitors, other PDE inhibitors, cal 1449 (1) Administration of a single formula obtained cium channel blockers, muscarinic m1 and m2 modulators, simultaneous formulation of the compound of the adenosine receptor modulators, ampakines, Glycine trans present invention with a concomitant drug, porter 1 inhibitors, NMDA-R modulators, mGluR modula 1450 (2) Simultaneous administration via the same tors, dopamine modulators, serotonin modulators, selective administration route for two kinds of formulas obtained serotonin reuptake inhibitors, serotonin and norepinephrine by independent formulations of the compound of the reuptake inhibitors, norepinephrine and dopamine reuptake present invention and a concomitant drug, inhibitors, triple reuptake inhibitors, cannabinoid modula 1451 (3) Administrations at different times via the tors, and cholinesterase inhibitors (e.g., donepezil, rivas same administration route for two kings of formulas tigimine, and galantamine). In such combinations, each obtained by independent formulations of the compound active ingredient can be administered either in accordance of the present invention and a concomitant drug, with their usual dosage range or a dose below their usual 1452 (4) Simultaneous administration via different dosage range, and can be administered either simultaneously administration routes for two kinds of formulas obtained or sequentially. by independent formulations of the compound of the 1447 Drugs suitable in combination with the compounds present invention and a concomitant drug, of the present invention include, but are not limited to, other 1453 (5) Administrations at different times via differ Suitable schizophrenia drugs such as Haldol, CloZaril. ent administration routes for two kinds of formulas Zyprexa, Risperdal, Abilify, Geodon, Invega, and Seroquel; obtained by independent formulations of the compound bipolar disorder drug, including, but not limited to, Lithium, of the present invention and a concomitant drug. (For Zyprexa, Abilify, and Depakote; Parkinson's disease drugs, example, administration in the order of the composition including, but not limited to, Levodopa, Parlodel, Permax, of the present invention a concomitant drug, or admin Mirapex, Tasmar, Kemadrin, Artane, and Cogentin; agents istration in the reversed order). These forms of admin used in the treatment of major depression, including, but not istration are summarized below and abbreviated as a limited to, Elavil, Tofranil, Norpramin, Pamelor, Paxil, concomitant agent of the present invention. Prozac, Zoloft, Wellbutrin, Lexapro, Remeron, Effexor, 1454. When administering the concomitant agent of the Cymbalta: agents used in the treatment of Alzheimer's dis present invention, a concomitant drug and the compound of US 2012/0277430 A1 Nov. 1, 2012 39 the present invention can be administered at the same time, tant drug can be used in an amount ranging from 0.01 to 100 but the compound of the present invention can be adminis parts by weight relative to 1 part by weight of the compound tered after a concomitant drug is administered or after the of the present invention. compound of the present invention is administered, a con 1462 For example, the content of the compound of the comitant drug can be administered. When administering at present invention in the concomitant agent of the present different times, the time difference depends upon the active invention varies with the drug form of formulations. Gener ingredients to be administered, drug forms and methods of ally, it is present in a range from about 0.01 to 99.9 wt %, administration. For example, when a concomitant drug is preferably from about 0.1 to 50 wt % and more preferably administered first, the compound of the present invention can from about 0.5 to 20 wt % relative to the entire formula. be administered within 1 min. to 3 days, preferably within 10 1463. The content of a concomitant drug in the concomi min. to 1 day and more preferably within 15 min. to 1 hour tant agent of the present invention varies with the drug form of after the concomitant drug is administered. However, if the formulations. Generally it is present in a range from about compound of the present invention is administered first, a 0.01 to 99.9 wt %, preferably from about 0.1 to 50 wt % and concomitant drug can be administered within 1 min. to 1 day, more preferably from about 0.5 to 20 wt % relative to the preferably within 10 min. to 6 hours and more preferably entire formula. within 15 min. to 1 hour after the compound of the present invention is administered. 1464. The content of an additive such as carriers in the concomitant agent of the present invention varies with the 1455. If there are no problems with side effects of the drug form of formulations. Generally it is present in a range concomitant drugs, any dosages can be set. A daily dosage as from about 1 to 99.99 wt % and preferably from about 10 to a concomitant drug depends upon dosages, administration 90 wt % relative to the entire formula. Subjects, administration routes, target diseases, symptoms, etc. For example, in the case of oral administration in patients 1465. When the compound of the present invention and a with schizophrenia (adults, bodyweight of approximately 60 concomitant drug are formulated independently, the same kg), a normal daily dosage ranges from about 0.1 to 20 mg/kg contents can be applied. bodyweight, preferably from about 0.2 to 10 mg/kg body 1466 Since the dosages may fluctuate under various con weight and more preferably from about 0.5 to 10 mg/kg ditions as mentioned above, a dosage less than the aforemen bodyweight. It is preferable that this dosage is administered tioned dosages may be sufficient or it may be necessary to once daily to several times daily (e.g., 3 times). administer at a dosage exceeding the range. 1456. If the compound of the present invention is used in combination with a concomitant drug, the respective dosages EXAMPLES can be reduced within a safe range with consideration of the opposite effects of the respective drugs. 1467. The present invention will be explained in detail 1457. The concomitant agent of the present invention below with reference to the reference examples, embodi exhibits low toxicity. For example, the compound of the ments, formulation examples and experimental examples. present invention or (and) the aforementioned concomitant Since these are simply examples, the present invention will drug can be combined with a pharmaceutically acceptable not be limited to these examples and the present invention can carrier according to the known method to prepare a medical be modified in the range not deviating from the scope of the composition Such as tablets (including Sugar-coated tablets present invention. and film-coated tablets), powder agents, granular agents, cap Sules (including Soft capsules), liquids, injection Solutions, 1468. In the following reference examples and embodi Suppositories, Sustained-release agents, etc. These composi ments, “room temperature' indicates generally approxi tions can be administered safely orally or non-orally (e.g., mately 10° C. to 35° C. As for %, % in terms of yields including local, rectal and venous routes). indicates mol/mol %, '% in terms of the solvent used for 1458. The pharmaceutically acceptable carriers that can chromatography indicates Vol %, and % in other cases indi cates wt %. In the proton NMR spectrum, OH and NH protons be used for manufacturing the concomitant agent of the that cannot be identified due to broadbands are not recorded present invention can be the same as those used in the medical in the data. Kiesselgel 60 by Merck & Co., Inc. was used in composition of the present invention as mentioned above. silica gel chromatography and Chromatorex NH by Fuji Sily 1459. A mixing ratio between the compound of the present sia Chemical Ltd. was used in basic silica gel chromatogra invention and a concomitant drug in the concomitant agent of phy. the present invention can be selected appropriately based on the administration Subjects, administration routes and dis 1469 Abbreviations used in other sections of the text CaSCS. imply the following meanings. 1460. The aforementioned concomitant drugs can be com 1470 s: singlet bined at an appropriate proportion if two or more drugs are 1471 d: doublet combined. 1472 dd: doublet of doublets 1461. A dosage of the concomitant drug can be selected 1473 dt: doublet of triplets appropriately based on the dosages used clinically. In addi 1474 t: triplet tion, a mixing ratio between the compound of the present 1475 tt: triplet of triplets invention and a concomitant drug can be selected appropri ately based on the administration Subjects, administration 1476 td: triplet of doublets routes, target diseases, symptoms, combinations, etc. For 1477 q: quartet example, if the administration Subject is humans, a concomi 1478 septet: septet US 2012/0277430 A1 Nov. 1, 2012 40

1479 m: multiplet column temperature 40° C.). All masses were reported as 1480 br: broad those of the protonated parent ions. 1481 J: coupling constant Reference Example 1 1482 HZ: hertz 3-3-(Trifluoromethyl)phenylhydrazono pentane 1483 CDC1: deuterochloroform 2,4-dione 1484 DMSO-d: deutero-dimethyl sulfoxide 1513 1485 H-NMR: proton nuclear magnetic resonance 1486 HPLC: high performance liquid chromatography 1487 THF: tetrahydrofuran 1488 DMF: N,N-dimethylformamide 1489 DMSO: dimethylsulfoxide 1490 NMP: N-methylpyrrolidone 1491) HOBt: 1-hydroxybenzotriazole 1492 WSC: 1-ethyl-3-(3-dimethylaminopropyl)-carbo diimide hydrochloride 1493 HATU: hexafluorophosphate 2-(7-aza-1H-benzot riazole-1-yl)-1,1,3,3-tetramethyluronium FC 1494 DMTMM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4- methylmorpholinium chloride n-hydrate 1514 3-(Trifluoromethyl)aniline (34.6 g. 215 mmol) was 1495 DBU: 1,8-diazabicyclo[5.4.0-7-undecene dissolved in a mixture of concentrated hydrochloric acid (64 mL) and water (64 mL). To the resulting mixture was added 1496 LC-MS: liquid chromatography/mass spectroscopy dropwise at 0° C. a solution of sodium nitrite (16.6 g. 240 1497 ESI: electrospray ionization mmol) in water (100 mL). The mixture was stirred for 1 h at 1498 CDI: 1,1'-carbonyldiimidazole 0° C. To the resulting diazonium salt solution was added 1499 dba: dibenzylideneacetone dropwise a solution of pentane-2,4-dione (22.0g, 220 mmol) DIBAL. diisobutylaluminium hydride and sodium acetate (52.5 g. 640 mmol) in ethanol (225 mL) 1500 and water (80 mL) at room temperature. The mixture was 1501 DME: 1,2-dimethoxyethane stirred for 18 hat room temperature with a mechanical stirrer. 1502) DPPA: diphenylphosphoryl azide The orange precipitate was filtered off and washed with water 1503 HMPA: hexamethylphosphoric triamide (150 mLX3), 50 percent aqueous ethanol (100 mLX2), and 1504 selectfluor: 1-chloromethyl-4-fluoro-1,4-diazoni n-hexane (100 mL), and then dried in vacuo at 50° C. for 5 h abicyclo[2.2.2]octane bis(tetrafluoroborate) affording 52.7 g (90%) of 3-3-(trifluoromethyl)phenyl hydrazono pentane-2,4-dione as an orange solid. 1505 TEA: triethylamine 1515 H NMR (400 MHz, CDC1): 8 ppm 2.52 (s, 3H), 1506 TFA. trifluoroacetic acid 2.63 (s.3H), 7.45-7.44 (m, 1H), 7.58-7.51 (m, 2H), 7.66 (s, 1507 TMSC1: trimethylsilyl chloride 1H), 14.68 (s, 1H). LC-MS (MH) 273.10. 1508) Xantphos: 4,5-bis(diphenylphosphino)-9,9-dim ethylxanthene Reference Example 2 1509 Rt: retention time 3-3-(Dimethylamino)prop-2-enoyl-1-3-(trifluo 1510 All reagents and solvents were of commercial qual romethyl)phenylpyridazin-4(1H)-one ity and used without further purification. Column chromatog raphy was performed using Merck silica gel 60 (230-400 1516 mesh). The compounds and/or intermediates were purified by preparative high performance liquid chromatography (prep. HPLC) using a Gilson High through Put purification system. 1511. The columns were reversed phase YMC CombiPrep Pro C18, S-5 um, 19x50 mm. A gradient elution was used (flow rate 20 mL/min), typically starting with 5% acetonitrile/ 95% water and progressing to 100% acetonitrile over a Period of 7 min. All solvents contained 0.1% trifluoroacetic acid (TFA). 1512 Mass.spectrometric analysis was performed accord ing to liquid chromatography/mass spectroscopy (LCMS) methods. The method employed a Waters LC-MS System FC (Agilent HP1100 HPLC and a Micromass ZMD mass spec trometer for the LCMS instrument, a CAPCELL PAK C18, 1517. A mixture of 3-3-(trifluoromethyl)phenyl UG120, S-3 um, 1.5x35 mm for the chromatography column, hydrazono pentane-2,4-dione (4.3 g, 15.8 mmol) and N,N- and a solvent system that was a 5-95% gradient of acetonitrile dimethylformamide dimethylacetal (40 mL) was heated in an in water with 0.04%TFA over a 3.60 min period (flow rate 0.5 oil bath at 120° C. for 5 h. The solvent was removed under mL/min molecular weight range 200-800; cone Voltage 20V: reduced pressure to give quantitative yield of 3-3-(dimethy US 2012/0277430 A1 Nov. 1, 2012

lamino)prop-2-enoyl-1-3-(trifluoromethyl)phenylpy (DMF-DMA), and the mixture was refluxed for 4 h, then ridaZin-4(1H)-one as a black oil, which was used as is in the concentrated under reduced pressure to give crude 3-3-(dim next step without further purification. ethylamino)prop-2-enoyl-1-4-(trifluoromethyl)phenylpy 1518. LC-MS (MH)338.16. ridazin-4(1H)-one which was used to the next step without further purification. Reference Example 3 3-4-(Trifluoromethyl)phenylhydrazono pentane Reference Example 5 2,4-dione 3-(3-Chlorophenyl)hydrazonopentane-2,4-dione 1519 1524 O O

O O Me Me HN1 Me Me HN1

CF C

1520. To a solution of 4-(trifluoromethyl)aniline (1090 1525 To a solution of 3-chloroaniline (1000 mg, 7.87 mg, 6.80 mmol) in 5 mL of water and 5 mL of concentrated mmol) in 5 mL of water and 5 mL of concentrated hydrochlo hydrochloride solution, sodium nitrite (563 mg, 8.16 mmol) ride solution, sodium nitrite (652 mg, 9.45 mmol) in 4 mL of in 4 mL of water was added dropwise at 0°C., and the mixture water was added dropwise at 0°C., and the mixture was was stirred at 0°C. for 1 h. Then to the reaction mixture was stirred at 0°C. for 1 h. Then to the reaction mixture was added added dropwise a solution of sodium acetate (1670 mg, 20.40 dropwise a solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (748 mg, 7.48 mmol) in 10 mL of mmol) and acetylacetone (866mg, 8.66 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/ temperature overnight, filtered, washed with water, EtOH/ HO (1:1) and hexane, and dried to give 3-4-(trifluorom H2O (1:1) and hexane, and dried to give 3-(3-chlorophenyl) ethyl)phenylhydrazonopentane-2,4-dione (580 mg, 31%). hydrazonopentane-2,4-dione (450 mg, 24%). 1521 'H NMR (300 MHz, CDC1): 8 ppm 2.51 (s, 3H), 2.62 (s.3H), 7.44 (d. J–8.7 Hz, 2H), 7.69 (d. J=8.7 Hz, 2H), 1526 LCMS: m/z =23935C1, M+H. 14.59 (s, 1H). Reference Example 6 Reference Example 4 1-(3-Chlorophenyl)-3-3-(dimethylamino)prop-2- 3-3-(Dimethylamino)prop-2-enoyl-1-4-(trifluo enoylpyridaZin-4(1H)-one romethyl)phenylpyridazin-4(1H)-one 1522 1527

C

CF 1528 3-(3-Chlorophenyl)hydrazonopentane-2,4-dione (450 mg, 1.89 mmol) was dissolved in 10 mL of N,N-dim 1523 3-4-(Trifluoromethyl)phenyl ethylformamide dimethyl acetal (DMF-DMA), and the mix hydrazono pentane-2,4-dione (580 mg, 2.13 mmol) was dis ture was refluxed for 4 h, then concentrated under reduced solved in 10 mL of N,N-dimethylformamide dimethyl acetal pressure to give crude 1-(3-chlorophenyl)-3-3-(dimethy US 2012/0277430 A1 Nov. 1, 2012 42 lamino)prop-2-enoylpyridaZin-4(1H)-one which was used Reference Example 9 to the next step without further purification. 3-(4-Methoxyphenyl)hydrazonopentane-2,4-dione Reference Example 7 1534 3-(2-Methoxyphenyl)hydrazonopentane-2,4-dione O O 1529 Me Me O O HN1 Me Me HN1 MeO OMe

1535 To a solution of 4-methoxyaniline (1000 mg, 8.13 mmol) in 10 mL of acetic acid and 2 mL of concentrated 1530. To a solution of 2-methoxyaniline (1000 mg, 8.13 hydrochloride solution, sodium nitrite (673 mg, 9.76 mmol) mmol) in 10 mL of acetic acid and 2 mL of concentrated in 4 mL of water was added dropwise at 0°C., and the mixture hydrochloride solution, sodium nitrite (673 mg, 9.76 mmol) was stirred at 0°C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2000 mg, 24.39 in 4 mL of water was added dropwise at 0°C., and the mixture mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of was stirred at 0°C. for 1 h. Then to the reaction mixture was ethanol and 6 mL of water. The mixture was stirred at room added dropwise a solution of sodium acetate (2000 mg, 24.39 temperature overnight, filtered, washed with water, EtOH/ mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of H2O (1:1) and hexane, and dried to give 3-(4-methoxyphe ethanol and 6 mL of water. The mixture was stirred at room nyl)hydrazonopentane-2,4-dione (950 mg, 50%). temperature overnight, filtered, washed with water, EtOH/ 1536 H NMR (400 MHz, CDC1): 8 ppm 2.50 (s, 3H), H2O (1:1) and hexane, and dried to give 3-(2-methoxyphe 2.62 (s.3H), 3.86 (s, 3H), 6.96-6.98 (m, 2H), 7.38-7.41 (m, nyl)hydrazonopentane-2,4-dione (1500 mg, 79%). 2H), 14.99 (s, 1H). 1531 LCMS: m/z =235 M+H. Reference Example 10 Reference Example 8 3-3-(Dimethylamino)prop-2-enoyl-1-(4-methox 3-3-(Dimethylamino)prop-2-enoyl-1-(2-methox yphenyl)pyridazin-4(1H)-one yphenyl)pyridazin-4(1H)-one 1537 1532

MeO

OMe

1533 3-(2-Methoxyphenyl)hydrazonopentane-2,4-di 1538 3-(4-Methoxyphenyl)hydrazonopentane-2,4-di one (500 mg, 2.14 mmol) was dissolved in 10 mL of N.N- one (500 mg, 2.14 mmol) was dissolved in 10 mL of N.N- dimethylformamide dimethyl acetal (DMF-DMA), and the dimethylformamide dimethyl acetal (DMF-DMA), and the mixture was refluxed for 4h, then concentrated under reduced mixture was refluxed for 4h, then concentrated under reduced pressure to give crude 3-3-(dimethylamino)prop-2-enoyl pressure to give crude 3-3-(dimethylamino)prop-2-enoyl 1-(2-methoxyphenyl)pyridazin-4(1H)-one which was used to 1-(4-methoxyphenyl)pyridazin-4(1H)-one which was used to the next step without further purification. the next step without further purification. US 2012/0277430 A1 Nov. 1, 2012 43

Reference Example 11 Reference Example 13 3-(3-Fluorophenyl)hydrazonopentane-2,4-dione 3-(2-Fluorophenyl)hydrazonopentane-2,4-dione 1539 1544

1540. To a solution of 3-fluoroaniline (1000 mg, 9.00 1545. To a solution of 2-fluoroaniline (1000 mg, 9.00 mmol) in 5 mL of water and 5 mL of concentrated hydrochlo mmol) in 10 mL of acetic acid and 2 mL of concentrated ride solution, sodium nitrite (746 mg, 10.80 mmol) in 4 mL of hydrochloride solution, sodium nitrite (746 mg, 10.80 mmol) water was added dropwise at 0°C., and the mixture was in 4 mL of water was added dropwise at 0°C., and the mixture stirred at 0°C. for 1 h. Then to the reaction mixture was added was stirred at 0°C. for 1 h. Then to the reaction mixture was dropwise a solution of sodium acetate (2220 mg, 27.00 added dropwise a solution of sodium acetate (2220 mg, 27.00 mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/ temperature overnight, filtered, washed with water, EtOH/ HO (1:1) and hexane, and dried to give 3-(3-fluorophenyl) H2O (1:1) and hexane, and dried to give 3-(2-fluorophenyl) hydrazonopentane-2,4-dione (650 mg, 33%). hydrazonopentane-2,4-dione (1280 mg, 64%). 1541 "H NMR (400 MHz, CDC1): 8 ppm 2.50 (s, 3H), 1546 H NMR (400 MHz, CDC1): 8 ppm 2.51 (s, 3H), 2.62 (s.3H), 6.90 (dt, J=2.4, 8.0 Hz, 1H), 7.11 (dd, J=1.6, 8.0 2.62 (s.3H), 7.14-7.24 (m,3H), 7.77 (d. J=8.0 Hz, 1H), 14.71 HZ, 1H), 7.21 (td, J-24, 10.0 Hz, 1H), 7.34-7.39 (m, 1H), (s, 1H). 14.61 (s, 1H). Reference Example 14 Reference Example 12 3-3-(Dimethylamino)prop-2-enoyl-1-(2-fluorophe 3-3-(Dimethylamino)prop-2-enoyl-1-(3-fluorophe nyl)pyridazin-4(1H)-one nyl)pyridazin-4(1H)-one 1542 1547

1543) 3-(3-Fluorophenyl)hydrazonopentane-2,4-dione 1548 3-(2-Fluorophenyl)hydrazonopentane-2,4-dione (650 mg, 2.93 mmol) was dissolved in 10 mL of N,N-dim (600 mg, 2.70 mmol) was dissolved in 10 mL of N,N-dim ethylformamide dimethyl acetal (DMF-DMA), and the mix ethylformamide dimethyl acetal (DMF-DMA), and the mix ture was refluxed for 4 h, then concentrated under reduced ture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3-3-(dimethylamino)prop-2-enoyl pressure to give crude 3-3-(dimethylamino)prop-2-enoyl 1-(3-fluorophenyl)pyridazin-4(1H)-one which was used to 1-(2-fluorophenyl)pyridazin-4(1H)-one which was used to the next step without further purification. the next step without further purification. US 2012/0277430 A1 Nov. 1, 2012 44

Reference Example 15 Reference Example 17 3-(4-Fluorophenyl)hydrazonopentane-2,4-dione 3-(4-Chlorophenyl)hydrazonopentane-2,4-dione 1549 1554)

O O

Me Me HN1

F

1550. To a solution of 4-fluoroaniline (1000 mg, 9.00 1555. To a solution of 4-chloroaniline (1000 mg, 7.87 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (746 mg, 10.80 mmol) mmol) in 10 mL of acetic acid and 2 mL of concentrated in 4 mL of water was added dropwise at 0°C., and the mixture hydrochloride solution, sodium nitrite (652 mg, 9.45 mmol) was stirred at 0°C. for 1 h. Then to the reaction mixture was in 4 mL of water was added dropwise at 0°C., and the mixture added dropwise a solution of sodium acetate (2220 mg, 27.00 was stirred at 0°C. for 1 h. Then to the reaction mixture was mmol) and acetylacetone (990 mg, 9.90 mmol) in 10 mL of added dropwise a solution of sodium acetate (1936 mg, 23.61 ethanol and 6 mL of water. The mixture was stirred at room mmol) and acetylacetone (1023 mg, 10.23 mmol) in 10 mL of temperature overnight, filtered, washed with water, EtOH/ ethanol and 6 mL of water. The mixture was stirred at room H2O (1:1) and hexane, and dried to give 3-(4-fluorophenyl) temperature overnight, filtered, washed with water, EtOH/ hydrazonopentane-2,4-dione (1200 mg, 60%). H2O (1:1) and hexane, and dried to give 3-(4-chlorophenyl) 1551 "H NMR (300 MHz, CDC1): 8 ppm 2.49 (s.3H), hydrazonopentane-2,4-dione (1680 mg, 90%). 2.61 (s.3H), 7.09-7.15 (m, 2H), 7.37-7.41 (m, 2H), 14.85 (s, 1556 H NMR (400 MHz, CDC1): 8 ppm 2.49 (s.3H), 1H). 2.61 (s.3H), 7.33-7.39 (m, 4H), 14.70 (s, 1H). Reference Example 16 Reference Example 18 3-3-(Dimethylamino)prop-2-enoyl-1-(4-fluorophe 1-(4-Chlorophenyl)-3-3-(dimethylamino)prop-2- nyl)pyridazin-4(1H)-one enoylpyridaZin-4(1H)-one 1552 1557)

1553 3-(4-Fluorophenyl)hydrazonopentane-2,4-dione 1558. 3-(4-Chlorophenyl)hydrazonopentane-2,4-dione (650 mg, 2.93 mmol) was dissolved in 10 mL of N,N-dim (600 mg, 2.52 mmol) was dissolved in 10 mL of N,N-dim ethylformamide dimethyl acetal (DMF-DMA), and the mix ethylformamide dimethyl acetal (DMF-DMA), and the mix ture was refluxed for 4 h, then concentrated under reduced ture was refluxed for 4 hours, then concentrated under pressure to give crude 3-3-(dimethylamino)prop-2-enoyl reduced pressure to give crude 1-(4-chlorophenyl)-3-3- 1-(4-fluorophenyl)pyridazin-4(1H)-one which was used to (dimethylamino)prop-2-enoylpyridazin-4(1H)-one which the next step without further purification. was used to the next step without further purification. US 2012/0277430 A1 Nov. 1, 2012

Reference Example 19 Reference Example 21 3-(2-Methylphenyl)hydrazonopentane-2,4-dione 3-(3-Methylphenyl)hydrazonopentane-2,4-dione 1559 1563

O O O O

Me Me Me Me HN1 HN1 N Me

Me

1560. To a solution of 2-methylaniline (1000 mg, 9.34 1564. To a solution of 3-methylaniline (1000 mg, 9.34 mmol) in 10 mL of acetic acid and 2 mL of concentrated mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (774 mg, 11.21 mmol) hydrochloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0°C., and the mixture in 4 mL of water was added dropwise at 0°C., and the mixture was stirred at 0°C. for 1 h. Then to the reaction mixture was was stirred at 0°C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2299 mg, 28.04 added dropwise a solution of sodium acetate (2299 mg, 28.04 mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/ temperature overnight, filtered, washed with water, EtOH/ H2O (1:1) and hexane, and dried to give 3-(2-methylphenyl) H2O (1:1) and hexane, and dried to give 3-(3-methylphenyl) hydrazonopentane-2,4-dione (1000 mg. 49%). LCMS: hydrazonopentane-2,4-dione (500 mg, yield 24%). LCMS: m/Z 219 M*-i-H. m/Z=219 M*-i-H. Reference Example 20 Reference Example 22 3-3-(Dimethylamino)prop-2-enoyl-1-(2-meth 3-3-(Dimethylamino)prop-2-enoyl-1-(3-meth ylphenyl)pyridazin-4(1H)-one ylphenyl)pyridazin-4(1H)-one 1561 1565

Me

1562 3-(2-Methylphenyl)hydrazonopentane-2,4-dione 1566 3-(3-Methylphenyl)hydrazonopentane-2,4-dione (1000 mg. 4.59 mmol) was dissolved in 10 mL of N.N- (500 mg, 2.29 mmol) was dissolved in 10 mL of N,N-dim dimethylformamide dimethyl acetal (DMF-DMA), and the ethylformamide dimethyl acetal (DMF-DMA), and the mix mixture was refluxed for 4h, then concentrated under reduced ture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3-3-(dimethylamino)prop-2-enoyl pressure to give crude 3-3-(dimethylamino)prop-2-enoyl 1-(2-methylphenyl)pyridazin-4(1H)-one which was used to 1-(3-methylphenyl)pyridazin-4(1H)-one which was used to the next step without further purification. the next step without further purification. US 2012/0277430 A1 Nov. 1, 2012 46

Reference Example 23 Reference Example 25 3-(3-Methoxyphenyl)hydrazonopentane-2,4-dione 3-2-(Trifluoromethyl)phenylhydrazono pentane 2,4-dione 1567 1571

O O

Me Me HN1 N

FC

MeO

1568. To a solution of 3-methoxyaniline (1000 mg, 8.13 1572 To a solution of 2-(trifluoromethyl)aniline (1.09 g, mmol) in 10 mL of acetic acid and 2 mL of concentrated 6.80 mmol) in 5 mL of water and 5 mL of concentrated hydrochloride solution, sodium nitrite (673 mg, 9.76 mmol) hydrochloride solution, sodium nitrite (563 mg, 8.16 mmol) in 4 mL of water was added dropwise at 0°C., and the mixture in 4 mL of water was added dropwise at 0°C., and the mixture was stirred at 0°C. for 1 h. Then to the reaction mixture was was stirred at 0°C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (2000 mg, 24.39 added dropwise a solution of sodium acetate (1.67 g. 20.40 mmol) and acetylacetone (1057 mg, 10.57 mmol) in 10 mL of mmol) and acetylacetone (748 mg, 7.48 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/ temperature overnight, filtered, washed with water, EtOH/ H2O (1:1) and hexane, and dried to give 3-(3-methoxyphe HO (1:1) and hexane, and dried to give 3-2-(trifluorom nyl)hydrazonopentane-2,4-dione (840 mg. 44%). LCMS: ethyl)phenylhydrazonopentane-2,4-dione (634 mg., 33%). m/Z-235 M+H. 1573 H NMR (300 MHz, CDC1): 8 ppm 2.52 (s, 3H), 2.63 (s.3H), 7.24-7.29 (m. 1H), 7.60-7.66 (m, 2H), 7.96 (8.4 Reference Example 24 HZ, 1H), 15.06 (s, 1H). 3-3-(Dimethylamino)prop-2-enoyl-1-(3-methox Reference Example 26 yphenyl)pyridazin-4(1H)-one 3-3-(Dimethylamino)prop-2-enoyl-1-2-(trifluo 1569 romethyl)phenylpyridazin-4(1H)-one

1574)

FC MeO

1575 3-2-(Trifluoromethyl)phenyl 1570 3-(3-Methoxyphenyl)hydrazonopentane-2,4-di hydrazono pentane-2,4-dione (634 mg, 2.33 mmol) was dis one (500 mg, 2.14 mmol) was dissolved in 10 mL of N.N- solved in 10 mL of N,N-dimethylformamide dimethyl acetal dimethylformamide dimethyl acetal (DMF-DMA), and the (DMF-DMA), and the mixture was refluxed for 4 h, then mixture was refluxed for 4h, then concentrated under reduced concentrated under reduced pressure to give crude 3-3-(dim pressure to give crude 3-3-(dimethylamino)prop-2-enoyl ethylamino)prop-2-enoyl-1-2-(trifluoromethyl)phenylpy 1-(3-methoxyphenyl)pyridazin-4(1H)-one which was used to ridazin-4(1H)-one which was used to the next step without the next step without further purification. further purification. US 2012/0277430 A1 Nov. 1, 2012 47

Reference Example 27 reduced pressure to give crude 3-3-(dimethylamino)prop-2- 3-(4-Morpholin-4-ylphenyl)hydrazonopentane-2,4- enoyl-1-(4-morpholin-4-ylphenyl)pyridazin-4(1H)-one dione which was used to the next step without further purification. 1576 Reference Example 29 3-(Phenylhydrazono)pentane-2,4-dione 1581

N

O 1582 To a solution of aniline (2000 mg, 21.50 mmol) in 30 mL of acetic acid and 5 mL of concentrated hydrochloride 1577 To a solution of 4-morpholin-4-ylaniline (1000 mg, solution, sodium nitrite (1780 mg, 25.80 mmol) in 8 mL of 5.62 mmol) in 10 mL of acetic acid and 2 mL of concentrated water was added dropwise at 0° C., and the mixture was hydrochloride solution, sodium nitrite (465 mg. 6.74 mmol) stirred at 0°C. for 1 h. Then to the reaction mixture was added in 4 mL of water was added dropwise at 0°C., and the mixture dropwise a solution of sodium acetate (5290 mg, 64.50 was stirred at 0°C. for 1 h. Then to the reaction mixture was mmol) and acetylacetone (2795 mg, 27.95 mmol) in 20 mL of added dropwise a solution of sodium acetate (2764 mg., 33.71 ethanol and 12 mL of water. The mixture was stirred at room mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL of temperature overnight, filtered, washed with water, EtOH/ ethanol and 6 mL of water. The mixture was stirred at room H2O (1:1) and hexane, and dried to give 3-(phenylhydrazono) temperature overnight, filtered, washed with water, EtOH/ pentane-2,4-dione (2955 mg. 67%). H2O (1:1) and hexane, and dried to give 3-(4-morpholin-4- 1583) "H NMR (400 MHz, CDC1): 8 ppm 2.50 (s.3H), ylphenyl)hydrazonolpentane-2,4-dione (900 mg, 55%). 2.61 (s.3H), 7.21 (dd, J=8.0, 4.4 Hz, 1H), 7.41 (d. J=4.4 Hz, 1578 LCMS: m/z =290 M*-i-H). 4H), 14.74 (s, 1H). Reference Example 28 Reference Example 30 3-3-(Dimethylamino)prop-2-enoyl-1-(4-morpholin 3-3-(Dimethylamino)prop-2-enoyl-1-phenylpy 4-ylphenyl)pyridazin-4(1H)-one ridazin-4(1H)-one 1579 1584

1585 3-(Phenylhydrazono)pentane-2,4-dione (470 mg. 2.30 mmol) was dissolved in 10 mL of N,N-dimethylforma O mide dimethyl acetal (DMF-DMA), and the mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 3-3-(dimethylamino)prop-2-enoyl-1-phenylpy 1580 3-(4-Morpholin-4-ylphenyl)hydrazonopentane-2, ridzin-4(1H)-one which was used to the next step without 4-dione (900 mg, 3.11 mmol) was dissolved in 10 mL of further purification. N,N-dimethylformamide dimethyl acetal (DMF-DMA), and 1586) "H NMR of the crude product (400 MHz, DMSO the mixture was refluxed for 4 h, then concentrated under d): 8 ppm 2.84 (s.3H), 3.11 (s.3H), 5.50 (br. 1H), 6.55 (d. US 2012/0277430 A1 Nov. 1, 2012 48

J=8.0 Hz, 1H), 743-746 (m. 1H), 7.57 (t, J=7.6 Hz, 2H), 7.70 1592) H NMR of the crude product (400 MHz, DMSO (d. J=8.0 Hz, 2H), 8.81 (d. J=8.0 Hz, 1H). d): 8 ppm 2.38 (s, 3H), 2.84 (s, 3H), 3.10 (s, 3H), 6.53 (d. J=8.0 Hz, 1H), 7.37 (d. J=8.0 Hz, 2H), 7.58 (d. J=8.0 Hz, 2H), Reference Example 31 8.76 (d. J=8.0 Hz, 1H). 3-(4-Methylphenyl)hydrazonopentane-2,4-dione 1587 Reference Example 33 3-2-(Difluoromethoxy)phenylhydrazonopentane 2,4-dione 1593

Me Me HN1 N Me N 1588 To a solution of 4-methylaniline (1000 mg, 9.34 F mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (774 mg, 11.21 mmol) in 4 mL of water was added dropwise at 0°C., and the mixture 1594. To a solution of 2-(difluoromethoxy)aniline (1000 was stirred at 0°C. for 1 h. Then to the reaction mixture was mg, 6.25 mmol) in 15 mL of acetic acid and 2.5 mL of added dropwise a solution of sodium acetate (2299 mg, 28.04 concentrated hydrochloride solution, sodium nitrite (518 mg, mmol) and acetylacetone (1215 mg, 12.15 mmol) in 10 mL of 7.50 mmol) in 4 mL of water was added dropwise at 0°C., and ethanol and 6 mL of water. The mixture was stirred at room the mixture was stirred at 0°C. for 1 h. Then to the reaction temperature overnight, filtered, washed with water, EtOH/ mixture was added dropwise a solution of Sodium acetate H2O (1:1) and hexane, and dried to give 3-(4-methylphenyl) (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 hydrazonopentane-2,4-dione (480 mg, 24%). mmol) in 10 mL of ethanol and 6 mL of water. The mixture 1589 H NMR (400 MHz, CDC1): 8 ppm 2.36 (s, 3H), was stirred at room temperature overnight, filtered, washed 2.49 (s.3H), 2.60 (s, 3H), 7.21 (d. J=8.0 Hz, 2H), 7.32 (d. with water, EtOH/HO (1:1) and hexane, and dried give 3 J=8.0 Hz, 2H), 14.82 (s, 1H). 2-(difluoromethoxy)phenylhydrazonopentane-2,4-dione (1590 mg.94%). Reference Example 32 1595 LCMS: m/z 271 M*-i-H). 3-3-(Dimethylamino)prop-2-enoyl-1-(4-meth ylphenyl)pyridazin-4(1H)-one Reference Example 34 1590 1-2-(Difluoromethoxy)phenyl-3-3-(dimethy lamino)prop-2-enoylpyridazin-4(1H)-one

1596

Me

1591 3-(4-Methylphenyl)hydrazonopentane-2,4-dione (462 mg, 2.12 mmol) was dissolved in 10 mL of N,N-dim ethylformamide dimethyl acetal (DMF-DMA), and the mix 1597 3-2-(Difluoromethoxy)phenyl ture was refluxed for 4 h, then concentrated under reduced hydrazono pentane-2,4-dione (500 mg, 1.85 mmol) was dis pressure to give crude 3-3-(dimethylamino)prop-2-enoyl solved in 10 mL of N,N-dimethylformamide dimethyl acetal 1-(4-methylphenyl)pyridazin-4(1H)-one which was used to (DMF-DMA), and the mixture was refluxed for 4 hours, then the next step without further purification. concentrated under reduced pressure to give crude 1-2-(dif US 2012/0277430 A1 Nov. 1, 2012 49 luoromethoxy)phenyl-3-3-(dimethylamino)prop-2-enoyl luoromethoxy)phenyl-3-3-(dimethylamino)prop-2-enoyl pyridazin-4(1H)-one which was used to the next step without pyridazin-4(1H)-one which was used to the next step without further purification. further purification.

Reference Example 35 Reference Example 37 3-4-(Difluoromethoxy)phenylhydrazonopentane 3-3-(Difluoromethoxy)phenylhydrazonopentane 2,4-dione 2,4-dione 1603 1598 O O

O O Me Me Me Me HN1 HN1

-->UO F O 1599. To a solution of 3-(difluoromethoxy)aniline (1000 r mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concen trated hydrochloride solution, sodium nitrite (518 mg, 7.50 1604) To a solution of 4-(difluoromethoxy)aniline (1000 mmol) in 4 mL of water was added dropwise at 0°C., and the mg, 6.25 mmol) in 10 mL of acetic acid and 2 mL of concen mixture was stirred at 0° C. for 1 h. Then to the reaction trated hydrochloride solution, sodium nitrite (518 mg, 7.50 mixture was added dropwise a solution of Sodium acetate mmol) in 4 mL of water was added dropwise at 0°C., and the (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 mixture was stirred at 0° C. for 1 h. Then to the reaction mmol) in 10 mL of ethanol and 6 mL of water. The mixture mixture was added dropwise a solution of Sodium acetate was stirred at room temperature overnight, filtered, washed (1538 mg, 18.75 mmol) and acetylacetone (812 mg, 8.12 with water, EtOH/HO (1:1) and hexane, and dried to give mmol) in 10 mL of ethanol and 6 mL of water. The mixture 3-3-(difluoromethoxy)phenylhydrazono pentane-2,4-di was stirred at room temperature overnight, filtered, washed one (1500 mg, 89%). with water, EtOH/HO (1:1) and hexane, and dried to give 1600 LCMS: m/z =271 M*--H). 3-4-(difluoromethoxy)phenylhydrazono pentane-2,4-di one (1400 mg, yield 82%). Reference Example 36 1605 LCMS: m/z =271 M*--H). 1-3-(Difluoromethoxy)phenyl-3-3-(dimethy Reference Example 38 lamino)prop-2-enoylpyridazin-4(1H)-one 1-4-(Difluoromethoxy)phenyl-3-3-(dimethy lamino)prop-2-enoylpyridazin-4(1H)-one 1601 1606

1602 3-3-(Difluoromethoxy)phenyl hydrazono pentane-2,4-dione (800 mg, 2.96 mmol) was dis solved in 10 mL of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and the mixture was refluxed for 4 h, then concentrated under reduced pressure to give crude 1-3-(dif US 2012/0277430 A1 Nov. 1, 2012 50

1607 3-4-(Difluoromethoxy)phenyl enoyl-1-(2-morpholin-4-ylphenyl)pyridazin-4(1H)-one hydrazono pentane-2,4-dione (600 mg, 2.22 mmol) was dis which was used to the next step without further purification. solved in 10 mL of N,N-dimethylformamide dimethyl acetal (DMF-DMA), and the mixture was refluxed for 4 h, then Reference Example 41 concentrated under reduced pressure to give crude 1-4-(dif luoromethoxy)phenyl-3-3-(dimethylamino)prop-2-enoyl 3-(Pyridin-3-ylhydrazono)pentane-2,4-dione pyridazin-4(1H)-one which was used to the next step without 1613 further purification. Reference Example 39 O O 3-(2-Morpholin-4-ylphenyl)hydrazonopentane-2,4- dione Me Me 1608 HN1

O O 21

Me Me al N 1614 To 3-aminopyridine (564 mg. 6.00 mmol) were r HN1 added 4 mL of concentrated sulfuric acid and 1.2 mL of water N at 0°C., and the mixture was stirred at room temperature until it was clear. To the reaction mixture was added a solution of sodium nitrite (414 mg. 6.00 mmol) in water (1.2 mL) at 0°C. The mixture was stirred for several min (>15 min). The solu tion of diazonium salt was poured into the Solution of 2,4- 1609. To a solution of 2-morpholin-4-ylaniline (1000 mg. pentanedione (600 mg., 6.00 mmol) and potassium acetate 5.62 mmol) in 10 mL of acetic acid and 2 mL of concentrated (18.0 g, 180 mmol) in ethanol (120 mL) at 0°C. The mixture hydrochloride solution, sodium nitrite (465 mg. 6.74 mmol) was stirred at 0°C. for 30 min and at room temperature for 30 in 4 mL of water was added dropwise at 0°C., and the mixture min. The reaction mixture was added to 120 mL of saturated was stirred at 0°C. for 1 h. Then to the reaction mixture was NaCO aqueous solution. The mixture was extracted with added dropwise a solution of sodium acetate (2764 mg. 33.71 dichloromethane, washed with water and brine, dried over mmol) and acetylacetone (730 mg, 7.30 mmol) in 10 mL of Na2SO4, and concentrated under reduced pressure to give ethanol and 6 mL of water. The mixture was stirred at room 3-(pyridin-3-ylhydrazono)pentane-2,4-dione (242 mg, yield temperature overnight, filtered, washed with water, EtOH/ 20%). HO (1:1) and hexane, and dried to give 3-(2-morpholin-4- 1615 LCMS: m/z =206 M+H. ylphenyl)hydrazonopentane-2,4-dione (1000 mg, 62%). 1610 LCMS: m/z =290 M+H. Reference Example 42 3-3-(Dimethylamino)prop-2-enoyl-1-pyridin-3- Reference Example 40 ylpyridazin-4(1H)-one 3-3-(Dimethylamino)prop-2-enoyl-1-(2-morpholin 4-ylphenyl)pyridazin-4(1H)-one 1616

1611

1617 3-(Pyridin-3-ylhydrazono)pentane-2,4-dione (200 mg, 0.98 mmol) was dissolved in 10 mL of N,N-dimethylfor 1612 3-(2-Morpholin-4-ylphenyl)hydrazonopentane-2, mamide dimethyl acetal (DMF-DMA), and the mixture was 4-dione (1000 mg, 2.46 mmol) was dissolved in 10 mL of refluxed for 4 h, then concentrated under reduced pressure to N,N-dimethylformamide dimethyl acetal (DMF-DMA), and give crude 3-3-(dimethylamino)prop-2-enoyl-1-pyridin-3- the mixture was refluxed for 4 h, then concentrated under ylpyridazin-4(1H)-one which was used to the next step with reduced pressure to give crude 3-3-(dimethylamino)prop-2- out further purification. US 2012/0277430 A1 Nov. 1, 2012

1618 H NMR of the crude product (400 MHz, CDC1): 8 give crude 3-3-(dimethylamino)prop-2-enoyl-1-pyridin-4- ppm 2.90 (s.3H), 3.15 (s.3H), 5.64 (d. J=11.6 Hz, 1H), 6.74 ylpyridazin-4(1H)-one which was used to the next step with (d. J=8.4 Hz, 1H), 7.45-7.48 (m, 1H), 8.00-8.03 (m, 1H), 8.20 out further purification. (d. J=8.0 Hz, 1H), 8.65-8.66 (m, 1H), 8.88 (d. J=2.8 Hz, 1H). 1624 'H NMR of the crude product (400 MHz, CDC1): 8 ppm 2.92 (s, 3H), 3.16 (s, 3H), 5.56-5.58 (m, 1H), 6.73 (d. Reference Example 43 J=8.0Hz, 1H), 7.59 (dd, J=4.8, 1.6 Hz, 2H), 8.30 (d. J=8.0 Hz, 3-(Pyridin-4-ylhydrazono)pentane-2,4-dione 1H), 8.74 (dd, J=4.8, 1.6 Hz, 2H). 1619 Reference Example 45 3-(2-Chlorophenyl)hydrazonopentane-2,4-dione 1625

1620 4-Aminopyridine (470 mg, 5.00 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%) at -6° C. When the mixture reached to room 1626 To a solution of 2-chloroaniline (1000 mg, 7.87 temperature it was cooled to -6° C. and solid sodium nitrite mmol) in 10 mL of acetic acid and 2 mL of concentrated (350 mg, 5.00 mmol) was added during 10 min. Small pieces hydrochloride solution, sodium nitrite (652 mg, 9.45 mmol) of ice (50 g) were added into the solution. The mixture was in 4 mL of water was added dropwise at 0°C., and the mixture added at 0° C. to a Suspension of corresponding 2.4-pen was stirred at 0°C. for 1 h. Then to the reaction mixture was tanedione (500 mg, 5.00 mmol) and potassium acetate (20g) added dropwise a solution of sodium acetate (1940 mg, 23.62 in ethanol (250 mL). The solution was stirred for 15 min, mmol) and acetylacetone (1024 mg, 10.24 mmol) in 10 mL of added to 250 mL of saturated NaCO, aqueous solution, ethanol and 6 mL of water. The mixture was stirred at room extracted with dichloromethane, washed with water and temperature overnight, filtered, washed with water, EtOH/ brine, dried over NaSO, and concentrated under reduced H2O (1:1) and hexane, and dried to give 3-(2-chlorophenyl) pressure to give 3-(pyridin-4-ylhydrazono)pentane-2,4-di hydrazonopentane-2,4-dione (860 mg, 46%). one (149 mg, yield 14%). 1627 H NMR (400 MHz, CDC1): 8 ppm 2.52 (s, 3H), 1621 'H NMR (400 MHz, CDC1): 8 ppm 2.52 (s, 3H), 2.64 (s.3H), 7.11-7.15 (m. 1H), 7.34-7.37 (m. 1H), 7.42 (dd. 2.62 (s.3H), 7.27-7.29 (m, 2H), 8.59-8.61 (m, 2H), 14.23 (s, J=8.0, 1.2 Hz, 1H), 7.81 (dd, J=8.0, 1.2 Hz, 1H), 14.88 (s, 1H). 1H). Reference Example 44 Reference Example 46 3-3-(Dimethylamino)prop-2-enoyl-1-pyridin-4- 1-(2-Chlorophenyl)-3-3-(dimethylamino)prop-2- ylpyridazin-4(1H)-one enoylpyridaZin-4(1H)-one 1622 1628

C

1623 3-(Pyridin-4-ylhydrazono)pentane-2,4-dione (120 1629 3-(2-Chlorophenyl)hydrazonopentane-2,4-dione mg, 0.58 mmol) was dissolved in 10 mL of N,N-dimethylfor (500 mg, 2.10 mmol) was dissolved in 10 mL of N,N-dim mamide dimethyl acetal (DMF-DMA), and the mixture was ethylformamide dimethyl acetal (DMF-DMA), and the mix refluxed for 4 h, then concentrated under reduced pressure to ture was refluxed for 4 h, then concentrated under reduced US 2012/0277430 A1 Nov. 1, 2012 52 pressure to give crude 1-(2-chlorophenyl)-3-3-(dimethy dimethylformamide dimethylacetal (70 mL) was stirred at lamino)prop-2-enoylpyridaZin-4(1H)-one which was used 125° C. for 2.5 h. After this time, the reaction was directly to the next step without further purification. concentrated and then dissolved in methanol (80.0 mL). After 1630 "H NMR of the crude product (400 MHz, CDC1): 8 concentration, the crude product was purified by flash chro ppm 2.90 (s, 3H), 3.12 (s, 3H), 5.56-5.59 (m, 1H), 6.67 (d. matography (silica gel, methylene chloride to 95.5 methylene J=8.0 Hz, 1H), 7.42-7.45 (m, 2H), 7.52-7.57 (m, 2H), 7.91 (d. chloride/methanol) to afford 3-3-(dimethylamino)prop-2- J=8.0 Hz, 1H). enoyl-1-3-(methylsulfanyl)phenylpyridazin-4(1H)-one (16.3 g, 87%) as a yellow-brown solid. Reference Example 47 1636 HNMR (500MHz, DMSO-d) & 2.54 (s.3H), 2.83 3-3-(Methylsulfanyl)phenylhydrazonopentane-2, (s, 3H), 3.09 (s.3H), 5.23 (brs, 1H), 6.53 (d. J=8.0 Hz, 1H), 4-dione 7.29-7.32 (m, 1H), 743-7.53 (m, 4H),8.81 (d. J=8.0 Hz, 1H): APCI MS m/z. 316 M+H". 1631 Reference Example 49 1-3-(Methylsulfanyl)phenyl)-3-(1-phenyl-1H-pyra O O zol-5-yl)pyridazin-4(1H)-one and 1-3-(methylsulfa nyl)phenyl-3-(1-phenyl-1H-pyrazol-3-yl)pyridazin Me Me 4(1H)-one HN1 N 1637

MeS

1632 A solution of 3-(methylsulfanyl)aniline (13.9 g, 100 mmol) in hydrochloric acid (6 N, 100 mL) was cooled with an ice brine bath and treated with a solution of sodium nitrite (8.38 g. 121 mmol) in water (25 mL) dropwise to keep the temperature between -5° C. and 5° C. The in situ formed MeS diazonium solution was quickly added to a mixture of 2,4- pentanedione (10.2g, 102 mmol) and Sodium acetate (150 g, 183 mmol) in ethanol (170 mL) and water (60 mL) cooled to below 0°C. After stirring at 0°C. for 30 min, the suspension was filtered, washed with water (40 mL) and evaporated with toluene tO afford 3-3-(methylsulfanyl)phenyl hydrazono pentane-2,4-dione (23.10g.92%) as a yellow-red solid. 1633 H NMR (500 MHz, DMSO-d) 8 ppm 2.43 (s, 6H), 2.47 (s, 3H), 7.04-7.06 (m. 1H), 7.31-7.36 (m, 2H), 7.46 (s, 1H), 13.80 (brs, 1H): APCI MS m/z 251 M+H". MeS Reference Example 48 1638 A mixture of 3-3-(dimethylamino)prop-2-enoyl 3-3-(Dimethylamino)prop-2-enoyl-1-3-(methyl 1-3-(methylsulfanyl)phenylpyridazin-4(1H)-one (3.69 g, sulfanyl)phenylpyridazin-4(1H)-one 11.7 mmol) in methanol (80 mL) was treated with phenylhy 1634 drazine (2.66 g. 24.6 mmol) and the resulting mixture was stirred at reflux for 8 h. After this time, the reaction was directly concentrated to remove methanol and then dissolved in methylene chloride (100 mL). The solution was washed with 2N hydrochloride (60 mL), water (60 mL), and brine (60 mL). After concentration, the crude product was purified by flash chromatography (silica gel, methylene chloride to 95:5 methylene chloride/methanol) afforded 1-3-(methylsulfa nyl)phenyl-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)- one and 1-3-(methylsulfanyl)phenyl-3-(1-phenyl-1H-pyra Zol-3-yl)pyridazin-4(1H)-one (2.72 g. 65%) in a regiomeric ratio of about 1:1 as a white solid. 1639 H NMR for 2 isomers (500 MHz, DMSO-d) & MeS ppm 6.63 (d. J=8.0 Hz, 1H), 6.66 (d. J=7.9 HZ, 1H), 6.82-6.85 (m. 1H), 7.05 (s, 1H), 7.19-7.22 (m, 2H), 7.29 (t, J=8.0 Hz, 1635. A mixture of 3-3-(methylsulfanyl)phenyl 1H), 7.34-7.39 (m, 5H), 7.42 (d. J=7.1 Hz, 1H), 7.45-749 (m, hydrazono pentane-2,4-dione (14.9 g, 59.6 mmol) in N.N- 2H), 7.50-7.56 (m, 3H), 7.59 (d. J=9.3 Hz, 1H), 7.68 (s, 1H), US 2012/0277430 A1 Nov. 1, 2012

7.82 (d. J=1.7 Hz, 1H), 7.92 (d. J=7.8 Hz, 2H), 8.59 (d. J=2.4 ride/methanol) to afford 3-3-(dimethylamino)prop-2- HZ, 1H),8.84 (d. J=8.0 Hz, 1H), 8.89 (d. J=7.9 Hz, 1H): APCI enoyl-1-(3-hydroxyphenyl)pyridazin-4(1H)-one (1.72 g, MS m/z. 361 M+H". 66%) as a brown-red solid. 1645 HNMR (500MHz, DMSO-d) oppm 2.83 (s.3H), Reference Example 50 3.09 (s, 3H), 5.21-5.23 (m. 1H), 6.50 (d. J=8.0 Hz, 1H), 6.79-6.82 (m, 1H), 7.08-7.11 (m, 2H), 7.33 (t, J=8.1 Hz, 1H), 3-(3-Hydroxyphenyl)hydrazonopentane-2,4-dione 8.74 (d. J=8.0 Hz, 1H), 9.93 (s, 1H); ESI MS m/z 286 1640 M+H". Reference Example 52 1-(3-Hydroxyphenyl)-3-(1-phenyl-1H-pyrazol-5-yl) pyridazin-4(1H)-one 1646

HO

1641. A solution of 3-aminophenol (5.16 g, 47.3 mmol) in tetrafluoroboric acid (30 mL, 50% in water) was cooled with ice brine bath and treated with sodium nitrite (3.92 g, 56.8 mmol) in water (18 mL) dropwise to keep the bath tempera HO ture between -5°C. and 5° C. The in situ formed diazonium Solution was quickly added to a mixture of 2.4-pentanedione 1647. A mixture of 3-3-(dimethylamino)prop-2-enoyl (4.73 g, 47.3 mmol) and sodium acetate (100g, 73.5 mmol) in 1-(3-hydroxyphenyl)pyridazin-4(1H)-one (0.481 g, 1.69 ethanol (80 mL) and water (30 mL) below 0°C. After stirring mmol) in methanol (10 mL) was treated with phenylhydra at 0°C. for 30 min, the suspension was filtered, washed with Zine (0.462 g, 4.28 mmol) and the resulting mixture was water (70 mL) and evaporated with toluene to afford 3-(3- stirred at reflux for 14 h. After this time, the reaction was hydroxyphenyl)hydrazonopentane-2,4-dione (5.85g. 56%) directly concentrated to remove methanol and then dissolved as a brick-red solid. in methylene chloride (60 mL). The solution was washed with 1642 HNMR (500 MHz, DMSO-d) 8 ppm 2.42 (s, 6H), water (60 mL), and brine (20 mL). After concentrated with 3.44 (brs, 1H), 6.58-6.60 (m. 1H), 6.90-6.93 (m. 1H), 6.99 (d. silica gel, chromatography (silica, methylene chloride to 1:19 J=2.1 Hz, 1H), 7.15-7.18 (m, 1H); ESIMS m/z 221 M+H". methanol/methylene chloride) afforded 1-(3-hydroxyphe nyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one Reference Example 51 (0.360 g. 65%) as a brown-yellow solid. 3-3-(Dimethylamino)prop-2-enoyl-1-(3-hydrox 1648 H NMR (500 MHz, DMSO-d) 8 ppm 6.63 (d. yphenyl)pyridazin-4(1H)-one J=7.8 Hz, 1H), 6.85 (d. J=9.0 Hz, 1H), 7.21-7.23 (m, 2H), 7.35-7.39 (m,3H), 7.52-7.56 (m, 2H), 7.92 (d. J=7.9 Hz, 2H), 1643 8.59 (d. J=2.3 Hz, 1H), 8.81 (d. J=7.8 Hz, 1H), 10.0 (s, 1H): ESIMS m/z 331 M+H".

Reference Example 53 3-(1-Phenyl-1H-pyrazol-5-yl)-1-(3-sulfanylphenyl) pyridazin-4(1H)-one and 3-(1-phenyl-1H-pyrazol-3- yl)-1-(3-sulfanylphenyl)pyridazin-4(1H)-one 1649

HO

1644. A mixture of 3-(3-hydroxyphenyl)hydrazonopen tane-2,4-dione (2.02 g, 9.18 mmol) in N,N-dimethylforma mide dimethylacetal (20 mL) was stirred at 100° C. for 1 h. After this time, the reaction was directly concentrated and then dissolved in methanol (60 mL). After evaporation with silica gel, the crude product was purified by flash chromatog HS raphy (silica gel, methylene chloride to 92:8 methylene chlo US 2012/0277430 A1 Nov. 1, 2012 54

-continued -continued

N

N1

HS N l S C

1652. A solution of the crude mixture of 3-(1-phenyl-1H pyrazol-5-yl)-1-(3-sulfanylphenyl)pyridazin-4(1H)-one and 3-(1-phenyl-1H-pyrazol-3-yl)-1-(3-sulfanylphenyl)py 1650. A solution of 1-3-(methylsulfanyl)phenyl-3-(1- ridazin-4(1H)-one (0.325 g, 0.94 mmol), 2-chlorobenzimida phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one and 1-3-(me Zole (0.195 g, 1.27 mmol), and potassium carbonate (0.234g, thylsulfanyl)phenyl-3-(1-phenyl-1H-pyrazol-3-yl)py 1.70 mmol) in N-methylpyrrolidone (8.0 mL) was heated at ridazin-4(1H)-one (0.300 g, 0.83 mmol) and sodium 170° C. in a sealed tube for 24 hours. After that time, the t-butylthiolate (0.295 g, 2.63 mmol) in DMF (6 mL) was reaction was cooled to room temperature and diluted with heated at 170° C. in a sealed tube for 2.5 days. After that time, water (50 mL). Aqueous HCl (2 N, 0.800 mL, 1.60 mmol) was the reaction was cooled to room temperature and diluted with added and the reaction extracted with ethyl acetate (3x60 water (60 mL). Aqueous HCl (1 N. 2 mL, 2 mmol) was added mL). The combined organic phases were washed with aque and the reaction extracted with ethyl acetate (2x80 mL). The ous 5% LiC1 solution (100 mL) and saturated NaCl aqueous combined organic phases were washed with aqueous 5% LiCl solution (100 mL). The organics were dried (MgSO) and concentrated to a brown solid (0.312 g). The crude product solution (100 mL) and saturated NaCl aqueous solution (80 was used in the following reaction without further purifica mL). The organics were dried (MgSO4) and concentrated to tion or characterization. yield the mixture of the title compounds as a brown gum (0.325 g). LCMS analysis of the reaction product indicated Reference Example 55 that 2 isomers of the thiol product were produced in s1.5:1 ratio. The crude product was used in the following reaction Methyl 3-oxo-2-3-(trifluoromethyl)phenyl without further purification or characterization. hydrazonobutanoate 1653 Reference Example 54

1-3-(1H-Benzimidazol-2-ylsulfanyl)phenyl)-3-(1- O O phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one and 1-3-(1H-benzimidazol-2-ylsulfanyl)phenyl-3-(1- Me OMe phenyl-1H-pyrazol-3-yl)pyridazin-4(1H)-one HN1 1651

FC

1654. A slurry of 3-(trifluoromethyl)aniline (16.12g, 100 mmol) in 6 NHCl (100 mL) was cooled to 0°C. and treated dropwise with a solution of sodium nitrite (8.33 g, 121 mmol) in water (20 mL). The resulting pale yellow solution was poured into a slurry of methyl acetoacetate (11.62 g, 100 mmol) and sodium acetate (150 g) in ethanol (170 mL), pre-cooled to 0°C. The resulting orange slurry was stirred for 10 min. After that time, the product was collected by filtration and washed with water (500 mL). The crude material was dissolved in ethyl acetate (250 mL) and dried (MgSO). The product crystallized upon concentration of the ethylacetate to give 19.997 g (69%) of methyl 3-oxo-2-3-(trifluoromethyl) phenylhydrazonobutanoate as light yellow crystals. US 2012/0277430 A1 Nov. 1, 2012

1655 H NMR (300 MHz, CDC1) shows a mixture of ethyl)phenyl-1,4-dihydropyridazine-3-carbohydrazide isomers. Major isomer 8 ppm 2.62 (s, 3H), 3.90 (s, 3H), (0.607 g. 60%) as bright orange crystals. 737-7.45 (m, 1H), 7.46-7.54 (m, 1H), 7.58 (s, 1H), 7.67 (s, 1661 H NMR (300 MHz, CDC1) 8 ppm 4.34 (d. J–4.6 1H), 14.76 (brs, 1H); Minor isomer 8 ppm 2.52 (s.3H), 3.93 Hz, 2H), 6.93 (d. J=7.8 Hz, 1H), 7.66-7.79 (m, 2H), 7.86-8.00 (s, 3H), 7.37-7.45 (m. 1H), 7.46-7.54 (m, 2H), 7.56 (s, 1H), (m. 2H), 8.36 (d. J=7.8 Hz, 1H), 10.98 (brs, 1H): APCI MS 12.81 (brs, 1H): APCI MS m/z 289 CHFNO+H". m/Z 299 CHFNO+H". Reference Example 56 Reference Example 58 Methyl 4-oxo-1-3-(trifluoromethyl)phenyl-1,4- 4-oxo-1-3-(trifluoromethyl)phenyl-1,4-dihydropy dihydropyridazine-3-carboxylate ridazine-3-carboxamide 1656 1662

FC FC 1657. A solution of methyl 3-oxo-2-3-(trifluoromethyl) 1663 A solution of methyl 4-oxo-1-3-(trifluoromethyl) phenylhydrazonobutanoate (15.20 g, 52.7 mmol) in N.N- phenyl-1,4-dihydropyridazine-3-carboxylate (1.007 g., 3.38 dimethylformamide dimethylacetal (150 mL) was heated at mmol) in ammonia (7 N in MeOH, 12 mL, 84 mmol) was reflux for 2 h. After that time, the reaction was cooled to room heated under microwave heating conditions at 100° C. for 5 temperature and then on an ice water bath. The product was min. After that time the reaction was cooled to room tempera collected by filtration to give methyl 4-oxo-1-3-(trifluorom ture and concentrated to give a yellow solid. This was recrys ethyl)phenyl-1,4-dihydropyridazine-3-carboxylate (13.7 g. tallized from EtOAc to give 0.613 g (64%) of 4-oxo-1-3- 87%) as pale yellow crystals. (trifluoromethyl)phenyl-1,4-dihydropyridazine-3- 1658 H NMR (300 MHz, CDC1) 8 ppm 4.00 (s, 3H), carboxamide as colorless crystals. 6.80 (d. J=8.1 Hz, 1H), 7.61-7.76 (m, 2H), 7.76-7.91 (m, 2H), 1664 'H NMR (300 MHz, CDC1) 8 ppm 6.46 (brs, 1H), 8.28 (d. J=8.1 Hz, 1H): APCI MS m/z 299 CHFNO+ 6.94 (d. J=7.8 Hz, 1H), 7.59-7.80 (m, 2H), 7.84-8.01 (m, 2H), H. 8.38 (d. J=7.8 Hz, 1H), 9.68 (brs, 1H): APCI MS m/z 284 M+H". Reference Example 57 4-oxo-1-3-(trifluoromethyl)phenyl-1,4-dihydropy Reference Example 59 ridazine-3-carbohydrazide N-(Dimethylamino)methylidene-4-oxo-1-3-(trif luoromethyl)phenyl-1,4-dihydropyridazine-3-car 1659 boxamide

1665

NHNH2

FC 1660. A solution of methyl 4-oxo-1-3-(trifluoromethyl) FC phenyl-1,4-dihydropyridazine-3-carboxylate (1.019 g, 3.42 mmol) and hydrazine monohydrate (0.3 mL, 6.19 mmol) in 1666. A slurry of 4-oxo-1-3-(trifluoromethyl)phenyl-1, ethanol (10 mL) was heated under microwave conditions for 4-dihydropyridazine-3-carboxamide (0.54 g, 1.91 mmol) in 10 min at 120° C. After that time, the reaction was cooled to N,N-dimethylformamide dimethylacetal (10 mL) was heated room temperature and the product was collected by filtration under microwave heating conditions at 130° C. for 15 min. and washed with cold ethanol to give 4-oxo-1-3-(trifluorom After that time the reaction was cooled on an ice water bath US 2012/0277430 A1 Nov. 1, 2012 56 and the resulting crystals collected by filtration and washed 1671. A solution of 4-oxo-N-phenyl-1-3-(trifluorom with hexanes to give 0.491 g (76%) of N-(dimethylamino) ethyl)phenyl-1,4-dihydropyridazine-3-carboxamide (0.153 methylidene-4-oxo-1-3-(trifluoromethyl)phenyl-1,4-di g, 0.426 mmol), 1 H-benzod 1.2.3 triazole (0.201 g, 1.69 hydropyridazine-3-carboxamide as off white crystals. "H mmol) and thionyl chloride (0.06 mL, 0.82 mmol) in meth NMR (300 MHz, CDC1) 8 ppm 3.16 (s, 3H), 3.22 (s, 3H), ylene chloride (2 mL) was heated under microwave heating 6.72 (d. J=8.1 Hz, 1H), 757-7.71 (m, 2H), 7.74-7.85 (m. 1H), conditions at 80 watts of powerfor 10 min. After that time, the 7.89 (s, 1H), 8.25 (d. J=8.1 Hz, 1H), 8.70 (s, 1H). reaction was concentrated and the crude product purified by flash column chromatography (silica gel, hexanes to ethyl Reference Example 60 acetate) to give 0.114 g (58%) of 3-1 H-benzotriazol-1-yl 4-oxo-N-phenyl-1-3-(trifluoromethyl)phenyl-1,4- (phenylimino)methyl-1-3-(trifluoromethyl)phenylpy dihydropyridazine-3-carboxamide ridazin-4(1H)-one as a pale red solid that was used without 1667 further characterization. Reference Example 62 3-(4-Piperidin-1-ylphenyl)hydrazonopentane-2,4- dione 1672 O O

Me Me HN1 N FC 1668. A solution of aniline (0.360 mL, 3.95 mmol) in methylene chloride (10 mL) was cooled on an ice water bath then treated with a solution of trimethyl aluminum (2 M in toluene, 2.0 mL, 4.0 mmol). After the addition was complete, the reaction was allowed to warm to room temperature and N stirred for 30 min. At that point, methyl 4-oxo-1-3-(trifluo romethyl)phenyl-1,4-dihydropyridazine-3-carboxylate (0.595g, 2.00 mmol) was added and the reaction was heated O at reflux for 18 h. After that time, the reaction was cooled to room temperature and carefully quenched with HCl acqueous 1673 4-Piperidin-1-ylaniline (510 mg, 2.90 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 Solution (1 N, 5 mL). The organic layer was separated and the mL of nitric acid (65%) at -6°C. When the mixture reached aqueous layer was extracted with methylene chloride (3x10 to room temperature it was cooled to -6°C. and solid sodium mL). The combined organic extracts were washed with Satu nitrite (200 mg, 2.90 mmol) was added during 10 min. Small rated NaHCO aqueous solution (50 mL) and brine (50 mL), pieces of ice (50 g) were added into the solution. The mixture dried (MgSO), and concentrated. The residue was recrystal was added at 0°C. to a Suspension of corresponding 2,4- lized from ethyl acetate/hexanes to give 0.214 g (30%) of pentanedione (290 mg, 2.90 mmol) and potassium acetate (20 4-oxo-N-phenyl-1-3-(trifluoromethyl)phenyl-1,4-dihydro g) in ethanol (250 mL). The solution was stirred for 15 min, pyridazine-3-carboxamide as yellow crystals. added to 250 mL of saturated NaCO aqueous solution, 1669 H NMR (300 MHz. CDC1) 8 ppm 6.96 (d. J=7.7 extracted with dichloromethane, washed with water and brine, dried over NaSO, and concentrated under reduced HZ, 1H), 7.16 (t, J=7.4 Hz, 1H), 7.37 (t, J=7.9 Hz, 2H), pressure to give 3-(4-piperidin-1-ylphenyl)hydrazonopen 7.6.1-7.85 (m, 4H), 7.88-8.01 (m, 2H), 8.42 (d. J=7.8 Hz, 1H), tane-2,4-dione (570 mg, yield 68%). 12.19 (brs, 1H): APCI MS m/z 360M+H"; mp 181-182° C. 1674. LCMS: m/z-288 M+H. Reference Example 61 Reference Example 63 3-1H-Benzotriazol-1-yl(phenylimino)methyl-1-3- 3-3-(Dimethylamino)prop-2-enoyl-1-(4-piperidin (trifluoromethyl)phenylpyridazin-4(1H)-one 1-ylphenyl)pyridazin-4(1H)-one 1670 1675

US 2012/0277430 A1 Nov. 1, 2012 57

1676 3-(4-Piperidin-1-ylphenyl)hydrazonopentane-2, 1681 3-(4-Cyclohexylphenyl)hydrazonopentane-2,4- 4-dione (570 mg, 1.99 mmol) was dissolved in 10 mL of dione (406 mg, 1.42 mmol) was dissolved in 10 mL of N.N- N,N-dimethylformamide dimethyl acetal (DMF-DMA), and dimethylformamide dimethyl acetal (DMF-DMA), and the the mixture was refluxed for 4 h, then concentrated under mixture was refluxed for 4h, then concentrated under reduced reduced pressure to give crude 3-3-(dimethylamino)prop-2- pressure to give crude 1-(4-cyclohexylphenyl)-3-3-(dim enoyl-1-(4-piperidin-1-ylphenyl)pyridaZin-4(1H)-one ethylamino)prop-2-enoylpyridaZin-4(1H)-one which was which was used to the next step without further purification. used to the next step without further purification. 1682 H NMR of the crude product (400 MHz, CDC1): 8 Reference Example 64 ppm 1.25-1.28 (m. 2H), 1.39-1.44 (m, 4H), 1.86-1.88 (m. 3-(4-Cyclohexylphenyl)hydrazonolpentane-2,4- 4H), 2.52-2.54 (m. 1H), 2.90 (s.3H), 3.13 (s.3H), 5.62-5.64 dione (m. 1H), 6.71 (d. J=7.6 Hz, 1H), 7.32 (d. J=8.8 Hz, 2H), 7.49 1677 (d. J=8.8 Hz, 2H), 8.17 (d. J=8.0 Hz, 1H). Reference Example 66 O O 4-2-(1-Acetyl-2-oxopropylidene)hydrazinoben Zonitrile 1683 Me Me HN1

CN 1678. To a solution of 4-cyclohexylaniline (500 mg, 2.86 mmol) in 10 mL of acetic acid and 2 mL of concentrated 1684 4-Aminobenzonitrile (500 mg, 4.24 mmol) was hydrochloride solution, sodium nitrite (237 mg, 3.43 mmol) added to a solution of 3 mL of phosphoric acid (85%) and 2 in 4 mL of water was added dropwise at 0°C., and the mixture mL of nitric acid (65%) at -6° C. When the mixture reached was stirred at 0°C. for 1 h. Then to the reaction mixture was to room temperature it was cooled to -6°C. and solid sodium added dropwise a solution of sodium acetate (703 mg, 8.58 nitrite (292 mg, 4.24 mmol) was added during 10 min. Small mmol) and acetylacetone (372 mg, 3.72 mmol) in 10 mL of pieces of ice (50 g) were added into the solution. The mixture ethanol and 6 mL of water. The mixture was stirred at room was added at 0° C. to a Suspension of corresponding 2,4- temperature overnight, filtered, washed with water, EtOH/ pentanedione (424 mg. 4.24 mmol) and potassium acetate (20 HO(1:1) and hexane, and dried to give3-(4-cyclohexylphe g) in ethanol (250 mL). The solution was stirred for 15 min, nyl)hydrazonopentane-2,4-dione (420 mg, 51%). added to 250 mL of saturated NaCO aqueous solution, 1679 'H NMR (400 MHz, CDC1): 8 ppm 1.24-127 (m, extracted with dichloromethane, washed with water and 2H), 1.38-1.43 (m, 4H), 1.85-1.87 (im, 4H), 2.49-2.52 (m, brine, dried over NaSO, and concentrated under reduced 4H), 2.60 (s.3H), 7.25 (d. J=8.4 Hz, 2H), 7.35 (d. J=8.8 Hz, pressure to give 4-2-(1-acetyl-2-oxopropylidene)hydrazino benzonitrile (280 mg, 29%). 2H), 14.81 (s, 1H). 1685 H NMR (400 MHz, CDC1): 8 ppm 2.51 (s, 3H), Reference Example 65 2.63 (s.3H), 7.47 (dd, J=7.2, 1.6 Hz, 2H), 7.70 (dd, J=7.2, 1.6 1-(4-Cyclohexylphenyl)-3-3-(dimethylamino)prop Hz, 2H), 14.51 (s, 1H). 2-enoylpyridazin-4(1H)-one Reference Example 67 1680 4-3-3-(Dimethylamino)prop-2-enoyl-4-oxopy ridazin-1 (4H)-yl)benzonitrile 1686

CN US 2012/0277430 A1 Nov. 1, 2012 58

1687 4-2-(1-Acetyl-2-oxopropylidene)hydrazinoben 1693 3-4-(Methylsulfonyl)phenyl Zonitrile (266 mg, 1.16 mmol) was dissolved in 10 mL of hydrazonopentane-2,4-dione (500 mg, 1.77 mmol) was dis N,N-dimethylformamide dimethyl acetal (DMF-DMA), and solved in 10 mL of N,N-dimethylformamide dimethyl acetal the mixture was refluxed for 4 h, then concentrated under (DMF-DMA), and the mixture was refluxed for 4 h, then reduced pressure to give crude 4-3-3-(dimethylamino) concentrated under reduced pressure to give crude 3-3-(dim prop-2-enoyl-4-oxopyridazin-1 (4H)-yl)benzonitrile which ethylamino)prop-2-enoyl-1-4-(methylsulfonyl)phenylpy was used to the next step without further purification. ridazin-4(1H)-one which was used to the next step without 1688 H NMR of the crude product (400 MHz, CDC1): 8 further purification. ppm 2.96 (s.3H), 3.20 (s.3H), 6.13 (d. J=12.4 Hz, 1H), 7.35 Reference Example 70 (d. J=8.8 Hz, 2H), 7.62 (d. J=8.8 Hz, 2H), 7.83 (d. J=12.0 Hz, 3-4-(Morpholin-4-ylsulfonyl)phenyl 1H). hydrazonopentane-2,4-dione Reference Example 68 3-4-(Methylsulfonyl)phenylhydrazonopentane-2, 1694 4-dione 1689

SOMe 1695 4-(Morpholin-4-ylsulfonyl)aniline (300 mg, 1.24 mmol) was added to a solution of 3 mL of phosphoric acid 1690 4-(Methylsulfonyl)aniline (500 mg, 2.92 mmol) (85%) and 2 mL of nitric acid (65%) at -6° C. When the was added to a solution of 3 mL of phosphoric acid (85%) and mixture reached to room temperature it was cooled to -6°C. 2 mL of nitric acid (65%) at -6°C. When the mixture reached and solid sodium nitrite (85 mg, 1.24 mmol) was added dur to room temperature it was cooled to -6°C. and solid sodium ing 10 min. Small pieces of ice (50 g) were added into the nitrite (201 mg, 2.92 mmol) was added during 10 min. Small solution. The mixture was added at 0°C. to a suspension of pieces of ice (50 g) were added into the solution. The mixture corresponding 2.4-pentanedione (124 mg, 1.24 mmol) and was added at 0° C. to a suspension of corresponding 2,4- potassium acetate (20g) in ethanol (250 mL). The solution pentanedione (292 mg, 2.92 mmol) and potassium acetate (20 was stirred for 15 min, added to 250 mL of a saturated solu g) in ethanol (250 mL). The solution was stirred for 15 min, tion of NaCO, extracted with dichloromethane, washed added to 250 mL of saturated NaCO aqueous solution, with water and brine, dried over NaSO, and concentrated extracted with dichloromethane, washed with water and under reduced pressure to give 3-4-(morpholin-4-ylsulfo brine, dried over NaSO, and concentrated under reduced nyl)phenylhydrazono pentane-2,4-dione (375 mg, 86%). pressure tO give 3-4-(methylsulfonyl)phenyl 1696 H NMR (400 MHz, CDC1): 8 ppm 2.53 (s, 3H), hydrazono pentane-2,4-dione (780 mg.95%). 2.64 (s, 3H), 3.03 (t, J=4.8 Hz, 4H), 3.76 (t, J–4.8 Hz, 4H), 1691. HNMR (400 MHz, CDC1): 8 ppm 2.52 (s, 3H), 7.54 (dd, J=7.2, 2.0 Hz, 2H), 7.80 (d. J=8.8 Hz, 2H), 14.56 (s, 2.63 (s.3H), 3.08 (s.3H), 7.54 (dd, J=7.2, 2.0 Hz, 2H), 7.98 1H). (dd, J–7.2, 2.0 Hz, 2H), 14.78 (s, 1H). Reference Example 71 Reference Example 69 3-3-(Dimethylamino)prop-2-enoyl-1-4-(morpho 3-3-(Dimethylamino)prop-2-enoyl-1-4-(methyl lin-4-ylsulfonyl)phenylpyridazin-4(1H)-one sulfonyl)phenylpyridazin-4(1H)-one 1697

1692

SOMe US 2012/0277430 A1 Nov. 1, 2012 59

1698 3-4-(Morpholin-4-ylsulfonyl)phenyl 1703 4-2-(1-Acetyl-2-oxopropylidene)hydrazinoben hydrazonopentane-2,4-dione (300 mg, 0.85 mmol) was dis Zamide (540 mg, 2.19 mmol) was dissolved in 10 mL of solved in 10 mL of N,N-dimethylformamide dimethyl acetal N,N-dimethylformamide dimethyl acetal (DMF-DMA), and (DMF-DMA), and the mixture was refluxed for 4 h, then the mixture was refluxed for 4 h, then concentrated under concentrated under reduced pressure to give crude 3-3-(dim reduced pressure to give crude 4-3-3-(dimethylamino) ethylamino)prop-2-enoyl-1-4-(morpholin-4-ylsulfonyl) prop-2-enoyl-4-oxopyridazin-1 (4H)-yl)benzamide which phenylpyridazin-4(1H)-one which was used to the next step was used to the next step without further purification. without further purification. 1704 H NMR of the crude product (400 MHz, CDC1): 8 ppm 2.91 (s, 3H), 3.14 (s, 3H), 5.60-5.62 (m, 1H), 6.73 (d. Reference Example 72 J=8.0 Hz, 1H), 7.65 (d. J=8.8 Hz, 2H), 8.31 (d. J=8.0 Hz, 1H), 4-2-(1-Acetyl-2-oxopropylidene)hydrazinobenza 8.40 (d. J=9.2 Hz, 2H), 8.67 (s, 1H). mide Reference Example 74 1699 Methyl 3-oxo-2-3-(trifluoromethyl)phenyl hydrazono pentanoate O O 1705

Me Me O O

HN1 Et OMe HN1 N

CONH2 FC 1700 4-Aminobenzamide (1000 mg, 7.36 mmol) was 1706. A slurry of 3-(trifluoromethyl)aniline (8.03 g, 50 added to a solution of 6 mL of phosphoric acid (85%) and 4 mmol) in 6 NHCl (50 mL) was cooled to 0°C. and treated mL of nitric acid (65%) at -6° C. When the mixture reached dropwise with a solution of sodium nitrite (4.10 g. 60 mmol) in water (10 mL). The resulting pale yellow solution was to room temperature it was cooled to -6°C. and solid sodium poured into a suspension of methyl propionylacetate (6.50 g, nitrite (508 mg, 7.36 mmol) was added during 10 min. Small 50 mmol) and sodium acetate (24.00g, 292 mmol) in ethanol pieces of ice (100 g) were added into the solution. The mix (80 mL), pre-cooled to 0°C. The resulting yellow/orange ture was added at 0° C. to a suspension of corresponding slurry was stirred for 30 min. The product was collected by 2.4-pentanedione (736 mg, 7.36 mmol) and potassium filtration and washed with water (100 mL). The crude mate acetate (40 g) in ethanol (400 mL). The solution was stirred rial was dissolved in ethyl acetate (100 mL) and dried for 15 min, added to 250 mL of saturated NaCO aqueous (NaSO). The product crystallized upon concentration of the solution, extracted with dichloromethane, washed with water ethyl acetate to give (14.00 g, 93%) of methyl 3-oxo-2-3- and brine, dried over NaSO, and concentrated under RSSSri G.R. as a yellow/ reduced pressure to give 4-2-(1-acetyl-2-oxopropylidene) orange solid. hydrazinobenzamide (460 mg, 25%). 1707 H NMR (500 MHz, CDC1) shows a mixture of 1701 'H NMR (400 MHz, CDC1): 8 ppm 2.52 (s, 3H), isomers. Major isomer 8 ppm 1.18 (t, J–7.5 Hz, 3H), 2.96 (d. 2.62 (s.3H), 7.46 (d. J–8.4 Hz, 2H), 7.88 (d. J–8.4 Hz, 2H), J=7.5 Hz, 2H), 3.92 (s.3H), 7.39-7.42 (m. 1H), 7.48-7.55 (m, 14.62 (s, 1H). 2H), 7.56 (s, 1H), 12.75 (brs, 1H); Minor isomer 8 ppm 1.15 (t, J=7.5 Hz, 3H), 3.04 (q, J=7.5, 2H), 3.90 (s.3H), 7.39-7.42 Reference Example 73 (m. 1H), 7.48-7.55 (m, 2H), 7.67 (s, 1H), 14.76 (brs, 1H); ESI 4-3-3-(Dimethylamino)prop-2-enoyl-4-oxopy MS m/z. 303 M+H". ridazin-1 (4H)-yl)benzamide Reference Example 75 1702 Methyl 5-methyl-4-oxo-1-3-(trifluoromethyl)phe nyl-1,4-dihydropyridazine-3-carboxylate 1708

CONH FC US 2012/0277430 A1 Nov. 1, 2012 60

1709. A solution of methyl 3-oxo-2-3-(trifluoromethyl) Reference Example 77 phenylhydrazono pentanoate (4.00 g, 13.2 mmol) in N.N- 3-Acetyl-5-methyl-1-3-(trifluoromethyl)phenyl dimethylformamide dimethylacetal (33 mL) was heated at pyridazin-4(1H)-one reflux for 2.5 hours. After that time, the reaction was cooled to 1714) room temperature and the resulting Solid was collected by filtration and washed with a small amount of hexanes to give methyl 5-methyl-4-oxo-1-3-(trifluoromethyl)phenyl-1,4- dihydropyridazine-3-carboxylate (3.55g, 87%) as a pale yel low solid. 1710 "H NMR (500 MHz, CDC1) 8 ppm 2.19 (s.3H), 4.00 (s, 3H), 7.65-7.71 (m, 2H), 7.81-7.85 (m, 2H), 8.20 (s, 1H): APCI MS m/z. 313 M+H". Reference Example 76 N-Methoxy-N,5-dimethyl-4-oxo-1-3-(trifluorom FC ethyl)phenyl-1,4-dihydropyridazine-3-carboxamide 1715. To a solution of N-methoxy-N,5-dimethyl-4-oxo-1- 3-(trifluoromethyl)phenyl-1,4-dihydropyridazine-3-car 1711 boxamide (0.535 g, 1.6 mmol) in THF (10 mL) at -78°C. was added methylmagnesium bromide (1.1 mL, 3.2 mmol. 3M in diethyl ether). The reaction was stirred at that temperature for 1 h then quenched with Saturated ammonium chloride aque ous solution (5 mL) then water (2 mL) with slow warming to room temperature. The reaction mixture was diluted with ethyl acetate (20 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2x10 mL) and the combined organic extracts are washed with 1 NHCl aqueous solution (15 mL), brine (15 mL), dried (NaSO), filtered and concentrated to provide 3-acetyl-5-methyl-1-3- (trifluoromethyl)phenylpyridazin-4(1H)-one (0.463 g.98%) as a light yellow solid. 1716) "H NMR (500 MHz, CDC1,) 8 ppm 2.19 (s.3H), 2.69 (s.3H), 7.67-7.72 (m, 2H), 7.82-7.85 (m, 2H), 8.21 (s, 1H): APCI MS m/z 297 M+H". Reference Example 78 FC 3-3-(Dimethylamino)prop-2-enoyl-5-methyl-1-3- (trifluoromethyl)phenylpyridazin-4(1H)-one 1717

1712 To a stirred suspension of N.O-dimethylhydroxy lamine hydrochloride (0.468 g, 4.8 mmol) in dichlo romethane (5 mL) was added trimethylaluminum (2.4 mL. 4.8 mmol. 2 M solution in toluene) dropwise at 0°C. Follow ing addition, the suspension was stirred at 0°C. for 10 min then at room temperature for 30 minto provide a homogenous solution. The flask was then re-cooled in an ice bath. In a separate flask, methyl 5-methyl-4-oxo-1-3-(trifluorom ethyl)phenyl-1,4-dihydropyridazine-3-carboxylate (0.500 FC g, 1.6 mmol) was dissolved in dichloromethane (5 mL) and added dropwise and allowed to stir for 2 h. The reaction was 1718. A microwave vial containing 3-acetyl-5-methyl-1- quenched with water (5 mL) and 2 NHCl aqueous solution (2 3-(trifluoromethyl)phenylpyridazin-4(1H)-one (0.363 g, mL). The layers were separated and the aqueous layer was 1.2 mmol) and N,N-dimethylformamide dimethylacetal (2.5 extracted with dichloromethane (2x10 mL). The combined mL) was heated at 120° C. for 20 min. The crude material was organic extracts were washed with brine (20 mL), dried concentrated and purified by flash column chromatography (silica gel; methylene chloride to 1:9 methanol/methylene (NaSO), filtered and concentrated to provide N-methoxy chloride) to provide 3-3-(dimethylamino)prop-2-enoyl-5- N,5-dimethyl-4-oxo-1-3-(trifluoromethyl)phenyl-1,4-di methyl-1-3-(trifluoromethyl)phenylpyridazin-4(1H)-one hydropyridazine-3-carboxamide (0.535 g, 98%) as a yellow (0.365g, 87%) as an orange solid. solid. 1719 "H NMR (300 MHz, CDC1,) 8 ppm 2.18 (s, 3H), 1713 H NMR (500 MHz, CDC1) 8 ppm 2.18 (s, 3H), 2.92 (s.3H), 3.14 (s, 3H), 5.69-5.82 (m. 1H), 7.63-7.65 (m, 3.41 (s, 3H), 3.68 (s, 3H), 7.63-7.70 (m, 2H), 7.80-7.90 (m, 2H), 7.83-7.87 (n, 3H), 8.20 (s, 1H): APCI MS m/z. 352 2H), 8.21 (s, 1H): APCI MS m/z 342 M+H". M+H". US 2012/0277430 A1 Nov. 1, 2012 61

Reference Example 79 pale yellow crystals: mp 121-126° C.; H NMR (300 MHz, 3-3-(Dimethylamino)but-2-enoyl-1-3-(trifluorom CDC1): 8 ppm 151 (3H, s), 3.94 (3H, s), 4.68 (2H, s), 7.08 ethyl)phenylpyridazin-4(1H)-one 7.25 (3H, m), 7.63 (1H, dt, J=1.5, 7.9 Hz), 13.06 (1H, brs). Anal. Calcd for CHFNO: C, 53.73; H, 4.88: N, 10.44. 1720 Found: C, 53.69; H, 4.96: N, 10.47.

Reference Example 81 Methyl 1-(2-fluorophenyl)-5-methoxy-4-oxo-1,4- dihydropyridazine-3-carboxylate 1725

MeO

FC 1721. A slurry of 3-acetyl-1-3-(trifluoromethyl)phenyl pyridazin-4(1H)-one (0.369 g, 1.30 mmol) in N,N-dimethy lacetamide dimethylacetal (3.5 mL, 18.3 mmol) was heated under microwave conditions at 120° C. for 5 min. After this time, the reaction was cooled to room temperature and con centrated onto silica gel. The crude product was purified by column chromatography (silica gel, dichloromethane to 1726. A solution of methyl 2-(2-fluorophenyl)hydra 90:10 dichloromethane/methanol) to give 3-3-(dimethy Zono-4-methoxy-3-oxobutanoate (5.02 g, 18.7 mmol) in lamino)but-2-enoyl-1-3-(trifluoromethyl)phenylpy N,N-dimethylformamide dimethyl acetal (35 mL) was ridazin-4(1H)-one (0.314 g. 68%) as a yellow foam. refluxed for 1 h. After cooling to room temperature, the pre 1722) H NMR (500 MHz, CDC1) 8 ppm 2.71 (s, 3H), cipitate was collected by filtration and washed with hexane/ 3.07 (brs, 6H), 5.52 (s, 1H), 6.71 (d. J=8.0 Hz, 1H), 7.59-7.69 AcOEt (2/1) to give the title compound (4.70 g.90% yield) as (m. 2H), 7.76-7.85 (m, 1H), 7.87 (s, 1H), 8.21 (d. J=7.9 Hz, off-white crystals: mp 155-157° C.; H NMR (300 MHz, 1H): APCI MS m/z. 352 M+H". CDC1): 8 ppm 3.91 (3H, s), 3.97 (3H, s), 7.29-7.36 (2H, m), 7.44-7.51 (1H, m), 7.65 (1H, dt, J=1.9, 7.9 Hz), 7.77 (1H, d, Reference Example 80 J=2.3 Hz). Anal. Calcd for CHFNO: C, 56.12; H, 3.98: Methyl 2-(2-fluorophenyl)hydrazono-4-methoxy-3- N, 10.07. Found: C, 56.17; H, 3.97: N, 10.25. Oxobutanoate Reference Example 82 1723 1-(2-Fluorophenyl)-N,5-dimethoxy-N-methyl-4-oxo 1,4-dihydropyridazine-3-carboxamide O O 1727 MeO

OMe

N HN1 MeO F

1724. A solution of NaNO, (1.66g, 24 mmol) in HO (5 mL) was added dropwise at 0°C. to a mixture of 2-fluoroa niline (1.93 mL, 20 mmol) and 6 MHCl aqueous solution (20 mL, 120 mmol). After stirring for 15 min, the resulting aque 1728. To a solution of N.O-dimethylhydroxylamine ous Solution was added to a Suspension of methyl 4-methoxy hydrochloride (4.74 g, 48.6 mmol) and iPrNEt (8.47 mL, acetoacetate (2.59 mL, 20 mmol) and NaOAc (9.84g, 120 48.6 mmol) in CHCl (50 mL) was added AlMe (1.8 M mmol) in MeOH (40 mL) pre-cooled at 0°C. The reaction solution in toluene, 27 mL, 48.6 mmol) dropwise at 0°C. mixture was poured into water and extracted with AcOEt. The under Ar atmosphere. After stirring for 1 h, a solution of extract was washed with saturated NaHCO aqueous solution methyl 1-(2-fluorophenyl)-5-methoxy-4-oxo-1,4-dihydro and brine, dried over MgSO, and concentrated under pyridazine-3-carboxylate (4.51 g, 16.2 mmol) in CHCl (50 reduced pressure. The residue was recrystallized from hex mL) was added dropwise, and the mixture was stirred for 1 h ane/AcOEt to give the title compound (5.03 g, 94% yield) as at 0° C. The reaction mixture was poured into ice-water, US 2012/0277430 A1 Nov. 1, 2012 62 acidified with 1 M HCl aqueous solution, saturated with 1732 A solution of NaNO, (2.378 g., 34.5 mmol) in HO NaCl, and extracted with AcOEt five times. The combined (10 mL) was added dropwise at 0°C. to a solution of 2-(dif extracts were dried over MgSO4, and concentrated under luoromethoxy)aniline (3.59 mL, 28.7 mmol) in 6 M HCl reduced pressure. The residue was recrystallized from AcOEt aqueous solution (28.7 mL, 172 mmol). After stirring for 15 to give the title compound (3.23 g. 65% yield) as colorless min, the resulting aqueous solution was added to a Suspension of methyl 4-methoxyacetoacetate (3.72 mL, 28.7 mmol) and crystals: mp 152-154° C.; H NMR (300 MHz, CDC1): 8 NaOAc (14.14g, 172 mmol) in MeOH (50 mL) pre-cooled at ppm 3.39 (3H, s), 3.71 (3H, s), 3.91 (3H, s), 7.25-7.33 (2H, 0°C. The precipitate was collected by filtration, washed with m), 741-748 (1H, m), 7.65 (1H, dt, J=1.9, 7.9 Hz), 7.81 (1H, water, and dissolved in AcOEt. The organic solution was d, J-2.3 Hz). Anal. Calcd for CHFNO: C, 54.72: H, washed with water, saturated NaHCO aqueous solution and 4.59; N, 13.67. Found: C, 54.85; H, 4.54; N, 13.86. brine, dried over MgSO and concentrated under reduced pressure. The residue was washed with hexane/AcOEt (3/1) Reference Example 83 to give the title compound (8.70 g., 96% yield) as yellow 3-Acetyl-1-(2-fluorophenyl)-5-methoxypyridazin-4 crystals: "H NMR (300 MHz, CDC1): 8 ppm 3.51 (3H, s), (1H)-one 3.89 (3Hx0.5, s), 3.94 (3Hx0.5, s), 4.68 (1Hx0.5, s), 4.70 (1Hx0.5, s), 6.63 (1Hx0.5, t, J=72.7 Hz), 6.66 (1Hx0.5, t, 1729 J=72.3 Hz), 7.10-7.34 (4H, m), 7.67 (1Hx0.5, dd, J=8.3, 1.5 Hz), 7.90 (1Hx0.5, dd, J=8.3, 1.5 Hz), 13.14 (1Hx0.5, s),

14.96 (1Hx0.5, brs). Reference Example 85 MeO Methyl 1-2-(difluoromethoxy)phenyl-5-methoxy 4-oxo-1,4-dihydropyridazine-3-carboxylate 1733

F

MeO

1730 MeMgBr (1 M solution in THF, 30 mL, 30 mmol) was added dropwise at -78° C. to a solution of 1-(2-fluo rophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropy ridazine-3-carboxamide (3.20g, 10.4 mmol) in THF (30 mL). After stirring for 1 h, the reaction mixture was quenched with 1 MHClaqueous solution, saturated with NaCl, and extracted with AcOEt rive times. The combined extracts were dried over MgSO, and concentrated under reduced pressure. The 1734. A solution of methyl 2-[2-(difluoromethoxy)phe residue was recrystallized from AcOEt to give the title com nylhydrazono-4-methoxy-3-oxobutanoate (8.70 g. 27.5 pound (2.32 g, 85% yield) as pale yellow crystals: mp 154 mmol) in N,N-dimethylformamide dimethyl acetal (60 mL) was refluxed for 3 h and stirred at room temperature for 3 156° C.; H NMR (300 MHz, CDC1): 8 ppm 2.69 (3H, s), days. The precipitate was collected by filtration and washed 3.91 (3H, s), 727-7.38 (2H, m), 7.45-7.53 (1H, m), 7.65 (1H, with hexane/AcOEt (3/1) to give the title compound (7.92 g, dt, J=1.5, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for 88% yield) as yellow crystals: "H NMR (300 MHz, CDC1): CHFNO: C, 59.54; H, 4.23; N, 10.68. Found: C, 59.62: 8 ppm 3.89 (3H, s), 3.96 (3H, s), 6.55 (1H, d. J=72.7 Hz), H, 4.22: N, 10.79. 7.35-7.45 (2H, m), 7.49-7.56 (1H, m), 7.61 (1H, dd, J=7.9, Reference Example 84 1.5 Hz), 7.73 (1H, s). Reference Example 86 Methyl 2-[2-(difluoromethoxy)phenylhydrazono 1-2-(Difluoromethoxy)phenyl-N,5-dimethoxy-N- 4-methoxy-3-oxobutanoate methyl-4-OXO-1,4-dihydropyridazine-3-carboxamide 1731 1735

MeO MeO OMe US 2012/0277430 A1 Nov. 1, 2012

1736. To a solution of N.O-dimethylhydroxylamine 1740. A mixture of 3-acetyl-1-2-(difluoromethoxy)phe hydrochloride (5.27 g. 54.0 mmol) and iPrNEt (9.40 mL. nyl-5-methoxypyridazin-4(1H)-one (3.70 g, 11.93 mmol) 54.0 mmol) in CHCl (60 mL) was added AlMe (1.8 M and N,N-dimethylformamide dimethyl acetal (50 mL) was solution in toluene, 30.0 mL, 54.0 mmol) dropwise at 0°C. refluxed for 5 h and stirred overnight at room temperature. After stirring at 0°C. for 1 h, a solution of methyl 1-2- The precipitate was collected by filtration and washed with (difluoromethoxy)phenyl-5-methoxy-4-oxo-1,4-dihydro AcOEt to give the title compound (4.07 g., 93% yield) as pyridazine-3-carboxylate (5.87 g. 17.99 mmol) in CHC1. yellow crystals: "H NMR (300 MHz, CDC1): 8 ppm 2.90 (60 mL) was added dropwise, and the mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into ice-water (3H, s), 3.12 (3H, brs), 3.87 (3H, s), 5.87 (1H, brs), 6.31-6.82 and extracted with AcOEt. The extract was washed with (2H, m), 7.30-7.41 (2H, m), 743-7.50 (1H, m), 7.63 (1H, dd, brine, dried over MgSO, and concentrated under reduced J=7.8, 1.8 Hz), 7.74 (1H, s). pressure. The residue was washed with hexane/AcOEt (3/1) Reference Example 89 to give the title compound (4.79 g, 75% yield) as pale yellow Methyl 4-methoxy-3-oxo-2-3-(trifluoromethyl) crystals: "H NMR (300 MHz, CDC1): 8 ppm 3.38 (3H, s), phenylhydrazonobutanoate 3.68 (3H, s), 3.89 (3H, s), 6.52 (1H, t, J=72.6 Hz), 7.37 (2H, m), 7.46-7.53 (1H, m), 7.62(1H, dd, J=7.8, 1.5 Hz), 7.76 (1H, 1741 S). Reference Example 87 3-Acetyl-1-2-(difluoromethoxy)phenyl-5-methoxy O O pyridazin-4(1H)-one MeO 1737) OMe N

HN1 MeO

N1 N FC

1742. A solution of NaNO (4.14 g. 60 mmol) in HO (15 mL) was added dropwise at 0°C. to a mixture of 3-(trifluo romethyl)aniline (6.24 mL, 50 mmol) and 6 M HCl aqueous 1738 MeMgBr (1 M solution in THF, 40.4 ml, 40.4 mmol) was added dropwise at -78°C. to a solution of 1-2-(difluo solution (50 mL, 300 mmol). After stirring for 15 min, the romethoxy)phenyl-N,5-dimethoxy-N-methyl-4-oxo-1,4-di resulting aqueous solution was added to a Suspension of hydropyridazine-3-carboxamide (4.79 g, 13.48 mmol) in methyl 4-methoxyacetoacetate (7.31 mL, 50 mmol) and THF (500 mL). After stirring for 1 h, the reaction mixture was NaOAc (24.6g,300 mmol) in EtOH (80 mL) pre-cooled at 0° quenched with 1M HCl aqueous solution and warm to room C. The precipitate was collected by filtration, washed with temperature. The reaction mixture was concentrated under water, and dissolved in AcOEt. The organic solution was reduced pressure and extracted with AcOEt. The extract was washed with water and brine, dried over NaSO and con washed with brine, dried over MgSO4, and concentrated centrated under reduced pressure. The residue was crystal under reduced pressure. The residue was purified by silica gel lized from hexane/AcOEt to give the title compound (14.0 g, column chromatography eluting with hexane/AcOEt (1/1-0/ 1) and recrystallized from diisopropyl ether/AcOEt to give 88% yield) as pale yellow crystals: "H NMR (300 MHz, the title compound (3.33 g, 80% yield) as colorless crystals: CDC1): 8 ppm 3.51 (3Hx0.36, s), 3.52 (3Hx0.64, s), 3.90 'HNMR (300 MHz, CDC1): 8 ppm 2.68 (3H, s), 3.89 (3H, s), (3Hx0.36, s), 3.94 (3Hx0.64, s), 4.68 (2Hx0.64, s), 4.70 6.55 (1H, t, J=72.7 Hz), 7.36-7.45 (2H, m), 7.50-7.57 (1H, (2Hx0.36, s), 741-7.59 (3H+1Hx0.64 m), 7.71 (1Hx0.36, m), 7.61 (1H, dd, J=7.8, 1.7 Hz), 7.72 (1H, s). s), 13.00 (1Hx0.64, s), 14.87 (1Hx0.36, s). Reference Example 88 Reference Example 90 1-2-(Difluoromethoxy)phenyl-3-3-(dimethy Methyl 5-methoxy-4-oxo-1-3-(trifluoromethyl)phe lamino)prop-2-enoyl-5-methoxypyridazin-4(1H)- nyl-1,4-dihydropyridazine-3-carboxylate O 1743 1739

MeO MeO

FC US 2012/0277430 A1 Nov. 1, 2012 64

1744. A solution of methyl 4-methoxy-3-oxo-2-3-(trif 1748 MeMgBr (3 M solution in diethyl ether, 4 mL, 12 luoromethyl)phenylhydrazonobutanoate (14.0g, 44 mmol) mmol) was added dropwise at -78°C. to a solution of N.5- in N,N-dimethylformamide dimethyl acetal (100 mL) was dimethoxy-N-methyl-4-oxo-1-3-(trifluoromethyl)phenyl refluxed for 4 h. After cooling to room temperature, the pre 1,4-dihydropyridazine-3-carboxamide (2.09 g, 5.85 mmol) cipitate was collected by filtration and washed with hexane/ in THF (50 mL). After stirring for 1 h, the reaction mixture AcOEt (3/1) to give the title compound (12.9 g, 89% yield) as was quenched with Saturated NHCl acqueous solution and off-white crystals: mp 169-170° C.; H NMR (300 MHz, extracted with AcOEt three times. The combined extracts CDC1): 8 ppm 3.98 (3H, s), 3.99 (3H, s), 7.66-7.74 (2H, m), were washed with brine, dried over MgSO, and concentrated 7.83-7.89 (2H, m), 7.95 (1H, s). Anal. Calcd for under reduced pressure. The residue was purified by silica gel CHFNO: C, 51.23; H, 3.38; N, 8.53. Found: C, 51.15; column chromatography eluting with AcOEt/MeOH (1/0-10/ H, 3.47 N, 8.60. 1) and recrystallized from hexane/AcOEt to give the title compound (1.44g, 79% yield) as off-white crystals: mp 155 Reference Example 91 156°C.; H NMR (300 MHz, CDC1): 8 ppm 2.71 (3H, s), N.5-Dimethoxy-N-methyl-4-oxo-1-3-(trifluorom 3.98 (3H, s), 7.68-7.76 (2H, m), 7.83-7.88 (2H, m), 7.94 (1H, ethyl)phenyl-1,4-dihydropyridazine-3-carboxamide s). Anal. Calcd for CHFNO: C, 53.85; H, 3.55: N, 8.97. 1745 Found: C, 53.79; H, 3.59: N, 9.02. Reference Example 93 3-3-(Dimethylamino)prop-2-enoyl-5-methoxy-1- 3-(trifluoromethyl)phenylpyridazin-4(1H)-one MeO 1749

MeO

FC 1746 To a solution of N.O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr-NEt (4.70 mL. 27 mmol) in CHCl (30 mL) was added AlMe (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar FC atmosphere. After stirring for 1 h, a solution of methyl 5-methoxy-4-oxo-1-3-(trifluoromethyl)phenyl-1,4-dihy 1750. A solution of 3-acetyl-5-methoxy-1-3-(trifluorom dropyridazine-3-carboxylate (2.95 g, 9 mmol) in CHCl (30 ethyl)phenylpyridazin-4(1H)-one (1.39 g, 4.45 mmol) in mL) was added dropwise, and the mixture was stirred for 1 h N,N-dimethylformamide dimethyl acetal (15 mL) was at 0°C. The reaction mixture was poured into ice-water and refluxed for 3 h. After cooling to room temperature, the reac extracted with AcOEt. The extract was washed with brine, tion mixture was concentrated under reduced pressure, and dried over MgSO4, and concentrated under reduced pressure. the residue was dissolved in AcOEt. The organic solution was The residue was purified by basic silica gel column chroma washed with half-saturated brine, and the aqueous Solution tography eluting with AcOEt and recrystallized from hexane/ was extracted with AcOEt four times. The combined organic AcOEt to give the title compound (2.15 g. 67% yield) as layers were dried over MgSO, and concentrated under off-white crystals: mp 170-171° C.; H NMR (300 MHz, reduced pressure. The residue was recrystallized from AcOEt CDC1): 8 ppm 3.41 (3H, s), 3.71 (3H, s), 3.98 (3H, s), to give the title compound (1.46 g. 89% yield) as orange 7.63-7.71 (2H, m), 7.80-7.86 (1H, m), 7.88 (1H, s), 7.98 (1H, crystals: mp 176-178° C.; H NMR (300 MHz. CDC1): 8 s). Anal. Calcd for CHFNO: C, 50.42; H, 3.95; N. ppm 2.91 (3H, s), 3.14 (3H, s), 3.96 (3H, s), 5.80 (1H, d, 11.76. Found: C, 50.48; H, 4.07; N, 11.66. J=13.2 Hz), 7.61-7.68 (2H, m), 7.80 (1H, brs), 7.84-7.90 (2H, Reference Example 92 m), 7.96 (1H, s). Anal. Calcd for CHFNO: C, 55.59; H, 3-Acetyl-5-methoxy-1-3-(trifluoromethyl)phenyl 4.39; N, 11.44. Found: C, 55.32; H, 4.51; N, 11.30. pyridazin-4(1H)-one Reference Example 94 Methyl 2-(2-fluoro-4-iodophenyl)hydrazono-4- 1747 methoxy-3-oxobutanoate 1751) O O

MeO MeO OMe US 2012/0277430 A1 Nov. 1, 2012

1752. A solution of NaNO, (1.66g, 24 mmol) in HO (5 1756. To a solution of N.O-dimethylhydroxylamine mL) was added dropwise at 0°C. to a mixture of 2-fluoro-4- hydrochloride (8.78 g, 90 mmol) and iPr-NEt (15.7 mL. 90 iodoaniline (4.74g. 20 mmol) and 6 M HCl aqueous solution mmol) in CHCl (100 mL) was added AlMe (1.8M solution (20 mL, 120 mmol). After stirring for 15 min, the resulting in toluene, 50 mL. 90 mmol) slowly at 0°C. under Ar atmo aqueous solution was added to a suspension of methyl sphere. After stirring for 1 h, a solution of methyl 1-(2-fluoro 4-methoxyacetoacetate (2.59 mL. 20 mmol) and NaOAc 4-iodophenyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3- (9.84g, 120 mmol) in MeOH (40 mL) pre-cooled at 0°C. The carboxylate (12.1 g, 30 mmol) in CHCl (100 mL) was reaction mixture was poured into water and extracted with added slowly, and the mixture was stirred for 1 h at 0°C. The AcOEt. The extract was washed with saturated NaHCO reaction mixture was poured into ice-water and the organic aqueous solution and brine, dried over MgSO, and concen layer was separated. The aqueous layer was extracted with trated under reduced pressure. The residue was recrystallized AcOEt. The combined organic layers were washed with from hexane/AcOEt to give the title compound (6.29 g, 80% brine, dried over MgSO, and concentrated under reduced yield) as yellow crystals: mp 141-146°C.; H NMR (300 pressure. The residue was purified by basic silica gel column MHz, CDC1): 8 ppm 3.50 (3H, s), 3.93 (3H, s), 4.64 (2H, s), chromatography eluting with AcOEt to give the title com 7.35 (1H, t, J=8.5 Hz), 7.49-7.55 (2H, m), 12.97 (1H, brs). pound (9.96g, 77% yield) as a white amorphous solid: 'H Anal. Calcd for CHFINO: C, 36.57: H, 3.07: N, 7.11. NMR (300 MHz, CDC1): 8 ppm 3.39 (3H, s), 3.70 (3H, s), Found: C, 36.74; H, 3.10: N, 7.32. 3.90 (3H, s), 7.39 (1H, t, J=8.1 Hz), 7.63-7.67 (2H, m), 7.77 Reference Example 95 (1H, d, J=2.3 Hz). Methyl 1-(2-fluoro-4-iodophenyl)-5-methoxy-4-oxo Reference Example 97 1,4-dihydropyridazine-3-carboxylate 3-Acetyl-1-(2-fluoro-4-iodophenyl)-5-methoxypy 1753 ridazin-4(1H)-one 1757

MeO MeO

I 1754. A solution of methyl 2-(2-fluoro-4-iodophenyl)hy I drazono-4-methoxy-3-oxobutanoate (6.27g, 15.9 mmol) in 1758 MeMgBr (1 M solution in THF, 70 mL, 70 mmol) N,N-dimethylformamide dimethyl acetal (60 mL) was was added dropwise at -78°C. to a solution of 1-(2-fluoro refluxed for 3 h. After cooling to room temperature, the reac 4-iodophenyl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihy tion mixture was poured into water and extracted with AcOEt. dropyridazine-3-carboxamide (9.96g, 23 mmol) in THF (250 The extract was washed with water and brine, dried over mL). After stirring for 1 h, the reaction mixture was quenched MgSO4, and concentrated under reduced pressure. The resi with 1 M HCl aqueous solution and extracted with AcOEt. due was purified by silica gel column chromatography eluting The extract was washed with brine, dried over MgSO, and with AcOEt and recrystallized from MeOH to give the title concentrated under reduced pressure. The residue was puri compound (3.77g, 59% yield) as off-white crystals: mp 160 fied by silica gel column chromatography eluting with AcOEt 162° C.; H NMR (300 MHz, CDC1): 8 ppm 3.90 (3H, s), and recrystallized from MeOH to give the title compound 3.97 (3H, s), 7.36-7.41 (1H, m), 7.64-7.70 (2H, m), 7.73 (1H, (2.05g, 23% yield) as pale yellow crystals: mp 196-198°C.; d, J-2.6 Hz). Anal. Calcd for CHFINO: C, 38.64; H, H NMR (300MHz, CDC1): 8 ppm 2.67 (3H,s), 3.90 (3H, s), 2.49; N, 6.93. Found: C, 38.68; H, 2.59: N, 6.98. 7.36-7.41 (1H, m), 7.66-7.71 (2H, m), 7.73 (1H, d, J=2.6 Hz). Reference Example 96 Anal. Calcd for CHFINO: C, 40.23; H, 2.60: N, 7.22. 1-(2-Fluoro-4-iodophenyl)-N,5-dimethoxy-N-me Found: 40.25; H, 2.87; N, 7.28. thyl-4-oxo-1,4-dihydropyridazine-3-carboxamide Reference Example 98 Methyl 5-(methoxymethyl)-4-oxo-1-3-(trifluorom 1755 ethyl)phenyl-1,4-dihydropyridazine-3-carboxylate 1759)

MeO

MeO

FC US 2012/0277430 A1 Nov. 1, 2012 66

1760. A solution of NaNO, (2.48 g., 36 mmol) in HO (10 Reference Example 100 mL) was added dropwise at 0°C. to a mixture of 3-(trifluo 3-Acetyl-5-(methoxymethyl)-1-3-(trifluoromethyl) romethyl)aniline (3.75 mL, 30 mmol) and 6 M HCl aqueous phenylpyridaZin-4(1H)-one solution (30 mL, 180 mmol). After stirring for 15 min, the 1764 resulting aqueous Solution was added to a Suspension of methyl 5-methoxy-3-oxovalerate (4.37 mL, 30 mmol) and NaOAc (14.8g, 180 mmol) in EtOH (50 mL) pre-cooled at 0° C. After stirring for 5 min, the reaction mixture was poured into water and extracted with AcOEt. The extract was washed MeO with saturated NaHCO, aqueous solution and brine, dried over MgSO4, and concentrated under reduced pressure. 1761. A solution of the residue in N,N-dimethylforma mide dimethyl acetal (50 mL) was refluxed for 4 h. After cooling to room temperature, the precipitate was collected by filtration and recrystallized from AcOEt to give the title com pound (7.13 g. 69% yield) as a yellow solid: mp 138-140°C.; FC 'HNMR (300 MHz, CDC1): 8 ppm3.53 (3H, s), 4.00(3H, s), 449 (2H, d, J=1.5 Hz), 7.65-7.73 (2H, m), 7.82-7.85 (1H, m), 1765 MeMgBr (1 M solution in THF, 16 mL, 16 mmol) 7.89 (1H, s), 8.38 (1H, t, J=1.5 Hz). Anal. Calcd for was added dropwise at -78°C. to a solution of N-methoxy CHFNO: C, 52.64; H, 3.83; N, 8.18. Found: C, 52.50; 5-(methoxymethyl)-N-methyl-4-oxo-1-3-(trifluoromethyl) H, 3.89; N, 8.17. phenyl-1,4-dihydropyridazine-3-carboxamide (1.95 g, 5.25 mmol) in THF (50 mL). After stirring for 1 h, the reaction Reference Example 99 mixture was quenched with saturated NHCl adueous solu tion and extracted with AcOEt. The extract was washed with N-Methoxy-5-(methoxymethyl)-N-methyl-4-oxo-1- brine, dried over MgSO and concentrated under reduced 3-(trifluoromethyl)phenyl-1,4-dihydropyridazine pressure. The residue was purified by silica gel column chro 3-carboxamide matography eluting with AcOEt and recrystallized from hex ane/AcOEt to give the title compound (1.42g, 83% yield) as 1762 a pale yellow solid: mp 141-143° C.; H NMR (300 MHz, CDC1): 8 ppm 2.68 (3H, s), 3.54 (3H, s), 4.50 (2H, d, J=1.5 Hz), 7.66-7.74 (2H, m), 7.81-7.87 (1H, m), 7.89 (1H, s), 8.38 (1H, t, J=1.5 Hz). Anal. Calcd for CHFNO: C, 55.22; H, 4.02: N, 8.59. Found: C, 55.26; H, 3.95; N, 8.58. MeO Reference Example 101 3-Acetyl-1-3-(trifluoromethyl)phenylpyridazin-4 (1H)-one 1766

FC

1763 To a solution of N.O-dimethylhydroxylamine hydrochloride (2.63 g, 27 mmol) and iPr-NEt (4.70 mL. 27 mmol) in CHCl (30 mL) was added AlMe (1.8 M solution in toluene, 15 mL, 27 mmol) dropwise at 0° C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 5-(methoxymethyl)-4-oxo-1-3-(trifluoromethyl)phenyl-1, F 4-dihydropyridazine-3-carboxylate (3.08 g. 9 mmol) in CHCl (30 mL) was added dropwise, and the mixture was F stirred for 1 h at 0°C. The reaction mixture was poured into F ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under 1767. A mixture of 3-3-(trifluoromethyl)phenyl reduced pressure. The residue was purified by silica gel col hydrazono pentane-2,4-dione (5.00 g, 18.4 mmol) and N,N- umn chromatography eluting with AcOEt and recrystallized dimethylformamide dimethyl acetal (2.44 mL, 18.4 mmol) in from hexane/AcOEt to give the title compound (1.99 g, 60% DMF (100 mL) was heated to 80° C. for 4h. The mixture was yield) as an off-white solid: mp 157-159° C.; H NMR (300 diluted with 1 M HCl aqueous solution, extracted with MHz, CDC1): 8 ppm 3.41 (3H, s), 3.53 (3H, s), 3.67 (3H, s), EtOAc, washed with brine, dried over NaSO filtered, con 4.50 (2H, d, J=1.1 Hz), 7.62-7.71 (2H, m), 7.79-7.85 (1H, m), centrated in vacuo, purified by column chromatography on 7.90 (1H, s), 8.39 (1H, t, J=1.1 Hz). Anal. Calcd for silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/ CHFNO: C, 51.75; H, 4.34; N, 11.32. Found: C, 51.77: MeOH=100/0 to 80/20) and triturated with EtOAc/hexane to H, 4.25: N, 11.24. yield the title compound (3.38 g. 65% yield) as a pale yellow US 2012/0277430 A1 Nov. 1, 2012 67 solid: "H NMR (DMSO-d 300 MHz): 8 ppm 2.55 (3H, s), with saturated NaHCO aqueous solution and brine, dried 6.75 (1H, d, J=8.0Hz), 7.78-7.88 (2H, m), 8.06-8.16 (2H, m), over MgSO, and concentrated under reduced pressure. 8.96 (1H, d, J=8.2 Hz). 1772. A solution of the residue and NaOMe (2.70 g, 50 mmol) in MeOH (50 mL) was stirred for 30 min at room Reference Example 102 temperature. The reaction mixture was poured into 1 M HCl 3-Acetyl-5-bromo-1-3-(trifluoromethyl)phenyl aqueous solution and extracted with AcOEt. The extract was pyridazin-4(1H)-one washed with brine, dried over MgSO4, and concentrated 1768 under reduced pressure. 1773. A suspension of the residue, Mel (3.11 mL, 50 mmol), and KCO (10.4g, 75 mmol) in DMF (50 mL) was stirred for 1 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO, and con centrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/ AcOEt (1/1) and recrystallized from hexane/AcOEt to give the title compound (1.83 g, 22% yield) as a pale yellow solid: mp 124-125° C.; H NMR (300 MHz, CDC1): 8 ppm 3.94 F (3H, s), 3.95 (3H, s), 6.32 (1H, s), 7.57-7.62 (1H, m), 7.65 7.68 (1H, m), 7.80-7.84 (1H, m), 7.88 (1H, s). Anal. Calcd for F CHFNO: C, 51.23; H, 3.38; N, 8.53. Found: C, 51.29: F H, 3.40; N, 8.52. 1769 To a solution of 3-acetyl-1-3-(trifluoromethyl)phe nylpyridazin-4(1H)-one (1.00 g, 3.54 mmol) in AcOH (3.5 Reference Example 104 mL) was added Br (0.181 mL, 3.54 mmol) at room tempera N,4-Dimethoxy-N-methyl-6-oxo-1-3-(trifluorom ture. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water and NaHCO, aqueous solu ethyl)phenyl-1,6-dihydropyridazine-3-carboxamide tion, extracted with EtOAc, dried over MgSO filtered, con centrated in vacuo and purified by column chromatography 1774 on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title compound (332 mg, 26% yield) as a pale yellow solid: "H NMR (DMSO-d 300 MHz): 8 ppm 2.57 (3H, s), 7.79-7.91 (2H, m), 8.09-8:17 (1H, m), 8.22 (1H, s), 9.58 (1H, s). Reference Example 103 Methyl 4-methoxy-6-oxo-1-3-(trifluoromethyl)phe nyl-1,6-dihydropyridazine-3-carboxylate 1770) FC

1775. To a solution of NO-dimethylhydroxylamine hydrochloride (1.58 g. 16.2 mmol) and iPr-NEt (2.82 mL, 16.2 mmol) in CHCl (13 mL) was added AlMe (1.8 M solution in toluene, 9.0 mL, 16.2 mmol) dropwise at 0°C. under Ar atmosphere. After stirring for 1 h, a solution of methyl 4-methoxy-6-oxo-1-3-(trifluoromethyl)phenyl-1,6- dihydropyridazine-3-carboxylate (1.77 g. 5.4 mmol) in CHCl (15 mL) was added dropwise, and the mixture was FC stirred for 1 h at 0°C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed 1771. A solution of NaNO, (2.07 g., 30 mmol) in HO (10 with brine, dried over MgSO4, and concentrated under mL) was added dropwise at 0°C. to a mixture of 3-(trifluo reduced pressure. The residue was purified by silica gel col romethyl)aniline (3.12 mL. 25 mmol) and 6 M HCl aqueous umn chromatography eluting with AcOEt and crystallized solution (25 mL, 150 mmol). After stirring for 15 min, the from hexane/AcOEt to give the title compound (1.48g, 83% resulting aqueous solution was added to a Suspension of dim yield) as a white solid: mp 127-129° C.; H NMR (300 MHz, ethyl 1,3-acetonedicarboxylate (3.61 mL. 25 mmol) and CDC1): 8 ppm 3.37 (3H, s), 3.64 (3H, s), 3.91 (3H, s), 6.30 NaOAc (12.3g, 150 mmol) in EtOH (40 mL) pre-cooled at 0° (1H, s), 7.55-7.60 (1H, m), 7.62-7.65 (1H, m), 7.82-7.86 (1H, C. After stirring for 10 min, the reaction mixture was poured m), 7.88 (1H, s). Anal. Calcd for CHFNO: C, 50.42; H, into water and extracted with AcOEt. The extract was washed 3.95; N, 11.76. Found: C, 50.47; H, 3.99; N, 11.83. US 2012/0277430 A1 Nov. 1, 2012 68

Reference Example 105 1780. A solution of the residue and phenylhydrazine (0.551 mL, 5.19 mmol) in MeOH (5 mL) was refluxed for 2h. 6-Acetyl-5-methoxy-2-3-(trifluoromethyl)phenyl After cooling to room temperature, the reaction mixture was pyridazin-3 (2H)-one poured into 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over 1776 MgSO4, and concentrated under reduced pressure. The resi due was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and recrystallized from hexane/ AcOEt to give the title compound (323 mg, 45% yield) as a white solid: mp 165-167° C.; H NMR (300 MHz, CDC1): 8 ppm 3.73 (3H, s), 6.27 (1H, s), 6.78 (1H, d, J=1.9 Hz), 7.31-7.50 (8H, m), 7.52-7.58 (1H, m), 7.77 (1H, d, J=1.9 Hz). LC-MS (ESI) m/z 413 M+H". Anal. Calcd for CHFNO: C, 61.17; H, 3.67; N, 13.59. Found: C, 61.12: H, 3.72; N, 13.54. Reference Example 107 4-oxo-1-3-(trifluoromethyl)phenyl-1,4-dihydropy ridazine-3-carboxylic acid FC 1781

1777 MeMgBr (1 M solution in THF, 4 mL, 12 mmol) was added dropwise at -78°C. to a solution of N,4-dimethoxy N-methyl-6-oxo-3-(trifluoromethyl)phenyl-1,6-dihydro pyridazine-3-carboxamide (1.43 g, 4 mmol) in THF (15 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NHClaqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO, and concentrated under reduced pressure. The residue was puri fied by Silica gel column chromatography eluting with hex ane/AcOEt (1/1) and recrystallized from hexane/AcOEt to give the title compound (566 mg, 45% yield) as a white solid: mp 136-138° C.; H NMR (300 MHz, CDC1): 8 ppm 2.57 (3H, s), 3.93 (3H, s), 6.31 (1H, s), 7.63 (1H, t, J=7.9 Hz), 7.69 (1H, d, J=7.9 Hz), 7.84-7.88 (1H, m), 7.91 (1H, s). Anal. Calcd for CHFNO: C, 53.85; H, 3.55: N, 8.97. Found: 1782. To a suspension of methyl 4-oxo-1-3-(trifluorom C, 53.96; H, 3.57; N, 8.96. ethyl)phenyl-1,4-dihydropyridazine-3-carboxylate (10.0 g, 33.5 mmol) in MeOH (150 mL) was added 1 MNaOHaque ous solution (50 mL) at 0°C. The mixture was stirred at room Reference Example 106 temperature for 30 min. To the suspension was added 1 M HCl aqueous solution (50 mL) at 0°C. The mixture was 5-Methoxy-6-(1-phenyl-1H-pyrazol-5-yl)-2-3-(trif concentrated in vacuo. The precipitates were collected by luoromethyl)phenylpyridazin-3 (2H)-one filtration, washed with water and dried in vacuo at 50° C. to yield the title compound (9.25 g, 97% yield) as a pale yellow 1778 solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 7.02 (1H, d, J–7.7 Hz), 7.81-7.96 (2H, m), 8.06-8.21 (2H, m), 9.16 (1H, d,

J=7.7 Hz). Reference Example 108 N-Methoxy-N-methyl-4-oxo-1-3-(trifluoromethyl) phenyl-1,4-dihydropyridazine-3-carboxamide 1783

FC

1779 A solution of 6-acetyl-5-methoxy-2-3-(trifluorom ethyl)phenylpyridazin-3 (2H)-one (540 mg, 1.73 mmol) in N,N-dimethylformamide dimethyl acetal (5 mL) was refluxed for 3 h. After cooling to room temperature, the reac tion mixture was concentrated under reduced pressure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO, and concentrated under reduced pressure. US 2012/0277430 A1 Nov. 1, 2012 69

1784. A mixture of 4-oxo-1-3-(trifluoromethyl)phenyl 1788. A solution of 3-phenyl-1H-pyrazole (4.08 g. 28.3 1,4-dihydropyridazine-3-carboxylic acid (2.00 g, 7.04 mmol) mmol) and NBS (5.04 g. 28.3 mmol) in DMF (40 mL) was and CDI (1.26g, 7.74 mmol) in THF (20 mL) was heated to stirred for 1 h at room temperature. The reaction mixture was 40° C. for 2 h. To the solution were added N-methoxymetha poured into water and extracted with AcOEt. The extract was namine hydrochloride (1.03 g, 10.6 mmol) and i-PrNEt washed with water and brine, dried over MgSO, and con (1.84 mL, 10.6 mmol) at room temperature. The solution was centrated under reduced pressure. The residue was recrystal stirred at room temperature for 20h. The mixture was diluted lized from hexane/AcOEt to give the title compound (5.84g, with water, extracted with EtOAc, washed with brine, dried 93% yield) as a white solid: mp 114-116° C.; H NMR (300 over NaSO, filtered, concentrated in vacuo and purified by MHz, CDC1): 8 ppm 7.39-7.50 (3H, m), 7.64 (1H, s), 7.77 column chromatography on silica gel (hexane/EtOAc=50/50 (2H, d, J=6.8 Hz), 10.73 (1H, brs). to 0/100 and EtOAc/MeOH=100/0 to 80/20) to yield the crude title compound (2.40g) as a pale yellow solid: 'HNMR Reference Example 111 (DMSO-d 300 MHz): 8 ppm 3.28 (3H, s), 3.61 (3H, s), 6.67 4-Bromo-3-phenyl-1-trityl-1H-pyrazole (1H, d, J=7.9 Hz), 7.77-7.90 (2H, m), 8.00-8.14 (2H, m), 8.99 (1H, d, J=7.9 Hz). 1789 Reference Example 109 3-Propanoyl-1-3-(trifluoromethyl)phenylpyridazin 4(1H)-one 1785

1790. A suspension of 4-bromo-3-phenyl-1H-pyrazole (6.13 g, 27.5 mmol), trityl chloride (15.3g, 55.0 mmol), and KCO (11.4g, 82.5 mmol) in DMF (100 mL) was stirred for 60hat 90°C. After cooling to room temperature, the reaction mixture was poured into water and extracted with AcOEt. The F extract was washed with water and brine, dried over MgSO, F concentrated under reduced pressure. The residue was recrys F tallized from hexane/THF to give the title compound (8.00 g, 63% yield) as a white solid: mp 181-183° C.; H NMR (300 1786 To a solution of N-methoxy-N-methyl-4-oxo-3- MHz, CDC1): 8 ppm 7.16-7.22 (6H, m), 7.28-7.41 (13H, m), (trifluoromethyl)phenyl-1,4-dihydropyridazine-3-carboxa 7.87-7.91 (2H, m). Anal. Calcd for C.H. BrN: C, 72.26; H, mide (1.20 g, 3.52 mmol) in THF (20 mL) was added EtMgBr 4.55; N, 6.02. Found: C, 72.43; H, 4.66: N, 5.91. (1.0M in THF, 7.04 mL, 7.04 mmol)at -78°C. under N. The mixture was stirred at -78° C. for 1 h. The reaction was Reference Example 112 quenched with saturated NHClaqueous solution at -78°C. 3-Amino-1-3-(trifluoromethyl)phenylpyridazin-4 The mixture was warmed to room temperature, extracted with (1H)-one EtOAc, dried over NaSO filtered, concentrated in vacuo and purified by column chromatography on silica gel (hex 1791 ane/EtOAc=50/50 to 0/100) to yield the title compound (767 mg, 74% yield) as a pale yellow solid: "H NMR (DMSO-d 300 MHz): 8 ppm 1.06 (3H, t, J–7.2 Hz), 2.99 (2H, q, J=7.2 Hz), 6.73 (1H, d, J=8.3 Hz), 7.79-7.88 (2H, m), 8.06-8.17 NH2 (2H, m), 8.97 (1H, d. J=8.3 Hz). Reference Example 110 4-Bromo-3-phenyl-1H-pyrazole 1787 F

F Br F

1792. A mixture of 4-oxo-1-3-(trifluoromethyl)phenyl 1,4-dihydropyridazine-3-carboxylic acid (5.00 g, 17.6 mmol), DPPA (5.67 mL, 26.4 mmol) and EtN (3.65 mL, 26.4 mmol) intoluene (35 mL) was heated to 100° C. for 2 h. To the US 2012/0277430 A1 Nov. 1, 2012 70 mixture was added 8 MNaOHaqueous solution (22 mL) at 0° 1796. A mixture of 3-bromo-1-3-(trifluoromethyl)phe C. The mixture was stirred at room temperature for 2 h, nylpyridazin-4(1H)-one (500 mg, 1.57 mmol), (trimethylsi diluted with brine, extracted with EtOAc, dried over NaSO, lyl)acetylene (0.222 mL, 1.57 mmol), EtN (0.329 mL, 2.36 filtered, and concentrated in vacuo. The residue was washed mmol), CuI (4.5 mg, 0.0236 mmol), Pd(PPh)C1 (55.1 mg, with EtOAc/i-PrO and filtered. The filtrate was concentrated 0.0785 mmol) and PPhs (10.3 mg, 0.0393 mmol) in TI-IF (7.5 in vacuo, purified by column chromatography on basic silica mL) was heated to 40°C. for 8 hunder Ar. To the suspension was added (trimethylsilyl)acetylene (0.111 mL, 0.785 gel (hexane/EtOAc=50/50 to 0/100) and washed with EtOAc/ mmol). The suspension was heated to 40° C. for 14h under hexane to yield the title compound (2.50 g, 56% yield) as a Ar. To the suspension was added (trimethylsilyl)acetylene pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 ppm (0.0888 mL, 0.628 mmol). The suspension was heated to 40° 6.17 (1H, d, J=7.5 Hz), 6.52 (2H, brs), 7.67-7.81 (2H, m), C. for 96 h under Ar. The mixture was diluted with brine, 8.04 (1H, d, J=7.5 Hz), 8.10 (1H, s), 8.75 (1H, d, J=7.5 Hz). extracted with EtOAc, dried over MgSO filtered, concen Reference Example 113 trated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100) to yield the title 3-Bromo-1-3-(trifluoromethyl)phenylpyridazin-4 compound (148 mg, 28% yield) as a brown solid: "H NMR (1H)-one (DMSO-d,300MHz): 8 ppm 0.26 (9H, s), 6.64 (1H, d. J–7.9 1793 Hz), 7.75-7.92 (2H, m), 8.00-8.15 (2H, m), 8.90 (1H, d, J=8.3 Hz). Reference Example 115 3-Ethynyl-1-3-(trifluoromethyl)phenylpyridazin-4 Br (1H)-one 1797

F

F F F

1794) To DMF (18 mL) were added isoamyl nitrite (2.44 F mL, 18.3 mmol) and CuBr (1.89 g, 8.46 mmol) at 0°C. To the F mixture was dropwise added a solution of 3-amino-1-3- 1798. A mixture of 1-3-(trifluoromethyl)phenyl-3-(tri (trifluoromethyl)phenylpyridazin-4(1H)-one (1.80 g, 7.05 methylsilyl)ethynylpyridazin-4(1H)-one (148 mg, 0.439 mmol) in DMF (7.2 mL) at 0°C. The mixture was stirred at 0° mmol) in MeOH (3 mL) and 1 MNaOHaqueous solution (5 C. for 1 h and at 60° C. for 3 h. The mixture was diluted with mL) was stirred at 0°C. for 5 min and at room temperature for brine, extracted with EtOAc, washed with brine, dried over 2 h. The mixture was neutralized with 1 M HCl aqueous MgSO filtered, concentrated in vacuo, purified by column solution at 0° C. The mixture was extracted with EtOAc, chromatography on silica gel (hexane/EtOAc=50/50 to washed with brine, dried over NaSO, filtered, concentrated 0/100) and triturated with hexane to yield the title compound in vacuo and purified by column chromatography on silica gel (1.85g.82% yield) as a white solid: 'HNMR (DMSO-d,300 (hexane/EtOAc=50/50 to 0/100) to yield the title compound MHz): 8 ppm 6.64 (1H, d, J=7.7 Hz), 7.78-7.87 (2H, m), (69 mg, 59% yield) as a pale red solid: "H NMR (DMSO-d 300 MHz): 8 ppm 4.70 (1H, s), 6.65 (1H, d, J=7.9 Hz), 8.01-8.07 (1H, m), 8.08 (1H, s), 9.00 (1H, d, J–7.7 Hz). 7.76-7.92 (2H, m), 7.99-8.17 (2H, m), 8.93 (1H, d, J=7.9 Hz). Reference Example 114 Reference Example 116 1-3-(Trifluoromethyl)phenyl)-3-(trimethylsilyl) 3-(Hydroxymethyl)-1-3-(trifluoromethyl)phenyl ethynylpyridazin-4(1H)-one pyridazin-4(1H)-one 1795 1799

US 2012/0277430 A1 Nov. 1, 2012

1800. To a solution of methyl 4-oxo-1-3-(trifluorom J=8.2 Hz), 7.81-7.91 (2H, m), 8.08-8.15 (1H, m), 8.16 (1H, s), ethyl)phenyl-1,4-dihydropyridazine-3-carboxylate (2.00 g, 8.98 (1H, d, J=8.0 Hz), 10.07 (1H, s). 6.70 mmol) in THF (134 mL) was added DIBAL (1.5 M in toluene, 13.4 mL. 20.1 mmol) at -78°C. The solution was Reference Example 118 stirred at -78°C. for 1 h, gradually warmed to room tempera 5-Methoxy-4-oxo-1-3-(trifluoromethyl)phenyl-1,4- ture, stirred at room temperature for 18 h, diluted with 1 M dihydropyridazine-3-carboxylic acid HCl aqueous solution at 0°C., extracted with EtOAc, washed with brine, dried over MgSO filtered, concentrated in vacuo 1803 and purified by column chromatography on silica gel (hex

ane/EtOAc=50/50 to 0/100 and EtOAC/MeOH=10070 to 70/30) to yield the title compound (509 mg, 28% yield) as a pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 ppm MeO 4.53 (2H, d, J=6.0 Hz), 5.11-5.16 (1H, m), 6.48 (1H, d, J-8.0 Hz), 7.76-7.84 (2H, m), 8.08-8.16 (1H, m), 8.19 (1H, s), 8.94 (1H, d, J=8.0 Hz). Reference Example 117 4-Oxo-1-3-(trifluoromethyl)phenyl-1,4-dihydropy ridazine-3-carbaldehyde 1801

1804) To a suspension of methyl 5-methoxy-4-oxo-1-3- (trifluoromethyl)phenyl-1,4-dihydropyridazine-3-carboxy late (10.0 g, 30.5 mmol) in MeOH (100 mL) was added 1 M NaOH acqueous solution (61 mL) at 0°C. The mixture was stirred at room temperature for 30 min. To the solution was added 1 MHClaqueous solution (61 mL) at 0°C. The mixture was concentrated in vacuo. The precipitates were collected by filtration, washed with water and dried in vacuo at 60° C. to yield the title compound (8.78 g.92% yield) as a pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 3.98 (3H, s), 7.82-8.01 (2H, m), 8.11-8.34 (2H, m), 8.97 (1H, s), 15.00 (1H, brs). Reference Example 119 1802. To a solution of oxalyl chloride (0.175 mL, 2.07 3-Amino-5-methoxy-1-3-(trifluoromethyl)phenyl mmol) in THF (7.5 mL) was added DMSO (0.294 mL, 4.14 pyridazin-4(1H)-one mmol) at -78°C. To the suspension was added a solution of 3-(hydroxymethyl)-1-3-(trifluoromethyl)phenylpyridazin 1805 4(1H)-one (509 mg, 1.88 mmol) in THF (7.5 mL) at -78°C. The suspension was stirred at -78°C. for 1 h. To the mixture was added Et-N (1.05 mL, 7.52 mmol) at -78°C. The mixture was gradually warmed to room temperature, stirred at room MeO temperature for 18 h, diluted with 1M HCl aqueous solution, extracted with EtOAc, washed with saturated NaHCO aque ous solution and brine, dried over NaSO filtered, concen trated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/ MeOH=100/0 to 70/30). To a solution of oxalyl chloride (0.477 mL, 5.64 mmol) in THF (19 mL) was added DMSO (0.801 mL, 11.3 mmol) at -78°C. To the suspension was added a mixture of the above residue in THF (9.5 mL) at -78° C. The suspension was stirred at -78° C. for 2 h. To the mixture was added Et-N (3.14 mL, 22.6 mmol) at -78°C. The mixture was gradually warmed to room temperature, stirred 1806. A mixture of 5-methoxy-4-oxo-1-3-(trifluorom at room temperature for 17 h, diluted with 1M HCl aqueous ethyl)phenyl-1,4-dihydropyridazine-3-carboxylic acid solution, extracted with EtOAc, washed with saturated (6.00 g, 19.1 mmol), DPPA (6.16 mL, 28.6 mmol) and EtN NaHCO, aqueous solution and brine, dried over NaSO, (3.99 mL, 28.6 mmol) in toluene (60 mL) was heated to 100° filtered, concentrated in vacuo and purified by column chro C. for 2 h. To the mixture was added 8 M NaOH aqueous matography on silica gel (hexane/EtOAc=50/50 to 0/100) to solution (23.8 mL) at 0°C. The mixture was stirred at room yield the title compound (257 mg, 51% yield) as a yellow temperature for 3 h, extracted with EtOAc, dried over solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 6.87 (1H, d, NaSO filtered and concentrated in vacuo. The residue was US 2012/0277430 A1 Nov. 1, 2012 72 washed with EtOAc/i-PrO and filtered. The filtrate was con 300 MHz): 8 ppm 7.19 (1H, d, J-49 Hz), 7.27-7.44 (3H, m), centrated in vacuo, purified by column chromatography on 7.46-7.58 (3H, m), 8.06 (2H, s). basic silica gel (hexane/EtOAc=50/50 to 0/100) and recrys tallized with EtOAc/hexane to yield the title compound (3.57 Reference Example 122 g, 66% yield) as a pale yellow solid: "H NMR (DMSO-d Methyl 4-methoxy-3-oxo-2-(pyridin-4-ylhydrazono) 300 MHz): 8 ppm 3.83 (3H, s), 6.31 (2H, s), 7.64-7.79 (2H, butanoate m), 8.13 (2H, s), 8.64 (1H, s). 1811 Reference Example 120 O (2-Phenylfuran-3-yl)boronic acid MeO COMe 1807 HN N

O (HO)2B N r 2 N

1812 4-Aminopyridine (3.6 g., 38 mmol) was added to a mixture of phosphoric acid (10 mL, 150 mmol) and nitric acid (5 mL, 78 mmol) at -6° C. Sodium nitrite (3.2g, 46 mmol) 1808. To a mixture of 3-bromo-2-phenylfuran (6.70 g, was added portionwise to the mixture at -6° C., and then crushed ice (ca. 25 g) was added into the solution. After 30.0 mmol) and B(Oi-Pr) (10.4 mL, 45.0 mmol) in THF (67 stirring at -6°C. for 10 min, the mixture was poured into a mL) was added n-Bulli (1.65 M in hexane, 36.4 mL, 60 suspension of methyl 4-methoxyacetoacetate (5.0 mL, 38 mmol) at -78°C. The mixture was stirred at -78°C. for 30 mmol) and sodium acetate (44g, 540 mmol) in MeCH (100 min and at 0°C. for 30 min. The mixture was diluted with 1 mL) at 0°C. The mixture was partitioned between AcOEt and M HCl aqueous solution at 0°C., extracted with EtOAc, water. The aqueous layer was extracted with AcOEt. The washed with brine, dried over NaSO, filtered, concentrated combined organic extract was washed with brine, dried over in vacuo and triturated with EtOAc/hexane to yield the title MgSO filtered and concentrated under reduced pressure. compound (2.23 g, 40% yield) as a green solid: "H NMR The residual solid was washed with AcOEt/hexane (1/3) to (DMSO-de, 300 MHz): 8 ppm 6.64 (1H, d, J=1.4 Hz), 7.21 give the title compound (1.8 g. 19% yield) as a yellow solid: 7.45 (3H, m), 7.69 (1H, d, J=1.6 Hz), 8.00-8.08 (2H, m). "H NMR (300 MHz, CDC1): 8 ppm 3.48-3.53 (3H, m), 3.89-3.95 (3H, m), 4.64-4.69 (2H, m), 7.17-7.34 (2H, m), Reference Example 121 8.54-8.60 (2H, m), 12.65 (1H, brs). (2-Phenylthiophen-3-yl)boronic acid Reference Example 123 Methyl 5-methoxy-4-oxo-1-pyridin-4-yl-1,4-dihy 1809 dropyridazine-3-carboxylate 1813

S (HO)2B N MeO COMe

1810. To a mixture of 3-bromo-2-phenylthiophene (1.99 g, 8.32 mmol) and B(Oi-Pr) (1.81 mL, 12.5 mmol) in TI-IF r2 (20 mL) was added n-Bulli (1.65 Min hexane, 10.1 mL, 16.6 N mmol) at -78°C. The mixture was stirred at -78°C. for 30 min and at 0°C. for 30 min. The mixture was diluted with 1 1814. A mixture of methyl 4-methoxy-3-oxo-2-(pyridin M HCl aqueous solution at 0°C., extracted with EtOAc, 4-ylhydrazono)butanoate (18 g. 70 mmol) and N,N-dimeth washed with brine, dried over NaSO, filtered, concentrated ylformamide dimethyl acetal (28 mL. 210 mmol) in toluene in vacuo and purified by column chromatography on silica gel (210 mL) was refluxed for 4 h. The mixture was concentrated (hexane/EtOAc=90/10 to 0/100) to yield the title compound under reduced pressure to give black crystals. The crystals (87.4 mg, 5% yield) as a white solid: "H NMR (DMSO-d were washed with 2-propanol/AcOEt (1:4) to give the title US 2012/0277430 A1 Nov. 1, 2012 73 compound (8.2 g 45% yield) as pale yellow crystals: "H organic layer was dried over MgSO4, filtered and concen NMR (300 MHz, CDC1): 8 ppm 3.99 (3H, s), 4.00 (3H, s), trated under reduced pressure. The middle layer was 7.62 (2H, dd, J–4.5, 1.5 Hz), 8.01 (1H, s), 8.79 (2H, dd, J=4.5, extracted with CHCl (50 mLX4), and the combined extracts 1.5 Hz). were dried over MgSO filtered and concentrated under reduced pressure. Two of the residues were combined and Reference Example 124 chromatographed on basic silica gel (0/100-10/90 MeOH/ 5-Methoxy-4-oxo-1-pyridin-4-yl-1,4-dihydropy AcOEt) to give the title compound (9.6 g. 100% yield) as a ridazine-3-carboxylic acid pale yellow oil: "H NMR (300 MHz, CDC1): 8 ppm 3.40 (3H, s), 3.68 (3H, s), 3.98 (3H, s), 7.61 (2H, dd, J=4.8, 1.5 1815 Hz), 8.08 (1H, s), 8.73 (2H, dd, J–4.8, 1.5 Hz).

Reference Example 126 3-Acetyl-5-methoxy-1-pyridin-4-ylpyridazin-4(1H)- MeO O 1819

MeO r2 Me N

1816 To a solution of methyl 5-methoxy-4-oxo-1-pyri din-4-yl-1,4-dihydropyridazine-3-carboxylate (0.50 g, 1.9 mmol) in MeOH (10 mL) and THF (10 mL) was added 1 M NaOHaqueous solution (3.0 mL, 3.0 mmol), and the mixture r 2 was stirred at room temperature overnight. The mixture was N concentrated under reduced pressure. To the residue was added 1 M HCl aqueous solution (3.1 mL). The formed pre 1820. To a solution of N,5-dimethoxy-N-methyl-4-oxo-1- cipitate was collected by filtration, washed with water and pyridin-4-yl-1,4-dihydropyridazine-3-carboxamide (9.6 g. dried to give the title compound (0.47 g. 99% yield) as an 33 mmol) in THF (100 mL) was added dropwise 1 M off-white solid: "H NMR (300 MHz, DMSO-d): 8 ppm 3.98 MeMgBr in THF (66 mL, 66 mmol) at -78° C. for 15 min. (3H, s), 7.97 (2H, dd, J=4.7, 1.7 Hz), 8.83 (2H, dd, J=4.7, 1.7 After stirring at -78°C. for 1 h, the mixture was quenched Hz), 8.92 (1H, s), 14.63 (1H, brs). with 1 M HCl aqueous solution (70 mL). The mixture was warmed to room temperature, basified with 1 MNaOHaque Reference Example 125 ous solution, washed with AcOEt. The aqueous layer was N.5-Dimethoxy-N-methyl-4-oxo-1-pyridin-4-yl-1,4- extracted with CHCl (50 mLx4). The combined extract was dihydropyridazine-3-carboxamide dried over MgSO, filtered and concentrated under reduced pressure to give the title compound (2.1 g, 26% yield) as 1817 yellow crystals: "H NMR (300 MHz, CDC1): 8 ppm 2.70 (3H, s), 3.98 (3H, s), 7.64 (2H, dd, J=4.7, 1.6 Hz), 8.04 (1H, s), 8.79 (2H, dd, J–4.7, 1.6 Hz). MeO Reference Example 127 Methyl 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihy dropyridazine-3-carboxylate 1821

r 2 N MeO 1818 To a mixture of 5-methoxy-4-oxo-1-pyridin-4-yl-1, 4-dihydropyridazine-3-carboxylic acid (8.2 g, 33 mmol), HOBt (7.6 g., 50 mmol) and WSC (9.5g, 50 mmol) in DMF (160 mL) was added N.O-dimethylhydroxylamine hydro chloride (6.5 g. 66 mmol) and TEA (14 mL, 100 mmol), and the mixture was stirred at room temperature overweekend. The mixture was concentrated under reduced pressure. The residue was diluted with water, saturated with KCO, and extracted with AcOEt. (There were three layers.) The highest US 2012/0277430 A1 Nov. 1, 2012 74

1822 To a suspension of quinolin-8-amine (10.0 g. 69.4 1826. A mixture of 5-methoxy-4-oxo-1-quinolin-8-yl-1, mmol) in 6 M HCl aqueous solution (69.4 mL) was added a 4-dihydropyridazine-3-carboxylic acid (2.59 g, 8.71 mmol), solution of NaNO (5.74 g. 83.2 mmol) in water (13.9 mL) at DPPA (2.81 mL, 13.1 mmol) and Et-N (1.82 mL, 13.1 mmol) 0°C. To a suspension of methyl 4-methoxy-3-oxobutanoate in toluene (26 mL) was heated to reflux for 1 h. To the (8.98 mL, 69.4 mmol) and NaOAc (104 g) in EtOH (118 mL) suspension were added DMF (52 mL), DPPA (2.81 mL, 13.1 was added the above solution at 0°C. The mixture was stirred mmol) and Et-N (1.82 mL, 13.1 mmol) at room temperature. at 0°C. for 10 min. The precipitates were collected by filtra The mixture was heated to 100° C. for 1.5 h. To the mixture tion, washed with water and EtOAc, and dried. To the solid was added 8 MNaOH aqueous solution (10.9 mL) at 0°C. was added N,N-dimethylformamide dimethyl acetal (255 The mixture was stirred at room temperature for 1.5 h, mL) at room temperature. The mixture was heated to reflux extracted with EtOAc, dried over NaSO, filtered, concen for 2.5 h and cooled to room temperature. The precipitates trated in vacuo, purified by column chromatography on basic were collected by filtration, washed with hexane and dried to silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/ yield the title compound (16.6 g., 77% yield) as a gray solid: MeOH=100/0 to 80/20) and on silica gel (EtOAc/ H NMR (DMSO-d 300 MHz): 8 ppm 3.77 (3H, s), 3.80 MeOH=100/0 to 50/50) and triturated with EtOAc/hexane to (3H, s), 7.72 (1H, dd, J=8.5, 4.0 Hz), 7.81 (1H, t, J=7.9 Hz), yield the title compound (479 mg, 20% yield) as a pale yellow 8.09 (1H, d, J=7.2 Hz), 8.25 (1H, d, J=8.3 Hz), 8.58 (1H, s), solid: "H NMR (DMSO-d 300 MHz): 8 ppm 3.75 (3H, s), 8.65 (1H, s), 8.97-9.04 (1H, m). 6.11 (2H, s), 7.67 (1H, dd, J=8.5, 4.4 Hz), 7.72-7.80 (1H, m), Reference Example 128 7.99 (1H, dd, J=7.6, 1.5 Hz), 8.12 (1H, dd, J=8.3, 1.1 Hz), 5-Methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropy 8.48-8.61 (2H, m), 8.99 (1H, dd, J–4.4, 1.7 Hz). ridazine-3-carboxylic acid Reference Example 130 1823 3-Bromo-5-methoxy-1-quinolin-8-ylpyridazin-4 (1H)-one 1827

MeO

MeO Br

N 21 N 1824. To a suspension of methyl 5-methoxy-4-oxo-1- quinolin-8-yl-1,4-dihydropyridazine-3-carboxylate (5.00 g, 16.1 mmol) in MeOH (64 mL) were added 1 MNaOH adue 1828 To DMF (3 mL) were added isoamyl nitrite (0.387 ous solution (64 mL) and THF (64 mL) at 0°C. The mixture mL, 2.91 mmol) and CuBr (299 mg, 1.34 mmol) at 0°C. To was heated to 80°C. The homogeneous mixture was cooled to the mixture was added a solution of 3-amino-5-methoxy-1- 0°C. To the mixture was added 1 MHClaqueous solution (64 quinolin-8-ylpyridazin-4(1H)-one (300 mg, 1.12 mmol) in mL) at 0°C. The mixture was stirred at room temperature for DMF (3 mL) at 0°C. The mixture was stirred at 0°C. for 1 h 1 hand concentrated in vacuo. The precipitates were collected and at 60° C. for 2.5 h. The mixture was diluted with water, by filtration, washed with water and dried in vacuo at 60° C. extracted with EtOAc, washed with brine, dried over MgSO, to yield the title compound (3.59 g, 75% yield) as a fresh filtered, concentrated in vacuo, purified by column chroma colored solid: "H NMR (DMSO-d, 300 MHz): 8 ppm 3.86 tography on basic silica gel (hexane/EtOAc=50/50 to 0/100 (3H, s), 7.73 (1H, dd, J–8.4, 4.3 Hz), 7.81-7.89 (1H, m), 8.12 and EtOAc/MeOH=100/0 to 70/30) and triturated with (1H, dd, J=7.4, 1.4 Hz), 8.30 (1H, dd, J–8.4, 1.2 Hz), 8.61 EtOAc/hexane to yield the title compound (148 mg, 41% (1H, dd, J=8.5, 1.6 Hz), 8.96-9.05 (2H, m). yield) as a pale yellow solid: "H NMR (DMSO-de, 300MHz): 8 ppm 3.78 (3H, s), 7.72 (1H, dd, J=8.3, 4.2 Hz), 7.82 (1H, t, Reference Example 129 J=8.0 Hz), 8.10 (1H, d, J=7.2 Hz), 8.25 (1H, d, J=8.3 Hz), 3-Amino-5-methoxy-1-quinolin-8-ylpyridazin-4 8.59 (1H, dd, J=8.3, 1.5 Hz), 8.73 (1H, s), 9.01 (1H, dd, J=4.2, (1H)-one 1.5 Hz). 1825 Reference Example 131 (1-Phenyl-1H-pyrazol-5-yl)boronic acid 1829 MeO NH2

N 21 US 2012/0277430 A1 Nov. 1, 2012

1830. To a solution of 1-phenyl-1H-pyrazole (12.8 g. 88.9 4-methoxyacetoacetate (2.2 mL, 17 mmol) and Sodium mmol) in THF (355 mL) was dropwise added n-Bulli (1.63 M acetate (9.0g, 110 mmol) in MeOH (40 mL) pre-cooled at 0° solution in hexane, 57.2 mL. 93.3 mmol) at -78°C. under N. C. The mixture was partitioned between AcOEt and water. The mixture was stirred at -78°C. for 1 h. To the mixture was The organic layer was washed with brine, dried over MgSO, added B(Oi-Pr) (82.0 mL,355 mmol) at -78°C. The mixture filtered and concentrated under reduced pressure. was stirred at -78° C. for 1 h, gradually warmed to room 1835. A solution of the residue in N,N-dimethylforma temperature and stirred at room temperature overnight. The mide dimethyl acetal (20 mL, 150 mmol) was refluxed for 3 h. pH of the mixture was adjusted to 5 with 1 M HCl aqueous The mixture was concentrated under reduced pressure. The Solution. The mixture was concentrated in vacuo, extracted residual solid was washed with AcOEt/hexane (1/3) to give with EtOAc, washed with brine, dried over NaSO filtered, the title compound (4.1 g, 71% yield) as an orange solid: "H concentrated in vacuo and crystallized with MeOH/EtOAc/ NMR (300 MHz, CDC1): 8 ppm 3.96 (3H, s), 3.99 (3H, s), hexane to yield the title compound (12.6 g., 76% yield) as a 7.15 (1H, dd, J=8.0, 1.1 Hz), 723-7.30 (1H, m), 7.56 (1H, dd, pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 ppm J=8.5, 1.1 Hz), 8.01 (1H, s). 6.73 (1H, brs), 7.28-7.39 (1H, m), 7.39-7.54 (4H, m), 7.66 Reference Example 134 (1H, s). 1-(2,2-Difluoro-1,3-benzodioxol-4-yl)-5-methoxy-4- Reference Example 132 OXO-1,4-dihydropyridazine-3-carboxylic acid 1-Phenyl-5-(4.4.5.5-tetramethyl-1,3,2-dioxaborolan 1836 2-yl)-1H-pyrazole 1831 MeO

Me O N B ( N 1.)N Me / O Me Me

1832 To a mixture of (1-phenyl-1H-pyrazol-5-yl)boronic 1837 To a solution of methyl 1-(2,2-difluoro-1,3-benzo acid (8.57 g. 45.6 mmol) in toluene (86 mL) was added dioxol-4-yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3- pinacol (5.39 g, 45.6 mmol) at room temperature. The mix carboxylate (4.1 g, 12 mmol) in THF (100 mL) and MeOH ture was heated to 40° C. for 2 days. The mixture was con (50 mL) was added 1 MNaOH adueous solution (18 mL, 18 centrated in vacuo and triturated with hexane to yield the title mmol), and the mixture was stirred at room temperature for 1 compound (7.93 g. 64% yield) as a pale yellow solid: "H h. The mixture was concentrated under reduced pressure, and NMR (DMSO-de, 300 MHz): 8 ppm 1.23 (12H, s), 6.84 (1H, acidified with 1 M HCl aqueous solution. The mixture was s), 7.34-7.59 (5H, m), 7.75 (1H, d, J=1.9 Hz) diluted with AcOEt, washed with water and brine, dried over MgSO filtered and concentrated under reduced pressure to Reference Example 133 give the title compound (3.8 g. 97% yield) as a yellow amor phous solid: 'HNMR (300 MHz, CDC1): 8 ppm 4.06(3H, s), Methyl 1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5- 7.22-7.26 (1H, m), 7.34 (1H, t, J=8.3 Hz), 7.72(1H, dd, J=8.3, methoxy-4-OXO-1,4-dihydropyridazine-3-carboxylate 1.1 Hz), 8.29 (1H, s). 1833 Reference Example 135 1-(2,2-Difluoro-1,3-benzodioxol-4-yl)-N,5- dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine 3-carboxamide

MeO COMe 1838

N1 xii) MeO 1834. A solution of sodium nitrite (1.4g, 21 mmol) in HO (10 mL) was added dropwise to a solution of 2,2-difluoro-1, 3-benzodioxol-4-amine (3.0g, 17 mmol) in 6 MHClaqueous solution (18 mL, 108 mmol) at 0°C. After stirring for 15 min at 0°C., the mixture was added to a suspension of methyl US 2012/0277430 A1 Nov. 1, 2012 76

1839. To a mixture of 1-(2,2-difluoro-1,3-benzodioxol-4- 1843. A solution of 3-acetyl-1-(2,2-difluoro-1,3-benzo yl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylic dioxol-4-yl)-5-methoxypyridazin-4(1H)-one (2.3 g, 7.1 acid (3.8 g. 12 mmol), HOBt (2.7g, 17 mmol) and WSC (3.4 g, 17 mmol) in DMF (50 mL) was added N.O-dimethylhy mmol) in N,N-dimethylformamide dimethyl acetal (75 mL) droxylamine hydrochloride (2.3 g, 23 mmol) and EtN (4.9 was refluxed for 3 h. The mixture was concentrated under mL, 35 mmol), and the mixture was stirred at room tempera reduced pressure. The brown crystals were washed with ture overnight. The mixture was diluted with water (200 mL) AcOEt/hexane (1/1) to give the title compound (2.0 g, 74% and extracted with AcOEt (250 mLx2). The combined organic layer was washed with Saturated NaHCOs aqueous yield) as yellow crystals: "H NMR (300 MHz, CDC1): 8 ppm solution and brine, dried over MgSO filtered and concen 2.91 (3H, s), 3.14 (3H, s), 3.94 (3H, s), 5.78 (1H, d, J=11.7 trated under reduced pressure to give orange crystals. The Hz), 7.10 (1H, dd, J=8.3, 1.1 Hz), 7.23 (1H, t, J=8.3 Hz), 7.63 crystals were washed with AcOEt/hexane (1/4) to give the (1H, d, J=8.7 Hz), 7.79 (1H, brs), 8.03 (1H, s). title compound (2.7 g. 62% yield) as pale yellow crystals: "H NMR (300 MHz, CDC1): 8 ppm 3.41 (3H, s), 3.71 (3H, s), 3.96 (3H, s), 7.12 (1H, dd, J=7.9, 1.1 Hz), 7.23 (1H, d, J=8.7 Reference Example 138 Hz), 7.57 (1H, dd, J=8.7, 1.1 Hz), 8.06 (1H, s). Reference Example 136 4-(Benzyloxy)-2-fluoroaniline 3-Acetyl-1-(2,2-difluoro-1,3-benzodioxol-4-yl)-5- methoxypyridaZin-4(1H)-one 1844 1840

MeO NH2 F

O

1841. To a solution of 1-(2,2-difluoro-1,3-benzodioxol-4- yl)-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine 3-carboxamide (2.7g, 7.2 mmol) in THF (70 mL) was added dropwise 1 M MeMgBr in THF (14 mL, 14 mmol) at -78°C. for 15 min. After stirring at -78°C. for 1 h, the mixture was quenched with 1 M HCl aqueous solution (30 mL). The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO filtered and concentrated under reduced pressure to give the title compound (2.3 g, 99% yield) as yellow crystals: 1845. A suspension of 3-fluoro-4-nitrophenol (6.28 g. 40 'HNMR (300 MHz, CDC1): 8 ppm 2.69(3H, s), 3.95 (3H, s), mmol), benzyl bromide (5.00 mL, 42 mmol), and KCO 7.17 (1H, dd, J=7.9, 1.1 Hz), 7.26-7.32(1H, m), 7.55 (1H, dd, (6.63 g, 48 mmol) in acetone (80 mL) was refluxed for 2 h. J=8.7, 1.1 Hz), 8.00 (1H, s). After cooling to room temperature, the reaction mixture was Reference Example 137 poured into water and extracted with AcOEt. The extract was 1-(2,2-Difluoro-1,3-benzodioxol-4-yl)-3-3-(dim washed with brine, dried over MgSO4, and concentrated ethylamino)prop-2-enoyl-5-methoxypyridazin-4 under reduced pressure. The residue was recrystallized from (1H)-one hexane/AcOEt to give 4-(benzyloxy)-2-fluoro-1-nitroben 1842 Zene (16.0 g, 92% yield) as a pale yellow solid. 1846. A solution of NaSO (34.8 g. 200 mmol) in HO

(200 mL) was added to a mixture of 4-(benzyloxy)-2-fluoro 1-nitrobenzene (16.0 g. 64.7 mmol), THF (150 mL), and MeO EtOH (150 mL), and the mixture was stirred for 30 min at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (5.84g, 42% yield) as a light brown oil: "H NMR (300 MHz, CDC1): 8 ppm 3.42 (2H, brs), 4.97 (2H, s), 6.60 (1H, ddd, J=1.1, 2.6, 8.7 Hz), 6.67-6.74 (2H, m), 7.28-7.43 (5H, m). US 2012/0277430 A1 Nov. 1, 2012 77

Reference Example 139 1850. A solution of methyl 2-4-(benzyloxy)-2-fluo Methyl 2-4-(benzyloxy)-2-fluorophenylhydra rophenylhydrazono-4-methoxy-3-oxobutanoate (8.46 g. Zono-4-methoxy-3-oxobutanoate 22.6 mmol) in N,N-dimethylformamide dimethyl acetal (80 1847 mL) was refluxed for 3 h. After cooling to room temperature, O the reaction mixture was concentrated under reduced pres MeO COMe sure. The residue was diluted with AcOEt, washed with water and brine, dried over MgSO, and concentrated under reduced pressure. The residue was purified by silica gel col HN N umn chromatography eluting with THF and recrystallized from hexane/THF to give the title compound (8.12 g, 93% F yield) as a white solid: mp 143-144° C.; H NMR (300 MHz, CDC1): 8 ppm 3.89 (3H, s), 3.96 (3H, s), 5.12 (2H, s), 6.83-6.91 (2H, m), 7.33-744 (5H, m), 7.48-7.54 (1H, m), 7.69 (1H, d, J=2.3 Hz). Anal. Calcd for CHFNOs: C, O 62.50; H, 4.46; N, 7.29. Found: C, 62.40; H, 4.59; N, 7.26.

Reference Example 141 1-4-(Benzyloxy)-2-fluorophenyl-N,5-dimethoxy N-methyl-4-oxo-1,4-dihydropyridazine-3-carboxam 1848. A solution of NaNO, (2.07 g., 30 mmol) in HO (5 ide mL) was added dropwise at 0°C. to a mixture of 4-(benzy loxy)-2-fluoroaniline (5.43 g, 25 mmol) and 6 M HCl aque 1851 ous solution (25 mL, 150 mmol). After stirring for 15 min, the resulting aqueous Solution was added to a Suspension of methyl 4-methoxyacetoacetate (3.24 mL. 24 mmol) and NaOAc (12.3 g, 150 mmol) in MeOH (50 mL) pre-cooled at 0° C. The reaction mixture was poured into water and MeO Me extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was recrystallized from hexane/AcOEt to give OMe the title compound (8.48 g.91% yield) as a yellow solid: "H NMR (300 MHz, CDC1): 8 ppm 3.500 (3Hx0.46, s), 3.502 F (3Hx0.54, s), 3.88 (3Hx0.54, s), 3.92 (3Hx0.46, s), 4.65 (2Hx0.46, s), 4.68 (2Hx0.54, s), 5.06 (2Hx0.54, s), 5.07 (2Hx0.46, s), 6.75-6.86 (2H, m), 7.32-7.44 (5H, m), 7.53 (1Hx0.46, t, J=9.0 Hz), 7.76 (1Hx0.54, t, J=9.0 Hz), 13.12 (1Hx0.46, brs), 15.13 (1Hx0.54, brs). O Reference Example 140 Methyl 1-4-(benzyloxy)-2-fluorophenyl-5-meth oxy-4-oxo-1,4-dihydropyridazine-3-carboxylate 1849

1852 To a solution of N.O-dimethylhydroxylamine MeO COMe hydrochloride (5.27 g. 54 mmol) and iPr-NEt (9.41 mL, 54 mmol) in CHCl (50 mL) was added AlMe (1.8 M solution in toluene, 30 mL, 54 mmol) slowly at 0°C. under Ar atmo sphere. After stirring for 1 h, a solution of methyl 1-4-(ben Zyloxy)-2-fluorophenyl-5-methoxy-4-OXO-1,4-dihydropy ridazine-3-carboxylate (8.07 g. 21 mmol) in CHCl (50 mL) was added slowly, and the mixture was stirred for 1 h at 0°C. The reaction mixture was poured into ice-water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The resi due was purified by basic silica gel column chromatography eluting with AcOEt to give the title compound (7.79 g, 90% yield) as a pale yellow amorphous solid: "H NMR (300 MHz, CDC1): 8 ppm 3.38 (3H, s), 3.70 (3H, s), 3.89 (3H, s), 5.11 (2H, s), 6.82-6.91 (2H, m), 7.33-7.45 (5H, m), 7.48-7.55 (1H, m), 7.73 (1H, d, J=1.9 Hz). US 2012/0277430 A1 Nov. 1, 2012 78

Reference Example 142 due was partitioned between AcOEt and water. The organic layer was washed with brine, dried over MgSO filtered and 3-Acetyl-1-4-(benzyloxy)-2-fluorophenyl-5-meth concentrated under reduced pressure. The residue was chro oxypyridazin-4(1H)-one matographed on silica gel (0/100-5/95 AcOEt/hexane) to give a yellow oil. The residual oil was dissolved in THF (150 mL), 1853 and 1 M HCl aqueous solution (50 mL) was added to the mixture. After stirring at room temperature for 1 h, the mix

ture was basified with 8 M NaOH adueous solution and extracted with diethyl ether. The organic layer was washed with brine, dried over MgSO filtered and concentrated MeO under reduced pressure. The residue was chromatographed on silica gel (0/100-5/95 AcOEt/hexane) to give the title compound (4.2g, 85% yield) as a pale yellow oil: "H NMR (300 MHz, DMSO-d): 8 ppm 5.36 (2H, s), 6.75-6.85 (1H, F m), 6.89-6.94 (1H, m), 7.12 (1H, dd, J=11.7, 2.3 Hz). Reference Example 144 Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl hydrazono-4-methoxy-3-oxobutanoate 1857 O

O MeO COMe

HN1 N 1854 MeMgBr (1 M solution in THF, 56.4 mL, 56.4 mmol) was added dropwise at -78°C. to a solution of 1-4- F (benzyloxy)-2-fluorophenyl-N,5-dimethoxy-N-methyl-4- oxo-1,4-dihydropyridazine-3-carboxamide (7.77 g. 18.8 mmol) in THF (120 mL). After stirring for 1 h, the reaction mixture was quenched with 1 M HCl aqueous solution and extracted with AcOEt. The extract was washed with brine, OCF dried over MgSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatogra 1858. A solution of sodium nitrite (1.9 g, 28 mmol) in HO phy eluting with AcOEt and crystallized from hexane/AcOEt (10 mL) was added dropwise to a solution of 2-fluoro-4- to give the title compound (5.86g, 85% yield) as a paleyellow (trifluoromethoxy)aniline (4.6 g. 24 mmol) in 6 M HCl (24 mL, 144 mmol) at 0°C. After stirring for 15 min at 0°C.; the solid: mp 101-103° C.; H NMR (300 MHz, CDC1): 8 ppm mixture was added to a suspension of methyl 4-methoxyac 2.67 (3H, s), 3.89 (3H, s), 5.13 (2H, s), 6.84-6.93 (2H, m), etoacetate (3.1 mL. 24 mmol) and Sodium acetate (12 g, 144 7.34-7.44 (5H, m), 7.48-7.55 (1H, m), 7.69 (1H, d, J=2.3 Hz). mmol) in MeOH (50 mL) pre-cooled at 0°C. The formed Anal. Calcd for CHFNO: C, 65.21; H, 4.65; N, 7.60. precipitate was collected by filtration, washed with water and Found: C, 65.37; H, 4.68; N, 7.47. dried under reduced pressure to give the title compound (4.8 g, 58% yield) as yellow crystals: "H NMR (300 MHz, Reference Example 143 CDC1): 8 ppm 3.51 (3H, s), 3.94 (3H, s), 4.65 (2H, s), 2-Fluoro-4-(trifluoromethoxy)aniline 7.06-7.14 (2H, m), 7.59-7.68 (1H, m), 12.98 (1H, brs). Reference Example 145 1855 Methyl 1-2-fluoro-4-(trifluoromethoxy)phenyl-5- methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate NH2 1859 F

MeO

OCF

1856. A mixture of 4-bromo-3-fluoro(trifluoromethoxy) benzene (6.6 g. 26 mmol), benzophenone imine (6.4 mL, 38 mmol), Pd(dba) (0.58 g. 0.64 mmol), Xantphos (1.5g, 2.6 mmol) and sodium tert-butoxide (3.7 g., 38 mmol) in 1,4- dioxane (120 mL) was stirred at 100° C. under N atmosphere for 5 h. After stirring at room temperature overnight, the OCF mixture was concentrated under reduced pressure. The resi US 2012/0277430 A1 Nov. 1, 2012 79

1860. A solution of methyl 2-2-fluoro-4-(trifluo 1864. To a mixture of 1-2-fluoro-4-(trifluoromethoxy) romethoxy)phenylhydrazono-4-methoxy-3-oxobutanoate phenyl-5-methoxy-4-OXO-1,4-dihydropyridazine-3-car (3.8 g., 11 mmol) and N,N-dimethylformamide diisopropyl acetal (9.5 mL, 54 mmol) in toluene (60 mL) was refluxed for boxylic acid (3.8 g., 11 mmol), HOBt (2.5 g. 16 mmol) and 5 h. The mixture was concentrated under reduced pressure. WSC (3.1 g, 16 mmol) in DMF (50 mL) was added N.O- The residue was diluted with AcOEt, washed with water and dimethylhydroxylamine hydrochloride (2.1 g, 22 mmol) and brine. The organic layer was dried over MgSO filtered and EtN (4.5 mL, 32 mmol), and the mixture was stirred at room concentrated under reduced pressure. The residue was chro temperature overnight. The mixture was diluted with water matographed on silica gel (10/90-100/0 AcOEt/hexane) to give the title compound (3.4g, 86% yield) as pale yellow (200 mL) and extracted with AcOEt (250 mLx2). The com crystals: "H NMR (300 MHz, CDC1): 8 ppm 3.91 (3H, s), bined organic layer was washed with saturated NaHCO 3.97 (3H, s), 7.17-7.25 (2H, m), 7.68-7.76 (2H, m). aqueous solution and brine, dried over MgSO, filtered and Reference Example 146 concentrated under reduced pressure. 1-2-Fluoro-4-(trifluoromethoxy)phenyl-5-meth 1865. To a solution of the residue in THF (100 mL) was oxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid added dropwise 1 M MeMgBr in THF (18 mL, 18 mmol) at -78° C. for 15 min. After stirring at -78° C. for 1 h, the 1861 mixture was quenched with 1 M HCl aqueous solution (50 mL). The mixture was warmed to room temperature and extracted with AcOEt. The organic layer was washed with brine, dried over MgSO, filtered and concentrated under MeO reduced pressure to give the title compound (2.8 g. 75% yield) as a yellow oil: "H NMR (300 MHz, CDC1): 8 ppm 2.68 (3H, s), 3.91 (3H, s), 7.18-7.25 (2H, m), 7.69-7.77 (2H, m). Reference Example 148 Methyl 2-(3-bromo-2-fluorophenyl)hydrazono-4- methoxy-3-oxobutanoate OCF 1866 1862. To a solution of methyl 1-2-fluoro-4-(trifluo romethoxy)phenyl-5-methoxy-4-oxo-1,4-dihydropy O O ridazine-3-carboxylate (3.4g, 9.3 mmol) in THF (150 mL) MeO was added 1 MNaOH adueous solution (14 mL, 14 mmol), OMe and the mixture was stirred at room temperature for 30 min. The mixture was acidified with 1M HClaqueous solution and N concentrated under reduced pressure. The residue was diluted HN with AcOEt, washed with water and brine, dried over MgSO, filtered and concentrated under reduced pressure to give the F title compound (3.2g, 97% yield) as a pale yellow amorphous solid: "H NMR (300 MHz, DMSO-d): 8 ppm 3.88 (3H, s), 7.52-7.59 (1H, m), 7.86 (1H, dd, J=10.8, 2.5 Hz), 7.97 (1H, t, Br J=8.7 Hz), 8.91 (1H, d. J=1.1 Hz), 14.83 (1H, brs). Reference Example 147 3-Acetyl-1-(2-fluoro-4-(trifluoromethoxy)phenyl-5- methoxypyridaZin-4(1H)-one 1867 To a solution of tert-butyl (3-bromo-2-fluorophe 1863 nyl)carbamate (7.23 g, 24.9 mmol) in EtOAc (125 mL) was added 4 M HCl/EtOAc (62 mL) at 0°C. The mixture was

stirred at room temperature for 12 h and concentrated in vacuo. The residue was diluted with 6 M HCl aqueous solu MeO tion (62 mL). To the Suspension was added a solution of NaNO, (2.06 g, 29.9 mmol) in water (5 mL) at 0°C. To a Suspension of methyl 4-methoxy-3-oxobutanoate (3.22 mL. 24.9 mmol) and NaOAc (92.9 g) in EtOH (84 mL) was added the above mixture at 0°C. The mixture was stirred at 0°C. for 20 min. The precipitates were collected by filtration, diluted with EtOAc, washed with NaHCO, aqueous solution, dried over MgSO, filtered and concentrated in vacuo to yield the title compound (5.36 g. 62% yield) as a brown solid: 'HNMR OCF (DMSO-d 300 MHz): 8 ppm 3.30 (3H, s), 3.75-3.94 (3H, m), 4.56-4.71 (2H, m), 7.15-7.34 (1H, m), 7.37-7.59 (1H, m), 7.63-7.80 (1H, m), 12.26 (1H, s). US 2012/0277430 A1 Nov. 1, 2012 80

Reference Example 149 Reference Example 151 1-(3-Bromo-2-fluorophenyl)-N,5-dimethoxy-N-me Methyl 1-(3-bromo-2-fluorophenyl)-5-methoxy-4- thyl-4-oxo-1,4-dihydropyridazine-3-carboxamide OXO-1,4-dihydropyridazine-3-carboxylate 1872

1868

MeO

MeO

Br Br 1873. A mixture of 1-(3-bromo-2-fluorophenyl)-5-meth oxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (3.76 g. 1869. A mixture of methyl 2-(3-bromo-2-fluorophenyl) 11.0 mmol) and CDI (1.95 g, 12.1 mmol) in THF (38 mL) was heated to 40° C. for 2 h. To the solution were added N.O- hydrazono-4-methoxy-3-oxobutanoate (5.36 g. 15.4 mmol) dimethylhydroxylamine hydrochloride (1.60 g, 16.4 mmol) in N,N-dimethylformamide dimethyl acetal (54 mL) was and i-PrNEt (2.86 mL, 16.4 mmol) at room temperature. The heated to reflux for 2 hand cooled to 0°C. The precipitates mixture was stirred at room temperature for 18 h. The mixture were collected by filtration, washed with hexane and dried to was diluted with water and 1 M HCl aqueous solution, yield the title compound (4.16 g, 75% yield) as a brown solid: extracted with EtOAc, dried over NaSO, filtered, concen H NMR (DMSO-d 300 MHz): 8 ppm 3.80 (3H, s), 3.83 trated in vacuo and purified by column chromatography on (3H, s), 7.40 (1H, td, J=8.1, 1.1 Hz), 7.75-7.84 (1H, m), 7.94 basic silica gel (EtOAc/MeOH=100/0 to 80/20) to yield the (1H, ddd, J=8.1, 6.4, 1.7 Hz), 8.60 (1H, d. J=1.9 Hz). title compound (4.22 g, >99% yield) as a white solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 3.25 (3H, s), 3.58 (3H, s), 3.80 (3H, s), 7.39 (1H, td, J=8.1, 1.5 Hz), 7.78 (1H, ddd, Reference Example 150 J=8.2, 6.9, 1.5 Hz), 7.92 (1H, ddd, J=8.0, 6.3, 1.5 Hz), 8.58 (1H, s). 1-(3-Bromo-2-fluorophenyl)-5-methoxy-4-oxo-1,4- dihydropyridazine-3-carboxylic acid Reference Example 152 3-Acetyl-1-(3-bromo-2-fluorophenyl)-5-methoxypy 1870 ridazin-4(1H)-one 1874

MeO MeO

Br Br

1871 To a suspension of methyl 1-(3-bromo-2-fluorophe 1875 To a solution of 1-(3-bromo-2-fluorophenyl)-N.5- nyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-car (4.16g, 11.7 mmol) in MeOH (46 mL) was added 1 MNaOH boxamide (4.22 g, 10.9 mmol) in THF (218 mL) was added aqueous solution (23 mL) at 0°C. The mixture was stirred at MeMgBr (1.0 M in THF, 16.4 mL, 16.4 mmol) at -78° C. room temperature for 1 h. To the solution was added 1 MHCl under N. The mixture was stirred at -78° C. for 2 h. The aqueous solution (23 mL) at 0°C. The mixture was concen reaction was quenched with saturated NHCl aqueous solu trated in vacuo. The precipitates were collected by filtration, tion at -78°C. The mixture was diluted with NaHCO aque washed with water and dried in vacuo at 50° C. to yield the ous solution, extracted with EtOAc, dried over NaSO fil title compound (3.76g,94% yield) as a pale yellow solid: "H tered, concentrated in vacuo and purified by column NMR (DMSO-d 300 MHz): 8 ppm 3.87 (3H, s), 7.43 (1H, chromatography on silica gel (EtOAc/MeOH=100/0 to td, J=8.1, 1.5 Hz), 7.76-7.85 (1H, m), 7.98 (1H, ddd, J=8.0, 50/50) to yield the title compound (3.48 g., 93% yield) as a 6.5, 1.3 Hz), 8.86 (1H, s), 14.84 (1H, brs). yellow solid: 'H-NMR (DMSO-de, 300 MHz): 8 ppm 2.50 US 2012/0277430 A1 Nov. 1, 2012

(3H, s), 3.80 (3H, s), 7.36-7.46 (1H, m), 7.77-7.85 (1H, m), 18.1 mmol) in N,N-dimethylformamide dimethyl acetal (63 7.89-7.99 (1H, m), 8.57 (1H, d, J=1.9 Hz). mL) was heated to reflux for 2.5 h. The mixture was concen trated in vacuo and purified by column chromatography on Reference Example 153 silica gel (hexane/EtOAc=5 0/50 to 0/100 and EtOAc/ MeOH=100/0 to 70/30) and on basic silica gel (hexane/ Methyl 4-methoxy-3-oxo-2-(2.2,6-trifluoro-1,3- EtOAc=50/50 to 0/100) to yield the title compound (1.53 g, benzodioxol-5-yl)hydrazonobutanoate 24% yield) as a pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 3.79 (3H, s), 3.82 (3H, s), 7.94 (1H, d, J–9.4 1876 Hz), 8.04 (1H, d, J–6.4 Hz), 8.54 (1H, s). Reference Example 155 O O 5-Methoxy-4-oxo-1-(2.2,6-trifluoro-1,3-benzo dioxol-5-yl)-1,4-dihydropyridazine-3-carboxylic MeO acid OMe 1880 HN N

F MeO OH

O O F F F

1877. To a suspension of 2.2,6-trifluoro-1,3-benzodioxol O 5-amine (4.95 g, 25.9 mmol) in 6 M HCl aqueous solution (25.9 mL) was added a solution of NaNO, (2.15 g, 31.1 O mmol) in water (5.2 mL) at 0°C. To a suspension of methyl F 4-methoxy-3-oxobutanoate (3.35 mL, 25.9 mmol) and F NaOAc (38.9 g) in EtOH (44 mL) was added the above 1881. To a suspension of methyl 5-methoxy-4-oxo-1-(2, solution at 0°C. The mixture was stirred at 0°C. for 10 min. 2,6-trifluoro-1,3-benzodioxol-5-yl)-1,4-dihydropyridazine The precipitates were collected by filtration, washed with 3-carboxylate (1.53 g, 4.27 mmol) in MeOH (17 mL) was water, dissolved in EtOAc, washed with brine and NaHCO added 1 M NaOH acqueous solution (8.5 mL) at 0°C. The aqueous solution, dried over MgSO filtered and concen mixture was stirred at room temperature for 30 min. To the trated in vacuo to yield the title compound (6.31 g, 70% yield) mixture was added 1 M HCl aqueous solution (8.5 mL) at 0° as a red solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 3.33 C. The mixture was concentrated in vacuo. The precipitates (3H, s), 3.82 (3H, s), 4.66 (2H, s), 7.57-7.92 (2H, m), 12.32 were collected by filtration, washed with water and dried in (1H, brs). vacuo at 60°C. to yield the title compound (1.18 g. 80% yield) as a pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 Reference Example 154 ppm 3.86 (3H, s), 7.98 (1H, d, J–9.4 Hz), 8.03 (1H, d, J=6.4 Methyl 5-methoxy-4-oxo-1-(2,2,6-trifluoro-1,3-ben Hz), 8.79 (1H, s), 14.77 (1H, brs). Zodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylate Reference Example 156 3-Amino-5-methoxy-1-(2.2,6-trifluoro-1,3-benzo 1878 dioxol-5-yl)pyridazin-4(1H)-one 1882

MeO

MeO

1879. A mixture of methyl 4-methoxy-3-oxo-2-(2.2.6- trifluoro-1,3-benzodioxol-5-yl)hydrazonobutanoate (6.31 g, US 2012/0277430 A1 Nov. 1, 2012

1883. A mixture of 5-methoxy-4-oxo-1-(2.2,6-trifluoro 1887 To a suspension of 2,2,3,3,7-pentafluoro-2,3-dihy 1,3-benzodioxol-5-yl)-1,4-dihydropyridazine-3-carboxylic dro-1,4-benzodioxin-6-amine (4.87 g. 20.2 mmol) in 6 M acid (1.18 g, 3.42 mmol), DPPA (1.10 mL, 5.13 mmol) and HCl aqueous solution (20.2 mL) was added a solution of NaNO, (1.67 g, 24.2 mmol) in water (4 mL) at 0°C. The EtN (0.715 mL, 5.13 mmol) in toluene (12 mL) was heated mixture was stirred at 0°C. for 15 min. To a suspension of to 100° C. for 1 h. To the mixture was added 8 M NaOH methyl 4-methoxy-3-oxobutanoate (2.61 mL. 20.2 mmol) aqueous solution (4.3 mL) at 0°C. The mixture was stirred at and NaOAc (303 g) in EtOH (34 mL) was added the above room temperature for 1 h, extracted with EtOAc, dried over solution at 0°C. The mixture was stirred at 0°C. for 15 min. NaSO, filtered, concentrated in vacuo and purified by col The precipitates were collected by filtration, washed with umn chromatography on basic silica gel (hexane/EtOAc=50/ water, dissolved in EtOAc, washed with brine, dried over 50 to 0/100) and recrystallized with EtOAc/hexane to yield MgSO filtered and concentrated in vacuo to yield the title the title compound (704 mg. 65% yield) as a white solid: "H compound (6.84 g. 85% yield) as a red solid: "H NMR NMR (DMSO-d,300MHz): 8 ppm 173 (3H, s), 6.21 (2H, s), DMSO-de, 300 MHz): 8 ppm 3.33 (3H, s), 3.82 (3H, s), 4.68 7.85 (1H, d, J=9.4 Hz), 7.90 (1H, d, J=6.4 Hz), 8.33 (111, s). 2H, s), 7.66-7.93 (2H, m), 12.16 (1H, brs). Reference Example 157 Reference Example 159 3-Bromo-5-methoxy-1-(2.2,6-trifluoro-1,3-benzo Methyl 5-methoxy-4-oxo-1-(2,2,3,3,7-pentafluoro-2, dioxol-5-yl)pyridazin-4(1H)-one 3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydropy ridazine-3-carboxylate 1884 1888

MeO MeO

F F

O O O F O F F F 1885. To a mixture of isoamyl nitrite (0.22 mL, 1.65 F F mmol) and CuBr (0.17g, 0.762 mmol) in DMF (2 mL) was 1889. A mixture of methyl 4-methoxy-3-oxo-2-(2.2.3.3. added a mixture of 3-amino-5-methoxy-1-(2.2,6-trifluoro-1, 7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)hydra 3-benzodioxol-5-yl)pyridazin-4(1H)-one (200 mg. 0.635 Zonobutanoate (6.84g, 17.2 mmol) in N,N-dimethylforma mmol) in DMF (4 mL) at 0°C. The mixture was stirred at 0° mide dimethyl acetal fis mL) was heated to reflux for 2.5 h. C. for 1 h and at 60° C. for 2 h. The mixture was diluted with The mixture was concentrated in vacuo, diluted with brine, water and brine, extracted with EtOAc, dried over NaSO, extracted with EtOAc, dried over MgSO filtered, concen filtered, concentrated in vacuo and purified by column chro trated in vacuo and purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/ matography on silica gel (hexane/EtOAc=50/50 to 0/100) to MeOH-100/0 to 70/30) and on basic silica gel (hexane/ yield the title compound (145 mg, 60% yield) as a pale yellow EtOAc=80/20 to 0/100 and EtOAc/MeOH-100/0 to 70/30) to solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 3.79 (3H, s), yield the title compound (2.58 g., 37% yield) as a pale yellow 7.93 (1H, d, J=9.5 Hz), 8.02 (1H, d, J=6.4 Hz), 8.59 (1H, d, solid: "H NMR (DMSO-d 300 ME: 8 ppm 3.79 (3H, s), J=1.5 Hz). 3.83 (3H, s), 8.01 (1H, d, J=10.2 Hz), 8.16 (1H, d, J–7.2 Hz s Reference Example 158 8.58 (1H, s). Methyl 4-methoxy-3-oxo-2-(2,2,3,3,7-pentafluoro Reference Example 160 2,3-dihydro-1,4-benzodioxin-6-yl)hydrazonobu 5-Methoxy-4-oxo-1-(2,2,3,3,7-pentafluoro-2,3-dihy tanoate dro-1,4-benzodioxin-6-yl)-1,4-dihydropyridazine-3- 1886 carboxylic acid 1890

MeO MeO OMe US 2012/0277430 A1 Nov. 1, 2012

1891 To a solution of methyl 5-methoxy-4-oxo-1-(2.2.3, 1895. To a mixture of isoamyl nitrite (0.473 mL, 3.56 3.7-pentafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-di mmol) and CuBr (367 mg, 1.64 mmol) in DMF (5 mL) was hydropyridazine-3-carboxylate (2.58 g. 6.31 mmol) in added a mixture of 3-amino-5-methoxy-1-(2,2,3,3,7-pen MeOH (26 mL) was added 1 MNaOH adueous solution (13 tafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)pyridazin-4 mL) at 0°C. The mixture was stirred at room temperature for (1H)-one (500 mg, 1.37 mmol) in DMF (2.5 mL) at 0°C. The 90 min. To the mixture was added 1 M HCl aqueous solution mixture was stirred at 0°C. for 1 h and at 60° C. for 2.5 h. The (13 mL) at 0°C. The mixture was concentrated in vacuo. The mixture was diluted with water and brine, extracted with precipitates were collected by filtration, washed with water EtOAc, dried over MgSO, filtered, concentrated in vacuo, and dried in vacuo at 60°C. to yield the title compound (2.33 purified by column chromatography on silica gel (hexane/ g, 94% yield) as a white solid: "H NMR (DMSO-de, 300 EtOAc=50/50 to 0/100) and crystallized with EtOH/hexane MHz): 8 ppm 3.86 (3H, s), 8.06 (1H, d, J=10.2 Hz), 8.17 (1H, to yield the title compound (381 mg, 65% yield) as a white d, J=6.8 Hz), 8.82 (1H, s), 14.66 (1H, brs). solid: "H NMR (DMSO-d 300 MHz): 8 ppm 3.79 (3H, s), Reference Example 161 8.02(1H, d, J=10.5 Hz), 8.14 (1H, d, J=6.8 Hz), 8.63 (1H, s). 3-Amino-5-methoxy-1-(2,2,3,3,7-pentafluoro-2,3- Reference Example 163 dihydro-1,4-benzodioxin-6-yl)pyridazin-4(1H)-one 1-2-Fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl-N, 1892 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropy ridazine-3-carboxamide 1896 MeO

MeO

(M N 1893. A mixture of 5-methoxy-4-oxo-1-(2,2,3,3,7-pen M/ tafluoro-2,3-dihydro-1,4-benzodioxin-6-yl)-1,4-dihydropy ridazine-3-carboxylic acid (2.33 g, 5.91 mmol), DPPA (1.90 1897. A mixture of 1-(3-bromo-2-fluorophenyl)-N.5- mL, 8.86 mmol) and Et-N (1.23 mL, 8.86 mmol) in toluene dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-car (23 mL) was heated to 100° C. for 90 min. To the mixture was boxamide (500 mg, 1.29 mmol), 1-methyl-4-(4.4.5.5-tetram added 8 M NaOH adueous solution (7.4 mL) at 0°C. The ethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (295 mg, 1.42 mixture was stirred at room temperature for 2 h, extracted mmol), NaCO (302 mg, 2.85 mmol) and Pd(PPh) (74.5 with EtOAc, dried over NaSO filtered, concentrated in mg, 0.0645 mmol) in DME (11.4 mL) and water (2.9 mL) was vacuo, purified by column chromatography on basic silica gel heated to reflux for 15 hunder Ar. The mixture was diluted with water, extracted with EtOAc, washed with brine, dried (hexane/EtOAc=50/50 to 0/100) and on silica gel (hexane/ over NaSO filtered, concentrated in vacuo, and purified by EtOAc=80/20 to 0/100) and triturated with EtOAc/hexane to column chromatography on basic silica gel (EtOAC/ yield the title compound (1.12 g, 53% yield) as a white solid: MeOH=100/0 to 70/30) to yield the title compound (345 mg, H NMR (DMSO-d 300 MHz): 8 ppm 3.73 (3H, s), 6.24 69% yield) as a white solid: "H NMR (DMSO-d,300MHz): (2H, s), 7.92 (1H, d, J=10.5 Hz), 7.99 (1H, d, J=6.8 Hz), 8.37 8 ppm 3.25 (3H, s), 3.59 (3H, s), 3.80 (3H, s), 3.90 (3H, s), (1H, d, J=1.5 Hz). 7.35-7.44 (1H, m), 7.50-7.59 (1H, m), 7.84-7.94 (1H, m), Reference Example 162 7.97 (1H, s), 8.23 (1H, d, J=2.5 Hz), 8.58 (1H, s). 3-Bromo-5-methoxy-1-(2,2,3,3,7-pentafluoro-2,3- Reference Example 164 dihydro-1,4-benzodioxin-6-yl)pyridazin-4(1H)-one 3-Acetyl-1-(2-fluoro-3-(1-methyl-1H-pyrazol-4-yl) 1894 phenyl-5-methoxypyridazin-4(1H)-one 1898 MeO

MeO

F

(N N M/ US 2012/0277430 A1 Nov. 1, 2012

1899. To a solution of 1-2-fluoro-3-(1-methyl-1H-pyra 1903. A mixture of methyl 2-(2-fluoro-5-iodophenyl)hy Zol-4-yl)phenyl-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihy drazono-4-methoxy-3-oxobutanoate (14.2g, 35.9 mmol) in dropyridazine-3-carboxamide (345 mg, 0.890 mmol) in THF N,N-dimethylformamide dimethyl acetal (142 mL) was (100 mL) was added MeMgBr (1.0 M in THF, 2.67 mL, 2.67 heated to reflux for 1.5 hand cooled to 0°C. The precipitates mmol) at -78°C. under N. The mixture was stirred at -78° were collected by filtration, washed with hexane and dried to C. for 100 min. The reaction was quenched with saturated yield the title compound (11.3 g 78% yield) as a pale yellow NHCl aqueous solution at -78° C. The mixture was solid: "H NMR (DMSO-d 300 MHz): 8 ppm 3.80 (3H, s), extracted with EtOAc, dried over NaSO filtered, concen 3.82 (3H, s), 7.37 (1H, dd, J=10.6, 8.7 Hz), 7.90-8.01 (1H, m), trated in vacuo and purified by column chromatography on 8.14 (1H, dd, J=7.2, 2.3 Hz), 8.55 (1H, s). silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title Reference Example 167 compound (243 mg, 80% yield) as a white solid: "H NMR 1-(2-Fluoro-5-iodophenyl)-5-methoxy-4-oxo-1,4- (DMSO-de, 300 MHz): 8 ppm 2.51 (3H, brs), 3.81 (3H, s), dihydropyridazine-3-carboxylic acid 3.91 (3H, s), 7.38-7.46 (1H, m), 7.54-7.64 (1H, m), 7.86-7.95 (1H, m, J=15.0, 1.7 Hz), 7.98 (1H, s), 8.25 (1H, d, J=2.3 Hz), 1904 8.58 (1H, d, J=1.9 Hz). Reference Example 165 Methyl 2-(2-fluoro-5-iodophenyl)hydrazono-4- methoxy-3-oxobutanoate MeO 1900

O O

MeO OMe HN1 N 1905 To a suspension of methyl 1-(2-fluoro-5-iodophe F nyl)-5-methoxy-4-oxo-1,4-dihydropyridazine-3-carboxylate (11.3 g, 28.1 mmol) in MeOH (112 mL) was added 1 M NaOH acqueous solution (56 mL) at 0°C. The mixture was stirred at room temperature for 90 min. To the mixture was I added 1 MHClaqueous solution (56 mL) at 0°C. The mixture was concentrated in vacuo. The precipitates were collected by 1901 To a suspension of 2-fluoro-5-iodoaniline (9.83 g, filtration, washed with water and dried in vacuo at 60° C. to 41.5 mmol) in 6 M HCl aqueous solution (83.0 mL) was yield the title compound (9.96g, 91% yield) as a yellow solid: added a solution of NaNO (3.43 g, 49.8 mmol) in water (8.3 H NMR (DMSO-d 300 MHz): 8 ppm 3.88 (3H, s), 7.42 mL) at 0°C. To a suspension of methyl 4-methoxy-3-oxobu (1H, dd, J–10.6, 8.7 Hz), 8.00 (1H, ddd, J=8.7, 4.5, 2.3 Hz), tanoate (5.37 mL, 41.5 mmol) and NaOAc (124 g) in EtOH 8.16 (1H, dd, J=7.2, 2.3 Hz), 8.85 (1H, s), 14.86 (1H, brs). (70 mL) was added the above solution at 0°C. The mixture Reference Example 168 was stirred at 0°C. for 10 min. The precipitates were collected by filtration, washed with water, dissolved in EtOAc, washed 1-(2-Fluoro-5-iodophenyl)-N,5-dimethoxy-N-me with brine, dried over MgSO filtered and concentrated in thyl-4-oxo-1,4-dihydropyridazine-3-carboxamide vacuo to yield the title compound (14.2g, 87% yield) as a red 1906 solid: "H NMR (DMSO-de, 300 MHz): 8 ppm 3.31 (3H, s),

3.83 (3H, s), 4.64 (2H, s), 7.03-7.41 (1H, m), 7.43-7.66 (1H, m), 7.85-8.07 (1H, m), 12.20 (1H, brs). Reference Example 166 MeO Methyl 1-(2-fluoro-5-iodophenyl)-5-methoxy-4-oxo 1,4-dihydropyridazine-3-carboxylate 1902

MeO 1907. A mixture of 1-(2-fluoro-5-iodophenyl)-5-meth oxy-4-oxo-1,4-dihydropyridazine-3-carboxylic acid (9.96 g. 25.5 mmol) and CDI (4.55g, 28.1 mmol) in THF (200 mL) was heated to 40°C. for 30 min and 50° C. for 90 min. To the mixture was added DMF (20 mL). The mixture was stirred at 50° C. for 70 min. To the solution were added N.O-dimeth ylhydroxylamine hydrochloride (3.74 g. 38.3 mmol) and i-PrNEt (6.67 mL, 38.3 mmol) at room temperature. The solution was stirred at room temperature for 16h. The mixture US 2012/0277430 A1 Nov. 1, 2012

was concentrated in vacuo, diluted with water and 1 M HCl 1911. To a mixture of 1-2-fluoro-5-(1-methyl-1H-pyra aqueous solution, extracted with EtOAc, washed with Satu Zol-4-yl)phenyl-N,5-dimethoxy-N-methyl-4-oxo-1,4-dihy rated NaHCO, aqueous solution, dried over NaSO filtered, dropyridazine-3-carboxamide (267mg, 0.687 mmol) in THF concentrated in vacuo and purified by column chromatogra (80 mL) was added MeMgBr (1.0 M in THF, 2.06 mL 2.06 phy on silica gel (hexane/EtOAc=20/80 to 0/100 and EtOAc/ mmol) at -78°C. under N. The mixture was stirred at -78° MeOH=100/0 to 0/100) and triturated with MeOH/EtOH/ C. for 2h. To the mixture was added MeMgBr (1.0 M in THF, hexane to yield the title compound (9.11 g, 82% yield) as a 0.687 mL, 0.687 mmol) at -78°C. The mixture was stirred at pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 ppm -78°C. for 1 h. To the mixture was added MeMgBr (1.0 M in 3.24 (3H, s), 3.56 (3H, s), 3.80 (3H, s), 7.36 (1H, dd, J=10.6, TI-IF, 1.37 mL, 1.37 mmol) at -78° C. The mixture was 8.7 Hz), 7.93 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.12 (1H, dd, stirred at -78° C. for 3 h. The reaction was quenched with J–7.4, 2.1 Hz), 8.53 (1H, s). saturated NHCl aqueous solution at -78°C. The mixture was diluted with saturated NaHCO aqueous solution, Reference Example 169 extracted with EtOAc, dried over NaSO, filtered, concen 1-2-Fluoro-5-(1-methyl-1H-pyrazol-4-yl)phenyl-N, trated in vacuo and purified by column chromatography on 5-dimethoxy-N-methyl-4-oxo-1,4-dihydropy silica gel (EtOAc/MeOH=100/0 to 70/30) to yield the title ridazine-3-carboxamide compound (201 mg. 85% yield) as a yellow solid: "H NMR 1908 (DMSO-d 300 MHz): 8 ppm 2.52 (3H, s), 3.82 (3H, s), 3.87 (3H, s), 7.53 (1H, dd, J=10.6, 8.7 Hz), 7.78 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 7.92-8.00 (2H, m), 8.23 (1H, s), 8.56 (1H, d, MeO J=1.5 Hz). Reference Example 171 1-(Difluoromethyl)-1H-pyrazole-4-boronic acid pinacol ester F 1912 F

e N-Me N / N 1909. A mixture of 1-(2-fluoro-5-iodophenyl)-N,5- )-ch dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-car 1913. A suspension of 1H-pyrazole-4-boronic acid pina boxamide (500 mg, 1.15 mmol), 1-methyl-4-(4.4.5.5-tetram col ester (5.16 g. 26.6 mmol), CFCICONa (4.86 g. 31.9 ethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (264 mg, 1.27 mmol), and 18-crown-6 (1.41 g, 5.32 mmol) in CHCN (100 mmol), NaCO (268 mg, 2.53 mmol) and Pd(PPh3)4 (66.4 mL) was refluxed for 20h. After cooling to room temperature, mg, 0.0575 mmol) in DME (10.1 mL) and water (2.5 mL) was the reaction mixture was poured into water and extracted with heated to reflux for 14 h under Ar. The mixture was diluted AcOEt. The extract was washed with brine, dried over with water, brine and saturated NaHCO aqueous solution, MgSO, and concentrated under reduced pressure. The resi extracted with EtOAc, dried over NaSO filtered, concen due was purified by basic silica gel column chromatography trated in vacuo, and purified by column chromatography on eluting with AcOEt to give the title compound (3.03 g, 47% basic silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/ yield) as a yellow oil: "H NMR (300 MHz, CDC1): 8 ppm MeOH=100/0 to 60/40) to yield the title compound (267 mg, 1.33 (12H, s), 7.22(1H, t, J=60.7 Hz), 7.89 (1H, s), 8.13 (1H, 60% yield) as a pale yellow solid: "H NMR (DMSO-de, 300 S). MHz): 8 ppm 3.25 (3H, s), 3.59 (3H, s), 3.82 (3H, s), 3.87 Reference Example 172 (3H, s), 7.51 (1H, dd, J=10.4, 8.9 Hz), 7.73-7.80 (1H, m), tert-Butyl 1-3-fluoro-4-5-methoxy-4-oxo-3-(1- 7.89-7.97 (2H, m), 8.23 (1H, s), 8.58 (1H, s). phenyl-1H-pyrazol-5-yl)pyridazin-1 (4H)-yl) Reference Example 170 phenyl hydrazinecarboxylate 3-Acetyl-1-(2-fluoro-5-(1-methyl-1H-pyrazol-4-yl) 1914 phenyl-5-methoxypyridazin-4(1H)-one

1910

MeO

MeO US 2012/0277430 A1 Nov. 1, 2012

1915. A suspension of 1-(2-fluoro-4-iodophenyl)-5-meth 1919 2-Aminobenzonitrile (5.00 g, 42.37 mmol) was oxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one added to a solution of 30 mL of phosphoric acid (85%) and 20 (2.44 g. 5.0 mmol), tert-butyl carbazate (0.727g, 5.5 mmol), mL of nitric acid (65%) at -6°C., followed by sodium nitrite CuI(0.0095g, 0.05 mmol), 1,10-phenanthroline (0.072g, 0.4 (3.50 g, 50.78 mmol) in 10 mL of water dropwise at 0°C., and mmol), and CsCO, (2.28 g, 7.0 mmol) in DMF (25 mL) was stirred for 5 hat 100° C. under Ar atmosphere. After cooling the mixture was stirred at 0° C. for 30 min. Then, to the to room temperature, the reaction mixture was poured into reaction mixture was added dropwise a solution of potassium water and extracted with AcOEt three times. The combined acetate (12.45 g, 127.11 mmol) and acetylacetone (5.51 g, extracts were washed with water and brine, dried over 55.08 mmol) in 80 mL of ethanol and 48 mL of water. The MgSO, and concentrated under reduced pressure. The resi mixture was stirred at room temperature overnight, filtered, due was purified by basic silica gel column chromatography washed with water, EtOH/HO (1/1) and hexane, and dried to eluting with AcOEt and crystallized from hexane/AcOEt to give the title compound (4.00 g, 41% yield): 'H NMR (400 give the title compound (2.04 g, 83% yield) as a pale yellow solid: mp 163-165° C.; H NMR (300 MHz, CDC1): 8 ppm MHz, CDC1): 8 ppm 2.50 (3H, s), 2.63 (3H, s), 7.21-7.25 1.58 (9H, s), 3.90 (3H, s), 4.36 (2H, s), 6.31 (1H, t, J=9.0 Hz), (1H, m), 7.62-7.66 (2H, m), 7.77-7.79 (1H, m), 15.01 (1H, s). 7.28-7.45 (7H, m), 7.55 (1H, dd, J=2.3, 14.3 Hz), 7.78 (2H, d, J=1.9 Hz). Anal. Calcd for CHFNO: C, 60.97; H, 5.12: Reference Example 175 N, 17.06. Found: C, 61.20; H, 5.13: N, 16.81. 3-(Biphenyl-2-ylhydrazono)pentane-2,4-dione Reference Example 173 3-(2-(1-Methylethyl)phenylhydrazono}pentane-2, 1920 4-dione 1916

O O

HN1 N

1921 Biphenyl-2-amine (500 mg, 2.96 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of 1917 2-(1-Methylethyl)aniline (2.00 g, 14.81 mmol) was nitric acid (65%) at -6°C., followed by sodium nitrite (254 added to a solution of 12 mL of phosphoric acid (85%) and 8 mg, 3.55 mmol) in 1 mL of water dropwise at 0°C., and the mL of nitric acid (65%) at -6°C., followed by sodium nitrite mixture was stirred at 0°C. for 30 min. Then, to the reaction (1.23g, 17.78 mmol) in 4 mL of water dropwise at 0°C., and mixture was added dropwise a solution of potassium acetate the mixture was stirred at 0° C. for 30 min. Then, to the (870 mg, 8.88 mmol) and acetylacetone (385 mg, 3.85 mmol) reaction mixture was added dropwise a solution of potassium in 60 mL of ethanol and 32 mL of water. The mixture was acetate (4.35 g, 44.43 mmol) and acetylacetone (1.92g, 19.25 mmol) in 80 mL of ethanol and 20 mL of water. The mixture stirred at room temperature overnight, filtered, washed with was stirred at room temperature overnight, filtered, washed water, EtOH/HO (1/1) and hexane, and dried to give the title with water, EtOH/HO (1/1) and hexane, and dried to give the compound (420 mg, 51% yield): 'H NMR (400 MHz, title compound (0.98 g., 27% yield): 'H NMR (400 MHz, CDC1): 8 ppm 2.51 (3H, s), 2.52 (3H, s), 7.29-7.60 (9H, m), CDC1): 8 ppm 1.34 (6H, d, J=6.8 Hz), 2.52 (3H, s), 2.63 (3H, 14.63 (1H, s). s), 3.12-3.21 (1H, m), 7.19-7.23 (1H, m), 7.28-7.34 (2H, m), 7.77-8.00 (1H, m), 15.23 (1H, brs). Reference Example 176 Reference Example 174 2-2-(1-Acetyl-2-oxopropylidene)hydrazinoben 3-(2-Ethoxyphenyl)hydrazonopentane-2,4-dione Zonitrile 1922 1918

EtO NC US 2012/0277430 A1 Nov. 1, 2012

1923 2-Ethoxyaniline (2.00 g, 14.60 mmol) was added to 1927 2-(Trifluoromethoxy)aniline (1.00 g, 5.64 mmol) a solution of 12 mL of phosphoric acid (85%) and 8 mL of was added to a solution of 6 mL of phosphoric acid (85%) and nitric acid (65%) at -6°C., followed by sodium nitrite (1.21 4 mL of nitric acid (65%) at -6°C., followed by sodium nitrite g, 17.52 mmol) in 10 mL of water dropwise at 0°C., and the (389 mg, 5.64 mmol. 1.0 equiv.) in 2 mL of water dropwise at mixture was stirred at 0°C. for 30 min. Then, to the reaction 0°C., and the mixture was stirred at 0°C. for 30 min. Then to mixture was added dropwise a solution of potassium acetate the reaction mixture was added dropwise a mixture of potas (4.29 g, 43.80 mmol) and acetylacetone (1.90 g, 18.98 mmol) in 60 mL of ethanol and 25 mL of water. The mixture was sium acetate (1.66 g. 16.92 mmol) and acetylacetone (564 stirred at room temperature overnight; filtered, washed with mg, 5.64 mmol) in 80 mL of ethanol and 48 mL of water. The water, EtOH/HO (1/1) and hexane, and dried to give the title mixture was stirred at room temperature overnight, filtered, compound (2.00 g, 55% yield): 'H NMR (400 MHz, CDC1): washed with water, EtOH/HO (1/1) and hexane, and dried to 8 ppm 1.57 (3H, t, J=7.2 Hz), 2.53 (3H, s), 2.63 (3H, s), 4.20 give the title compound (1.3 g, 80% yield): 'H NMR (400 (2H, t, J=7.2 Hz), 7.03-7.07 (1H, m), 7.14-7.18 (1H, m), MHz, CDC1): 8 ppm2.54 (s.3H), 2.65 (s.3H), 7.20-7.24 (m, 7.74-7.84 (2H, m), 14.86 (1H, s). 1H), 7.33-7.42 (m, 2H), 7.87 (dd, J–8.4, 1.6 Hz, 1H), 14.86 (s, 1H). Reference Example 177 3-2-(1-Methylethoxy)phenylhydrazonopentane Reference Example 179 2,4-dione 3-(2-Phenoxyphenyl)hydrazonopentane-2,4-dione 1924 1928

N Cr?)HN1 1925 2-(1-Methylethoxy)aniline (1.00 g. 6.62 mmol) was added to a solution of 6 mL of phosphoric acid (85%) and 4 1929 2-Phenoxyaniline (2.00 g, 10.81 mmol) was added mL of nitric acid (65%) at -6°C., followed by sodium nitrite to a solution of 12 mL of phosphoric acid (85%) and 8 mL of (0.55g, 7.95 mmol) in 2 mL of water dropwise at 0°C., and nitric acid (65%) at -6°C., followed by sodium nitrite (0.90 the mixture was stirred at 0° C. for 30 min. Then, to the g, 12.97 mmol) in 2 mL of water dropwise at 0°C., and the reaction mixture was added dropwise a solution of potassium mixture was stirred at 0°C. for 30 min. Then, to the reaction acetate (1.95 g. 19.86 mmol) and acetylacetone (0.86 g, 8.61 mixture was added dropwise a mixture of potassium acetate mmol) in 40 mL of ethanol and 10 mL of water. The mixture (3.18 g. 32.43 mmol) and acetylacetone (1.40 g, 14.05 mmol) was stirred at room temperature overnight, filtered, washed in 80 mL of ethanol and 48 mL of water. The mixture was with water, EtOH/HO (1/1) and hexane, and dried to give the stirred at room temperature overnight, filtered, washed with title compound (0.53 g, 30% yield): 'H NMR (400 MHz, water, EtOH/HO (1/1) and hexane, and dried to give the title CDC1): 8 ppm 1.28-1.41 (6H, m), 2.50 (3H, s), 2.63 (3H, s), compound (1.00 g, 31% yield): 'H NMR (400 MHz, CDC1): 4.53-4.59 (1H, m), 7.21-7.25 (1H, m), 7.62-7.66 (2H, m), 8 ppm 2.50 (3H, s), 2.63 (3H, s), 7.26-7.88 (9H, m), 14.91 7.77-7.79 (1H, m), 15.01 (1H, s). (1H, s). Reference Example 178 Reference Example 180 3-2-(Trifluoromethoxy)phenyl 3-2-(Methylsulfinyl)phenylhydrazono pentane-2, hydrazonopentane-2,4-dione 4-dione 1926 1930 US 2012/0277430 A1 Nov. 1, 2012

1931 2-(Methylsulfinyl)aniline (0.50 g, 3.22 mmol) was 1935 N-(4-Aminophenyl)acetamide (1000 mg. 6.66 added to a solution of 3 mL of phosphoric acid (85%) and 2 mmol) was added to a solution of 6 mL of phosphoric acid mL of nitric acid (65%) at -6°C., followed by sodium nitrite (0.27g, 3.87 mmol) in 2 mL of water dropwise at 0°C., and (85%) and 4 mL of nitric acid (65%) at -6° C. When the the mixture was stirred at 0° C. for 30 min. Then, to the mixture reached to room temperature, it was cooled to -6°C. reaction mixture was added dropwise a mixture of potassium and solid sodium nitrite (460 mg. 6.66 mmol) was added acetate (0.95 g, 9.66 mmol) and acetylacetone (0.42 g, 4.19 during 10 min. Small piece of ice (50 g) was added into the mmol) in 80 mL of ethanol and 48 mL of water. The mixture solution. The mixture was added at 0°C. to a suspension of was stirred at room temperature overnight, filtered, washed 2.4-pentanedione (666 mg, 6.66 mmol) and potassium with water, EtOH/HO (1/1) and hexane, and dried to give the title compound (0.66 g., 77% yield): 'H NMR (400 MHz, acetate (40 g) in ethanol (400 mL). The solution was stirred CDC1): 8 ppm 2.07 (3H, s), 2.55 (3H, s), 2.64 (3H, s), for 15 min, and then was added to 250 mL of saturated 7.29-7.87 (4H, m), 15.06 (1H, s). NaCO aqueous solution, extracted with dichloromethane, Reference Example 181 washed with water and brine, dried over NaSO, and con 3-3-(Trifluoromethoxy)phenyl centrated under reduced pressure to give the title compound hydrazonopentane-2,4-dione (1400 mg, 80% yield): 'H NMR (400 MHz, CDC1): 8 ppm 2.22 (3H, s), 2.48 (3H, s), 2.60 (3H, s), 7.22 (1H, brs), 7.38 1932 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.8 Hz), 14.84 (1H, s). Reference Example 183 3-4-(Dimethylamino)phenylhydrazono pentane 2,4-dione HN1 N 1936

F

F> O

1933 3-(Trifluoromethoxy)aniline (1.00 g, 5.64 mmol) O O was added to a solution of 0.6 mL of phosphoric acid (85%) and 4 mL of nitric acid (65%) at -6°C., followed by sodium nitrite (389 mg, 5.64 mmol) in 2 mL of water dropwise at 0° C., and the mixture was stirred at 0°C. for 30 min. Then to the reaction mixture was added dropwise a mixture of potassium HN1 N acetate (1.66 g. 16.92 mmol) and acetylacetone (564 mg, 5.64 mmol) in 80 mL of ethanol and 48 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/HO (1/1) and hexane, and dried to give the title compound (1.2 g 74% yield): 'H NMR (400 MHz, CDC1): 8 ppm 2.49 (s.3H), 2.61 (s.3H), 7.05-7.08 (m. 1H), 7.25-7.27 (m, 1H), 7.32 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 14.59 N (s, 1H). 1N Reference Example 182 N-4-2-(1-Acetyl-2-oxopropylidene)hydrazino phenyl)acetamide 1934 1937 N,N-Dimethylbenzene-1,4-diamine (500 mg, 3.67 mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%) at -6° C. When the mixture reached to room temperature, it was cooled to -6°C. and sodium nitrite (253 mg, 3.67 mmol) was added during 10 min. Small piece of ice (50 g) was added into the solution. The mixture was added at 0°C. to a suspension of 2.4-pentanedi one (367 mg, 3.67 mmol) and potassium acetate (20g) in ethanol (250 mL). The solution was stirred for 15 min, and then was added to 250 mL of saturated NaCO aqueous solution, extracted with dichloromethane, washed with water and brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (870 mg. 96% yield) as a brown solid: "H NMR (400 MHz, CDC1): 8 ppm 2.89 (3H, s), 2.93 (3H, s), 2.96 (3H, s), 3.16 (3H, s), 7.77-7.83 (4H, m), 14.80 (1H, brs). US 2012/0277430 A1 Nov. 1, 2012 89

Reference Example 184 1941 4-(1H-1,2,4-Triazol-1-yl)aniline (500 mg, 3.12 3-4-(4-Methylpiperazin-1-yl)phenyl mmol) was added to a solution of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%) at -6° C. When the hydrazonopentane-2,4-dione mixture reached to room temperature, it was cooled to -6°C. 1938 and sodium nitrite (216 mg, 3.12 mmol) was added during 10 min. Small piece of ice (50 g) was added into the solution. The mixture was added at 0°C. to a suspension of 2.4-pentanedi one (312 mg, 3.12 mmol) and potassium acetate (20g) in ethanol (250 mL). The solution was stirred for 15 min, and then was added to 250 mL of saturated NaCO, aqueous solution, extracted with dichloromethane, washed with water and brine, dried over NaSO, and concentrated under reduced pressure to give the title compound (600 mg, 71% yield) as a brown solid: "H NMR (400 MHz, CDC1): 8 ppm 2.54 (3H, s), 2.63 (3H, s), 7.55 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.8 Hz), 8.12 (1H, s), 8.54 (1H, s), 14.76 (1H, s). Reference Example 186 3-4-(Trifluoromethoxy)phenyl hydrazonopentane-2,4-dione 1942 O O 1939 4-(4-Methylpiperazin-1-yl)aniline (1000 mg, 5.24 HN mmol) was added to a solution of 6 mL of phosphoric acid (85%) and 4 mL of nitric acid (65%) at -6° C. When the mixture reached to room temperature, it was cooled to -6°C. and sodium nitrite (361 mg, 5.24 mmol) was added during 10 min. Small piece of ice (50 g) was added into the solution. The mixture was added at 0°C. to a suspension of 2.4-pentanedi F O one (524 mg, 5.24 mmol) and potassium acetate (30 g) in Dr ethanol (400 mL). The solution was stirred for 15 min, and F then was added to 250 mL of saturated NaCO, aqueous 1943 4-(Trifluoromethoxy)aniline (1.00 g. 6.9 mmol) solution, extracted with dichloromethane, washed with water was added to a solution of 6 mL of phosphoric acid (85%) and and brine, dried over NaSO, and concentrated under 4 mL of nitric acid (65%) at -6°C., followed by sodium nitrite reduced pressure to give the title compound (610 mg. 39% (0.601 g, 8.7 mmol. 1.2 equiv.) in 10 mL of water dropwise at yield): 'H NMR (400 MHz, CDC1): 8 ppm 2.40 (3H, s), 2.50 0°C., and the mixture was stirred at 0°C. for 30 min. Then to (3H, s), 2.62 (3H, s), 3.10 (4H, t, J–5.2 Hz), 3.25 (4H, t, J–4.8 the reaction mixture was added dropwise a mixture of potas Hz), 7.30 (2H, d, J=8.8 Hz), 7.37 (2H, d, J=7.6 Hz), 15.08 sium acetate (2.028 g. 20.7 mmol. 3.0 equiv.) and acetylac (1H, brs). etone (0.8 mL, 7.0 mmol. 1.0 equiv.) in 20 mL of ethanol. The mixture was stirred at room temperature for 15 min, filtered, Reference Example 185 extract with AcOEt, washed with brine and dried to give crude 3-4-(1H-1,2,4-Triazol-1-yl)phenyl product (1.58 g. 88% yield), which was used directly to the hydrazonopentane-2,4-dione next step. "H NMR (400 MHz, CDC1): 8 ppm 2.50 (s.3H), 2.61 (s.3H), 7.26-7.28 (m, 2H), 7.40-743 (m, 2H), 14.69 (s. 1940 1H). Reference Example 187 3-2-Fluoro-3-(trifluoromethyl)phenyl hydrazonopentane-2,4-dione 1944 O O

HN1 N

F

F

F US 2012/0277430 A1 Nov. 1, 2012 90

1945. To a solution of 2-fluoro-3-(trifluoromethyl)aniline 1949. A solution of sodium nitrite (0.96 g. 14 mmol) in (1.0 g, 5.58 mmol) in 8 mL of acetic acid and 1.3 mL of H2O (5 mL) was added dropwise to a solution of 2,2-difluoro concentrated hydrochloride solution, sodium nitrite (462 mg, 1,3-benzodioxol-4-amine (2.0 g, 12 mmol) in 6 M HCl aque 6.69 mmol) in 2.1 mL of water was added dropwise at 0°C., ous solution (12 mL, 72 mmol) at 0°C. After stirring for 15 and the mixture was stirred at 0° C. for 1 h. Then to the min at 0°C., the mixture was added to a suspension of 2,4- reaction mixture were added sodium acetate (1.37 g. 16.8 pentanedione (1.2 mL, 12 mmol) and sodium acetate (5.9 g, mmol) and acetylacetone (726 mg, 7.26 mmol). The mixture 72 mmol) in MeOH (20 mL) pre-cooled at 0°C. The formed precipitate was collected by filtration, washed with water and was stirred at room temperature for 2 h, filtered, washed with dissolved in AcOEt. The organic solution was washed with water, EtOH/HO (1/1) and hexane, and dried to give the title saturated NaHCO aqueous solution and brine, dried over compound (900 mg, 55% yield). "H NMR (400 MHz, MgSO filtered and concentrated under reduced pressure to CDC1): 8 ppm 2.51 (s.3H), 2.63 (s.3H), 7.30-7.34 (m. 1H), give the title compound (3.0g, 90% yield) as orange crystals: 7.38-7.41 (m. 1H), 7.94-7.96 (m, 1H), 14.66 (s, 1H). "H NMR (300 MHz, CDC1): 8 ppm 2.49 (3H, s), 2.63 (3H, s), Reference Example 188 6.88 (1H, dd, J=8.0, 1.1 Hz), 7.13 (1H, t, J=8.1 Hz), 7.30 (1H, dd, J=8.5, 1.1 Hz), 14.56 (1H, brs). 3-(2,3-Difluorophenyl)hydrazonopentane-2,4-dione Reference Example 190 1946 3-2-Fluoro-4-(trifluoromethyl)phenyl hydrazonopentane-2,4-dione 1950 O O

HN1 N

F

F

1947. To a solution of 2,3-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated hydrochloride solution, sodium nitrite (600 mg, 9.3 mmol) in 2.7 mL of water was added dropwise at 0°C., and the mixture was stirred at 0°C. for 1 h. Then to the reaction mixture was added dropwise a mixture of sodium acetate (1.78 g. 21.7 1951 To a solution of 2-fluoro-4-(trifluoromethyl)aniline mmol. 3.0 equiv.) and acetylacetone (1 g, 10 mmol. 1.3 (1.0 g, 5.58 mmol) in 8 mL of acetic acid and 1.3 mL of equiv.). The mixture was stirred at room temperature for 2 h, concentrated hydrochloride Solution, Sodium nitrite (462 mg, filtered, washed with water, EtOH/HO (1/1) and hexane, and 6.69 mmol) in 2.1 mL of water was added dropwise at 0°C., dried to give the title compound (900 mg, 48% yield): 'H and the mixture was stirred at 0° C. for 1 h. Then to the NMR (400 MHz, CDC1): 8 ppm 2.49 (s.3H), 2.61 (s, 3H), reaction mixture were added sodium acetate (1.37 g. 16.8 6.93-7.00 (m, 1H), 7.11-7.17 (m. 1H), 7.50-7.56 (m, 1H), mmol. 3.0 equiv.) and acetylacetone (726 mg, 7.26 mmol. 1.3 14.64 (s, 1H). equiv.) The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/HO (1/1) and hexane, and Reference Example 189 dried to give the title compound (720 mg, yield 44%); H 3-(2,2-Difluoro-1,3-benzodioxol-4-yl)hydrazono NMR (400 MHz, CDC1): 8 ppm 2.51 (s.3H), 2.63 (s, 3H), pentane-2,4-dione 742-7.50 (m, 2H), 7.86 (t, J=8.0 Hz, 1H), 14.56 (s, 1H). Reference Example 191 1948 tert-Butyl 4-(difluoromethoxy)-2-fluorophenyl carbamate O O 1952

Me Me NHBoc HN1 N

F>{ O OCHF US 2012/0277430 A1 Nov. 1, 2012

1953. A solution of 4-(difluoromethoxy)-2-fluorobenzoic 1958. A solution of 1-bromo-2-fluoro-4-(trifluo acid (1 g, 4.85 mmol), DPPA (1.6 g. 5.83 mmol) and EtN romethoxy)benzene (8g, 30.8 mmol) in 170 mL of THF was (0.59 g, 5.83 mmol) in 16 mL oft-BuOH was refluxed for 4h, cooled to -40°C., and then i-PrMgBr (0.4 mol/L in THF, 91 and then concentrated. The residue was dissolved in dichlo mL) was injected. After being stirred for 3 h, CO was romethane (40 mL), washed with 1M HCl aqueous solution, injected for 2 hat 0°C. The mixture was washed with 1M HCl dried over NaSO4, and concentrated under reduced pressure. aqueous solution, separated. The aqueous layer was extracted The crude product was purified by flash column chromatog with CHCl2. The combined organic layers were dried over raphy on silica gel (petroether/AcOEt=4/1) to get the title Na2SO4, and concentrated under reduced pressure. The resi compound (850 mg, yield 63%) as a yellow solid: "H NMR due was washed with petroether to give the title compound (6 (400 MHz, CDC1): 8 ppm 1.53 (s, 9H), 6.44 (t, J–73.6 Hz, 1H), 6.89-6.92 (m. 1H), 7.24-7.27 (m. 1H), 7.37-7.41 (m, g, 87% yield): 'HNMR (400 MHz, CDC1): 8 ppm 7.05-7.12 1H). (m. 2H), 8.10 (t, J=8.4 Hz, 1H). Reference Example 192 Reference Example 194 3-4-(Difluoromethoxy)-2-fluorophenyl hydrazonopentane-2,4-dione tert-Butyl 2-fluoro-4-(trifluoromethoxy)phenyl 1954 carbamate 1959

NHBoc

F

OCF

1960. A solution of 2-fluoro-4-(trifluoromethoxy)benzoic acid (3 g, 13.4 mmol), DPPA (4.4g, 16.1 mmol) and Et-N (1.63 g, 16.1 mmol) in 130 mL oft-BuOH was refluxed for 4 h, and then concentrated. The residue was dissolved indichlo romethane (200 mL), washed with 1M HClaqueous solution, 1955. A solution of tert-butyl 4-(difluoromethoxy)-2- dried over NaSO, and concentrated under reduced pressure. fluorophenylcarbamate (850 mg, 3.07 mmol) in 300 mL of The crude product was purified by flash column chromatog HCl in AcOEt was stirred overnight and concentrated under raphy on silica gel (petroether/AcOEt=4/1) to get the title reduced pressure. compound (2g, 50% yield) as a yellow solid: 'H NMR (400 1956 To a solution of the residue in 5.5 mL of acetic acid MHz, CDC1): 8 ppm 1.27 (s, 9H), 6.97-703 (m, 1H), 7.21 and 0.9 mL of concentrated hydrochloride solution, sodium 7.27 (m, 1H), 7.37-7.41 (m, 1H). nitrite (239 mg, 3.39 mmol) in 1.4 mL of water was added dropwise at 0°C., and the mixture was stirred at 0°C. for 1 h. Reference Example 195 Then to the reaction mixture were added sodium acetate (703 mg, 8.47 mmol. 3.0 equiv.) and acetylacetone (367 mg, 3.67 3-2-Fluoro-4-(trifluoromethoxy)phenyl mmol. 1.3 equiv.). The mixture was stirred at room tempera hydrazonopentane-2,4-dione ture for 2 h, filtered, washed with water, EtOH/HO (1/1) and hexane, and dried to give the title compound (300 mg, 37% 1961 yield): 'H NMR (400 MHz, CDC1): 8 ppm 2.49 (s.3H), 2.62 (s.3H), 6.51 (t, J=72.8 Hz, 1H), 6.95-7.04 (m, 2H), 7.73-7.77 (m. 1H), 14.70 (s, 1H). O O Reference Example 193 2-Fluoro-4-(trifluoromethoxy)benzoic acid 1957 HN1 N

F COH

F O

OCF US 2012/0277430 A1 Nov. 1, 2012 92

1962. A solution of tert-butyl 2-fluoro4-(trifluo 1967 To a solution of 4-chloro-2-fluoroaniline (1 g, 6.87 romethoxy)phenylcarbamate (2 g. 6.8 mmol) in 300 mL of mmol) in 9.8 mL of acetic acid and 1.6 mL of concentrated HCl in AcOEt was stirred for 3 h at 0° C. and concentrated hydrochloride solution, sodium nitrite (568 mg, 8.24 mmol) under reduced pressure. in 2.6 mL of water was added dropwise at 0°C., and the 1963 To a solution of the residue in 20 mL of acetic acid and 3.5 mL of concentrated hydrochloride solution, sodium mixture was stirred at 0° C. for 1 h. Then to the reaction nitrite (507 mg, 7.34 mmol) in 5 mL of water was added mixture were added sodium acetate (1.69 g, 20.6 mmol) and dropwise at 0°C., and the mixture was stirred at 0°C. for 1 h. acetylacetone (893 mg, 8.93 mmol). The mixture was stirred Then to the reaction mixture were added sodium acetate (1.5 at room temperature for 2 h, filtered, washed with water, g, 18.3 mmol. 3.0 equiv.) and acetylacetone (793 mg, 7.93 EtOH/HO (1/1) and hexane, and dried to give the title com mmol. 1.3 equiv.). The mixture was stirred at room tempera pound (1 g, 57% yield): "H NMR (400 MHz, CDC1): 8 ppm ture for 2 h, filtered, washed with water, EtOH/HO (1/1) and 2.49 (s.3H), 2.60 (s, 3H), 7.15-7.25 (m, 2H), 7.69 (t, J–8.4 hexane, and dried to give the title compound (920 mg, 50% yield): 'H NMR (400MHz, CDC1): 8 ppm 2.50 (s.3H), 2.63 HZ, 1H), 14.64 (s, 1H). (s, 3H), 7.08-7.13 (m, 2H), 7.78 (t, J=8.8 Hz, 1H), 14.65 (s, Reference Example 198 1H). 3-2-Fluoro-5-(trifluoromethyl)phenyl Reference Example 196 hydrazonopentane-2,4-dione 3-(2,4-Difluorophenyl)hydrazonopentane-2,4-dione 1968 1964

O O O O

N HN1 N HN1 F F

F

F F F 1969 2-Fluoro-5-(trifluoromethyl)aniline (2.00 g, 15.6 1965. To a solution of 2,4-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated mmol) was added to a solution of 15.6 mL of HOAc and 2.6 hydrochloride solution, sodium nitrite (600 mg, 9.3 mmol) in mL of concentrated HCl, stirred, followed by sodium nitrite 2.7 mL of water was added dropwise at 0°C., and the mixture (0.925 g, 13.4 mmol) in 4 mL of water dropwise at 0°C., and was stirred at 0°C. for 1 h. Then to the reaction mixture was the mixture was stirred at 0°C. for 60 min. Then potassium added dropwise a mixture of sodium acetate (1.78 g. 21.7 acetate (3.28 g, 3.5 mmol) and acetylacetone (1.83 mL, 14.5 mmol) and acetylacetone (1 g, 10 mmol). The mixture was mmol) were added dropwise. The mixture was stirred at room stirred at room temperature for 2 h, filtered, washed with temperature overnight, filtered. The precipitate was dissolved water, EtOH/HO (1/1) and hexane, and dried to give the title in CHCl, washed with water, dried over NaSO and con compound (550 mg, 30% yield): 'H NMR (400 MHz, centrated under reduced pressure to give the title compound CDC1): 8 ppm 2.48 (s.3H), 2.61 (s.3H), 6.91-7.00 (m, 2H), (2.06 g. 64% yield): 'HNMR (400 MHz, CDC1): 8 ppm 2.53 7.70-7.76 (m. 1H), 14.72 (s, 1H). (s, 3H), 2.64 (s.3H), 7.26-6.30 (m. 1H), 7.39-7.42 (m. 1H), Reference Example 197 7.99-8.01 (m. 1H), 14.62 (s, 1H). 3-(4-Chloro-2-fluorophenyl)hydrazonopentane-2,4- dione Reference Example 199 1966 3-(2,5-Difluorophenyl)hydrazonopentane-2,4-dione 1970

C US 2012/0277430 A1 Nov. 1, 2012

1971) 2,5-Difluoroaniline (2.10g, 15.5 mmol) was added 1975. A solution of 3-3-(dimethylamino)prop-2-enoyl to a solution of 21.6 mL of HOAc and 3.6 mL of concentrated 1-3-(trifluoromethyl)phenylpyridazin-4(1H)-one (2.70 g. 8 HCl, stirred, followed by sodium nitrite (1.28 g. 18.6 mmol) mmol) and NH-NH.HO (1.94 mL, 40 mmol) in MeOH (25 in 6 mL of water dropwise at 0°C., and the mixture was stirred mL) was refluxed overnight. After cooling to room tempera at 0°C. for 60 min. Then potassium acetate (4.56 g., 46.5 mmol) and acetylacetone (2.07 mL. 20.15 mmol) were added ture, the reaction mixture was poured into 1 M HCl aqueous dropwise. The mixture was stirred at room temperature over solution and extracted with AcOEt. The extract was washed night, filtered. The precipitate was dissolved in CHCl, with brine, dried over MgSO4, and concentrated under washed with water, dried over NaSO and concentrated reduced pressure. The residue was purified by basic silica gel under reduced pressure to give a crude product (4.00 g. 67% column chromatography eluting with AcOEt and recrystal yield), which was used directly to the next step: 'HNMR (400 lized from AcOEt to give the title compound (0.969 g, 40% MHz, CDC1): 8 ppm 2.51 (s.3H), 2.62 (s.3H), 6.79-6.83 (m, yield) as an off-white solid: mp 192-194° C.; H NMR (300 1H), 7.09-7.15 (m, 1H), 743-747 (m. 1H), 14.57 (s, 1H) MHz, CDC1): 8 ppm 6.82 (1H, d, J=7.9 Hz), 7.03 (1H, d, J=1.9 Hz), 7.69 (1H, d, J=1.9 Hz), 7.72-7.76 (2H, m), 7.83 Reference Example 200 7.89 (1H, m), 7.91-7.93 (1H, m), 8.33 (1H, d, J–7.9 Hz), 3-(2,6-Difluorophenyl)hydrazonopentane-2,4-dione 12.85 (1H, brs). LC-MS (ESI) m/Z307 M+H". Anal. Calcd for CHFNO: C, 54.91; H, 2.96: N, 18.29. Found: C, 1972 54.92; H, 2.99; N, 18.33.

Reference Example 202 3-(4-Morpholin-4-ylphenyl)hydrazonopentane-2,4- dione 1976

O O

1973 To a solution of 2,6-difluoroaniline (1.0 g, 7.75 mmol) in 11.1 mL of acetic acid and 1.69 mL of concentrated -N hydrochloride solution, sodium nitrite (600 mg, 9.3 mmol) in 2.7 mL of water was added dropwise at 0°C., and the mixture was stirred at 0°C. for 1 h. Then to the reaction mixture were added sodium acetate (1.78 g. 21.7 mmol) and acetylacetone (1 g, 10 mmol). The mixture was stirred at room temperature for 2 h, filtered, washed with water, EtOH/HO (1:1) and O hexane, and dried to give the title compound (400 mg, 21% yield): 'H NMR (400 MHz, CDC1): 8 ppm 2.43 (s.3H), 2.61 (s.3H), 6.97-7.03 (m, 2H), 7.05-7.15 (m, 1H), 14.42 (s, 1H). O Reference Example 201 3-(1H-Pyrazol-5-yl)-1-3-(trifluoromethyl)phenyl pyridaZin-4(1-1)-one 1977 4-Morpholin-4-ylaniline (653 mg, 3.67 mmol) was 1974 added to a mixture of 3 mL of phosphoric acid (85%) and 2 mL of nitric acid (65%) at -6°C. When the resulting mixture reached to room temperature, it was cooled to -6° C. and sodium nitrite (253 mg, 3.67 mmol) was added during 10 min. Small piece of ice (50 g) was added into the solution. The mixture was added at 0°C. to a suspension of 2.4-pentanedi one (367 mg, 3.67 mmol) and potassium acetate (20g) in ethanol (250 mL). The solution was stirred for 15 min, and then added to 250 mL of saturated NaCO aqueous solution, extracted with dichloromethane, washed with water and brine, dried over anhydrous NaSO4, and concentrated under reduced pressure to give the title compound (870 mg. 82% FC yield) as a brown solid: "H NMR (400 MHz, CDC1): 8 2.50 (3H, s), 2.61 (3H, s), 3.15-3.18 (4H, m), 3.80-3.83 (4H, m), 6.98-7.03 (2H, m), 7.45-7.50 (2H, m), 14.37 (1H, s). US 2012/0277430 A1 Nov. 1, 2012 94

Reference Example 203 ppm 2.50 (3H, s), 3.80 (3H, s), 7.38 (1H, dd, J=11.0, 8.7 Hz), 7.95 (1H, ddd, J=8.7, 4.5, 2.3 Hz), 8.15 (1H, dd, J=7.2, 2.3 3-3-(Dimethylamino)prop-2-enoyl-1-(4-morpholin Hz), 8.52 (1H, d, J=1.5 Hz). 4-ylphenyl)pyridazin-4(1H)-one Reference Example 205 1-2-Fluoro-4-(1H-pyrazol-1-yl)phenyl-N,5- 1978 dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine 3-carboxamide 1982

MeO

F

N OO 1979 3-(4-Morpholin-4-ylphenyl)hydrazonopentane-2, W . 4-dione (500 mg, 1.73 mmol) was dissolved in 10 mL of 1983. A suspension of 1-(2-fluoro-4-iodophenyl)-N.5- N,N-Dimethylformamide dimethyl acetal. The mixture was dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-car boxamide (1.73 g, 4 mmol), pyrazole (0.408 g. 6 mmol), refluxed for 4 hand concentrated under reduced pressure to CuO (0.057 g., 0.4 mmol), salicylaldoxime (0.219 g, 1.6 give the title compound as a brown oil which was used to the mmol), and CsCO (2.60 g, 8 mmol) in CHCN (8 mL) was next step without further purification: "H NMR (400 MHz, refluxed for 6 hunder Ar atmosphere. After cooling to room CDC1): 8 2.85-2.90 (3H, m), 3.10-3.14 (3H, m), 3.18-3.21 temperature, the reaction mixture was poured into water and (4H, m), 3.85-3.88 (4H, m), 5.63-5.66 (1H, m), 6.68 (1H, d, extracted with AcOEt. The extract was washed with brine, J=8.0 Hz), 6.94-6.96 (2H, m), 7.45-7.48 (2H, m), 7.72 (1H, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chroma brs), 8.12 (1H, d, J=8.0 Hz). tography eluting with AcOEt and recrystallized from MeOH/ HO to give the title, compound (0.370 g. 25% yield) as a Reference Example 204 white solid: mp 187-189° C.; H NMR (300 MHz, CDC1): 8 ppm 3.40 (3H, s), 3.72 (3H, s), 3.93 (3H, s), 6.55 (1H, dd, 3-Acetyl-1-(2-fluoro-5-iodophenyl)-5-methoxypy J=1.5, 2.3 Hz), 7.60 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.77 ridazin-4(1H)-one (3H, m), 7.84 (1H, d, J=2.3 Hz), 7.98 (1H, d, J=2.6 Hz). Anal. Calcd for CHFNO: C, 54.69; H, 4.32: N, 18.76. Found: 1980 C, 54.58; H, 4.40; N, 18.67. Reference Example 206 3-Acetyl-1-(2-fluoro-4-(1H-pyrazol-1-yl)phenyl-5- MeO methoxypyridazin-4(1H)-one 1984

MeO

I 1981 To a mixture of 1-(2-fluoro-5-iodophenyl)-N.5- dimethoxy-N-methyl-4-oxo-1,4-dihydropyridazine-3-car boxamide (4.33 g, 10.0 mmol) in THF (1.0 L) was added MeMgBr (1.0 M in THF, 20.0 mL. 20.0 mmol) at -78° C. under N. The mixture was stirred at -78° C. for 2 h. The reaction was quenched with Saturated NHCl aqueous solu tion at -78° C. The mixture was diluted with saturated NaHCO aqueous solution, extracted with EtOAc, dried over NaSO, filtered, concentrated in vacuo, purified by column chromatography on silica gel (hexane/EtOAc=50/50 to 0/100 1985 MeMgBr (1 M solution in THF, 2.8 mL, 2.8 mmol) and EtOAc/MeOH=100/0 to 0/100) and triturated with was added dropwise at -78°C. to a solution of 1-2-fluoro EtOAc/hexane to yield the title compound (3.58g.92% yield) 4-(1H-pyrazol-1-yl)phenyl-N,5-dimethoxy-N-methyl-4- as a pale yellow solid: "H NMR (DMSO-de, 300 MHz): 8 oxo-1,4-dihydropyridazine-3-carboxamide (351 mg 0.94 US 2012/0277430 A1 Nov. 1, 2012

mmol) in THF (100 mL). After stirring for 1 h, the reaction 1989. A mixture of methyl 4-methoxy-3-oxo-2-(pyridin mixture was quenched with 1 M HCl aqueous solution and 3-ylhydrazono)butanoate (52 g, 210 mmol) in N,N-dimeth extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. ylformamide dimethyl acetal (80 mL, 600 mmol) was The residue was purified by silica gel column chromatogra refluxed for 30 min. The mixture was allowed to cool to room phy eluting with AcOEt and recrystallized from MeOH/HO temperature and stayed at room temperature overnight. The to give the title compound (223 mg, 72% yield) as a pale formed crystals were collected by filtration and washed with yellow solid: mp 159-161° C.; H NMR (300 MHz, CDC1): AcOEt to give the title compound (35 g. 64% yield) as pale 8 ppm 2.69(3H, s), 3.93 (3H, s), 6.56 (1H, dd, J=1.5, 2.3 Hz), 7.64 (1H, ddd, J=1.1, 2.3, 9.0 Hz), 7.71-7.79 (4H, m), 7.99 yellow crystals: "H NMR (300 MHz, CDC1): 8 ppm 3.98 (1H, d, J-2.6 Hz). Anal. Calcd for CHFNO: C, 58.54; (3H, s), 3.98 (3H, s), 7.48-7.54 (1H, m), 7.96 (1H, s), 8.04 H, 3.99; N, 17.07. Found: C, 58.42; H, 4.01: N, 16.98. (1H, ddd, J–8.4, 2.6, 1.5 Hz), 8.71 (1H, dd, J=4.9, 1.5 Hz), Reference Example 207 8.93 (1H, d, J=2.6 Hz). Methyl 4-methoxy-3-oxo-2-(pyridin-3-ylhydrazono) butanoate Reference Example 209 1986 5-Methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropy O ridazine-3-carboxylic acid hydrochloride MeO COMe 1990

N HN1 rs MeO N 21

1987. A solution of 3-aminopyridine (20g, 210 mmol) in N 6 M HCl aqueous solution (200 ml, 1200 mmol) was cooled with ice bath. To the solution was added dropwise a solution HCI of sodium nitrite (18 g. 260 mmol) in water (40 mL). After N 21 stirring at 0°C. for 5 min, the mixture was added to a mixture of sodium acetate (130 g. 1300 mmol) and methyl 4-meth oxyacetoacetate (28 ml, 210 mmol) in EtOH (300 ml) and 1991. A solution of methyl 5-methoxy-4-oxo-1-pyridin water (150 ml) at 0°C., and the mixture was stirred at 0°C. for 3-yl-1,4-dihydropyridazine-3-carboxylate (2.0 g, 7.7 mmol) 1 h. The mixture was diluted with water (150 ml), extracted in 6 MHClaqueous solution (20 ml) was refluxed for 4h. The with AcOEt (500 mlx3). The combined organic layer was washed with saturated NaHCO, aqueous solution (300 mlx3) mixture was concentrated under reduced pressure to give the and brine (300 ml), dried over NaSO, filtered and concen title compound (2.1 g, 95% yield) as off-white crystals: "H trated under reduced pressure to give the title compound (52 NMR (300 MHz, DMSO-d): 8 ppm 3.98 (3H, s), 7.78 (1H, g, 97% yield) as a brown oil: "H NMR (300 MHz, CDC1): 8 dd, J=8.7, 4.5Hz), 8.36-8.42(1H, m), 8.79 (1H, dd, J=4.5, 1.1 ppm 3.50 (3Hx/2, s), 3.51 (3Hx/2, s), 3.89 (3Hx/2, s), 3.93 (3Hx/2, s), 4.67 (2Hx/2, s), 4.70 (2Hx/2, s), 7.35-7.43 (1H, Hz), 9.02 (1H, s), 9.15 (1H, d, J=2.6 Hz). m), 7.67-7.74 (1Hx/2, m), 7.84-7.91 (1Hx/2, m), 8.41-8.49 (1H, m), 8.64-8.71 (1H, m), 12.90 (1Hx/2, s), 14.76 (1Hx/2, Reference Example 210 brs). Reference Example 208 N,5-Dimethoxy-N-methyl-4-oxo-1-pyridin-3-yl-1,4- Methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihy dihydropyridazine-3-carboxamide dropyridazine-3-carboxylate 1988 1992

MeO COMe MeO US 2012/0277430 A1 Nov. 1, 2012 96

1993. A mixture of 5-methoxy-4-oxo-1-pyridin-3-yl-1,4- 1997. A solution of NaNO (7.9 g, 115 mmol) in HO (20 dihydropyridazine-3-carboxylic acid hydrochloride (1.0 g, mL) was added dropwise at 0°C. to a mixture of 4-bromo-2, 3.5 mmol), N.O-dimethylhydroxylamine hydrochloride 5-difluoroaniline (20 g, 96 mmol) and 6 M HCl aqueous (0.52g, 5.3 mmol), TEA (1.5 ml, 11 mmol) and O-benzot solution (96 mL, 576 mmol). After stirring for 15 min, the riazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate resulting aqueous solution was added to a Suspension of (1.2g, 3.9 mmol) in DMF (15 ml) was stirred at room tem methyl 4-methoxyacetoacetate (12.4 mL. 96 mmol) and perature overnight. The mixture was diluted with AcOEt. The NaOAc (34g,576 mmol) in MeOH (165 mL) pre-cooled at 0° precipitate was filtered off and the filtrate was concentrated C. The precipitate was collected by filtration, washed with under reduced pressure. The residue was chromatographed water and dried at room temperature to give the title com on basic silica gel (0/100-20/80 MeOH/AcOEt) to give the pound (37 g, 100% yield) as ared solid: "H NMR (300 MHz, title compound (0.81 g, 79% yield) as white crystals: "H DMSO-d): 8 ppm 3.34 (3H, s), 3.83 (3H, s), 4.68 (2H, s), NMR (300 MHz, CDC1): 8 ppm 3.41 (3H, s), 3.71 (3H, s), 7.70 (1H, dd, J=9.7, 7.0 Hz), 7.89 (1H, dd, J=10.6, 6.1 Hz), 3.98 (3H, s), 7.48 (1H, dd, J=8.3, 4.5 Hz), 7.97 (1H, s), 12.16 (1H, s). 8.00-8.05 (1H, m), 8.67 (1H, dd, J–4.5, 1.3 Hz), 8.91 (1H, d, Reference Example 213 J=2.6 Hz). Methyl 1-(4-bromo-2,5-difluorophenyl)-5-methoxy Reference Example 211 4-oxo-1,4-dihydropyridazine-3-carboxylate 3-Acetyl-5-methoxy-1-pyridin-3-ylpyridazin-4(1H)- 1998 O

1994

1. MeO Me

F

rs F N 2 Br 1995 To a solution of N,5-dimethoxy-N-methyl-4-oxo-1- 1999. A solution of methyl 2-(4-bromo-2,5-difluorophe pyridin-3-yl-1,4-dihydropyridazine-3-carboxamide (0.40 g, nyl)hydrazono-4-methoxy-3-oxobutanoate (33 g, 90 mmol) 1.4 mmol) in THF (10 ml) was added dropwise 1 M MeMgBr in N,N-dimethylformamide dimethyl acetal (72 mL) was in THF (3.0 ml, 3.0 mmol) at -78°C. After stirring at -78°C. stirred at 110°C. for 3 h. After cooling to room temperature, for 2 h, the mixture was quenched with water (0.5 ml) and the mixture was concentrated under reduce pressure. To the stirred at room temperature for 0.1 h. The mixture was con residue were added MeOH and silica gel The mixture was centrated under reduced pressure. The residue was parti evaporated and purified by silica gel column chromatography tioned between CHCl (25 ml) and brine. The aqueous layer was extracted with CHCl (25 mlx3). The combined organic eluting with hexane/AcOEt (1/0 to 0/1) and then AcOEt/ layer was dried over NaSO filtered and concentrated under MeOH (4/1) to give the title compound (27.9 g, 83% yield) as reduced pressure to give the title compound (0.21 g, 62% a brown gum: "H NMR (300 MHz, DMSO-ds): 8 ppm 3.80 yield) as yellow crystals: "H NMR (300 MHz, CDC1): 8 ppm (3H, s), 3.83 (3H, s), 8.01 (1H, dd, J=8.7, 6.8 Hz), 8.15 (1H, 2.70 (3H, s), 3.97 (3H, s), 7.49-7.56 (1H, m), 7.95 (1H, s), dd, J=9.8, 6.0 Hz), 8.55 (1H, d, J=1.5 Hz). LC-MS (ESI) m/z 8.01-8.08 (1H, m), 8.72 (1H, dd, J=4.7, 1.3 Hz), 8.95 (1H, d, 376 M+H". J=2.6 Hz). Reference Example 214 Reference Example 212 1-(4-Bromo-2,5-difluorophenyl)-5-methoxy-4-oxo Methyl 2-(4-bromo-2,5-difluorophenyl)hydrazono 1,4-dihydropyridazine-3-carboxylic acid 4-methoxy-3-oxobutanoate 2000 1996

Br Br